CN101987081A - Controlled release preparation - Google Patents

Abstract

The invention discloses a controlled release preparation with improved performance. The controlled release preparation comprises a core containing medicament and a controlled release film covering the outside of the core and being almost insoluble in water as well as stomach and intestines digestive juice. The controlled release film comprises particulate matters of a water soluble medicinal additive, the water-soluble medicinal additive is covered by a polymer film which can be soluble in the stomach and/or intestines digestive juice but almost insoluble in water, the polymer and the medicinal additive can not produce chemical reaction or can produce chemical reaction but do not produce water-insoluble non-gaseous products and the pharmaceutically unacceptable products, and the amount of the polymer is no more 700% of that of the medicinal additive. The invention also discloses a preparation method of the controlled release preparation. The controlled release preparation has the advantages of improved medicament release reproducibility, reduced medicament release lag time, accelerated medicament release and improved bioavailability, can realize located controlled release, delayed controlled release and interval type or pulse type controlled release of the medicament in the gastrointestinal tract, and the like.

Description

A kind of controlled release preparation

Technical field

The present invention relates to a kind of controlled release preparation.More particularly, the controlled release preparation that the present invention relates to a kind of performance improvement controlled release preparation that discharges of zero level particularly.The invention still further relates to the preparation method of this controlled release preparation.

Background technology

Some insoluble polymers particularly pass through the coating control drug release in the controlled release preparation that zero level discharges at controlled release preparation.Because the water-insoluble of polymer, usually need in the clothing film, form permeability (permeability) that micropore improves clothing film be beneficial to the on the low side and preparation total surface area of the dissolubility of the infiltration of moisture and the release of medicine, particularly medicine than hour.

So far, relevant coating membrane controlled release preparation technology has three typical case's representatives:

The one, be representative with US4629619: this type of technology disperses water-soluble porogen and is suspended in the organic solvent that contains insoluble polymer, by coating water-soluble substances is present in the clothing film of insoluble polymer, the water-soluble porogen in this clothing film is formed bigger micropore by the Digestive system dissolving in digestive tract.When being the preparation final molding, one of defective of this technology used organic solvent.

The 2nd, be representative with US5472712 and US5639476: this type of technology is dissolved in water-soluble porogen in the aqueous dispersions (body) (Aqueous polymeric dispersion) that contains insoluble polymer, by coating water-soluble substances is present in the clothing film of insoluble polymer, the water-soluble substances in this clothing film is formed very little micropore by the Digestive system dissolving in digestive tract.The advantage of this technology is to have avoided with an organic solvent.But many defectives are arranged also: the water solublity porogen exists in the clothing film with the unimolecule state, the pore size of micropore is limited by the molecular size of water solublity porogen, the aperture is little a lot of with hybrid state preparation (as US4629619), are unfavorable for penetrating of medicine that molecular radius is bigger; Therefore, when the permeability of coating membrane can satisfy application request, particularly on the low side the and preparation total surface area of the dissolubility of medicine hour, its mechanical strength very a little less than; The actual bad control in available duct, the production repeatability is relatively poor.

The 3rd, US6974591 is representative: one ground of this type of technology water insoluble but dissolve in acidity or alkalescence Digestive system the porogen dispersion and be suspended in the aqueous dispersions (body) (Aqueous polymeric dispersion) that contains insoluble polymer, by coating porogen is present in the clothing film of insoluble polymer, the porogen in this clothing film is formed bigger micropore by the Digestive system dissolving in digestive tract.This technology combines the advantage of preceding two class technology to a certain extent, has also overcome the shortcoming of preceding two class technology to a certain extent.But the defective of this technology is quite a few: as the dissolving of the formation of micropore or porogen be subjected to the height of the acid or alkaline power of Digestive system or pH value and digestion liquid measure what etc. body intrinsic factor influence degree bigger; The formation of micropore or porogen dissolving (the particularly porogen of non-polymer class such as potassium hydrogen tartrate) need the relatively long time, and the free list of medicine reveals higher time stickiness (the particularly porogen of non-polymer class such as potassium hydrogen tartrate).These factors will make the release behavior of medicine become unstable, body intrinsic factor drug release stability or repeatability variation occur.

It needs to be noted, with US4629619, US6974591 is the technology of representative, wherein with the polar small-molecule substance of Digestive system solubility as one porogen, with the insoluble non-polar polymer of Digestive system is one clothing membrane material, so it is very high biphase interface energy to occur during the two blend, the problem that the mutual compatibility and bonding force are very poor, the result causes and disperses inequality, granulous porogen also will become the stress concentration point in the clothing film, become the weak link in the clothing film, clothing film mechanical strength is significantly reduced, and then may make prominent release (dose-dumping) of controlled release preparation.These drawbacks have not only limited the addition of porogen in the clothing film, but also have a strong impact on formulation products performance, particularly medication completeness.(referring to " polymer chemistry and physics ", the Wang Zijie chief editor, China Light Industry Press publishes, 1992 04 month the 1st edition, the 345th page; " surface of high polymer and interface ", Wu Renjie chief editor, Science Press (Beijing), the 104th～10 page; Surface Modification Of Inorganic Fillers, Jiangxi chemical industry, calendar year 2001, the 4th phase, the 17th～18 page).

In addition, because the compatibility is very poor, particularly under the dampness effect, these water-soluble substanceses are separated out from polymeric film easily, so-called " scum " phenomenon occurs; Water-soluble substances stays micropore after separating out easily from polymeric film, micropore dwindles under effects such as surface tension and other factors such as steam even healing fully, it is unstable that thereby the release behavior that makes medicine becomes, and extrinsic factor drug release stability or repeatability variation occur.

In addition, US6974591 is that the technology of representative also uses the solvable but water-insoluble polymer of some Digestive systems as porogen.It is compatible and compatible fully that these polymer porogen and the insoluble polymer clothing of Digestive system membrane material are usually expressed as part.When two kinds of polymer are in contact with one another, at first moistening mutually at the interface, the phase counterdiffusion of biphase then macromolecular chain segment by warm-up movement, the result of diffusion makes two kinds of polymer produce the significant concentration gradient on the both sides, interface.This zone with obvious Concentraton gradient has constituted two alternate boundary layers.The thickness of boundary layer depends mainly on the compatibility of two kinds of polymer.Increase along with the compatibility, diffusion improves, and boundary is more and more fuzzyyer, and interfacial layer thickness is increasing, so that final boundary complete obiteration, become homogeneous blend, reach compatible fully (referring to the compatibility of polymer alloy and increase-volume, University Of Qingdao's journal, May nineteen ninety-five, the 10th volume, the 1st phase, the 91st page).Just because of this mutual scattering and permeating between polymer, interface prolongation in time between macromolecular porogen of result and clothing film becomes more and more fuzzyyer, the micropore that can form also in time prolongation becomes more and more fuzzyyer, it is non-constant that pore size also becomes, it is unstable that thereby the release behavior that makes medicine becomes, and extrinsic factor drug release stability or repeatability variation occur.

Therefore, also need the particularly controlled release preparation technology of preparing of zero level release of a kind of controlled release preparation in the reality, the advantage of above-mentioned prior art can be inherited or further be developed to this technology, can overcome many defectives of above-mentioned prior art again.

Goal of the invention

The controlled release preparation that one of the object of the invention just provides a kind of above-mentioned performance improvement is the controlled release preparation and the technology of preparing thereof that discharge of zero level particularly, and the preparation medicine that this technology makes discharges stability or repeatability is enhanced.

Specifically, the controlled release preparation that just provides a kind of above-mentioned performance improvement is the controlled release preparation and the technology of preparing thereof that discharge of zero level particularly, the release micropore size size of this controlled release preparation is more stable in storage and/or production process, be subjected to the influence of extrinsic factor littler, as in storage and/or production process, water solublity porogen in this controlled release preparation release-controlled film is difficult for separating out from polymeric film, and macromolecular porogen in this controlled release preparation and the interface between clothing film are spread the release instability that thickens and cause mutually and be limited in certain acceptable scope.

The controlled release preparation that one of the object of the invention just provides a kind of above-mentioned performance improvement is the controlled release preparation and the technology of preparing thereof that discharge of zero level particularly, the formation receptor intrinsic factor influence degree of the release micropore of this controlled release preparation is littler, has release sexual behaviour in the better medicine body.

The controlled release preparation that one of the object of the invention just provides a kind of above-mentioned performance improvement is the controlled release preparation and the technology of preparing thereof that discharge of zero level particularly, and the required time of the formation of the release micropore of this controlled release preparation shortens, and the time stickiness that the stripping of medicine shows is littler.

The controlled release preparation that one of the object of the invention just provides a kind of above-mentioned performance improvement is the controlled release preparation and the technology of preparing thereof that discharge of zero level particularly, the clothing film mechanical strength of this controlled release preparation is enhanced, being difficult for takes place to dash forward releases (dose-dumping), and the medication completeness is enhanced.

The controlled release preparation that one of the object of the invention just provides a kind of above-mentioned performance improvement is the controlled release preparation and the technology of preparing thereof that discharge of zero level particularly, this controlled release preparation can realize that medicine positioning controlled-release in gastrointestinal tract discharges, as stomach, intestinal, colon release-controlled release, particularly intestinal, colon release-controlled release;

The controlled release preparation that one of the object of the invention just provides a kind of above-mentioned performance improvement is the controlled release preparation and the technology of preparing thereof that discharge of zero level particularly, and this controlled release preparation can be realized medicine delay time controlled release release, clearance-type or the release of pulsed controlled release in gastrointestinal tract;

Other purposes of the present invention are referring to following description.

Summary of the invention

The controlled release preparation that the present invention relates to a kind of performance improvement is the controlled release preparation that discharges of zero level particularly, and this controlled release preparation comprises:

A), the nuclear core that contains a kind of medicine;

B), be overlying on the clothing film of above-mentioned nuclear core outward, wherein, this clothing film comprises pharmaceutically acceptable plasticizer, pharmaceutically acceptable be insoluble to or the polymer of water-soluble hardly and harmonization of the stomach intestinal digestion liquid and be embedded in that wherein the quilt as porogen contains pharmaceutically acceptable plasticizer or do not contain plasticizer pharmaceutically acceptable dissolve in stomach and/or intestinal digestion liquid but be insoluble to or the particulate matter of water-soluble medical additive of coating of water-insoluble polymer clothing film almost, above-mentioned water-soluble medical additive and above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-insoluble polymer chemical reaction can not take place in the Digestive system or chemical reaction can take place but do not generate water insoluble and room temperature (25 ℃) be the product and the pharmaceutically unacceptable product of solid or liquid in vivo down, and above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or 700% (w/w) that almost consumption of water-insoluble polymer clothing film is no more than the consumption of above-mentioned water-soluble medical additive.

1), preparation contains a kind of core material of medicine the controlled release preparation that is coated by clothing film that the invention still further relates to a kind of performance improvement is the preparation method of the controlled release preparation that discharges of zero level particularly, and this method comprises following several basic step:; 2), to the particulate matter of water-soluble medical additive with contain pharmaceutically acceptable plasticizer or do not contain plasticizer pharmaceutically acceptable dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost the solution or the dispersion liquid of water-insoluble polymer coat the clothing film, above-mentioned water-soluble medical additive and above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-insoluble polymer chemical reaction can not take place in the Digestive system in vivo or chemical reaction can take place but do not generate the product and the pharmaceutically unacceptable product of water-fast on-gaseous (be under the room temperature (25 ℃) for solid or liquid), and above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or 700% (w/w) that almost consumption of water-insoluble polymer clothing film is no more than the consumption of above-mentioned water-soluble medical additive; 3), to the above-mentioned core material that contains a kind of medicine with pharmaceutically acceptable be insoluble to or the solution or the dispersion liquid of the polymer of water-soluble hardly and harmonization of the stomach intestinal digestion liquid coat clothing film of containing pharmaceutically acceptable plasticizer, wherein, be dispersed with in the solution of this polymer or the dispersion liquid as porogen by above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or the particulate matter of above-mentioned water-soluble medical additive of coating of water-insoluble polymer clothing film almost, the solution of this polymer or dispersion liquid do not dissolve do not degrade or hardly dissolving or degrade hardly described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or water-insoluble polymer almost; 4), in case of necessity, to above-mentioned clothing film heal (wearing out) handle.

Term " active component ", " bioactive ingredients ", " medical active component ", " active matter ", " activating agent " that the present invention uses reaches " bioactive substance ", " medicine " etc. and is meant that any material has detectable biological effect and comprises any physiological, diagnosis, preventative or pharmacological effect when it bestows live body.This term is intended to include but not limited to material any pharmacy, therapeutic, preventative, the threpsology.

That the term " clothing film " that the present invention uses is meant the hydrophobicity that contains q.s (polymer) material on the nuclear core outer surface that is coated on controlled release preparation and have sufficient mechanical strength and keep controlled release preparation its contained medicine or be in harmony the treatment activating agent when placing the not disruptive coating membrane of aqueous solution drug release process, this coating membrane can delay to discharge above-mentioned controlled release preparation to be placed in aqueous solution.

The term that the present invention uses " comprises " and reaches " containing " and be meant and include but not limited to or can also comprise other one-tenth similar implication of grading except this thing.

The term " a kind of " that the present invention uses be meant be at least a kind of, can be a kind of for having only, also can be two kinds or multiple.

" pharmaceutically acceptable " that the present invention relates to is meant and can be mixed with each other in preparation and do not have illeffects mutually and can not reduce preparation stability and/or effectiveness and be applicable to the part or the meaning of whole body administration.

The amplitude of variation of the term " about " amount of being meant that the present invention uses is ± 30%, and (for example certain amount is p, but then the span of p is 0.7p～1.3p), preferably be ± 20%, is ± 10% best.

The term " porogen " that the present invention uses is meant and helps to form the hole or improve the permeability of clothing film or the material of water permeability in clothing film of the present invention, and porogen can dissolved from clothing film (dissolved) in applied environment, leach (extracted), degraded (leached) and/or chemical reaction (generating water-soluble product and/or gas) fall and form the hole.

The specific embodiment

One object of the present invention just provides the particularly controlled release preparation that discharges of zero level of a kind of controlled release preparation, the dispersion that this controlled release preparation coats by skin or be embedded in wherein as porogen contained pharmaceutically acceptable plasticizer or do not contained plasticizer pharmaceutically acceptable dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost the clothing film of the particulate matter of water-soluble medical additive of coating of water-insoluble polymer clothing film come control drug release.This porogen forms the release duct in Digestive system.

Wish not exclusively to be subjected to this principle or theoretical restriction, since as porogen dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-fast macromolecule polyalcohol granule in a part of space replaced by water-soluble medical additive, between polymer the mutual scattering and permeating of (being between porogen clothing film and clothing film) be limited within the specific limits (because of porogen polymer and water-soluble medical additive compatibility poor, mutual hardly scattering and permeating), have at least a certain amount of immovable space to form big or small metastable micropore in the middle of the porogen polymer beads, thereby make the release behavior of medicine become relatively stable within the specific limits; Simultaneously,, receptor intrinsic factor very fast relatively because of the dissolving in water of water-soluble medical additive influences less relatively usually, after it replaces porogen polymer beads interior section space, need the amount of dissolved porogen polymer to reduce, the time stickiness that the stripping of medicine shows will diminish relatively, and the influence of drug release receptor intrinsic factor also will diminish relatively.In addition, behind the water-soluble medical additive of porogen polymer overmold, can prevent that also water-soluble medical additive from separating out (" scum ") under wet environment from controlled release polymer clothing film.Because of from, the stability or the repeatability of drug release are enhanced.

Water-soluble medical additive has very high polarity usually, and the polymer of clothing film is generally hydrophobic, so the two compatibility is very poor; Some mechanical performance of water-soluble medical additive is relatively poor, as bigger fragility, and dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-fast porogen polymer usually (with respect to hydrophobic clothing film material polymers) a certain amount of acidity and/or alkaline isopolarity group are arranged, so the two has the compatibility relatively preferably; In addition, dissolve in stomach and/or intestinal digestion liquid but be insoluble to or the affinity of almost water-fast porogen polymer and hydrophobic clothing film material polymers usually greater than the affinity of water-soluble medical additive and hydrophobic clothing film material polymers, because of dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-fast porogen polymer often contains more hydrophobicity gene.Therefore, water-soluble medical additive dissolved in stomach and/or intestinal digestion liquid but be insoluble to or almost water-fast polymer overmold after can improve the mechanical performance of clothing film.

Need further be pointed out that especially, after being replaced by water-soluble medical additive as a part of space in the macromolecule polyalcohol granule of porogen, need dissolved or degraded span (its implication is defined by following " Δ r ") significantly reduces as the macromolecule polyalcohol granule of porogen, gastro-intestinal Fluid only needs the sub-fraction clothing membrane polymer water-soluble medical additive of corrosion clothing film the inside fast just in the corrosion thin layer, after the quick corrosion of water-soluble medical additive is intact, the surface of greater amount polymer clothing film is exposed in the gastro-intestinal Fluid, thereby polymer clothing film corrosion speed is accelerated greatly, the time stickiness that the medicine stripping shows also diminishes thereupon greatly, the medicine dissolution rate is accelerated greatly, the influence of polymer clothing film corrosion receptor intrinsic factor also significantly reduces thereupon, and the repeatability or the stability of drug release are improved greatly.Below explain with a mathematical model, suppose water-soluble medical additive with dissolve in stomach and/or intestinal digestion liquid but be insoluble to or the two density of almost water-fast clothing membrane polymer is respectively ρ ₁, ρ ₂, the two particle diameter (radius) is respectively r ₁, r ₂, the two weight is respectively W ₁, W ₂, then there is following relation between the two weight and particle diameter:

$\frac{W_1}{{\mathrm{<figure-callout\; id="2"\; label="W"\; filenames="HDA0000023366100000011.png,HDA0000023366100000012.png"\; state="\{\{state\}\}">W</figure-callout>}}_2}=\frac{{\mathrm{\&rho;}}_2{{\mathrm{<figure-callout\; id="2"\; label="r"\; filenames="HDA0000023366100000011.png,HDA0000023366100000012.png"\; state="\{\{state\}\}">r</figure-callout>}}_2}^3}{{\mathrm{\&rho;}}_2({{\mathrm{<figure-callout\; id="2"\; label="r"\; filenames="HDA0000023366100000011.png,HDA0000023366100000012.png"\; state="\{\{state\}\}">r</figure-callout>}}_2}^3-{{\mathrm{<figure-callout\; id="2"\; label="r"\; filenames="HDA0000023366100000011.png,HDA0000023366100000012.png"\; state="\{\{state\}\}">r</figure-callout>}}_2}^3)}$

Can get water-soluble medical additive coating weightening finish W by following formula ₂/ W ₁Increase Δ r/r with the particle diameter of particulate matter ₁The pass be:

$\frac{\mathrm{\&Delta;<figure-callout\; id="2"\; label="r\; r"\; filenames="HDA0000023366100000011.png,HDA0000023366100000012.png"\; state="\{\{state\}\}">r</figure-callout>}}{r_{}}=\frac{r_2-r_2}{{\mathrm{<figure-callout\; id="2"\; label="r"\; filenames="HDA0000023366100000011.png,HDA0000023366100000012.png"\; state="\{\{state\}\}">r</figure-callout>}}_2}=\sqrt[2]{1+\frac{{\mathrm{\&rho;}}_2{\mathrm{<figure-callout\; id="2"\; label="W"\; filenames="HDA0000023366100000011.png,HDA0000023366100000012.png"\; state="\{\{state\}\}">W</figure-callout>}}_2}{{\mathrm{\&rho;}}_2{\mathrm{<figure-callout\; id="1"\; label="W"\; filenames="HDA0000023366100000011.png"\; state="\{\{state\}\}">W</figure-callout>}}_1}}-1$

When above-mentioned water-soluble medical additive with dissolve in stomach and/or intestinal digestion liquid but be insoluble to or the two density of almost water-fast clothing membrane polymer compares ρ ₁/ ρ ₂Be approximately at 1 o'clock, can be by following formula in the hope of the water-soluble medical additive coating weightening finish of difference W ₂/ W ₁The particle diameter of following particulate matter increases Δ r/r ₁Value, see following table for details:

W 2/W 1	Δr/r 1(being similar to)
		7	100.0％
6	91.3％
		5	81.7％
4	71.0％
		3	58.7％
2	44.2％

1	26.0％
		0.8	21.6％
0.5	14.5％
		0.4	11.9％
0.3	9.14％
		0.2	6.27％
0.1	3.23％
		0.05	1.64％
0.03	0.990％
		0.02	0.662％
0.01	0.332％

Data can get from table, that water-soluble medical additive is dissolved in stomach and/or intestinal digestion liquid but be insoluble to or almost water-fast clothing membrane polymer coats weightening finish more for a long time, and particle diameter amplification is very little, usually less than 1/3rd of polymer overmold weightening finish amplitude.

What particularly point out in addition is, pharmaceutical release time in advance, the time stickiness that the medicine stripping shows reduces, to the controlled release preparation advantageous particularly of positioning controlled-release release.The limited time that the controlled release preparation of positioning controlled-release release is detained at specific position, as the release of small intestinal positioning controlled-release, especially the release of stomach positioning controlled-release is shorter, particularly the release of conlon targeting controlled release is short especially, and relative conventional formulation of the time of controlled release preparation release will grow, thereby, shifting to an earlier date of pharmaceutical release time, be equivalent to the prolongation of the time of effective release, thereby help the performance of curative effect of medication, help putting forward the high bioavailability of medicine.

