CA2059855C - Controlled release compositions - Google Patents
Controlled release compositions Download PDFInfo
- Publication number
- CA2059855C CA2059855C CA002059855A CA2059855A CA2059855C CA 2059855 C CA2059855 C CA 2059855C CA 002059855 A CA002059855 A CA 002059855A CA 2059855 A CA2059855 A CA 2059855A CA 2059855 C CA2059855 C CA 2059855C
- Authority
- CA
- Canada
- Prior art keywords
- composition according
- crenellations
- composition
- controlled release
- carrier
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/08—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of suppositories or sticks
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
Abstract
Controlled release compositions comprising a water sweliable carrier and an active material having crenellated surface exhibit improved release properties. Suppositories and pessaries of generally cylindrical shape having four or five crenellations spaced equally around the perimeter and extending substantially along the length of the cylinder are preferred.
Suppositories comprising four or five rounded crenellations which release morphine sulphate are especially useful.
Suppositories comprising four or five rounded crenellations which release morphine sulphate are especially useful.
Description
20~~8~~
CONTROLLED RELEASE COMPOSITIQN~
This invention relates to compositions designed to release an active ingredient into an aqueous medium in a controlled manner.
A considerable number of proposals to use carriers especially polymeric carriers in the formulation of controlled release compositions exist in the art. In their simplest form these compositions release their active contents at a rate which is proportional to t~~ where t is the time elapsed since the device was exposed to the aqueous medium. This is essentially due to the increase in the diffusion path length which the active material must traverse before being released with time.
Such devi ces are not i deal si