The data that go out according to last tabular, be used for of the present invention above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or (in other words " water-soluble medical additive coating weightening finish to ") 700% (w/w) of the consumption of water-insoluble polymer clothing film before the consumption of porogen is no more than above-mentioned water-soluble medical additive coating usually almost, preferable 300% (w/w) that is no more than the preceding consumption of above-mentioned water-soluble medical additive coating, more preferably about 2～about 200% (w/w), more preferably about 2～about 100% (w/w), more preferably about 3～about 50% (w/w), (amplitude of variation of the term " about " amount of being meant is ± 30% (for example certain amount is p about best 3～about 30% (w/w) in addition, then but the span of p is 0.7p～1.3p), preferably be ± 20%, be ± 10% best, do not indicate especially that its elsewhere implication all herewith).Usually less coating weightening finish is unfavorable for forming complete clothing film, and more weightening finish will reduce Expected Results.

Term used herein " water-soluble medical additive " is meant that the dissolubility (25 ℃ of temperature) in water is not less than 33mg/ml, preferably be not less than 50mg/ml, more preferably be not less than 100mg/ml, more preferably be not less than 500mg/ml, be not less than 1000mg/ml's best, mean diameter is generally 1～500 μ m, preferably be 5～250 μ m, more preferably be 10～150 μ m, be best 25～100 μ m's and with dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-insoluble polymer (and containing other compositions in the clothing film of this polymer) chemical reaction can not take place in the Digestive system in vivo or chemical reaction can take place but do not generate the product of water-fast on-gaseous and the pharmaceutically inorganic matter of making medicinal auxiliary agent or the Organic substance of unacceptable product, do not indicate its elsewhere implication especially all herewith.Too small dissolubility is unfavorable for forming the hole.Excessive or too small particle diameter may cause the problem that repeatability that production repeatability, thing discharge or less stable etc. are difficult to predict in production.

Can be used for water-soluble medical additive example of the present invention and include but not limited to water-soluble aminoacid, oligopeptide (2-10 peptide), water-soluble monosaccharide and pharmaceutically acceptable derivates thereof, oligosaccharide (2-6 sugar) and pharmaceutically acceptable derivates thereof, water-soluble sodium, the inorganic salt of potassium or ammonium ion, water-soluble carbon number is no more than 6 organic acid and water-soluble sodium thereof, potassium or ammonium ion salt, water-soluble carbon number is no more than 6 organic base and water-soluble salt thereof, water-soluble nonionic surfactant, water-soluble pharmaceutically acceptable non-ionic polyalcohol (preferably is water-soluble, it is low viscous that (term " low viscosity " is meant that 2% viscosity in aqueous solution is not higher than 300 centipoises (mPas) herein, do not indicate especially that implication is all herewith), and their mixture.

The example that can be used for water-soluble aminoacid of the present invention or oligopeptide as, but be not limited thereto: alanine, glycine, serine, valine, agedoite, lysine, glutamine, methionine, arginine, hydroxyproline, proline, power peptide (L-alanyl-L-glutamine), glutathion.

Available water-soluble monosaccharide and pharmaceutically acceptable derivates thereof comprise, but be not limited to left-handed and/or dextral monosaccharide and sugar alcohol thereof, the example as, but be not limited thereto: triose (as D-glyceraldehyde and dihydroxy acetone), tetrose is (as the D-erythrose, the D-Erythrulose, erythritol), pentose is (as D-ribose, the D-2-deoxyribose, the D-xylose, L-arabinose), pentulose is (as the D-ribulose, the D-xylulose, xylitol), hexose is (as glucose, galactose, mannitol, mannose), ketohexose is (as fructose, sorbose)), heptose is (as the D-mannoheptulose, the D-sedoheptulose).

The example of available water-soluble oligosaccharide and pharmaceutically acceptable derivates thereof as, but be not limited thereto: disaccharidase (as the poly-disaccharide of maltose, lactose, sucrose, cellobiose, gentiobiose, 6-(.alpha.-D-galactosido)-D-glucose., Sargassum disaccharide, hydroxyl isomaltulose, maltose alcohol, lactitol, trehalose, shell), trisaccharide (as Raffinose, the poly-trisaccharide of shell), tetrose (as stachyose, take off the poly-tetrose of acetyl shell), pentasaccharides (as verbascose, maltopentaose), six sugar (as MALTOHAXAOASE).

The example of the inorganic salt of available water-soluble sodium, potassium or ammonium ion as, but be not limited thereto: the salt of halogen equilibrium ion such as bromine, fluorine, iodine and muriatic water-soluble sodium, potassium or ammonium ion, the salt of water-soluble sodium, potassium or the ammonium ion of phosphate radical, hydrogen phosphate, sulfate radical, bisulfate ion, inferior sulfate radical, bisulfite, pyrosulfurous acid root, nitrate anion, carbonate, bicarbonate radical and percarbonic acid root.

The example that available water-soluble carbon number is no more than 6 organic acid and water-soluble sodium, potassium or ammonium ion salt as, but be not limited thereto: adipic acid, anti-/ maleic acid, malic acid, citric acid, Tartaric acid, phytic acid, succinic acid, glycolic acid with and sodium salt, potassium salt, ammonium salt.

The example that available water-soluble carbon number is no more than 6 organic base as, but be not limited thereto: water-soluble alkali acidic amino acid, meglumine and and water-soluble salt.

The example of available water-soluble nonionic surfactant as, but be not limited thereto: (as Brij 35, Brij 98 for water-soluble polyoxyethylene alkyl ether class surfactant, Cremophor A6, Cremophor A25, Ethylan 2560, Ritox 35, and Ritox 721, Texofor A1P, Texofor A10, Texofor A14, Texofor A30, Texofor A45, Texofor A60, Volpo S10, Volpo S20, Volpo S20, Volpo CS10, Volpo CS20, Volpo L4, Volpo L23), water-soluble polyoxyethylene castor oil class surfactant (as Jeechem CA-200, Jeechem CAH-60, Jeechem CAH-100, Jeechem CAH-200, Lipocol HCO-60), Polysorbate 61, Polysorbate65, water-soluble Myrj 45 class surfactant is (as Polyoxyl 150 distearate, Polyoxyl 32distearate, Polyoxyl 100stearate, Polyoxyl 50stearate).

Available pharmaceutically acceptable water-soluble, the example of non-ionic polyalcohol as, but be not limited thereto: water-soluble cyclodextrin and cyclodextrin derivative are (as alpha-cyclodextrin, gamma-cyclodextrin, 2,6 DM-, hydroxypropyl/ethyl-beta-schardinger dextrin-, side chain-beta-schardinger dextrin-, glycosyl-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, water-soluble low-molecular-weight cyclodextrin (as molecular weight 3000-6000)), dextrates (Dextrates), water-soluble pharmaceutically acceptable oligosaccharide (degree of polymerization 7-20) is (as oligofructose (degree of polymerization 7-20), oligomeric isomaltose (degree of polymerization 7-20)), water-soluble glucosan (is the glucosan of 1200-2000 as molecular weight), (the low viscous product following as trade name: WP 02 for hydroxyethyl-cellulose, WP and QP 09, WP and QP 3, WP and QP 40, WP and QP300), hydroxyethylmethyl-cellulose, hydroxypropyl cellulose (the low viscous product following: Klucel JF as trade name, Klucel LF, Klucel EF), hydroxypropyl methylcellulose (the low viscous product following: Methocel K100 Premium LVEP as trade name, Methocel F50 Premium, Methocel E3Premium LV, Methocel E5 Premium LV, MethocelE6 Premium LV, Methocel E15Premium LV, Methocel E50 Premium LV, low viscosity level Metolose60SH, low viscosity level Metolose 65SH, low viscosity level Metolose 90SH), low viscosity methylcellulose (the product following: A15-LV) as trade name, polyvinyl alcohol, polyvidone (the low viscous product following: K-11/14 as trade name, K-16/18, K-24/27, K-28/32, K-85/95), molecular weight is the PEG (Polyethylene Glycol) of 2000-20000.

Can be used for water-soluble medical additive of the present invention preferably is selected from dissolving and not influenced by acid, alkali in the Digestive system and slack-off, more preferably also be not subjected to the influence of enzyme in the Digestive system and microorganism substantially and slack-off water-soluble medical additive reduces greatly thereby body intrinsic factors such as acid in the drug release receptor, alkali, enzyme and microorganism are influenced.Suitable dissolving substantially not gastrointestinal be subjected to acid in the Digestive system, alkali influence and slack-off water-soluble medical additive example includes but not limited to: water-soluble monosaccharide, disaccharidase, sugar alcohol and water-soluble oligosaccharide (2-6 sugar) or the oligosaccharide (degree of polymerization 7-20) formed by them, water-soluble neutral inorganic, water-soluble nonionic surfactant, pharmaceutically acceptable water-soluble, nonionic type polymer (preferably is water-soluble, it is low viscous that (term " low viscosity " is meant that 2% viscosity in aqueous solution is not higher than 300 centipoises (mPas) herein, do not indicate especially that its elsewhere implication all herewith), and their mixture pharmaceutically acceptable polymer).

Above-mentioned available dissolving is not subjected to the acid in the Digestive system substantially, alkali, the influence of enzyme and microorganism and slack-off water-soluble monosaccharide, disaccharidase, sugar alcohol and water-soluble oligosaccharide (3-6 sugar) example of forming by them as, but be not limited thereto: triose (as D-glyceraldehyde and dihydroxy acetone), tetrose is (as the D-erythrose, the D-Erythrulose, erythritol), pentose is (as D-ribose, the D-2-deoxyribose, the D-xylose, L-arabinose, pentulose is (as the D-ribulose, the D-xylulose, xylitol), hexose (glucose, galactose, mannitol, mannose, ketohexose is (as fructose, sorbose)), heptose is (as the D-mannoheptulose, the D-sedoheptulose), disaccharidase is (as maltose, lactose, sucrose, cellobiose, gentiobiose, 6-(.alpha.-D-galactosido)-D-glucose., the Sargassum disaccharide, hydroxyl isomaltulose, maltose alcohol, lactitol, trehalose), trisaccharide (as Raffinose), tetrose (as stachyose), pentasaccharides is (as verbascose, maltopentaose), six sugar (as MALTOHAXAOASE).

Above-mentioned available dissolving be not subjected to the influence of acid, alkali, enzyme and microorganism in the Digestive system substantially and slack-off water-soluble neutral inorganic example as, but be not limited thereto: the salt of neutral water-soluble halogen equilibrium ion such as muriatic sodium, potassium salt; Neutral water-soluble anionic species is as sodium, the potassium salt of nitrate anion.

Above-mentioned available dissolving is not subjected to the acid in the Digestive system substantially, alkali, the example of the influence of enzyme and microorganism and slack-off water-soluble nonionic surfactant as, but be not limited thereto: water-soluble polyoxyethylene alkyl ether is (as Brij 35, Brij 98, Cremophor A6, Cremophor A25, Ethylan 2560, Ritox 35, Ritox 721, Texofor A1P, TexoforA10, Texofor A14, Texofor A30, Texofor A45, Texofor A60, Volpo S10, Volpo S20, VolpoS20, Volpo CS10, Volpo CS20, Volpo L4, Volpo L23), water-soluble polyoxyethylene castor oil class surfactant (as Jeechem CA-200, Jeechem CAH-60, Jeechem CAH-100, Jeechem CAH-200, Lipocol HCO-60), Polysorbate 61, and Polysorbate 65, water-soluble Myrj 45 is (as Polyoxyl 150distearate, Polyoxyl 32distearate, Polyoxyl 100stearate, Polyoxyl 50 stearate).

Above-mentioned available dissolving is not subjected to the acid in the Digestive system substantially, alkali, the example of the influence of enzyme and microorganism and slack-off pharmaceutically acceptable water-soluble non-ionic polyalcohol as, but be not limited thereto: water-soluble cyclodextrin and nonionic cyclodextrin derivative are (as alpha-cyclodextrin, gamma-cyclodextrin, 2,6 DM-, hydroxypropyl/ethyl-beta-schardinger dextrin-, side chain-beta-schardinger dextrin-, glycosyl-cyclodextrin, water-soluble nonionic low-molecular-weight cyclodextrin (as molecular weight 3000-6000)), dextrates (Dextrates), water-soluble pharmaceutically acceptable oligosaccharide (degree of polymerization 7-20) is (as oligofructose (degree of polymerization 7-20), oligomeric isomaltose (degree of polymerization 7-20)), water-soluble glucosan (is the glucosan of 1200-2000 as molecular weight), (the low viscous product following as trade name: WP 02 for hydroxyethyl-cellulose, WP andQP 09, WP and QP 3, WP and QP 40, WP and QP 300), hydroxypropyl cellulose (the low viscous product following: Klucel JF as trade name, Klucel LF, Klucel EF), hydroxyethylmethyl-cellulose, hydroxypropyl methylcellulose (the low viscous product following: Methocel K100 Premium LVEP as trade name, Methocel F50 Premium, Methocel E3 Premium LV, Methocel E5 Premium LV, Methocel E6 Premium LV, Methocel E15Premium LV, Methocel E50 Premium LV, low viscosity level Metolose 60SH, low viscosity level Metolose 65SH, low viscosity level Metolose 90SH), low viscosity methylcellulose (the product following: A15-LV) as trade name, polyvinyl alcohol, polyvidone (the low viscous product following: K-11/14 as trade name, K-16/18, K-24/27, K-28/32, K-85/95), molecular weight is the PEG (Polyethylene Glycol) of 2000-20000.

Preferably, water-soluble medical additive contains or is added with disintegrating agent, is beneficial to the dispersion and the dissolving of water-soluble medical additive, more gives full play to its effect.It is well known to those skilled in the art can be used for disintegrating agent of the present invention, and more specifically is described in Journal of Pharmaceutical Sciences (85 volumes, No.11, in November, 1996).Be preferred for disintegrating agent of the present invention and include but not limited to, low hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose or calcium, cellulose fibre, cross linked polyacrylate, crosslinked Amberlite resin, alginate, carboxymethyl starch or the Microcrystalline Starch that replaces, microcrystalline Cellulose and composition thereof.With the microcrystalline Cellulose is preferred.An available water-soluble medical additive example is the spheroidal particle product that contains crystalline cellulose and lactose, Freund Industrial Co. for example, Ltd. (Japan) commodity Nonpareil series of products by name of making, 100～200 μ m and contain crystalline cellulose (3 parts) and spheroidal particle product Nonpareil 105 (70-140), 100～200 μ m of lactose (7 parts) and contain crystalline cellulose (4.5 parts) and the spheroidal particle product Nonpareil 105T (70-140) of lactose (5.5 parts); 150～250 μ m and contain crystalline cellulose (3 parts) and the spheroidal particle product Nonpareil NP-7 of lactose (7 parts): 3,150～250 μ m and contain crystalline cellulose (the spheroidal particle product Nonpareil NP-5 of (5 parts) and lactose (5 parts): 5, or the like.

The consumption of disintegrating agent is 5～50% (w/w) of the consumption of water-soluble medical additive, preferable 10～40%.The consumption discomfort of disintegrating agent in water-soluble medical additive is too high, especially dynamical super-disintegrant.May damage clothing film because of its expansion amplitude is excessive.

Be meant mainly in term used herein " dissolve in stomach and/or intestinal digestion liquid but be insoluble to or water-insoluble polymer almost " and be not more than 30mg/ml by the dissolubility in water (25 ℃ of temperature), preferably be not more than 10mg/ml, more preferably be not more than 1mg/ml, be not more than 0.1mg/ml's but can not indicated its elsewhere implication especially all herewith best by the pharmaceutically acceptable polymer of dissolving such as acid, alkali, enzyme and/or microorganism in stomach and/or the intestinal digestion liquid or degraded.Can be used for of the present invention dissolve in stomach and/or intestinal digestion liquid but be insoluble to or but but almost water-fast clothing membrane material includes but not limited to gastric solubility polymer, enteric polymer, not only polymer, enzyme and/or microorganism degradable polymer, Biodegradable polymeric and their mixture of enteric but also gastric solubleness.

The polymer of gastric solubility and/or enteric solubility is generally the polymer that contains acidity and/or basic group.

Be applicable to gastric solubility polymer of the present invention, be generally at pH6 or more soluble and have a polymer substance of film property in the water of low value, comprise and include but not limited to that (a) has the cellulose derivative of list or disubstituted amido, (b) has the polythene derivative of list or disubstituted amido, (c) has the acrylate copolymer of mono-substituted amino, (d) other class chitosan (Chitosan) and their mixture.(a) special example includes but not limited to, benzylamino-methyl cellulose, diethylamino methyl cellulose, piperidyl ethylhydroxyethylcellulose, cellulose acetate diethylamino acetate and their mixture; (b) special example includes but not limited to vinyl diethylamide-vinyl acetate co-polymer, ethylene benzyl amine-vinyl acetate co-polymer, poly-acetal acetic acid diethylamino vinyl acetate, ethylene piperidyl-acetyl acetal ethylene copolymer, poly-diethylamino methyl styrene and their mixture; (c) special example includes but not limited to the Eudragit E (trade name of Rohm-Pharma, be methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer), polymethylacrylic acid dimethylamino ethyl ester and their mixture; (d) the special example of other classes includes but not limited to chitosan (Chitosan).Wherein, more preferably the gastric solubility polymer is poly-acetal diethylamino vinylacetate or EudragitE.

Be applicable to enteric polymer of the present invention, be generally have film property and can be in pH5 or higher water dissolved polymers, include but not limited to (1) carboxyl alkyl cellulose, (2) has the cellulose derivative of the monoester bond of binary acid, (3) has the polyvinyl derivant of dibasic acid monoester key, (4) its polymers of maleic acid-ethylene, (5) acrylic polymer, (6) other classes and their mixture.(1) special example includes but not limited to carboxymethyl cellulose, carboxymethylethylcellulose (CMEC) and their mixture, (2) special example includes but not limited to the phthalic acid ester acid cellulose, the succinic acid acetyl cellulose, O-phthalic acid methyl cellulose ester, phthalic acid hydroxymethyl ethyl cellulose esters, phthalic acid hydroxypropyl emthylcellulose ester, succinic acid hydroxypropyl emthylcellulose ester and analog and their mixture; (3) special example includes but not limited to the dibasic acid monoester of polyvinyl, phthalic acid polyvinyl alcohol ester for example, phthalic acid polyethylene butyl ester, acetyl group acetal phthalic acid polyvinyl ester and analog and their mixture; (4) special example includes but not limited to vinylacetate-copolymer-maleic anhydride, butyl vinyl ether-copolymer-maleic anhydride, styrene-maleic acid monoester copolymer and their mixture; (5) special example includes but not limited to acrylic acid methyl ester .-methacrylic acid copolymer, the styrene-propene acid copolymer, acrylic acid methyl ester .-methacrylic acid-1-Octyl acrylate copolymer, Eudragit L and S, Eudragit FS (conlon targeting is used) and their mixture; (6) the special example of other classes includes but not limited to Lac.Wherein more preferably enteric polymer is a carboxymethyl cellulose, carboxymethylethylcellulose, phthalic acid hydroxypropyl emthylcellulose ester, succinic acid hydroxypropyl methyl acetyl cellulose, Eudragit L, Eudragit S, Eudragit FS or Lac.

But but be applicable to the polymer of not only enteric of the present invention but also gastric solubleness, be generally and have film property and can dissolved polymers in pH4.5 or lower water and pH6 or higher water, include but not limited to vinylpyridine-acrylic copolymer, have carboxymethyl polysaccharide or the polyethylene amino acid derivatives and their mixture of single or dibasic amino.The special example of vinylpyridine-acrylic copolymer includes but not limited to 2-methyl-5-vinylpyrine/methacrylic acid methyl/methacrylic acid copolymer, 2-methyl-5-vinylpyrine/acrylic acid methyl ester ./methacrylic acid copolymer, 2-vinyl-5-vinylpyridine/methacrylic acid/styrol copolymer, 2-vinyl-5-vinylpyridine/methacrylic acid/methyl methacrylate acid copolymer, 2-vinylpyridine/methacrylic acid/methacrylic acid copolymer, 2-vinylpyridine/methacrylic acid/acrylonitrile copolymer and their mixture.Special example with carboxymethyl polysaccharide of single or dibasic amino includes but not limited to carboxymethyl piperidyl starch, carboxymethyl benzylamino cellulose and their mixture.The special example of polyvinyl amino acid derivatives includes but not limited to gather-2-(ethenylphenyl) glycine, N-vinyl glycine-styrol copolymer and their mixture.

The example of suitable Biodegradable polymeric includes but not limited to natural biological degradation polyalcohol (as fibrin and collagen), aliphatic polyester series is (as polylactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, polylactide-poly-Acetic acid, hydroxy-, bimol. cyclic ester, polycaprolactone, polylactide-caprolactone), poly-ammonia and copolymer thereof, polyamino acid, poe, polybutylcyanoacrylate, polyacrylic, poly (3-hydroxybutyrate) and copolymer thereof, polyanhydries, poly (methyl vinyl ether-maleic acid), polyurethanes, bioerodable type hydrogel is (as with N-vinyl pyrrole ketone or acrylamide and N, the aquogel polymer that N '-methylene forms the acrylamide copolymerization, after obtaining containing the unsaturated prepolymer of vinyl with unsaturated diacid and low molecular weight diol condensation, make it the crosslinked erosion type hydrogel that promptly obtains the main chain hydrolysis with vinylpyrrolidone (VP)) and their mixture.

The example of suitable enzyme and/or microorganism degradable polymer include but not limited to contain azo bond or disulfide bond polymer (as the polymer of forming by acrylic resin and azo fragrance crosslinked group, by different coating materials (or vinyl monomer) by with the polymerization single polymerization monomer that contains the azo aromatic group (as by acrylic resin and can be by azo replacement or the unsubstituted divinyl azo aromatic radical styrene of azo fragrance crosslinked group group of first wife's degraded also) crosslinked or polymer that copolymerization makes), the special polyase (as glycosidase) that can be produced by enterobacteria decompose but insoluble in water or can not be by the small intestinal digestive enzyme that digest and polysaccharide insoluble in water (as pectin, dextran, galactomannan, 9-D-glucose thuja acid etc.) and their mixture.

Dissolve in stomach and/or intestinal digestion liquid but be insoluble to or (kind) of almost water-fast clothing membrane material selected except considering the compatibility with the clothing film polymer usually according to decisions such as the character of medicine and drug release requirement, clinical practices.As for (as to alkali labile, that acid is easily molten, that stomach or stomach near-end such as duodenum have an absorption window or stomach or portion of nearly stomach end office (EO) played therapeutical effect) the suitable selection of the medicine gastric solubility polymer that is fit under one's belt or nearly stomach end absorbs; For be adapted at absorbing in the intestinal (as unsettled to acid, alkali is easily molten, to the strong toxic and side effects of stomach as stomach is had than the strong stimulation effect, intestinal local directly rise therapeutical effect, the intestinal segment basic absorption good, be that maybe need delaying time of basic absorption position discharges with the intestinal segment) the suitable enteric polymer of selecting of medicine; For be adapted at absorbing in the colon (as to (as the peptide, protein-based) of digestive enzyme sensitivity, be used for (local, directly) treatment colon position disease, to digestive tract top (as stomach, small intestinal) have strong toxic and side effects if any discharging than maybe need delaying time of strong stimulation effect) medicine is suitable selects polymer such as Eudragit S, Eudragit FS, colon enzyme and/or microorganism be degradable.Medicine need be taken the back and crosses certain hour and be absorbed that to play a role (be that drug release takes stickiness again for another example, i.e. time-delay discharges) preparation can select dissolving of clothing film or slow degradation polymer such as Biodegradable polymeric (as the aliphatic polyester base polymer), digestive enzyme and/or digestive tract microbial degradation slowly polymer (as polysaccharide, pectin, Resina persicae).Wherein, for be adapted at absorbing in the intestinal (as unsettled to acid, alkali is easily molten, to the strong toxic and side effects of stomach as stomach is had than the strong stimulation effect, intestinal local directly rise therapeutical effect, the intestinal segment basic absorption good, be that maybe need delaying time of basic absorption position discharges with the intestinal segment) medicine suitable select enteric polymer in the present invention for most preferably.

Usually, above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-insoluble polymer and above-mentioned water-soluble medical additive chemical reaction can not take place in the Digestive system in vivo or chemical reaction can take place but do not generate the product and the pharmaceutically unacceptable product of water-fast on-gaseous (be under the room temperature (25 ℃) for solid or liquid), this is because the product for solid or liquid generates under water insoluble and the room temperature (25 ℃) if having, they will adhere to or be deposited in the small delivery aperture that has generated, thereby release is obstructed, and speed is slack-off.

In addition, that utilization dissolves in stomach and/or intestinal digestion liquid but be insoluble to or the kind of the different-thickness (as increasing progressively of clothing film thickness) of almost water-fast clothing film and clothing membrane material, kind that drug release rate is regulated material and different amounts thereof (drug release rate regulate increasing progressively of material consumption or successively decrease, see for details hereinafter) etc. can obtain ball or the sheet that different time at interval discharges medicine, they are combined (as encapsulated or bond together) and can obtain pulsed or clearance-type drug delivery system.

Preferred porogen of the present invention promptly by above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost the particulate matter example of water-soluble medical additive of coating of water-insoluble polymer clothing film be, dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-insoluble polymer to be selected from the water-insoluble polymeric material that can be dissolved in Digestive system that contains acidity and/or basic group be the polymer of enteric solubility and/or gastric solubility, by water-soluble medical additive of its coating be selected from Acidity of Aikalinity with polymer just in time opposite and neutralization reaction takes place in the Digestive system with it but do not generate the product of water-fast on-gaseous (being to be solid or liquid under the room temperature (25 ℃)) and water-soluble room temperature of unacceptable product (25 ℃) solid-state pharmaceutically acceptable alkaline matter or acidic materials down pharmaceutically in vivo, above-mentioned available alkaline matter is selected from, but be not limited to: water-soluble sodium, inorganic alkaline salt potassium or ammonium ion, water-soluble carbon number is no more than 6 the following solid-state organic base of room temperature (25 ℃) (as hexamethylene diamine, the grape methylamine) and be alkalescence salt, water-soluble carbon number is no more than the sodium that is alkalescence of 6 organic multicomponent acid, salt potassium or ammonium ion and their mixture, above-mentioned available acidic materials are selected from, but are not limited to: water-soluble carbon number is no more than 6 the following solid-state organic acid of room temperature (25 ℃) (as adipic acid, instead/maleic acid, malic acid, citric acid, Tartaric acid, phytic acid, succinic acid) and be tart sodium, acid salt potassium or ammonium ion.Because of acid or alkaline water-soluble medical additive and Acidity of Aikalinity polymer in contrast have stronger adhesion in the clothing film, help improving clothing film mechanical performance, and the dissolving or the degraded of this polymer there is good facilitation, pharmaceutical release time is earlier shifted to an earlier date, bigger the reducing of time stickiness that the medicine stripping shows.

Preferred porogen of the present invention promptly by above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost the particulate matter example of water-soluble medical additive of coating of water-insoluble polymer clothing film be, dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-insoluble polymer to be selected from the water-insoluble polymeric material that can be dissolved in Digestive system that contains acidic-group be the polymer of enteric solubility, by water-soluble medical additive of its coating in the Digestive system in vivo with it generated reactive gas (include but not limited to CO ₂, SO ₂, O ₂, Cl ₂) but do not generate the water-soluble medical additive that reaches the product that pharmaceutically can not connect under water insoluble and the room temperature (25 ℃) for the product of solid or liquid, the sodium of available example of the water-soluble medical additive of this class such as bicarbonate radical, potassium or ammonium salt, the sodium of carbonate, potassium or ammonium salt, glycine carbonate, the carbonate of L-lysine, arginic carbonate, amino acid whose sodium, potassium or ammonium carbonate, contain sodium, the carbonate of potassium or ammonium glycosyl, the sodium of inferior sulfate radical, potassium or ammonium salt, the sodium of bisulfite, potassium or ammonium salt, the sodium of pyrosulfurous acid root, potassium or ammonium, sodium, the percarbonate of potassium or ammonium, and their mixture.They not only have stronger adhesion with tart polymer in the clothing film, help improving clothing film mechanical performance, and the dissolving or the degraded of this polymer there is stronger facilitation, this be because, two-way interaction's primary product is water-soluble polymer salt and useful especially gas such as carbon dioxide, sulfur dioxide etc., and other products are water or soluble small molecular salt, so be particularly conducive to dissolve in stomach and/or intestinal digestion liquid but be insoluble to or the almost dissolving of water-insoluble polymer, thereby be particularly conducive to the quick formation of release micropore, pharmaceutical release time is shifted to an earlier date more significantly, reduce the stripping time lag more significantly, impel the quick stripping of medicine, improve drug bioavailability.

Above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost in the water-insoluble polymer clothing film (doing), dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-insoluble polymer consumption is arranged preferably is 35%～100% weight ratio, 50%～100% weight ratio more preferably, 65%～100% weight ratio best, this be based on above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or the gross dry weight amount of water-insoluble polymer clothing film almost.In case of necessity, can add plasticizer and other universal additives that can add in this clothing film, see for details hereinafter.

By above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-soluble medical additive of coating of water-insoluble polymer clothing film the consumption of particulate matter (being porogen, stomach and/or enteric coating+water-soluble core material) in dispersion liquid (body) suspendible coating solution thus in the technical field technical ability those skilled in the art according to the character of medicine and desired rate of releasing drug decision.The consumption of porogen is usually according to decisions such as the kind of its particle diameter, clothing film polymer and consumption thereof, the character of medicine, desirable rate of releasing drug, be generally 5%～95% (weight ratio or volume ratio), preferably be 25%～90%, more preferably be 40%～85%, this is based on the gross dry weight amount or the volume of clothing film component.The porogen of usually relative high level helps improving the mechanical performance of clothing film.

Because the consumption of porogen is the principal element of the porosity of influence or decision clothing film, therefore, the porosity of clothing film is usually located at 5%～95%, preferably is positioned at 25%～90%, more preferably is positioned at 40%～85%.Term used herein " porosity " is meant that the left space of porogen dissolving or degraded back in the clothing film accounts for the ratio of the volume of former complete clothing film, does not indicate its elsewhere implication all herewith especially.For simple and Convenient Calculation, and because of the dissolving or the degraded of porogen do not influence the inherent or external size of former clothing film, " porosity " also can account for the ratio of the weight of whole former clothing film with the weight of the porogen in the clothing film and represent approx.So " porosity " can be calculated with following two kinds of computing formula in the present invention:

Formula 1:

Formula 2:

In order to delay above-mentionedly to dissolve in Digestive system but the dissolving or the degraded of water-fast clothing film, the regulating medicine rate of release, can add drug release rates such as acid or basic medicinally additive at the clothing film and regulate materials, can add and dissolve in Digestive system but materials such as just in time opposite acid of the alkalescence of water-insoluble polymer or acidity or alkali delay drug release rate at the clothing film as an embodiment.An embodiment and for example adds organic acid such as citric acid and promotes the dissolving of clothing film in gastric solubility polymer clothing film, or adds organic base such as basic amino acid, meglumine etc. delay the dissolving of clothing film.An embodiment adds organic acid such as citric acid and delays the dissolving of clothing film in enteric polymer clothing film for another example.As another embodiment, in Biodegradable polymeric clothing film, as aliphatic polyester series (as polylactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, polylactide-poly-Acetic acid, hydroxy-, bimol. cyclic ester, polycaprolactone, polylactide-caprolactone), polyamino acid, poe, polybutylcyanoacrylate, add organic base such as basic amino acid, meglumine etc. or organic acid such as citric acid etc. and promote the dissolving of clothing film.Can be used for this acid, alkali for not can with dissolve in Digestive system but the room temperature (25 ℃) of the insoluble product of water-fast clothing membrane polymer water generation reaction solid-state alkaline matter or acidic materials down, suitablely can be used for alkaline matter of the present invention and be selected from, but be not limited to: water-soluble sodium, the inorganic alkaline salt of potassium or ammonium ion, water-soluble carbon number is no more than 6 the following solid-state organic base of room temperature (25 ℃) and is alkaline salt, water-soluble carbon number is no more than the sodium that is alkalescence of 6 organic multicomponent acid, the salt of potassium or ammonium ion and their mixture, above-mentioned available alkaline matter is selected from, but is not limited to: acidic materials are selected from water-soluble carbon number and are no more than 6 the following solid-state organic acid of room temperature (25 ℃) and are tart sodium, the acid salt of potassium or ammonium ion.These materials dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-fast clothing film in consumption and kind thus in the technical field technical ability those skilled in the art according to the character of clothing membrane material and desired decisions such as rate of releasing drug, be generally 1%～50% (weight ratio), preferably be 3%～30%, more preferably be 5%～20%, this is based on the dry weight of clothing film component.For prevent above-mentioned in preparation process by water dissolution, but the clothing film wrap that skim dissolves in stomach and/or intestinal digestion liquid outward again but be insoluble to or almost water-fast clothing, perhaps adopt non-water packaging technique.The clothing layer thickness be generally the internal layer clothing thickness 1%～100%, preferably be 2%～50%, more preferably be 3%～30%.

In order to obtain the higher function performance of clothing film, preferably, dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-fast clothing membrane polymer select for use mix fully with the clothing film polymer or part compatible be non-complete incompatible polymers, the polymer that particularly mixes fully.More preferably, in order further to obtain clothing film drug release stability preferably, dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-fast clothing membrane polymer and clothing film polymer phase dissolubility higher, above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost the consumption before the more water-soluble medical additive coating of consumption of water-insoluble polymer clothing film is lower; For example, when dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-fast clothing membrane polymer when selecting the polymer that mixes fully with the clothing film polymer for use, above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost the consumption of water-insoluble polymer clothing film be that consumption before above-mentioned water-soluble medical additive coating is 3～50% (weight), 5～30% (weight) preferably; When dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-fast clothing membrane polymer when selecting the polymer that mixes with the clothing film polymer moieties for use, above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost the consumption before consumption and the above-mentioned water-soluble medical additive coating of water-insoluble polymer clothing film compare can be relative more, as be 5～80% (weight) of the consumption before water-soluble medical additive coating, preferably 10～50% (weight), more preferably 15～30% (weight).

Introduce the determination methods of the compatibility between polymer below.Also there is " similar compatibility " principle in the compatibility between polymer, thereby can be used for estimating the compatibility of blend polymer.As Eudragit E, Eudragit L, Eudragit S, EudragitFS and Eudragit RL, Eudragit RS the good compatibility is arranged.

Since solubility parameter can characterize polymers the size of intermolecular cohesion, thereby can be used for estimating the compatibility of blend polymer.Generally, especially for nonpolar amorphous polymer blend, when the difference of the solubility parameters of two polymer less than 0.5 or the difference of the solubility parameters of polymer and organic solvent less than 1.5 the time, the two just can be with the arbitrary proportion mixing, system just has the good compatibility.When having very strong polarity and can form hydrogen bond for the co-mixing system that contains crystalline polymer or polymer molecule, can adopt two dimension or three-dimensional solubility parameter to judge that the compatibility of system is (referring to Shaw M.T., J Appl Polym Sci, 1974,18:449).

1), the cosolvent method the following easier method of exemplary application of the present invention proves or predicts the compatibility between polymer and polymer:, two kinds of macromolecules are dissolved into respectively with in a kind of solvent, mix mutually then, judge the polymer-polymer miscibility size according to two solution mixing situations.2), microscopic method, but with the phase contrast microscope method particularly its mixed phase of electron microscope method direct observation hold degree.3), the solution viscosity method, the viscosity of solution can disclose the compatibility of polymer blend solution, and is to the percentage composition of polymer mapping, linear as its relation with viscosity under different polymer concentrations, shows to reach the compatible fully of molecular level between polymer; Being tied to form non-linearly as its pass, then is that part is compatible; When being complete incompatible co-mixing system, then it concerns S-type curve.4), by the use of thermal means and dynamic mechanical analysis method (surveying vitrification point Tg), three kinds of Tg variation tendencies can appear in special recommendation the method for the present invention, polymer alloy system, suppose that the Tg of two kinds of polymer in the bianry alloy system is respectively Tg ₁And Tg ₂(Tg ₁＜Tg ₂), (1), complete compatible system: a Tg only occurs, Tg ₁＜Tg＜Tg ₂(2), complete incompatible system: two Tg occur, be respectively Tg ₁And Tg ₂(3), the compatible system of part: two Tg occur ₁', Tg ₂', Tg ₁＜Tg ₁'＜Tg ₂'＜Tg ₂

The evaluation of the compatibility between more or more detailed polymer and clothing membrane polymer or Forecasting Methodology can be with reference to pertinent literatures, as, the prediction of the polymer alloy compatibility and sign, Ye Jiajia etc., engineering plastics are used, 2007, the 35th volume, the 12nd phase, the 81st～83 page; Improve the progress of polymer blending material interface compatibility, Dong Meng etc., paint spraying and plating, in October, 2006, the 4th the 5th phase of volume, the 24th～29 page; Compatibility prediction and sign between the polymer of high polymer alloy film, Gu Xiaoyu etc., polymer material science and engineering, in January, 2004, the 20th the 1st phase of volume, the 5th～8 page; Polyblend: the compatibility of II. polymer, Rhizoma Zingiberis Recens northern Shandong, macromolecule circular, in JIUYUE, 1993, the 3rd phase, the 178th～184 page; The compatibility of polyblend and Theoretical Calculation thereof, Lv Feijie etc., tropical agriculture science, 1985 02 phases, the 15th～19 page.

The polymer that is suitable for clothing film of the present invention can be insoluble to or block polymer or copolymer water-soluble hardly and harmonization of the stomach intestinal digestion liquid for pharmaceutically acceptable, is generally hydrophobic polymer.Suitable be insoluble to or polymer water-soluble hardly and harmonization of the stomach intestinal digestion liquid can be selected from but is not limited to be insoluble to or cellulose esters, acrylic acid (ester) base polymer, polyvinyl acetate esters, polyvinyl chloride and the compositions thereof of water-soluble hardly and harmonization of the stomach intestinal digestion liquid.The suitable polymers example of preferred example includes but not limited to ethyl cellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate (cellulose acetate propionate), celluloid, three cellulose valerates, the lacceroic acid cellulose, three Palmic acid celluloses, the disuccinic acid cellulose, two Palmic acid celluloses, polyvinylacetate, methacrylic acid (ester) polymer, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, the vinyl chloride-ethylene acetate copolymer, Merlon, polymethyl methacrylate, ethyl acrylate-Methyl metacrylate 99 polymer, polrvinyl chloride, polyethylene, polyisobutylene, poly (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride) and compositions.

Can adopt the commercial latex of supplying of above-mentioned polymer, pseudo-latex and emulsion bag clothing film, (EC) has as ethyl cellulose:

With

, acrylic resin has:

RS30D,

RE30D reaches

RL30D, acetate fiber rope (CA) has: CA398-10 latex, polyvinyl acetate has: Kollicoat SR 30D and KOLLIDON SR.

Another is adoptable to be insoluble to or the examples of polymer of water-soluble hardly and harmonization of the stomach intestinal digestion liquid contains aqueous dispersions (body) coating solution of the terpolymer of 80～95% polrvinyl chloride, 0.5～19% polyvinylacetate and 0.5～10% polyvinyl alcohol for US4557925 provided.

Another is available to be insoluble to or examples of polymer water-soluble hardly and harmonization of the stomach intestinal digestion liquid is aqueous dispersions (body) coating solution that contains the polyvinylacetate copolymer of 50～100% polrvinyl chloride and 0～50%.

The ratio of clothing film polymer in drying is according to the kind of selected polymer, the kind and the decisions such as consumption, the character of medicine, selected dosage form and desirable release pattern thereof thereof of porogen, be generally 5%～95% weight ratio, preferably 10%～75%, more preferably 15%～60%, this is based on the dry weight of clothing film component.Other universal additives that can add in this clothing film see below.

For mechanical performance and the drug release stability that improves or strengthen clothing film, the dimensional stability and the intensity of the toughness of the glassy state that polymer occurs when especially improving temperature and being lower than its glass transition temperature (Tg) and impact resistance and/or the elastomeric state that polymer occurs when improving temperature and being higher than its glass transition temperature (Tg), the present invention can add mechanical performance improving agent such as the reinforcing agent of polymer and/or flexibilizer at clothing film.

The common consumption 0.5%～40% of mechanical performance improving agent (weight ratio), preferably 1%～25%, more preferably 2%～15%, this is based on the dry weight of clothing membrane component.

In order to obtain the clothing film of excellent properties, the present invention can add two or more insoluble polymer and form agent as hybrid films.In order to make these film forming polymers that the compatibility preferably be arranged, make it bonding force increase between polymer, form stable structure, make decentralized photo and continuous phase even, difficult being separated, the present invention can add in coating solution by compatible compatilizers of effect such as block or grafting.The common consumption of compatilizer be film forming polymer weight 0.1%～40%, preferably 0.5%～25%, more preferably 1%～10%.

In the coating solution that the present invention relates to, can add the universal additive material.The addition of universal additive material in the drug coating layer and application are that the professional is familiar with.General additive comprises but is not limited to antitack agent (separating medium), stabilizing agent, pigment, defoamer, antioxidant, short penetrating agent, polishing material, spice or flavoring agent.They are used as processing aid, and should guarantee safe and reproducible preparation method and long time stored stability or give pharmaceutical dosage form additional advantageous feature.They add before processing in the polymer of preparation, can influence the permeability of clothing layer, and this can be used as additional adjusting parameter equally.

Dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-fast clothing film and clothing film in being described below of additive commonly used.

Plasticizer

For improving the quality of clothing film, add in the coating of the being everlasting prescription plasticizer with the glass transition temperature (Tg) that reduces polymer to suitable scope, and the film forming ability of raising coating material, the pliability and the intensity of enhancing clothing film are improved the coherent condition of clothing film to substrate.Suitable glass transition temperature (Tg) scope is generally 0～70 ℃, preferably is 10～50 ℃, and be best is 15～40 ℃ goodly.

Can utilize in case of necessity that plasticizer of different nature is for example water-soluble, in the water in indissoluble or the water insoluble plasticizer regulate the rate of releasing drug of clothing film.

One ground of plasticizer is liquid substance or low-melting solid matter of high boiling point, low volatility and micromolecule (Mr is about 150～800, preferably is 300～500) that can be miscible with polymer.The example of accessible plasticizer such as physiology compatible by C ₆～C ₄₀(preferred C ₆～C ₃₀, preferred especially C ₁₀～C ₁₆) aliphatic or aromatic series one is to tricarboxylic acid and C ₁～C ₈(preferred C ₂～C ₆, preferred especially C ₂～C ₅) the lipophilic ester that forms of aliphatic alcohol.The example of this plasticizer such as dibutyl phthalate, diethyl phthalate, dibutyl sebacate, ethyl sebacate, citric acid triethyl group ester, acetyl triethyl citrate, glycerol triacetate, tributyl certain herbaceous plants with big flowers two acid esters, Isosorbide Dinitrate, sucrose ester.The example of other accessible plasticizers such as glycerol, propylene glycol, Polyethylene Glycol, Oleum Ricini.

Plasticizer dosage is according to the character of desired clothing film, as glass transition temperature, mechanical performance etc., the kind of plasticizer, the kind of film former (being the water-insoluble film forming polymer), consumption etc. and decide, usually consumption is 5～50% (weight ratios), preferred 10～40% (weight ratios), preferred especially 10～30% (weight ratios), this is based on the dry weight of clothing membrane component.

Antitack agent (separating medium)

Antitack agent (separating medium) is generally useful hydrophobic material, and one adds in the injection suspension.They stop the gathering of examining between film forming stage.The preferred Talcum that uses, magnesium stearate or calcium stearate, the silicic acid of porphyrize, Kaolin or HLB value are 3～8 nonionic emulsifier.Common consumption in clothing layer of the present invention is 0.5～100% (weight ratio) of polymer.In particularly advantageous embodiment, separating medium adds as final coating with conc forms.Undertaken by spraying coated with powder type or by the suspension of 5～30% solid contents.The consumption of requirement when being manufactured in the polymeric layer lacks, and accounts for 0.1～2% of pharmaceutical dosage form weight.

Stabilizing agent

Stabilizing agent is preferably emulsifying agent or surfactant, and certain interfacial activity material is promptly arranged, and dispersion liquid (body) is played Stabilization.The suitable stabilizers example is if any diethanolamine, monoethanolamine, triethanolamine, fatty acid, hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), nonoxynolum, octoxinol, oleic acid, poloxamer, polyoxyethylene 50 stearate, polyethylene glycol fatty acid class (Polyoxyl fatty acid), polyethylene glycol alkyl ether (Polyoxyl hydrocarbon ether), polysorbate (Tween), sorbitan ester (Span), fatty acid salt, polyvidone, sodium lauryl sulfate, cetyl stearyl sodium sulfate, sucrose stearate fat, Spheron MD 30/70 and composition thereof.The content of stabilizing agent is 1～15% (weight ratio), preferred 5～10% (weight ratios), and this is based on the wet weight of dispersion liquid (body) coating solution component.

Pigment

Be generally used in the clothing film.Seldom add with the solubility pigment form.One disperses aluminium oxide or iron oxide pigment to add.Titanium dioxide is as Chinese white.The addition of pigment is 20～60% (weight ratios) of polymeric blends in clothing layer of the present invention.Yet because pigment binding ability height, addition also can be as high as 100% (weight ratio).

Defoamer

One ground of defoamer is dimethicone.

The additive of all uses must be pharmaceutically acceptable in principle in the clothing film, is nontoxic, in medicine patient is safe from danger.

Explain with regard to core material below.

The core material that can be used for coating of the present invention includes but not limited to the sheet of rule or irregular form, granule, ball, crystal, medicine carrying resin.Granule, ball or crystalline size are generally 0.01～2.5mm, and the size of sheet is usually at 2.5～30mm.They contain the bioactive substance (or active substance) that is up to 95% and other pharmacy auxiliary agent that is up to 99.9% (weight ratio) usually.

Being used for active component of the present invention (or medicine or bioactive substance) has no particular limits usually.As the used active component of the present invention, can be above-mentioned any pharmaceutically or the threpsology on have material therapeutical effect or preventive effect.It is as follows to can be used for active component of the present invention: central stimulants, analgesic, antipyretic analgesic, anti-inflammation analgesia medicine, antigout drug, antiparkinsonian drug, psychosis, antianxiety drugs, antidepressant, antuepileptic, tranquilizer, hypnotic, anticonvulsant, the automonic thing, calcium is picked up drug resistance, the medicine of treatment chronic cardiac insufficiency, anti-arrhythmic, control angina pectoris medicine, peripheral vasodilators, hypotensor, blood lipid regulation medicine and antiatherosclerotic, medicine for respiratory system, antacid and treatment peptic ulcer disease medicine, the gastrointestinal antispasmodic medicine, digestant, Bendectin, emetic and the intestines and stomach promote medicine, the liver and gall diseases adjuvant drug, medicine for urological system, influence the medicine of blood and hemopoietic system, antihistaminic, anaphylaxis medium sustained-release agent, adrenocortical hormone and thyroliberin, gonadal hormone and short gonadal hormone, pancreas hormone and other influence the medicine of blood glucose, thyroid hormones medicine and antithyroid drug, penicillins, cephalosporins, beta-lactamase inhibitor, aminoglycoside, Tetracyclines, Macrolide, antituberculotic, antifungal agent, antiviral agents, antitumor drug, influence the medicine of body's immunity, vitamin and Amitin, appetrol or Chinese herbal medicine extract.

Because, the osmotic pump type preparation can synchronously be released preparation to the various compositions in the Chinese herbal medicine extract, do not exist the active component that occurs because of constitutive property is different to discharge nonsynchronous problem, therefore, the present invention need to be specially adapted to the controlled release preparation of controlled release Chinese herbal medicine extract, particularly osmotic pump type preparation preparation.

The exemplary drugs that is particularly suitable for making gastric solubility film control controlled release preparation in the present invention includes but not limited to ciprofloxacin, captopril, furosemide, ursodesoxycholic acid, compound digestive enzyme, Chinese medicine gynecological a thousand pieces of gold, irbesartan, glimepiride, leflunomide, midecamycin, Irb, amoxicillin, cefuroxime, rocephin, cefpodoxime, clarithromycin, Loracarbef, azithromycin, cefixime, cefadroxil, acyclovir, diltiazem

, captopril, simvastatin, lovastatin, etodolac, ketorolac, ranitidine, famotidine, fexofenadine, pseudoephedrine, phenylpropanolamine, dextromethorphan, Chlo-amine, bromocriptine, ciclosporin, crust oxygen sweet smell, allopurinol, (+)-α-aminomethyl-2-methoxyl group sulfonic acid amido benzyl alcohol (patent application EP842148 embodiment 3.6 is disclosed) or 3 '-(2-amino-1-ethoxy-4 '-fluorine methanesulfonic acid aniline (NS49).Other examples such as benzamides, object lesson such as paspertin metoclopramide, veralipride, alizapride, clebopride, more particularly amisulpride, tiapride, sulpiride and salt thereof; In addition, also have α 1-to pick up anti-agent, object lesson such as terazosin and alfuzosin and their salt, especially alfuzosin hydrochloride.

The exemplary drugs that is particularly suitable for making enteric film control controlled release preparation in the present invention includes but not limited to: 5-aminosalicylic acid and salt thereof such as zinc salt; acamprosate calcium; aranidipine; Alendronate sodium; azithromycin; azintamide and compound preparation thereof; aspirin; esomeprazole and salt thereof such as magnesium salt; sodium salt; strontium salt; ilaprazole, eucalyptus globulus lemon pinane, osaminethacine; omeprazole and salt thereof such as magnesium salt; sodium salt; oxaprozin, Pyrmetazole, benzoic methyl nitroazole; bisacodyl; piroxicam, propylthiouracil, bromelain and compound preparation thereof; hepatocyte growth-promoting factors; aceclofenac, cefalexin trimethoprim, garlicin; Elastase; C14H25N4NaO11P2, dirithromycin, fourth disulfonic acid ademetionine; fourth disulfonic acid sulfo-ademetionine; the Tosi ademetionine, ademetionine, sodium aminosalicylate; Faropenem sodium; fenoprofen calcium, nitrofurantoin, coenzyme Q10; cattle tire liver is extracted and compound preparation, glutamine and compound preparation thereof, anorethindrane dipropionate and compound preparation thereof; phosphoesterases complex; glipizide metformin compound preparation, glutathion, reduced glutathion; bone peptide; diammonium glycyrrhizinate, cinmetacin, cyclophosphamide and compound preparation thereof; erythromycin; pentoxifylline, thiamphenicol, kitasamycin; thiamazole; mefenamic acid, arginine ketoprofen, clarithromycin; matrine; reorganization B subunit/thalline cholera vaccine compound preparation, bacillus subtilis bigeminy viable bacteria compound preparation, Birid Triple Viable; aspisol; RABEPRAZOLE SODIUM, ranitidine, tiopronin; gentamycin sulfate; ferrous sulfate glycine complex, norfloxacin, rufloxacin; lomefloxacin; cloricromen, sulfasalazine, altretamine; Roxithromycin; wheat is examined phenol sodium, fosfomycin and salt thereof such as calcium salt, mepartricin; meloxicam; Mei Takawei, metacycline, Magnesium aspartate hydrochloride; paroxetine; mifepristone, misoprostol, carase; naproxen; Cerebrolysin Vial, nimesulide, Tegafur-uracil mixt. compound preparation; Perprazole; pantoprazole and salt thereof such as sodium salt, aescine, troxerutin and encephalic protein hydrolysate compound preparation; didanosine; lysozyme, adenosine triphosphate, triphenyl diamidine; Serrapeptase; Sparfloxacin, telmisartan, diclofenac sodium; ketone ibuprofen; sodium sulfate, cytochrome C, thymosin; duloxetine; doxycycline, metformin, fluoxetine; sinomenine; acetyl levocarnitine, acetylspiramycin, levamisole; kallidinogenase; pancreatin, insulin, aspirin; pentoxifylline; simvastatin, Tremella fuciformis spores polysaccharide, colloidal bismmth pectin; taurine; calf blood protein-removed extraction, indole Racine, Lumbrukinase; dexketoprofen; Zaltoprofen, neutral protease, levonorgestrel; the levonorgestrel quinestrol; chlorophyll copper sodium, Yi Lila azoles, etodolac; magnesium isoglycyrrhetate, vitamin E Nicotinate.

The Chinese medicine preparation example that is particularly suitable for making enteric film control controlled release preparation in the present invention includes but not limited to: Bulbus Allii extract, Radix Et Caulis Acanthopanacis Senticosi extract, Fel Ursi, Cordyceps mycelium, Sanguis Draxonis, oryz aspergillus enzyme and pancreatin (fervent those Shens), hyphae zhiling, myrtol, cinobufacin or commodity are called BIYUANSHU, anti-inflammatory and choleretic, FUTONGNING, dragon stilbene thrombolytic, Ci Dan, Fupoganmao, compound eucommia bark, 'Compound berberine, the flu health, favour blood is given birth to, the enzyme spirit is fallen, the blood sugar lowering first, Omphalia, dewatering is transferred fat, dragon perfume (or spice) is relievingd asthma, brain arteries and veins Thailand, the antiinflammatory of relievining asthma, seven is living quiet, seven give birth to power, XINNAOKANG, Maixuekang, handkerchief Zhu ball, open spleen, the prostatitis is flat, the sudden and violent red cough-relieving of a kind of reed mentioned in ancient books, Cacumen Securinegae Suffruticosae, tonifying YIN is quenched one's thirst, heart of a lotus seed ginseng, fat arteries and veins health, Ji after one's own heart, the stilbene dragon, Radix Notoginseng is logical relaxes, NANBAO, spring blood peace, it is good to control sense, Siberian cocklebur osmanthus tetrahydro-isoquinolin, cure-all, red astragalus root for removing blood stasis, compound eucommia bark is good for bone, GENGNIANAN, anti-consumptive disease, six drugs containing rehmanniae, the Six-element Radix Aucklandiae, the thrombolytic nicergoline, refreshing peace, XUESAITONG, cough-relieving, compound taxol, embolism extinguishing, cold reducing-fever, a kind of reed mentioned in ancient books connects, gram numbness bone Thailand, the Chinese patent medicine of NAOLIQING or manyzoned polypore gantai.

The representational example of medicine that is particularly suitable for making colon soluble film control controlled release preparation in the present invention includes but not limited to: balsalazide, sulfasalazine, Olsalazine, 5-aminosalicylic acid and salt thereof such as zinc salt, ibuprofen, hydrogenation Bo Nisong, dexamethasone, budesonide, beclometasone, fluticasone, tixocortol (tioxocortal), hydrocortisone, metronidazole, tinidazole, metronidazole, the full rhzomorph of ring, methotrexate, domperidone, 5-fluorouracil, Laxadin, Senna fruit (senna), thymosin, insulin, vassopressin, growth hormone, colony stimulating factor, calcitonin, immunoglobulin, glibenclamide, DILTIAZEM HCl, verapamil, nifedipine, sulfur first third proline, benazepril, enalapril, theophylline, naproxen, Ciclofenaziae, acyclovir, omeprazole, Lovastain, Alendros, Desmopressin, metformin, metoprolol, cisapride, tetrahydroaminoacridine, their mixture and microecologic regulator (probiotics).

The exemplary drugs that is particularly suitable for making the control controlled release preparation that time-delay discharges in the present invention includes but not limited to gepirone (Gepirone), Risedronate, paroxetine and salt thereof, moxonidine, a-thioctic acid and derivant thereof, biguanides (as metformin and salt thereof) medicine, gabapentin, 1R, 2S-methoxamine, clarithromycin, proton pump inhibitor and salt thereof (as lansoprazole, omeprazole, pantoprazole, rabeprazole, esomeprazole, Tenatoprazole).

Be used for active matter of the present invention and comprise its pharmaceutically available salt form of following active component, free acid form, free alkali form, hydrate, optical isomer and various crystal formation.

Core material can also contain other pharmacy auxiliary agent except active substance, as slow controlled-release material, porogen, filler, binding agent, disintegrating agent, short disintegrating agent, lubricant (comprising fluidizer, antitack agent), osmotic pressure active substance (being osmotic pressure promoter), short osmopolymer bases such as (permeation-promoter).In addition, can also comprise solubilizing agent, suspending agent, sweeting agent, aromatic, pigment, absorbent and surfactant (as playing effects such as moistening, dispersion, solubilising, emulsifying).Pharmacy auxiliary agent and consumption thereof thus the art those skilled in the art according to selections such as the character of practical situation such as medicine, desirable rate of releasing drug.

The preparation method of controlled release preparation

Another object of the present invention just relates to a kind of preparation method of controlled release preparation of performance improvement, elaborates with regard to each basic step in the preparation method of controlled release preparation below.

1), preparation contains a kind of core material of medicine

The method that preparation contains a kind of core material of medicine has no particular limits.Usually preparation method is by direct pressing method with compositions such as active medicinal matter, pharmacy auxiliary agents; do, the pressing method of wet or sintered particles; extrude and rounding subsequently; wet or dry state pelletize or directly make ball (for example on the disk) or powder (powder bed) is bonded to the ball (particle) of non-activity material or contains on the granule of active substance, perhaps further in a certain way as make sheet to above-mentioned granule.

2), preparation porogen-promptly to the particulate matter of water-soluble medical additive coat contain pharmaceutically acceptable plasticizer or do not contain plasticizer dissolve in stomach and/or intestinal digestion liquid but be insoluble to or water-insoluble polymer clothing film almost

In one embodiment, water-soluble medical additive disperseed and be suspended in contain pharmaceutically acceptable plasticizer or do not contain plasticizer dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost (the organic or water) solution of water-insoluble polymer or (organic or water) dispersion liquid (wherein, the granularity of described polymer in organic dispersions usually should with polymer the granularity of aqueous dispersions quite or thinner) in (in case of necessity, can add other additives of clothing film, as plasticizer), mix homogeneously.Utilize the solution of above-mentioned gained or suspension by casting, soak coating processes such as the libation at an ancient wedding ceremony, brushing or spraying core material prepared the clothing layer.Preferably adopt spraying method to carry out.

In another embodiment, water-soluble medical additive is suspended in the air, to this particles suspended thing spray contain pharmaceutically acceptable plasticizer or do not contain plasticizer dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost (the organic or water) solution of water-insoluble polymer or (organic or water) dispersion liquid (in case of necessity, can add other additives of clothing film, as plasticizer), adopt spraying method to carry out coating.

In a special embodiment, water-soluble medical additive with coat its dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-insoluble polymer can be in water or body Digestive system generation chemical reaction, under these situations, adopt solvent or the dispersant of the organic solvent of non-water (not moisture) as this polymer, carry out above-mentioned operation again, otherwise the two antedating response is in aqueous medium.

The content of polymer in (organic or water) solution is generally 1～15%, and preferably 2～10%, more preferably 3～8%.The content of polymer in (organic or water) dispersion liquid (body) is generally 2～30%, and preferably 5～20%, more preferably 8～15%.Aqueous dispersions (body) also can contain certain amount of organic solvent, and its content often is 1～20%, and preferably 1～10%, more preferably 2～5%.Polymer dispersion liquid particularly the granularity in organic dispersions should be not more than 50 μ m usually, one be not more than 10 μ m, preferably be not more than 1 μ m, more preferably be not more than 300nm, more preferably be not more than 100nm, more preferably be not more than 30nm, be not more than 10nm best.

To the particulate matter of water-soluble medical additive coat above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-insoluble polymer clothing film whether complete coating depend on the two can be in water or body Digestive system generation chemical reaction and below clothing film coating process in whether use aqueous medium, if promptly the two can be in water or body Digestive system generation chemical reaction and the described clothing film coating process solvent or the dispersant that adopt water to make the clothing film polymer as the dispersant or the aqueous organic solvent of clothing film polymer, usually require then that particulate matter to water-soluble medical additive coats above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-insoluble polymer clothing film must be complete, this clothing film is necessary for 0 to the permeability of water, as handling by healing described below, otherwise the two antedating response is in aqueous medium; If described clothing film coating process adopts solvent or the dispersant of the organic solvent of non-water as the clothing film polymer, do not require usually to the particulate matter of water-soluble medical additive coat above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-insoluble polymer clothing film must be complete.

Film forming procedure does not rely on coating process and is undertaken by energy input, can finish by convection current (heat), radiation (infrared or microwave) or conduction.To fall as the solvent evaporation of solvent or suspending agent use for coating thus, necessary words also may be used the vacuum accelerated evaporation.The higher drying efficiency of this process need, so the present invention often adopts high efficiency coating equipment (as fluid bed).

Water-soluble medical additive with above-mentioned contain pharmaceutically acceptable plasticizer or do not contain plasticizer dissolve in stomach and/or intestinal digestion liquid but be insoluble to or after almost the solution of water-insoluble polymer or dispersion liquid coat, the consumption of this polymer clothing film is no more than 700% (w/w) of the consumption before water-soluble medical additive coating usually, preferably be no more than 300% (w/w) of the preceding consumption of water-soluble medical additive coating, more preferably about 2～about 200% (w/w), more preferably about 2～about 100% (w/w), more preferably about 3～about 50% (w/w), about best 3～about 30% (w/w).

The temperature that coating is used should be higher than the minimum film formation temperature (MFT) (minimum film formation temperature is meant the minimum temperature of polymer formation seriality clothing film, and below minimum film formation temperature, polymer particle can not be out of shape and merge and film forming) of polymer.The temperature that coating is used exceeds 10～20 ℃ of minimum film formation temperature usually.If temperature is low excessively, may make the clothing film crack occur; The too high then too softening polymer of temperature causes the clothing film coalescence.

During coating, be preheated to 20～90 ℃ usually, preferably 30～70 ℃, more preferably 30～50 ℃, earlier with low hydrojet speed coating, coated skim clothing film to the core material surface after, improve hydrojet speed to coating again and finish.

Optimum or more suitable technological parameter art those skilled in the art is thus determined according to coating material and core material character and experimental result etc.Fluidized bed coating for example, process conditions such as its coating temperature, fluidisation air quantity, atomizing pressure and hydrojet speed all can quantitatively be controlled according to practical situation optimization.

3), coat clothing film

In a preferred embodiment, with porogen promptly by above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost the particulate matter of above-mentioned water-soluble medical additive of coating of water-insoluble polymer clothing film disperse and be suspended in above-mentionedly to contain pharmaceutically acceptable plasticizer or do not contain being insoluble to or (the organic or water) dispersion liquid (body) of the polymer of water-soluble hardly and harmonization of the stomach intestinal digestion liquid of plasticizer, particularly in the aqueous dispersions (body), mix homogeneously can also be added other clothing film additive base to part medicine in this dispersion liquid (body) in case of necessity.The pH value of above-mentioned aqueous dispersions (body) should this porogen coating membrane do not dissolve degrade or the pH value scope of dissolving or degraded hardly in, so the pH value of this aqueous dispersions (body) should be adjusted to before porogen adding usually that the porogen coating membrane does not dissolve or the pH value scope of degrading in.Above-mentioned be insoluble to or the content of polymer in dispersion liquid (body) of water-soluble hardly and harmonization of the stomach intestinal digestion liquid is generally 2～30%, preferably 5～20%, more preferably 8～15%.Dispersion liquid (body) also can contain a certain amount of can not dissolve dissolve in stomach and/or intestinal digestion liquid but be insoluble to or other solvents of almost water-fast clothing film, its content often is 1～20%, preferably 1～10%, more preferably 2～5%.Above-mentioned organic dispersions (body) should not dissolve or not degrade or hardly dissolving or degrade the porogen coating membrane hardly above-mentioned and be above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or water-insoluble polymer clothing film almost.

The suspension of dispersion liquid (body) that utilizes above-mentioned gained is by casting, dip, brush or coating process such as spraying preparing the clothing layer to core material.Preferably adopt spraying method to carry out.Film forming procedure does not rely on coating process and is undertaken by energy input.This can finish by convection current (heat), radiation (infrared or microwave) or conduction.Thus will be for coating evaporate as the water that suspending agent uses, necessary words also may be used the vacuum accelerated evaporation.The higher drying efficiency of this process need, so the present invention often adopts high efficiency coating equipment (as fluid bed, high-efficiency coating pot).

In another embodiment, the clothing film polymer is dissolvable in water in the suitable organic solvent, and add plasticizer (in case of necessity, can add other additives of clothing film), according to the method for preparing clothing film, it needs to be noted, this solvent should not dissolve or not degrade or hardly dissolving or degrade the porogen coating membrane hardly above-mentioned and be above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or water-insoluble polymer clothing film almost.

In a special embodiment, the porogen of chemical reaction can take place in water liquid with the polymer that coats it for above-mentioned core material material, preferably disperse it in the water-free organic solvent or dispersant of above-mentioned clothing film polymer, and this water-free organic solvent or dispersant do not dissolve do not degrade or hardly dissolving or degrade the porogen coating membrane hardly above-mentioned and be above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or water-insoluble polymer clothing film almost.

The consumption of clothing film material is generally 0.5～50% (weight) of the consumption before the core material coating, is preferably 5～30% (weight), best 10～20% (weight); Coatings thickness is generally 5～500 μ m, is preferably 50～300 μ m, more preferably 100～200 μ m.

The core material surface temperature should be higher than dispersion liquid (body) minimum film formation temperature (MFT) (minimum film formation temperature is meant that dispersion liquid (body) forms the minimum temperature of seriality clothing film, and below minimum film formation temperature, polymer particle can not be out of shape and merge and film forming) during coating.The core material surface temperature exceeds 10～20 ℃ of minimum film formation temperature usually in the present invention.If the core material surface temperature is low excessively, may make the clothing film crack occur, influence the preparation drug release feature; The too high then too softening polymer of core material surface temperature causes the clothing film coalescence.

During aqueous dispersions (body) coating, core material is preheated to 20～90 ℃ usually, preferably 30～70 ℃, more preferably 30～50 ℃, earlier with low hydrojet speed coating, coated skim clothing film to the core material surface after, improve hydrojet speed to coating again and finish, this operation can avoid moisture to infiltrate core material inside, causes storage process core material character to change.

Before aqueous dispersions (body) coating, also can carry out the sealing coat coating to core material according to reality, this helps: 1. avoid the hydrolysis in the coating process of water sensitivity medicine; 2. avoid water soluble drug to migrate to the clothing film with water evaporates; 3. improve the profile pattern of core material, reduce porosity, guarantee clothing film seriality; 4. improve the core material surface hydrophobic, be beneficial to sprawling of aqueous coatings liquid; 5. improve the core material friability, avoid the broken phenomenon in the coating process.According to practical situation, can select water-soluble material (as Gonak and hydroxypropyl fibrinolytic liquid) or polymer organic solution to carry out the sealing coat coating.Yet this arbitrary coating all should be fully thin, in order to avoid the Release Performance of harm preparation.

Optimum or more suitable technological parameter art those skilled in the art is thus determined according to coating material and core material character and experimental result etc.With fluidized bed coating is to fall, and process conditions such as coating temperature, fluidisation air quantity, atomizing pressure and hydrojet speed all can quantitatively be controlled according to practical situation optimization.

4), clothing film is handled in healing (wearing out)

After above-mentioned twice coating finished, polymer particle did not often merge fully in the clothing film, also has certain permeability.This is especially for above-mentioned core material material can that the porogen of chemical reaction takes place in water liquid be unfavorable when next step wraps clothing film with aqueous dispersions (body) with the polymer that coats it, because of moisture may ooze in wherein, they are reacted in preparation process, and losing it should have effect.

Clothing film is deposited further fusion phenomenon is taken place in the process.It is believed that, under the additional pressure of micropore (Δ P) effect that the interfacial tension between polymer-air produces, these minimum micropores slowly dwindle automatically, deposit fusion phenomenon takes place in the process, make the permeability of clothing film take place constantly to change, thereby make the drug release behavior of preparation become unstable.

Therefore, in the present invention, the processing of after coating is finished, healing.

In the present invention, handle (curing treating) for the healing of clothing film and comprise following process: after solvent or dispersant evaporate substantially in the above-mentioned clothing film, in enclosed environment, the above-mentioned core material that has coated controlled release polymer clothing film is placed under the temperature of the glass transition temperature that is higher than above-mentioned clothing film the long enough time until terminal point, polymer particle in the above-mentioned preparation clothing film is merged completely or almost completely, eliminate or eliminate the minimum micropore that forms in the coating process substantially and form complete densification or the clothing film of complete substantially densification, the permeance property of above-mentioned clothing film Release Performance in other words reaches the constant substantially in other words state of stable status.More particularly, exactly healing under the temperature of the vitrifying point that is higher than above-mentioned clothing film handle above-mentioned controlled release coat preparation until preparation till placement under the acceleration storage requirement the relative humidity of for example about 40 ± 2 ℃ temperature and 70% to 80% under 3 months and/or 6 months or longer its dissolution characteristic are unaffected basically.Perhaps in other words, the external stripping of the bioactive substance after handling just healing is compared with the external stripping of the bioactive substance that is placed 3 months and/or 6 months under the acceleration storage requirement the relative humidity of about 40 ± 2 ℃ temperature and 70% to 80% under, and the coated preparation of the processing of healing has stable dissolution characteristic.The meaning of term " stable " finishes, solidifies the dissolution characteristic comparison of coated preparation with firm curing in addition, its external stripping is in the acceptable limit, acceptable limit is by administrative organization, determines as Chinese drug and food management supervision office, U.S. food and drug administration etc.Substantially do not quickened the stable dissolution characteristic that storage requirement influences.

In special embodiment of the present invention, the porogen of chemical reaction can take place in water liquid with the polymer that coats it for above-mentioned core material material, before next step aqueous dispersions (body) bag clothing film with the polymer of the clothing film that contains this porogen, the processing (curing treating) of should healing of the clothing film of this porogen is 0 state terminal point to the permeance property of water to the clothing film of above-mentioned porogen, this healing is handled and is comprised following process: after the middle solvent of the clothing film of above-mentioned porogen or dispersant evaporate substantially, in enclosed environment, with above-mentioned porogen (promptly by above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or water-soluble medical additive of coating of water-insoluble polymer clothing film almost) the long enough time under the temperature of the glass transition temperature that is higher than above-mentioned clothing film of placing is 0 state terminal point to the permeance property of water until above-mentioned porogen clothing film, polymer particle in the above-mentioned porogen clothing film is merged fully, eliminate minimum micropore that forms in the coating process and the clothing film that forms complete densification, under above-mentioned state terminal point, above-mentioned porogen above-mentioned be insoluble to or the aqueous dispersions (body) of the polymer of water-soluble hardly and harmonization of the stomach intestinal digestion liquid in chemical reaction does not take place, will in the ensuing whole process that coats clothing film with aqueous dispersions (body) chemical reaction not take place at least.

In the present invention, the healing required time of processing is generally tens of hours even is longer.The temperature that the healing treatment of selected is selected should be higher than clothing film glass transition temperature, preferably be higher than clothing film glass transition temperature more than 10 ℃, more preferably be higher than 20～30 ℃ of clothing film glass transition temperatures, the healing treatment of selected temperature of selecting and should be not make the softening fully or fusing of composition in the coating material or clothing film coalescence degree of being does not take place.Preferably use certain humidity when healing is handled, because of clothing film under the effect of moisture or dampness, its glass transition temperature can significantly descend, and handles thereby help healing acceleration.

Healing is handled and can be carried out with heat treatment modes such as baking oven and fluid beds.Characteristics such as the fluid bed heat processing has efficiently, saves time can be finished coating and heat treatment operation in same equipment, the industrialization suitability is higher.Coating finishes back elevation system temperature, and material can promote film healing balance in same fluid unit relaying afterflow drying in the short time.But compare with the baking oven mode, the fluid bed mode is had relatively high expectations to funeral film mechanical performance, and heat treatment caudacoria healing degree is relatively low.So the present invention preferably adopts the baking oven heat treatment mode.

Under the higher thermal treatment temperature, enter in the clothing film in order to prevent that low melting point substance (as ibuprofen) from may move, cause the preparation release to accelerate degradation problem under phenomenon, the clothing film mechanical performance, can carry out the sealing coat coating to the medicine carrying core material, perhaps reduce heat treatment temperature.

Optimum or more suitable technological parameter, as healing temperature, humidity, time thus the art those skilled in the art determine according to experimental result etc.

If film has healed fully in coating process underpants, can not heal (wearing out) handles, as the preparation with Surelease (EC) aqueous dispersions (body) coating.

Can wrap the skim coating material with the surperficial globality of improving preparation or prevent that preparation bonds mutually in storage process with the preparation of above-mentioned either party's method preparation.Suitable coating material includes but not limited to disaccharide such as sucrose, polysaccharide such as maltodextrin and pectin and cellulose derivative such as hydroxypropyl emthylcellulose and hydroxypropyl cellulose, yet, arbitrary coating all should fully approach and be water-soluble, with the Release Performance of obstruction free preparation.

Pharmaceutical dosage form with above-mentioned either party's method preparation can directly use basically, as directly oral.Pack into as in capsule, bag (sachet) or the suitable many measuring containers with the also available measuring equipments such as small pieces, ball or granule of method for preparing.If possible, obtain new preparation such as tablet by proper method such as compacting with the ball of method for preparing or granule etc. mixing the back with other auxiliary agent, said preparation decomposes taking the back, and junior units most of or that all coat discharge.Can consider equally to be embedded in Polyethylene Glycol or lipid or other substrate with preparation suppository or vagina medicinal agent type by the controlled release preparation of method for preparing.The tablet that coats is packed with hemispherical container or multi-dose container, directly takes out before patient takes.

Described the present invention thus in detail, obviously also various changes can have been arranged within the scope of the invention to those skilled in the art, the present invention is not subjected to the described restriction of description.

The relative conventional art of the present invention has following technical advantage:

1), drug release repeatability or stability improve;

2), influence alleviates the body intrinsic factor to drug release;

3), influence alleviates extrinsic factor to drug release, separates out from polymeric film easily as preventing water-soluble substances, overcomes " scum " phenomenon;

4), the time stickiness of drug release reduces, drug release in advance, drug release is accelerated, bioavailability improves;

5), the clothing film mechanical performance strengthens;

6), can realize that medicine positioning controlled-release in gastrointestinal tract discharges, as stomach, intestinal, colon release-controlled release;

7), can realize that delay time controlled release release, clearance-type or pulsed controlled release of medicine discharges in gastrointestinal tract.

Description of drawings

Fig. 1 embodiment 1 and reference substance 1 simvastatin release in vitro test result

Fig. 2 embodiment 2 and reference substance 3 diltiazem hydrochloride release in vitro test results

Fig. 3 embodiment 3 and reference substance 5 metformin hydrochloride release in vitro test results

Fig. 4 embodiment 4 and reference substance 7 budesonide release in vitro test results

Fig. 5 embodiment 5 and reference substance 8 diclofenac sodium release in vitro test results

Fig. 6 embodiment 6 and reference substance 9 trapidils discharge test result outward

Embodiment

Below non-selective embodiment further described preferred embodiment in the scope of the invention. These embodiment also can have many variations within the scope of the invention.

Embodiment 1 and reference examples 1-2

1, preparation sample and photograph sample

1), prepare label by following prescription and technology:

Simvastatin, CABBOPOL 974P, the two citric acid monohydrate sodium, lactose and the polyvinylpyrrolidone that grind are mixed, carry out granulation with the ethanolic solution (containing required BHA) of moisture 10% (by weight); Wet granular material was forced 18 mesh sieves also dry 24 hours; Behind the whole grain, add the dolomol mixing, with the circular punch die compressed tablets of the spill of one 1/4 inch standard, used press power is 800～1000 pounds. The thickness of tablet is 3.89mm after the compacting, and hardness is 8～10kg.

2), preparation enteric coating film coated granule

Coating fluid prescription

# is described: carboxymethylethylcellulose is compatible with following clothing film polymer cellulose acetate after tested.

Coating solution by above-mentioned coating fluid prescription preparation carboxymethylethylcellulose. (Powrex Corp. (Japan) makes, and MP-10) adds sodium bicarbonate particle (particle diameter 300～400 orders, 38～48 μ m) to centrifugal fluidization dressing granulator. Respectively gasinlet temperature and the temperature of working off one's feeling vent one's spleen are controlled at 60～80 ℃ and 30～40 ℃, with the spray liquid spraying sodium hydrogen carbonate powder of above-mentioned preparation, sodium bicarbonate particle increases weight about 100%. (temperature is 55 ℃ in dry also healing, healing time is not less than 72 hours, until sodium ion does not wherein ooze out, do not seep water take place in and chemical reaction for to) after the gained particle through the circular sieves of 240 orders (61 μ m) and the circular sieves of 300 orders (48 μ m) screening, obtain containing the enteric coating film coated granule (particle diameter 48～61 μ m) that sodium acid carbonate is examined core.

3), preparation clothing film coating solution:

Cellulose acetate added make 5% solution in acetic acid ethyl ester-ethanol (95: 5) as oil phase, take the lauryl sodium sulfate aqueous solution of 3mg/ml as water; Use the high speed dispersing emulsification machine, low whipping speed is not less than 3000 rev/mins the lower water of condition and slowly is added dropwise to and forms w/o type emulsion in the oil phase, continues to drip until form the colostrum of O/W type. Colostrum is passed through high pressure homogenizer, 6 times repeatedly. Use Rotary Evaporators at 40 ℃, under the reduced pressure organic solvent is removed from gained emulsion.

4), bag clothing film:

The forward and backward bag of label bag clothing film is every wet protective finish. The dressing material of using every wet protective finish is for containing 4.5% hydroxypropyl methylcellulose (Pharmacoat, 603/ShinEtsu), 0.52% PEG 400 and the suspension of 1.5% micronized talcum. Coating conditions parameter: about 20 seconds of spraying time, about 30～40 seconds of blasting time, 50～55 ℃ of blast temperatures, 30～40 ℃ of label temperature. Be about 1% every wet protective finish dressing weightening finish.

Add the diacetine that adds enteric coating film coated granule in the aqueous dispersions (body) and be used as plasticizer at the above-mentioned cellulose acetate that makes, cellulose acetate wherein: enteric coating film coated granule: diacetine is 1: 2: 1 (weight ratio), be diluted with water to and contain 3% cellulose acetate suspension and make coating solution, in case of necessity, regulate in advance the pH value to 3.5 of cellulose acetate suspension～4.0. With the coating solution that makes to label bag clothing film. The weightening finish of clothing film dressing is 16%.

With timing automatic film coating machine dressing, the coating conditions parameter is: about 20 seconds of spraying time, about 30～40 seconds of blasting time, 50～70 ℃ of blast temperatures, 40～50 ℃ of label temperature.

5), healing clothing film

Healing processing carries out in airtight baking oven. The healing temperature is 65 ℃, and healing time is 30 hours.

6), preparation reference examples

Add the diacetine that adds the particle (particle diameter 48～61 μ m) of carboxymethylethylcellulose in the aqueous dispersions (body) and be used as plasticizer at the above-mentioned cellulose acetate that makes, wherein, cellulose acetate: carboxymethylethylcellulose particle: diacetine is 1: 2: 1 (weight ratio), is diluted with water to contain 3% cellulose acetate suspension and make coating solution. Then, prepare the reference examples 1 that clothing film contains the carboxymethylethylcellulose particle by above-mentioned method.

In the acetone soln of cellulose acetate, add the diacetine that adds respectively sodium bicarbonate particle (particle diameter 48～61 μ m) and be used as plasticizer, wherein, cellulose acetate: sodium acid carbonate: diacetine is 1: 2: 1 (weight ratio), makes coating solution with acetone diluted to the cellulose acetate suspension that contains 3%. Then, prepare the reference examples 2 that clothing film contains sodium bicarbonate particle by above-mentioned method.

2, vitro release test

Adopt Chinese Pharmacopoeia version oar in 2005 method to measure. Rotating speed is 50r/min, temperature is (37 ± 1) ℃, and mediator is used respectively simulated gastric fluid (pH1.2 hydrochloric acid solution) and contained the simulated intestinal fluid (pH6.0 phosphate buffer) of 0.4% lauryl sodium sulfate, contains each 900mL of simulated intestinal fluid (pH7.4 phosphate buffer) of 0.4% lauryl sodium sulfate. With the release conditions that flows through type (flow-through) ultraviolet specrophotometer supervision medicine. Fig. 1 has demonstrated the situation of medicine from controlled release coat tablet and reference examples 1 release.

The result shows that embodiment sample Chinese traditional medicine discharges comparatively fast, is subjected to the impact of acid-base value littler in simulated intestinal fluid, the time stickiness also littler, and that the reference examples Chinese traditional medicine discharges in simulated intestinal fluid is relatively slow, is subjected to the impact of acid-base value relatively large, the time stickiness also relatively large; The two Chinese traditional medicine does not all discharge in simulated gastric fluid substantially.

Embodiment 2 and reference examples 3-4

1), prepare label by following prescription and technology:

Diltiazem hydrochloride, Sodium citrate and PVP are mixed, carry out granulation with ethanol solution; Wet granular material was forced to pass 18 purpose sieves also dry 24 hours; Behind the whole grain, add the dolomol mixing, with the spill circle punch die compressed tablets of the standard of a 12mm, used press power is 1200～2000kg, press time 1～2s. Hardness is 6～10kg.

2), the molten clothing film of preparation stomach coated granule

Coating fluid prescription

* is described: after tested EUDRAGIT E100 and following clothing film polymer

RS 30 D、

RL 30 D parts are compatible, and compatibility is higher.

Solution by above-mentioned coating fluid prescription preparation EUDRAGIT E100. With spray dryer (TCSD: Japanese vehicle), with 80 ℃ of inlet temperatures, hot air flow 34～38mmH₂O, spray velocity 2g/min, this liquid of spray-drying, the distillation desolventizing, particle increases weight about 50%, (temperature is 45 ℃, and healing time is not less than 60 hours, until sodium ion does not wherein ooze out in dry also healing, do not seep water take place in and chemical reaction for to) after particle cross 230 and 270 purposes sieve, obtain the molten clothing film of the stomach coated granule (particle diameter 53～62 μ m) of the Sodium citrate nuclear core that the molten clothing film of stomach coats.

3), label is pressed following prescription and technology dressing:

Coating fluid prescription (1000 consumptions):

The solids content of aqueous dispersions (body) is 16 (weight) %.

With label dressing on the Hicoater/Fruend seed-coating machine. Coating conditions parameter: inlet temperature, 50～60 ℃; Outlet temperature, 30～35 ℃; 31～36 ℃ of label temperature; Label weightening finish 12.63%.

4), healing clothing film

Healing processing carries out in airtight baking oven. The healing temperature is 45 ℃, and healing time is 24 hours.

5), preparation contrast articles for use.

The Sodium citrate ball that the molten clothing film of stomach in the coating fluid prescription is coated changes the particle (particle diameter 53～62 μ m) of the EUDRAGIT E100 of dressing or the Sodium citrate particle of dressing (particle diameter 53～62 μ m) not into, reaches as stated above condition preparation contrast articles for use 3 or 4.

2, vitro release test

Adopt Chinese Pharmacopoeia version oar in 2005 method to measure. Rotating speed is 100r/min, and temperature is (37 ± 1) ℃, and mediator is with simulated gastric fluid I (hydrochloric acid solution of pH2.0), simulated gastric fluid II (hydrochloric acid solution of pH4.0) and each 1000mL of simulated intestinal fluid (pH7.5 phosphate buffer). Embodiment 2 and contrast are directly dropped into respectively in the stripping rotor with 3 samples, the 5mL that takes a sample at regular intervals, and replenish with volume stripping mediator. With 0.8 μ m filtering with microporous membrane, get subsequent filtrate, dilute with water is made the solution that contains approximately 8 μ g among every 1ml. In addition precision take by weighing through 2 hours diltiazem hydrochloride reference substance of 105 ℃ of dryings an amount of, be dissolved in water and quantitatively dilution make the solution that contains approximately 8 μ g among every 1ml. Get above-mentioned two kinds of solution, according to AAS (Chinese Pharmacopoeia version appendix in 2005 IV A), measure respectively trap at the wavelength place of 240nm, calculate every at the stripping quantity of different time. The results are shown in accompanying drawing 2.

The result shows that embodiment sample Chinese traditional medicine discharges comparatively fast, is subjected to the impact of acid-base value littler in simulated gastric fluid, the time stickiness also littler, and that the reference examples Chinese traditional medicine discharges in simulated gastric fluid is slower, is subjected to the impact of acid-base value bigger, the time stickiness also bigger; The two Chinese traditional medicine discharges in simulated intestinal fluid substantially.

Embodiment 3 and reference examples 5-6

1, preparation sample and photograph sample

1), prepare label by following prescription and technology:

PVP^*, molecular weight is 1,000,000; Dynamic viscosity (10%w/v, 20 ℃) is 300～700mPas.

Metformin hydrochloride and lauryl sodium sulfate are crossed 40 mesh sieves, mixing repeatedly; PVP K-90-F is dissolved in the pure water; The mixed powder of Metformin hydrochloride and lauryl sodium sulfate is inserted in the fluid bed; Spray into the solution granulation of PVP; 50～70 ℃ of inlet temperatures, air pressure 1～3bars, spray speed 10～100ml/min. Cross 18 mesh sieves behind the particle drying, add the dolomol mixing, with the spill circle punch die compressed tablets of the standard of a 12mm, used press power is 1200～2000kg, press time 1～2s. Hardness is 6～10kg.

2), preparation stomach and intestine two molten clothing film coated granules

Coating fluid prescription:

※ is described: 2-methyl-5-vinylpyrine/methacrylic acid methyl/methacrylic acid copolymer is almost completely compatible with following clothing film polymer poly ethene acetic acid after tested.

By above-mentioned coating fluid prescription preparation stomach and intestine two molten clothing film coated particle dressing suspensions. (TCSD: Japanese vehicle) spray-drying, particle increase weight about 80%, obtain the mannitol particles (particle diameter 18～30 μ m) that stomach and intestine two molten clothing films coat with spray dryer with the dressing suspension that obtains.

3), bag clothing film:

Label coating fluid prescription (1000 consumptions):

By above-mentioned prescription preparation coating solution, in case of necessity, regulate about pH value to 5. With label dressing on the Hicoater/Fruend seed-coating machine. Coating conditions parameter: inlet temperature, 50～60 ℃; Outlet temperature, 35～37 ℃; 36～38 ℃ of label temperature; Label weightening finish 13.96%.

3), healing clothing film

Healing processing carries out in airtight baking oven. The healing temperature is 45 ℃, and healing time is 24 hours.

4), preparation contrast articles for use.

The particle that stomach and intestine two molten clothing films in the coating fluid prescription are coated changes 2-methyl-5-vinylpyrine/methacrylic acid methyl/methacrylic acid copolymer particle (particle diameter 18～30 μ m) into, reaches as stated above the contrast articles for use 5 that the condition preparation contains copolymer.

With following coating solution above-mentioned label is reached the contrast articles for use 6 that the condition preparation contains sweet mellow wine as stated above. Coating fluid prescription: 1000 consumptions: polyvinylacetate 30g, mannitol particles (particle diameter 18～30 μ m) 45g, glyceryl triacetate 1.8g, titanium dioxide (particle diameter 20nm) 2g, ethanol 1000ml.

2, vitro release test

Adopt Chinese Pharmacopoeia version oar in 2005 method to measure. Rotating speed is 75r/min, and temperature is (37 ± 1) ℃, and mediator is with pH3.0 hydrochloric acid solution and each 1000mL of pH7.4 phosphate buffer. Embodiment and reference examples are directly dropped into respectively in the stripping rotor, the 5mL that takes a sample at regular intervals, and replenish with volume stripping mediator. Measure trap with AAS at the wavelength place of 235nm, and calculate release. The results are shown in accompanying drawing 3.

The result shows that the release of embodiment sample Chinese traditional medicine is very fast, the time stickiness also littler; The release of reference examples Chinese traditional medicine is relatively slow, the time stickiness also relatively large.

Embodiment 4 and reference examples 7

1), prepare label by following prescription and technology:

Budesonide (micronizing) is scattered in Aquacoat ECD 30 aqueous dispersions (body) that contain citroflex A-4 and polyoxyethylene sorbitan monoleate, and mixing makes coating solution; Sugar-pill is inserted in the fluid bed; Spray into above-mentioned coating solution granulation. Behind the particle drying, add lactose, polyethylene glycol oxide, dolomol and superfine silica gel powder mixing, with the spill circle punch die compressed tablets of the standard of a 12mm, used press power is 1200～2000kg, press time 1～2s. Hardness is 6～10kg.

2), the water miscible fine grained of preparation knot enteric coating film coating

Knot enteric coating film coating fluid prescription:

By the solution of above-mentioned coating fluid prescription preparation pectin-guar gum, use Na₂CO ₃Regulate pH value to 8. (Powrex Corp. (Japan) makes, and MP-10) adds sucrose ball (particle diameter 80～113 μ m contain 20% microcrystalline cellulose) to centrifugal fluidization dressing granulator. With the spray liquid spraying cane sugar powder of above-mentioned preparation, the sucrose ball increases about 10%. Subsequent drying, the gained particle obtains the particle that 120～175 purposes have the sugared core of knot enteric coating film dressing through the circular sieves of 175 orders (aperture 86 μ m) and the circular sieve screening of 120 orders (aperture 120 μ m).

3), label is pressed following prescription and technology bag clothing film:

Coating fluid prescription:

With the coating solution that makes to label bag clothing film. Adopt a miniature high-performance coating machine of Freund type HCT ((8 inches dishes), with coating solution to coat a thickness to tablet be 250 microns coating.

5), preparation contrast articles for use

Make the film of thickness 250～500 μ m in the polyfluortetraethylene plate top casting with the solution of the pectin-guar gum of above-mentioned preparation, ℃ lower pulverizing in temperature-40～-30 after dry, the gained particle obtains the particle of 120～175 purpose pectin-guar gums through the circular sieve of 175 orders and the circular sieve screening of 120 orders.

Particle with the pectin-guar gum of gained reaches the particle contrast articles for use 7 that the condition preparation contains pectin-guar gum as stated above.

2, vitro release test

Adopt Chinese Pharmacopoeia version oar in 2005 method to measure. Rotating speed is 75r/min, and temperature is (37 ± 1) ℃, and mediator is used respectively simulated gastric fluid (SGF)^★, simulated intestinal fluid (SIF)^★★And artificial colonic fluid (SCF)^★★★1000mL. Embodiment and reference examples are directly dropped in the stripping rotor respectively, and sample keeps changing SIF into after 2 hours in SGF, keeps changing SCF in 4 hours in SIF, carries out then the release test in SCF, the 5mL that takes a sample at regular intervals, and replenish with volume stripping mediator. Use HPLC (HP-1100, Hewlett-Packard, post: the μ Bondapak C-18) release of mensuration budesonide. The result as shown in Figure 4.

The result shows that the release of embodiment sample Chinese traditional medicine is very fast, the time stickiness also littler; The release of reference examples Chinese traditional medicine is slower, the time stickiness also bigger.

Note: simulated gastric fluid (SGF)^★: refer to the solution of a kind of pH1.2 herein, this solution of every 1000ml contains 2gNaCl, the dissolving of 3.2g pepsin and an amount of (about 7ml) HCl.

Simulated intestinal fluid (SIF)^★★: the kaliumphosphate buffer that contains 0.1% pancreatin that refers to a kind of pH7.5 herein, this solution preparation process is as follows, the potassium phosphate of 6.8g monatomic base is dissolved in the 250ml water, add then 190ml 0.2N NaOH, 400ml water and 10g pancreatin, add at last 0.2N NaOH, pH is adjusted to 7.5, be diluted with water to then 1000ml.

Artificial colonic fluid (SCF)^★★★: the buffer solution that refers to a kind of 50mM of containing phosphate, 26pg/ml Pectinex Ultra SPL (NovoNordisk) and 20unit/ml galactomannans enzyme (Novo Nordisk) herein.

Embodiment 5 and reference examples 8

1), prepare label by following prescription and technology:

C14H10Cl2NNaO2, hydroxypropyl methylcellulose, sweet mellow wine and PVP are mixed, carry out granulation with ethanol solution; Wet granular material was forced to pass 18 purpose sieves also dry 24 hours; Behind the whole grain, add dolomol and cataloid, mixing, with the spill circle punch die compressed tablets of the standard of a 9mm, used press power is 200～2000kg, press time 1～2s. Hardness is 5～10kg.

2), the water miscible fine grained of preparation knot enteric coating film coating

Knot enteric coating film coated particle coating fluid prescription:

By above-mentioned coating fluid prescription preparation knot enteric coating film coated particle dressing suspension. (PowrexCorp. (Japan) makes, and MP-10) adds cane sugar powder (particle diameter 48～58 μ m) to centrifugal fluidization dressing granulator. With the coating solution spraying cane sugar powder of above-mentioned preparation, cane sugar powder increases weight about 20%. The gained particle obtains the powder (particle diameter 53～62 μ m) that the 230-270 purpose contains Icing Sugar nuclear core through the circular sieves of 270 orders (53 μ m) and the circular sieves of 230 orders (62 μ m) screening after dry.

3), label is pressed following prescription and technology dressing:

Coating fluid prescription:

By above-mentioned prescription preparation coating solution, regulate in case of necessity pH value to 5～5.5. The solids content of aqueous dispersions (body) is 16 (weight) %.

With label dressing on the Hicoater/Fruend seed-coating machine. Coating conditions parameter: inlet temperature, 50～60 ℃; Outlet temperature, 40～42 ℃; 40 ℃ of label temperature; Label weightening finish 12%. Not hot healing processing behind the label dressing.

Wrap state clothing film before the bag one water-soluble film clothing. The dressing material that bag water-soluble film clothing is used is for containing 4.5% hydroxypropyl methylcellulose (Pharmacoat, 603/ShinEtsu), 0.52% PEG 400 and the aqueous solution of 1.5% micronized talcum. Coating conditions parameter inlet temperature, 55 ℃; Outlet temperature, 30 ℃. The weightening finish of water-soluble film clothing dressing is about 1%.

6), preparation contrast articles for use

Make the film of thickness 250～500 μ m in the polyfluortetraethylene plate top casting with the shellac coating solution of above-mentioned preparation, ℃ lower pulverizing in temperature-40～-30 after dry, the gained particle obtains the particle of 53～62 μ m through the circular sieves of 270 orders (53 μ m) and the circular sieves of 230 orders (62 μ m) screening.

Particle with gained reaches the particle contrast articles for use 8 that the condition preparation contains shellac as stated above.

2, vitro release test

Adopt Chinese Pharmacopoeia version oar in 2005 method to measure. Rotating speed is 100r/min, and temperature is (37 ± 1) ℃, and mediator is used respectively simulated gastric fluid (hydrochloric acid solution of pH1.2, no enzyme), simulated intestinal fluid (kaliumphosphate buffer of pH6.8, no enzyme) and phosphate buffer (pH7.8) 1000mL. Directly drop in the stripping rotor embodiment and reference examples respectively, sample keeps changing simulated intestinal fluid into after 2 hours in simulated gastric fluid, in simulated intestinal fluid, keep changing phosphate buffer (pH7.8) into after 4 hours, in phosphate buffer (pH7.8), carry out then the release test. Use AAS, measure respectively trap at the wavelength place of 287nm, calculate every at the stripping quantity of different time. The result as shown in Figure 5.

The result shows that the release of embodiment sample Chinese traditional medicine is very fast, the time stickiness also littler; The release of reference examples Chinese traditional medicine is slower, the time stickiness also bigger.

Embodiment 6 and reference examples 9

1), prepare label by following prescription and technology:

Trapidil, hydroxypropyl methylcellulose and sweet mellow wine are mixed, carry out granulation with the ethanolic solution of PVP; Wet granular material was forced to pass 25 purpose sieves also dry 24 hours; Behind the whole grain, add dolomol and cataloid, mixing, with the spill circle punch die compressed tablets of the standard of a 9mm, used press power is 1200～2000kg, press time 1～2s. Hardness is 6～10kg.

2), the preparation time-delay discharges the water miscible fine grained that the clothing film coats

Time-delay discharges clothing film coating fluid prescription (internal layer clothing):

Enteric coating film coating fluid prescription (outer clothing):

By above-mentioned coating fluid prescription prepared polymer poly (ε-caprolactone) and the solution of HP-50. With cane sugar powder (particle diameter: 53～61 μ m) put in the centrifugal fluidization granulator and roll, when blowing hot-air, to its spray earlier above-mentioned poly (solution of the solution of ε-caprolactone), the clothing layer thickness is 27～29 μ m (particle increases weight about 700%); Spray the solution of the solution of above-mentioned HP-50, the clothing layer thickness is about 1 μ m (particle increases weight about 5%) again. After drying, obtain the sugar-pill that packet delay discharges the clothing film.

3), bag clothing film:

The clothing film dressing is forward and backward all to be wrapped every wet protective finish. The dressing material of using every wet protective finish is for containing 4.5% hydroxypropyl methylcellulose (Pharmacoat, 603/ShinEtsu), 0.52% PEG 400 and the suspension of 1.5% micronized talcum. Coating conditions parameter: about 20 seconds of spraying time, about 30～40 seconds of blasting time, 50～55 ℃ of blast temperatures, 30～40 ℃ of label temperature. Be about 1% every wet protective finish dressing weightening finish before the dressing, be about 2% every wet protective finish dressing weightening finish behind the dressing.

Add the sugar-pill that adds packet delay release clothing film in the aqueous dispersions (body) and the diacetine of being used as plasticizer at the cellulose acetate that the method by embodiment 1 makes, cellulose acetate wherein: packet delay discharges the sugar-pill of clothing film: diacetine is 1: 2: 1 (weight ratio), be diluted with water to and contain 3% cellulose acetate suspension and make coating solution, regulate in case of necessity the pH value to 4.0 of cellulose acetate suspension～4.5. With the coating solution that makes to label bag clothing film. The weightening finish of clothing film dressing is 16%.

With timing automatic film coating machine dressing, the coating conditions parameter is: about 20 seconds of spraying time, about 30～40 seconds of blasting time, 50～70 ℃ of blast temperatures, 40～50 ℃ of label temperature.

5), healing clothing film

Healing processing carries out in airtight baking oven. The healing temperature is 65 ℃, and healing time is 30 hours.

6), preparation contrast articles for use

(ε-caprolactone) coating solution is made the film of thickness 250～500 μ m in the polyfluortetraethylene plate top casting with the poly of above-mentioned preparation, ℃ lower pulverizing in temperature-40～-30 after dry, the gained particle is through the circular sieves of 180 orders (80 μ m) and the circular sieves of 170 orders (90 μ m) screening, the particle of preparation 80～90 μ m, spray the solution of the solution of above-mentioned HP-50 with above-mentioned technology, the clothing layer thickness is about 1 μ m (particle increases weight about 5%) again. Reach as stated above the condition preparation with the particle of gained and contain poly (the particle contrast articles for use 9 of ε-caprolactone).

2, vitro release test

Adopt Chinese Pharmacopoeia version oar in 2005 method to measure. Rotating speed is 100r/min, and temperature is (37 ± 1) ℃, and mediator is with simulated intestinal fluid (kaliumphosphate buffer of pH6.8, no enzyme) 1000mL. Embodiment and reference examples are directly dropped in the stripping rotor respectively. With AAS (Chinese Pharmacopoeia version appendix in 2005 IV A), measure trap at the wavelength place of 300nm, calculate every at the stripping quantity of different time. The result as shown in Figure 6.

The result shows that the release of embodiment sample is very fast, and time lag is suitable, and the time-delay that can realize 5～6 hours discharges, and can satisfy clinical needs; And the reference substance release is extremely slow, and time lag is long, needs the 30-32 release of just beginning, with can not clinical practice.

Embodiment 7

Sodium bicarbonate particle among the embodiment 1 (particle diameter 300～400 orders, 38～48 μ m) weightening finish about 300%, obtain containing the particle (particle diameter 61～75 μ m) of sodium acid carbonate nuclear core with gained particle after the dry also healing of method through the circular sieves of 200 orders (75 μ m) and 240 orders circle sieves (61 μ m) screening. Press embodiment 1 described prescription and technology preparation enforcement 7 with particle obtained above (particle diameter 61～75 μ m).

Embodiment 8

Sodium bicarbonate particle among the embodiment 1 (particle diameter 300～400 orders, 38～48 μ m) weightening finish about 700%, obtain containing the particle (particle diameter 75～96 μ m) of sodium acid carbonate nuclear core with gained particle after the dry also healing of method through the circular sieves of 160 orders (96 μ m) and 200 orders circle sieves (75 μ m) screening. Press embodiment 1 described prescription and technology preparation enforcement 8 with particle obtained above (particle diameter 75～96 μ m).

Embodiment 9

Mannitol particles among the embodiment 3 (particle diameter 15～25 μ m) weightening finish is about 200%, makes gastrointestinal two molten clothing film coated pellet (particle diameter 23～38 μ m).Press embodiment 3 described prescriptions and prepared enforcement 9 with the above-mentioned granule that obtains (particle diameter 23～38 μ m).

Embodiment 10

Sucrose ball among the embodiment 4 increases weight about 2%.Other are constant, implement 10 with the above-mentioned granule that obtains by embodiment 4 described prescriptions and prepared.

Embodiment 11 and reference examples 10

Water miscible fine grained by following prescription and the coating of prepared enteric coating film

Coating fluid prescription

# is described: Eudragit L is compatible with clothing film polymer cellulose acetate part after tested.

Coating solution by above-mentioned coating fluid prescription preparation Eudragit L.(Powrex Corp. (Japan) makes, and MP-10) adds sodium carbonate particle (particle diameter 240～150 orders, 61～106 μ m) to centrifugal fluidization coating granulator.Respectively the gasinlet temperature and the temperature of working off one's feeling vent one's spleen are controlled at 60～80 ℃ and 30～40 ℃, with the spray liquid spraying sodium carbonate powder of above-mentioned preparation, sodium carbonate particle increases weight about 100%.(temperature is 45 ℃ in dry also healing, healing time was not less than 60 hours, do not ooze out until wherein sodium ion, do not seep water take place in and chemical reaction for to) back gained granule is through circular sieves of 200 orders (75 μ m) and the circular sieves of 115 orders (125 μ m) screening, obtains containing the enteric coating film coated granule (particle diameter 75～125 μ m) that sodium carbonate is examined core.

All the other press prescription and the prepared embodiment 11 and the reference examples 10 of embodiment 1 and reference examples 1, wherein, cellulose acetate in the embodiment 11 bag clothing films: enteric coating film coated granule: diacetine is 1: 1.5: 1 (weight ratio), and cellulose acetate in the reference examples 10 bag clothing films: Eudragit L granule (particle diameter 75～125 μ m): diacetine is 1: 1.5: 1 (weight ratio)

Embodiment 12 and reference examples 11

Water miscible fine grained by following prescription and the coating of prepared enteric coating film

Coating fluid prescription

Coating solution by above-mentioned coating fluid prescription preparation vinylacetate-copolymer-maleic anhydride.(Powrex Corp. (Japan) makes, and MP-10) adds glucose granule (particle diameter 300～400 orders, 38～48 μ m) to centrifugal fluidization coating granulator.Respectively the gasinlet temperature and the temperature of working off one's feeling vent one's spleen are controlled at 60～80 ℃ and 30～40 ℃, spray liquid spraying glucose granule with above-mentioned preparation, the glucose granule increases weight about 100%, the gained granule obtains containing the enteric coating film coated granule (particle diameter 48～61 μ m) of glucose nuclear core through circular sieves of 240 orders (61 μ m) and the circular sieves of 300 orders (48 μ m) screening.

Other press prescription and the prepared embodiment 12 of embodiment 1; Carboxymethylethylcellulose granule in the reference examples 1 (particle diameter 48～61 μ m) is changed into vinylacetate-copolymer-maleic anhydride granule (particle diameter 48～61 μ m), and other are constant, by the prescription of reference examples 1 and prepared reference examples 11 wherein.

Embodiment 13 and reference examples 12

Water miscible fine grained by following prescription and the coating of prepared enteric coating film

Coating fluid prescription

Coating solution by above-mentioned coating fluid prescription preparation phthalic acid polyvinyl alcohol ester.(Powrex Corp. (Japan) makes, and MP-10) adds trisodium citrate granule (particle diameter 150～100 orders, 106～150 μ m) to centrifugal fluidization coating granulator.Respectively the gasinlet temperature and the temperature of working off one's feeling vent one's spleen are controlled at 60～80 ℃ and 30～40 ℃, with the spray liquid spraying trisodium citrate granule of above-mentioned preparation, the trisodium citrate granule increases weight about 80%.(temperature is 55 ℃ in dry also healing, healing time was not less than 72 hours, do not ooze out until wherein sodium ion, do not seep water take place in and chemical reaction for to) back gained granule is through circular sieves of 115 orders (125 μ m) and the circular sieves of 80 orders (180 μ m) screening, obtains containing the enteric coating film coated granule (particle diameter 125～180 μ m) that trisodium citrate is examined core.

All the other press prescription and the prepared embodiment 13 and the reference examples 12 of embodiment 3 and reference examples 5, wherein 2-methyl-5-vinylpyrine/methacrylic acid methyl/methacrylic acid copolymer the granule (particle diameter 18～30 μ m) in the reference examples 5 bag clothing films changes phthalic acid polyvinyl alcohol ester (particle diameter 125～180 μ m) into, and other are constant.

Embodiment 14 and reference examples 13

1), presses the prescription and the prepared label of embodiment 2 labels

2), the water miscible fine grained that coats by following prescription and prepared gastric solubleness clothing film

Coating fluid prescription

Coating solution by above-mentioned coating fluid prescription preparation cellulose acetate diethylamino acetate.(Powrex Corp. (Japan) makes, and MP-10) adds citric acid granule (particle diameter 300～400 orders, 38～48 μ m) to centrifugal fluidization coating granulator.Respectively the gasinlet temperature and the temperature of working off one's feeling vent one's spleen are controlled at 60～80 ℃ and 30～40 ℃, with the spray liquid spraying citric acid granule of above-mentioned preparation, the citric acid granule increases weight about 100%.(temperature is 55 ℃ in dry also healing, healing time was not less than 72 hours, in taking place until not seeping water and chemical reaction for to) back gained granule is through circular sieves of 240 orders (61 μ m) and the circular sieves of 300 orders (48 μ m) screening, obtains containing the granule (particle diameter 48～61 μ m) that citric acid is examined core.

3), add citric acid granule that adds above-mentioned gastric solubleness clothing film coating in the aqueous dispersions (body) and the diacetine of using as plasticizer at the cellulose acetate that the method by embodiment 1 makes, cellulose acetate wherein: the citric acid granule that gastric solubleness clothing film coats: diacetine is 1: 2: 1 (weight ratio), be diluted with water to and contain 3% cellulose acetate suspension and make coating solution, the pH value of regulating the cellulose acetate suspension in case of necessity is to 6.5-7.8.With the coating solution that makes to above-mentioned label bag clothing film.The weightening finish of clothing film coating is 16%.

With timing automatic film coating machine coating, the coating conditions parameter is: about 20 seconds of spraying time, about 30～40 seconds of blasting time, 50～70 ℃ of blast temperatures, 40～50 ℃ of label temperature.

5), healing clothing film

Healing is handled and is carried out in airtight baking oven.The healing temperature is 65 ℃, and healing time is 36 hours.

6) prepare reference examples 13, as stated above, wherein the citric acid granule of gastric solubleness clothing film coating changes cellulose acetate diethylamino acetate (particle diameter 48～61 μ m) into, and other are constant.

Embodiment 15 and reference examples 14

1), presses the prescription and the prepared label of embodiment 2 labels

2), the water miscible fine grained that coats by following prescription and prepared gastric solubleness clothing film

Coating fluid prescription

Coating solution by above-mentioned coating fluid prescription preparation ethylene piperidyl-acetyl acetal ethylene copolymer.(Powrex Corp. (Japan) makes, and MP-10) adds sucrose granules (particle diameter 150～100 orders, 106～150 μ m) to centrifugal fluidization coating granulator.Respectively the gasinlet temperature and the temperature of working off one's feeling vent one's spleen are controlled at 60～80 ℃ and 30～40 ℃, spray liquid spraying sucrose granules with above-mentioned preparation, sucrose granules increases weight about 80%, the gained granule obtains containing the ethylene piperidyl-acetyl acetal ethylene copolymer coated granule (particle diameter 125～180 μ m) of sucrose nuclear core through circular sieves of 115 orders (125 μ m) and the circular sieves of 80 orders (180 μ m) screening.

3), bag clothing film:

Label coating fluid prescription (1000 consumptions):

By above-mentioned prescription preparation coating solution, in case of necessity, regulate about pH value to 5.With label coating on Hicoater/Fruend coating machine.Coating conditions parameter: inlet temperature, 50～60 ℃; Outlet temperature, 35～37 ℃; 36～38 ℃ of label temperature; Label weightening finish 13.96%.

3), healing clothing film

Healing is handled and is carried out in airtight baking oven.The healing temperature is 45 ℃, and healing time is 36 hours.

6) prepare reference examples 14, as stated above, wherein the sucrose granules of gastric solubleness clothing film coating changes ethylene piperidyl-acetyl acetal ethylene copolymer (particle diameter 48～61 μ m) into, and other are constant.

Embodiment 16 and reference examples 15

Water miscible fine grained by following prescription and the two molten clothing films coatings of prepared gastrointestinal

Coating fluid prescription

By the cellulosic coating solution of above-mentioned coating fluid prescription preparation carboxymethyl benzylamino.(Powrex Corp. (Japan) makes, and MP-10) adds sorbose granule (particle diameter 300～400 orders, 38～48 μ m) to centrifugal fluidization coating granulator.Respectively the gasinlet temperature and the temperature of working off one's feeling vent one's spleen are controlled at 60～80 ℃ and 30～40 ℃, spray liquid spraying sorbose granule with above-mentioned preparation, the sorbose granule increases weight about 100%, the gained granule obtains containing the granule (particle diameter 48～61 μ m) of sorbose nuclear core through circular sieves of 240 orders (61 μ m) and the circular sieves of 300 orders (48 μ m) screening.

Other press prescription and the prepared embodiment 16 of embodiment 3; Carboxymethylethylcellulose granule in the reference examples 5 (particle diameter 48～61 μ m) is changed into carboxymethyl benzylamino cellulose grain (particle diameter 48～61 μ m), and other are constant, by the prescription of reference examples 1 and prepared reference examples 15 wherein.

Embodiment 17 and reference examples 13

1), presses the prescription and the prepared label of embodiment 2 labels

2), the water miscible fine grained that coats by following prescription and prepared gastric solubleness clothing film

Coating fluid prescription

Suspendible coating solution by above-mentioned coating fluid prescription preparation chitosan (Chitosan).(Powrex Corp. (Japan) makes, and MP-10) adds citric acid granule (particle diameter 300～400 orders, 38～48 μ m) to centrifugal fluidization coating granulator.Respectively the gasinlet temperature and the temperature of working off one's feeling vent one's spleen are controlled at 70～80 ℃ and 40～50 ℃, with the spray liquid spraying citric acid granule of above-mentioned preparation, the citric acid granule increases weight about 100%.The gained granule obtains containing the granule (particle diameter 48～61 μ m) of citric acid nuclear core through circular sieves of 240 orders (61 μ m) and the circular sieves of 300 orders (48 μ m) screening.

3), label is pressed following prescription and technology bag clothing film:

Coating fluid prescription:

With the coating solution that makes to label bag clothing film.Adopt a miniature high-performance coating machine of Freund type HCT ((8 inches dishes), with coating solution to coat a thickness to tablet be 250 microns coating.

Test case 1 drug release stability test

Below carry out examine stability with regard to sample among the embodiment 1～6 and reference substance.The test of release in vitro degree is undertaken by the method among each embodiment.The results are shown in Table 1～6.

Release amount of medicine when table 1 embodiment 1 sample and contrast articles for use pH value 6.8

^※25 ℃ of expression temperature, the environment of relative humidity 90% (following identical);

^#40 ℃ of expression temperature, the environment of relative humidity 50% (following identical).

Release amount of medicine when table 2 embodiment 2 samples and contrast articles for use pH value 2.5

The release amount of medicine of table 3 embodiment 3 samples and contrast articles for use (pH6.8)

The release amount of medicine of table 4 embodiment 4 samples and contrast articles for use

The release amount of medicine of table 5 embodiment 5 samples and contrast articles for use

Result of the test shows, the embodiment sample that contains the water-soluble granular of but water-insoluble polymer overmold soluble by Digestive system all has drug release stability preferably, with respect to the soluble but reference substance of water-insoluble polymer of the water-soluble granular that contains coating not in the clothing film and Digestive system, the drug release stability of embodiment is enhanced.

In addition, under the environment of relative humidity 90% in the examine stability, the result observes clothing film and contains not that the water miscible particulate reference substance of coating (2,4,6) all has sample segment " scum " phenomenon to occur, i.e. water solublity pore material is separated out from clothing film; The embodiment sample is not observed this phenomenon.

Test case 2 clothing film measuring mechanical properties

Release-controlled film coating solution with preparation in embodiment 1-3 and the reference substance 2,4,6 is made the thin film that thickness is 150 μ m in the polyfluortetraethylene plate top casting, thin film is cut into the size of 1 * 7cm.Under INSTRON tensile strength tester, measure tensile strength then.The results are shown in Table 7.

Table 7 polymeric film tensile strength measurement result

The result shows that the embodiment mechanical performance is better than reference substance, and the water-soluble granular in the release-controlled film coating solution (porogen) is aggregated behind the thing coating with respect to coated granules not, and the mechanical performance of release-controlled film clothing film is enhanced.

Test case 3 drug dispositions discharge test

12 male and healthy experimenters, intersect once oral embodiment (1-3 at random, 7-9) sample and reference examples sample (1,3,5) are each 1, carry out drug disposition and discharge test (bioavailability study), blood drug level liquid chromatography (HPLC) or liquid-matter coupling method HPLC-MS/MS) measure.The results are shown in Table 8,9,10.

Release test result in the table 8 simvastatin body (meansigma methods ± SD, n=6)

Release test result in the table 9 diltiazem hydrochloride body (meansigma methods ± SD, n=6)

Release test result in the table 10 metformin hydrochloride body (meansigma methods ± SD, n=6)

The result shows that the release sexual behaviour is better than reference substance in the embodiment body, and degree of susceptibility is lower than reference substance in vivo; Embodiment medicine stripping time lag is littler, particularly contains the porogen that can react in vivo.

Claims (55)

1. the controlled release preparation of a performance improvement is characterized in that this controlled release preparation comprises:

A), the nuclear core that contains a kind of medicine;

B), be overlying on the clothing film of above-mentioned nuclear core outward, wherein, this clothing film comprises pharmaceutically acceptable plasticizer, pharmaceutically acceptable be insoluble to or the polymer of water-soluble hardly and harmonization of the stomach intestinal digestion liquid and be embedded in that wherein the quilt as porogen contains pharmaceutically acceptable plasticizer or do not contain plasticizer pharmaceutically acceptable dissolve in stomach and/or intestinal digestion liquid but be insoluble to or the particulate matter of water-soluble medical additive of coating of water-insoluble polymer clothing film almost, above-mentioned water-soluble medical additive and above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-insoluble polymer chemical reaction can not take place in the Digestive system or chemical reaction can take place but do not generate water insoluble and room temperature (25 ℃) be the product and the pharmaceutically unacceptable product of solid or liquid in vivo down, and above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or 700% (w/w) that almost consumption of water-insoluble polymer clothing film is no more than the consumption of above-mentioned water-soluble medical additive.

2. according to the controlled release preparation of claim 1, it is characterized in that described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or 300% (w/w) that almost consumption of water-insoluble polymer clothing film is no more than the consumption of described water-soluble medical additive.

3. according to the controlled release preparation of claim 1, it is characterized in that described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or about 2～about 200% (w/w) that almost consumption of water-insoluble polymer clothing film is the consumption of described water-soluble medical additive.

4. according to the controlled release preparation of claim 1, it is characterized in that described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or about 2～about 100% (w/w) that almost consumption of water-insoluble polymer clothing film is the consumption of described water-soluble medical additive.

5. according to the controlled release preparation of claim 1, it is characterized in that described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or about 3～about 50% (w/w) that almost consumption of water-insoluble polymer clothing film is the consumption of described water-soluble medical additive.

6. according to the controlled release preparation of claim 1, it is characterized in that described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or about 3～about 30% (w/w) that almost consumption of water-insoluble polymer clothing film is the consumption of described water-soluble medical additive.

7. according to controlled release preparation any in the aforementioned claim, it is characterized in that described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-insoluble polymer described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost the consumption in the water-insoluble polymer clothing film be 35% to 100% (w/w), this is based on the gross dry weight amount of this clothing film.

8. according to controlled release preparation any in the aforementioned claim, it is characterized in that described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-insoluble polymer described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost the consumption in the water-insoluble polymer clothing film be 50% to 100% (w/w), this is based on the gross dry weight amount of this clothing film.

9. according to controlled release preparation any in the aforementioned claim, it is characterized in that described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-insoluble polymer described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost the consumption in the water-insoluble polymer clothing film be 65% to 100% (w/w), this is based on the gross dry weight amount of this clothing film.

10. according to controlled release preparation any in the aforementioned claim, it is characterized in that described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-insoluble polymer and described be insoluble to or polymer phase water-soluble hardly and harmonization of the stomach intestinal digestion liquid compatible perhaps fully.

11. according to controlled release preparation any in the aforementioned claim, it is characterized in that described water-soluble medical additive is selected from water-soluble aminoacid, oligopeptide (2-10 peptide), water-soluble monosaccharide and pharmaceutically acceptable derivates thereof, oligosaccharide (2-6 sugar) and pharmaceutically acceptable derivates thereof, water-soluble sodium, the inorganic salt of potassium or ammonium ion, water-soluble carbon number is no more than 6 organic acid and water-soluble sodium thereof, potassium or ammonium ion salt, water-soluble carbon number is no more than 6 organic base and water-soluble salt thereof, water-soluble nonionic surfactant, pharmaceutically acceptable water-soluble non-ionic polyalcohol and their mixture.

12. according to controlled release preparation any in the aforementioned claim, it is characterized in that described water-soluble medical additive is selected from alanine, glycine, serine, valine, agedoite, lysine, glutamine, methionine, arginine, hydroxyproline, proline, power peptide (L-alanyl-L-glutamine), glutathion, the D-erythrose, the D-Erythrulose, erythritol, D-ribose, the D-2-deoxyribose, the D-xylose, L-arabinose, the D-ribulose, the D-xylulose, xylitol, glucose, galactose, mannitol, mannose, fructose, sorbose, the D-mannoheptulose, the D-sedoheptulose, maltose, lactose, sucrose, cellobiose, gentiobiose, 6-(.alpha.-D-galactosido)-D-glucose., the Sargassum disaccharide, hydroxyl isomaltulose, maltose, lactitol, trehalose, shell gathers disaccharide, Raffinose, and shell gathers trisaccharide, stachyose, take off the poly-tetrose of acetyl shell, verbascose, maltopentaose, MALTOHAXAOASE, adipic acid, instead/maleic acid, malic acid, citric acid, Tartaric acid, phytic acid, succinic acid and glycolic acid and their water-soluble sodium, potassium or ammonium ion salt, the water-soluble alkali acidic amino acid, meglumine and water-soluble salt thereof, chloride ion, bromide ion, fluorion, phosphate radical, hydrogen phosphate, sulfate radical, bisulfate ion, inferior sulfate radical, bisulfite, the pyrosulfurous acid root, nitrate anion, carbonate, the sodium of bicarbonate radical and percarbonic acid root, potassium or ammonium ion salt, water-soluble polyoxyethylene alkyl ether class surfactant, water-soluble polyoxyethylene castor oil class surfactant, water-soluble Myrj 45 class surfactant, water-soluble cyclodextrin and cyclodextrin derivative, water-soluble oligosaccharide (degree of polymerization 7-20), water-soluble glucosan, hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, the low viscosity methylcellulose, polyvinyl alcohol, polyvidone, molecular weight is PEG (Polyethylene Glycol) and their mixture of 2000-20000.

13. according to controlled release preparation any in the aforementioned claim, the mean diameter that it is characterized in that described water-soluble medical additive is 5～250 μ m.

14., it is characterized in that the dissolubility (temperature 25 ℃) of described water-soluble medical additive in water is not less than 100mg/ml according to controlled release preparation any in the aforementioned claim.

15., it is characterized in that also containing disintegrating agent in described water-soluble medical additive according to controlled release preparation any in the aforementioned claim.

16. according to controlled release preparation any in the aforementioned claim, but but it is characterized in that described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-insoluble polymer be selected from gastric solubility polymer, enteric polymer, not only polymer, Biodegradable polymeric, enzyme and/or microorganism degradable polymer and their mixture of enteric but also gastric solubleness.

17., it is characterized in that described gastric solubility polymer is selected from the cellulose derivative with list or disubstituted amido, the polythene derivative with list or disubstituted amido, the acrylate copolymer with mono-substituted amino, chitosan (Chitosan) and their mixture according to the controlled release preparation of claim 16.

18. controlled release preparation according to claim 16, it is characterized in that described gastric solubility polymer is selected from the benzylamino-methyl cellulose, diethylamino methyl cellulose, the piperidyl ethylhydroxyethylcellulose, cellulose acetate diethylamino acetate, vinyl diethylamide-vinyl acetate co-polymer, ethylene benzyl amine-vinyl acetate co-polymer, poly-acetal acetic acid diethylamino vinyl acetate, ethylene piperidyl-acetyl acetal ethylene copolymer, poly-diethylamino methyl styrene, methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer (being Eudragit E, the trade name of Rohm-Pharma), the polymethylacrylic acid dimethylamino ethyl ester, chitosan (Chitosan) and their mixture.

19., it is characterized in that described gastric solubility polymer is selected from Eudragit E according to the controlled release preparation of claim 16.

20., it is characterized in that described enteric polymer is selected from carboxyl alkyl cellulose, has the cellulose derivative of the monoester bond of binary acid, the polyvinyl derivant with dibasic acid monoester key, its polymers of maleic acid-ethylene, acrylic polymer and their mixture according to the controlled release preparation of claim 16.

21., it is characterized in that described enteric polymer is selected from carboxymethyl cellulose according to the controlled release preparation of claim 16; carboxymethylethylcellulose; the phthalic acid ester acid cellulose; the succinic acid acetyl cellulose; O-phthalic acid methyl cellulose ester; phthalic acid hydroxymethyl ethyl cellulose esters; phthalic acid hydroxypropyl emthylcellulose ester; succinic acid hydroxypropyl emthylcellulose ester; the dibasic acid monoester of polyvinyl; the phthalic acid polyvinyl alcohol ester; phthalic acid polyethylene butyl ester; acetyl group acetal phthalic acid polyvinyl ester; vinylacetate-copolymer-maleic anhydride; butyl vinyl ether-copolymer-maleic anhydride; the styrene-maleic acid monoester copolymer; acrylic acid methyl ester .-methacrylic acid copolymer; the styrene-propene acid copolymer; acrylic acid methyl ester .-methacrylic acid-1-Octyl acrylate copolymer; Eudragit L; Eudragit S; Eudragit FS; Lac and their mixture.

22., it is characterized in that described enteric polymer is selected from Eudragit S, Eudragit FS and their mixture according to the controlled release preparation of claim 16.

23. according to the controlled release preparation of claim 16, but but the polymer that it is characterized in that described not only enteric but also gastric solubleness be selected from vinylpyridine-acrylic copolymer, have carboxymethyl polysaccharide, polyethylene amino acid derivatives and their mixture of single or dibasic amino.

24. according to the controlled release preparation of claim 16, but it is characterized in that but the polymer of described not only enteric but also gastric solubleness is selected from 2-methyl-5-vinylpyrine/methacrylic acid methyl/methacrylic acid copolymer, 2-methyl-5-vinylpyrine/acrylic acid methyl ester ./methacrylic acid copolymer, 2-vinyl-5-vinylpyridine/methacrylic acid/styrol copolymer, 2-vinyl-5-vinylpyridine/methacrylic acid/methyl methacrylate acid copolymer, 2-vinylpyridine/methacrylic acid/methacrylic acid copolymer, 2-vinylpyridine/methacrylic acid/acrylonitrile copolymer, carboxymethyl piperidyl starch, carboxymethyl benzylamino cellulose, poly--2-(ethenylphenyl) glycine, N-vinyl glycine-styrol copolymer and their mixture.

25., it is characterized in that described Biodegradable polymeric is selected from natural biological degradation polyalcohol, aliphatic polyester series, poly-ammonia and copolymer, polyamino acid, poe, polybutylcyanoacrylate, polyacrylic, poly (3-hydroxybutyrate) and copolymer thereof, polyanhydries, poly (methyl vinylether-maleic acid), polyurethanes and their mixture according to the controlled release preparation of claim 16.

26., it is characterized in that described enzyme and/or microorganism degradable polymer are selected from the polymer that contains azo bond or disulfide bond according to the controlled release preparation of claim 16.

27., it is characterized in that described enzyme and/or microorganism degradable polymer are selected from pectin, dextran, galactomannan, 9-D-glucose thuja acid and their mixture according to the controlled release preparation of claim 16.

28. according to controlled release preparation any in the claim 1 to 10, it is characterized in that described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or polymer that almost water-insoluble polymer is selected from gastric solubility, described water-soluble medical additive be selected from the polymer of above-mentioned gastric solubility neutralization reaction takes place in the Digestive system in vivo but do not generate water insoluble and room temperature (25 ℃) down for the product of solid or liquid and pharmaceutically water-soluble room temperature of unacceptable product (25 ℃) be solid-state pharmaceutically acceptable acidic materials down; Perhaps described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or polymer that almost water-insoluble polymer is selected from enteric solubility, described water-soluble medical additive be selected from the polymer of above-mentioned enteric solubility neutralization reaction takes place in the Digestive system in vivo but do not generate water insoluble and room temperature (25 ℃) down for the product of solid or liquid and pharmaceutically water-soluble room temperature of unacceptable product (25 ℃) be solid-state pharmaceutically acceptable alkaline matter down.

29., it is characterized in that described acidic materials are selected from water-soluble carbon number and are no more than 6 room temperature (25 ℃) and are the acid salt of tart sodium, potassium or ammonium ion and their mixture for solid-state organic acid (as adipic acid, anti-/ maleic acid, malic acid, citric acid, Tartaric acid, succinic acid) or its down according to the controlled release preparation of claim 28; Perhaps described alkaline matter is selected from the inorganic alkaline salt of water-soluble sodium, potassium or ammonium ion, water-soluble carbon number and is no more than 6 room temperature (25 ℃) and is no more than the salt of the sodium, potassium or the ammonium ion that are alkalescence of 6 organic multicomponent acid and their mixture for solid-state organic base or its salt, water-soluble carbon number that is alkalescence down.

30. according to controlled release preparation any in the claim 1 to 10, it is characterized in that described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or polymer that almost water-insoluble polymer is selected from enteric solubility, described water-soluble medical additive be selected from can with the polymer of above-mentioned enteric solubility generated reactive gas but do not generate water insoluble and room temperature (25 ℃) and be water-soluble medical additive of the product of solid or liquid and the product that pharmaceutically can not connect down in the Digestive system in vivo.

31. according to controlled release preparation any in the claim 1 to 10, it is characterized in that described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or polymer that almost water-insoluble polymer is selected from enteric solubility, described water-soluble medical additive is selected from the sodium of bicarbonate radical, potassium or ammonium salt, the sodium of carbonate, potassium or ammonium salt, glycine carbonate, the carbonate of L-lysine, arginic carbonate, aminoacid sodium, potassium or ammonium carbonate, contain sodium, the carbonate of potassium or ammonium glycosyl, the sodium of inferior sulfate radical, potassium or ammonium salt, the sodium of bisulfite, potassium or ammonium salt, the sodium of pyrosulfurous acid root, potassium or ammonium salt, sodium, the percarbonate of potassium or ammonium, and their mixture.

32. according to controlled release preparation any in the aforementioned claim, it is characterized in that described porogen is promptly contained pharmaceutically acceptable plasticizer or do not contain plasticizer pharmaceutically acceptable dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost the consumption of particulate matter in described clothing film of water-soluble medical additive of coating of water-insoluble polymer clothing film be 5%～95% (weight ratio or volume ratio), based on the gross dry weight amount or the volume of clothing film.

33. according to controlled release preparation any in the aforementioned claim, it is characterized in that described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost also contain acid or the basic medicinally additive of regulating drug release rate in the water-insoluble polymer clothing film.

34., it is characterized in that described be insoluble to or polymer water-soluble hardly and harmonization of the stomach intestinal digestion liquid is selected from and is insoluble to or cellulose esters, acrylic acid (ester) base polymer, polyvinyl acetate esters, polyvinyl chloride and the compositions thereof of water-soluble hardly and harmonization of the stomach intestinal digestion liquid according to controlled release preparation any in the aforementioned claim.

35. according to controlled release preparation any in the aforementioned claim, it is characterized in that described be insoluble to or polymer water-soluble hardly and harmonization of the stomach intestinal digestion liquid is selected from ethyl cellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate (cellulose acetate propionate), celluloid, three cellulose valerates, the lacceroic acid cellulose, three Palmic acid celluloses, the disuccinic acid cellulose, two Palmic acid celluloses, polyvinylacetate, methacrylic acid (ester) polymer, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, Merlon, polymethyl methacrylate, ethyl acrylate-Methyl metacrylate 99 polymer, vinyl acetate-vinyl chloride copolymer, polrvinyl chloride, polyethylene, polyisobutylene, poly (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride) and compositions.

36., it is characterized in that described be insoluble to or polymer water-soluble hardly and harmonization of the stomach intestinal digestion liquid is selected from cellulose acetate, acetylbutyrylcellulose, cellulose acetate propionate (celluloseacetate propionate) and their mixture according to controlled release preparation any in the claim 1 to 35.

37., it is characterized in that described be insoluble to or polymer water-soluble hardly and harmonization of the stomach intestinal digestion liquid is selected from the terpolymer that contains 80～95% polrvinyl chloride, 0.5～19% polyvinylacetate and 0.5～10% polyvinyl alcohol, contains the polyvinylacetate copolymer of 50～100% polrvinyl chloride and 0～50% and their mixture according to controlled release preparation any in the claim 1 to 35.

38., it is characterized in that described clothing film also contains the reinforcing agent and/or the flexibilizer of pharmaceutically acceptable polymer according to controlled release preparation any in the aforementioned claim.

39., it is characterized in that described nuclear core is selected from the sheet of rule or irregular form, granule, ball, crystal or medicine carrying resin according to controlled release preparation any in the aforementioned claim.

40., it is characterized in that described medicine is selected from central stimulants according to controlled release preparation any in the aforementioned claim, analgesic, antipyretic analgesic, anti-inflammation analgesia medicine, antigout drug, antiparkinsonian drug, psychosis, antianxiety drugs, antidepressant, antuepileptic, tranquilizer, hypnotic, anticonvulsant, the automonic thing, calcium is picked up drug resistance, the medicine of treatment chronic cardiac insufficiency, anti-arrhythmic, control angina pectoris medicine, peripheral vasodilators, hypotensor, blood lipid regulation medicine and antiatherosclerotic, medicine for respiratory system, antacid and treatment peptic ulcer disease medicine, the gastrointestinal antispasmodic medicine, digestant, Bendectin, emetic and the intestines and stomach promote medicine, the liver and gall diseases adjuvant drug, medicine for urological system, influence the medicine of blood and hemopoietic system, antihistaminic, anaphylaxis medium sustained-release agent, adrenocortical hormone and thyroliberin, gonadal hormone and short gonadal hormone, pancreas hormone and other influence the medicine of blood glucose, thyroid hormones medicine and antithyroid drug, penicillins, cephalosporins, beta-lactamase inhibitor, aminoglycoside, Tetracyclines, Macrolide, antituberculotic, antifungal agent, antiviral agents, antitumor drug, influence the medicine of body's immunity, vitamin and Amitin, appetrol or Chinese herbal medicine extract or its mixture.

41., it is characterized in that described medicine is selected from LECOZOTAN (SRA-333) according to controlled release preparation any in the aforementioned claim, the amoxicillin, the amoxycillin with clavulanate potassium compound recipe, A Sidamo, aspirin-ligustrazine phosphate compound recipe, aspirin-dipyridamole compound recipe, piperazine ferulate, acyclovir, acetaminophen-pseudoephedrine hydrochloride-dexbrompheniramine maleate compound recipe, allopurinol, propylthiouracil, magnesium valproate, ibuprofen, aceclofenac, isosorbide mononitrate-aspirin compound recipe, isosorbide mononitrate, diazepam, metformin-rosiglitazone compound recipe, famciclovir, felodipine, fenofibrate, fexofenadine hydrochloride-pseudoephedrine hydrochloride compound recipe, fluvastatin sodium, acipimox and compound recipe, felodipine-spectinomycin hydrochloride compound recipe, lovastatin-nicotinic acid compound recipe, the vitamin B6 compound recipe, cetirizine-pseudoephedrine hydrochloride compound recipe, fexofenadine hydrochloride-pseudoephedrine hydrochloride compound recipe, guaifenesin-pseudoephedrine-dextromethorphan compound recipe, quetiapine fumarate, Metoprolol fumarate, the fumaric acid emedastine, glipizide-metformin hydrochloride compound recipe, gliquidone, glimepiride-metformin compound recipe, gliclazide, potassium citrate, Tamoxifen Citrate, Tamoxifen Citrate, the succinic acid desmethylvenlafaxine, ciprofloxacin, aniracetam, pentoxifylline, metronidazole, Tolterodine tartrate, Zolpidemtar Trate, clarithromycin, kurarinone, ranolazine, ribavirin, benproperine phosphate, ligustrazine phosphate, tiopronin, morphine sulfate, salbutamol sulfate, loratadine-acetaminophen-pseudoephedrine compound recipe, loratadine-pseudoephedrine compound recipe, rosiglitazone, Roxithromycin, lovastatin, Trimebutine Maleate, enalapril maleate-felodipine compound recipe, mesalazine, medetofazone, mizolastine, naftopidil, naproxen sodium, Ni Ketating, nimesulide, nitrendipine, nisoldipine, Paliperidone, Perprazole, darifenacin hydrobromide, galanthamine hydrobromide, huperzine A, bicyclol, stavudine, gastrodine, ketoprofen, cefaclor, cefixime, vitamin C controlled-releasing vaginal sheet, vitamin E Nicotinate, pseudoephedrine-naproxen sodium compound, urapidil, nicotinic acid, nicotinic acid-simvastatin compound recipe, BUPROPIONE HCl, ambroxol hydrochloride, ditropan XL, Betahistine Hydrochloride, metformin hydrochloride, valaciclovir hydrochlordide, ciprofloxacin, labetalol hydrochloride, Licardipine Hydrochloride, paroxetine hydrochloride, minipress, propafenone hydrochloride, propranolol hydrochloride, dihydromorphinone hydrochloride, tramadol hydrochloride, Trimetazidine Hydrochloride, tamsulosin hydrochloride, tamsulosin hydrochloride, albuterol hydrochloride, levofloxacin hydrochloride, ofloxacin, etodolac, indapamide, guaifenesin, guaifenesin-pseudoephedrine hydrochloride compound recipe, levodropropizine, bezafibrate, piribedil, theophylline, vincamine, dihydroergotoxine methanesulfonate, Carclura, spectinomycin hydrochloride, dihydrocodeine bitartrate, the carbidopa and levodopa compound recipe, morphine sulfate, the sulphuric acid celebrating is mould greatly, ferrous sulfate, potassium chloride, molsidomine, naftidrofuryl, nimodipine, diclofenac sodium, verapamil, dimension ferrum, nifedipine, diltiazem hydrochloride, propranolol hydrochloride, glipizide, diltiazem hydrochloride, indomethacin, acemetacin, theophylline-albuterol compound recipe, dexamethasone, acetaminophen, gliclazide, ferrous succinate, carbamazepine, codeine phosphate, ibuprofen and codeine, Malotilate, naproxen, lithium carbonate, cefalexin, alfuzosin hydrochloride, Buflomedil Hydrochloride, the hydrochloric acid Ticlopidine, ibudilast, dextromethorphan, sinomenine, the single nitre Coronex of 5-, sodium valproate, Benserazide, gentamycin sulfate-zirconium dioxide compound recipe, chlorphenamine maleate, barnidipine, bunazosin, gallopamil, methylphenidate hydrochloride, oxycodone hydrochloride.

42. according to controlled release preparation any in the claim 17 to 19, it is characterized in that described medicine be selected to alkali labile, acid is easily molten, stomach or stomach near-end such as duodenum have absorption window or to stomach or closely portion of stomach end office (EO) play the medicine of therapeutical effect.

43., it is characterized in that described medicine is selected from ciprofloxacin, captopril, furosemide, ursodesoxycholic acid, compound digestive enzyme, Chinese medicine gynecological a thousand pieces of gold, irbesartan, glimepiride, leflunomide, midecamycin, Irb, amoxicillin, cefuroxime, rocephin, cefpodoxime, clarithromycin, Loracarbef, azithromycin, cefixime, cefadroxil, acyclovir, diltiazem according to controlled release preparation any in the claim 17 to 19

Captopril, simvastatin, lovastatin, etodolac, ketorolac, ranitidine, famotidine, fexofenadine, pseudoephedrine, phenylpropanolamine, dextromethorphan, Chlo-amine, bromocriptine, ciclosporin, crust oxygen sweet smell, allopurinol, (+)-α-aminomethyl-2-methoxyl group sulfonic acid amido benzyl alcohol or 3 '-(2-amino-1-ethoxy-4 '-fluorine methanesulfonic acid aniline (NS49), paspertin metoclopramide, veralipride, alizapride, clebopride, amisulpride, tiapride, sulpiride and salt thereof, terazosin, alfuzosin and their salt.

44. according to controlled release preparation any in claim 20 to 21 or 30 to 31, it is characterized in that described medicine be selected from unsettled to acid, alkali is easily molten, to the strong toxic and side effects of stomach, to stomach have than the strong stimulation effect, intestinal local directly rise therapeutical effect, the intestinal segment basic absorption good, be the medicine that maybe need delay time and discharge at basic absorption position with the intestinal segment.

45., it is characterized in that described medicine is selected from 5-aminosalicylic acid and salt thereof according to controlled release preparation any in claim 20 to 21 or 30 to 31; acamprosate calcium; aranidipine; Alendronate sodium; azithromycin; azintamide and compound preparation thereof; aspirin; esomeprazole and salt thereof; ilaprazole; eucalyptus globulus lemon pinane; osaminethacine; omeprazole and salt thereof; oxaprozin; Pyrmetazole; benzoic methyl nitroazole; bisacodyl; piroxicam; propylthiouracil; bromelain and compound preparation thereof; hepatocyte growth-promoting factors; aceclofenac; the cefalexin trimethoprim; garlicin; Elastase; C14H25N4NaO11P2; dirithromycin; fourth disulfonic acid ademetionine; fourth disulfonic acid sulfo-ademetionine; the Tosi ademetionine; ademetionine; sodium aminosalicylate; Faropenem sodium; fenoprofen calcium; nitrofurantoin; coenzyme Q10; cattle tire liver is extracted and compound preparation; glutamine and compound preparation thereof; anorethindrane dipropionate and compound preparation thereof; phosphoesterases complex; glipizide metformin compound preparation; glutathion; reduced glutathion; bone peptide; diammonium glycyrrhizinate; cinmetacin; cyclophosphamide and compound preparation thereof; erythromycin; pentoxifylline; thiamphenicol; kitasamycin; thiamazole; mefenamic acid; the arginine ketoprofen; clarithromycin; matrine; reorganization B subunit/thalline cholera vaccine compound preparation; bacillus subtilis bigeminy viable bacteria compound preparation; Birid Triple Viable; aspisol; RABEPRAZOLE SODIUM; ranitidine; tiopronin; gentamycin sulfate; ferrous sulfate glycine complex; norfloxacin; rufloxacin; lomefloxacin; cloricromen; sulfasalazine; altretamine; Roxithromycin; wheat is examined phenol sodium; fosfomycin and salt thereof; mepartricin; meloxicam; Mei Takawei; metacycline; Magnesium aspartate hydrochloride; paroxetine; mifepristone; misoprostol; carase; naproxen; Cerebrolysin Vial; nimesulide; the Tegafur-uracil mixt. compound preparation; Perprazole; pantoprazole and salt thereof; aescine; the troxerutin and encephalic protein hydrolysate compound preparation; didanosine; lysozyme; adenosine triphosphate; triphenyl diamidine; Serrapeptase; Sparfloxacin; telmisartan; diclofenac sodium; ketone ibuprofen; sodium sulfate; cytochrome C; thymosin; duloxetine; doxycycline; metformin; fluoxetine; sinomenine; acetyl levocarnitine; acetylspiramycin; levamisole; kallidinogenase; pancreatin; insulin; aspirin; pentoxifylline; simvastatin; Tremella fuciformis spores polysaccharide; colloidal bismmth pectin; taurine; calf blood protein-removed extraction; the indole Racine; Lumbrukinase; dexketoprofen; Zaltoprofen; neutral protease; levonorgestrel; the levonorgestrel quinestrol; chlorophyll copper sodium; the Yi Lila azoles; etodolac; sinomenine; magnesium isoglycyrrhetate or vitamin E Nicotinate.

46., it is characterized in that described medicine is selected from Bulbus Allii extract according to controlled release preparation any in claim 20 to 21 or 30 to 31, Radix Et Caulis Acanthopanacis Senticosi extract, Fel Ursi, Cordyceps mycelium, Sanguis Draxonis, oryz aspergillus enzyme and pancreatin (fervent those Shens), hyphae zhiling, cinobufacin or commodity are called the standard myrtol, BIYUANSHU, anti-inflammatory and choleretic, FUTONGNING, dragon stilbene thrombolytic, Ci Dan, Fupoganmao, compound eucommia bark, 'Compound berberine, the flu health, favour blood is given birth to, the enzyme spirit is fallen, the blood sugar lowering first, Omphalia, dewatering is transferred fat, dragon perfume (or spice) is relievingd asthma, brain arteries and veins Thailand, the antiinflammatory of relievining asthma, seven is living quiet, seven give birth to power, XINNAOKANG, Maixuekang, handkerchief Zhu ball, open spleen, the prostatitis is flat, the sudden and violent red cough-relieving of a kind of reed mentioned in ancient books, Cacumen Securinegae Suffruticosae, tonifying YIN is quenched one's thirst, heart of a lotus seed ginseng, fat arteries and veins health, Ji after one's own heart, the stilbene dragon, Radix Notoginseng is logical relaxes, NANBAO, spring blood peace, it is good to control sense, Siberian cocklebur osmanthus tetrahydro-isoquinolin, cure-all, red astragalus root for removing blood stasis, compound eucommia bark is good for bone, GENGNIANAN, anti-consumptive disease, six drugs containing rehmanniae, the Six-element Radix Aucklandiae, the thrombolytic nicergoline, refreshing peace, XUESAITONG, cough-relieving, compound taxol, embolism extinguishing, cold reducing-fever, a kind of reed mentioned in ancient books connects, gram numbness bone Thailand, the Chinese patent medicine of NAOLIQING or manyzoned polypore gantai.

47. according to any one controlled release preparation in the claim 22,26 or 27, it is characterized in that described medicine be selected to the digestive enzyme sensitivity, that be used for (local or directly) treatment colon position disease, digestive tract top (as stomach, small intestinal) had strong toxic and side effects or the medicine that maybe need delay time and discharge than the strong stimulation effect arranged.

48. according to claim 22, any one controlled release preparation in 26 or 27, it is characterized in that described medicine is selected from willow nitrogen, sulfasalazine, Olsalazine, 5-aminosalicylic acid and salt thereof, ibuprofen, hydrogenation Bo Nisong, dexamethasone, budesonide, beclometasone, fluticasone, tixocortol (tioxocortal), hydrocortisone, metronidazole, tinidazole, metronidazole, the full rhzomorph of ring, methotrexate, domperidone, 5-fluorouracil, Laxadin, Senna fruit (senna), thymosin, insulin, vassopressin, growth hormone, colony stimulating factor, calcitonin, immunoglobulin, glibenclamide, DILTIAZEM HCl, verapamil, nifedipine, sulfur first third proline, benazepril, enalapril, theophylline, naproxen, Ciclofenaziae, acyclovir, omeprazole, Lovastain, Alendros, Desmopressin, metformin, metoprolol, cisapride, tetrahydroaminoacridine or microecologic regulator (probiotics).

49., it is characterized in that the medicine that described medicine is selected from needs time-delay to discharge according to the controlled release preparation of claim 25.

50. controlled release preparation according to claim 25, it is characterized in that described medicine is selected from gepirone (Gepirone), Risedronate, paroxetine and salt thereof, moxonidine, a-thioctic acid and derivant, metformin and salt thereof, gabapentin, 1R, 2S-methoxamine, clarithromycin, lansoprazole and salt thereof, omeprazole and salt thereof, pantoprazole and salt thereof, rabeprazole and salt thereof, esomeprazole and salt thereof, Tenatoprazole and salt thereof).

51. according to the preparation method of controlled release preparation any in the aforementioned claim, this method comprises following basic step:

1), preparation contains a kind of core material of medicine;

2), to the particulate matter of described water-soluble medical additive with contain pharmaceutically acceptable plasticizer or do not contain plasticizer pharmaceutically acceptable dissolve in stomach and/or intestinal digestion liquid but be insoluble to or the almost solution of water-insoluble polymer or the clothing film that dispersion liquid coats consumption in the described scope;

3), to the above-mentioned core material that contains a kind of medicine with pharmaceutically acceptable be insoluble to or the solution or the dispersion liquid of the polymer of water-soluble hardly and harmonization of the stomach intestinal digestion liquid coat clothing film of containing pharmaceutically acceptable plasticizer, wherein, be dispersed with in the solution of this polymer or the dispersion liquid as porogen by above-mentioned dissolve in stomach and/or intestinal digestion liquid but be insoluble to or the particulate matter of above-mentioned water-soluble medical additive of coating of water-insoluble polymer clothing film almost, the solution of this polymer or dispersion liquid do not dissolve do not degrade or hardly dissolving or degrade hardly described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or water-insoluble polymer almost.

52. preparation method according to claim 51, it is characterized in that described method also further coats described clothing film the core material that contains a kind of medicine and places under the temperature of the glass transition temperature that is higher than described clothing film healing to handle, have stable dissolution characteristic until this coating core material, healing is handled terminal point and is determined by the dissolution characteristic of the coating core material of the coating core material that relatively just finishes healing and handle and placement in the relative humidity acceleration storage requirement down of 40 ± 2 ℃ temperature and 70%-80% 3 months and/or 6 months.

53. according to controlled release preparation any in the claim 28 to 31 preparation method, it is characterized in that comprising with by described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost the particulate matter of described water-soluble medical additive of coating of water-insoluble polymer clothing film disperse and be suspended in described contain pharmaceutically acceptable plasticizer be insoluble to or the aqueous dispersions (body) of the polymer of water-soluble hardly and harmonization of the stomach intestinal digestion liquid before, will by described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost the particulate matter of described water-soluble medical additive of coating of water-insoluble polymer clothing film place under the temperature of the glass transition temperature that is higher than described clothing film and heal, 's 0 state terminal point until following described clothing film to the permeance property of water, under this state terminal point described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost water-insoluble polymer and described water-soluble medical additive chemical reaction does not take place in described aqueous dispersions (body), perhaps at least will to the described core material that contains a kind of medicine with described contain pharmaceutically acceptable plasticizer be insoluble to or the aqueous dispersions (body) of the polymer of water-soluble hardly and harmonization of the stomach intestinal digestion liquid coats in the process of clothing film chemical reaction does not take place.

54. according to the controlled release preparation of any one in the claim 28 to 31 the preparation method; It is characterized in that comprising with described contain pharmaceutically acceptable plasticizer or do not contain plasticizer dissolve in stomach and/or intestinal digestion liquid but be insoluble to or almost the water-free organic solution of water-fast polymer or dispersion liquid to described water-soluble medical additive coat the clothing film and will by described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or particle that almost water-fast polymer clothing film coats described water-soluble medical additive disperse and be suspended in described contain pharmaceutically acceptable plasticizer be insoluble to or hardly in the water-free organic solution or dispersion liquid of the polymer of water-soluble and stomach and intestinal digestion liquid, this organic solution or dispersion liquid do not dissolve do not degrade or hardly dissolving or degrade hardly described dissolve in stomach and/or intestinal digestion liquid but be insoluble to or water-fast polymer almost.

55. according to preparation method any in the claim 51 to 54, it is characterized in that further the controlled release preparation of preparation with measuring equipment incapsulate, in bag (sachet) or the suitable many measuring containers or further make tablet or further be prepared into suppository or further pack with hemispherical container or multi-dose container.

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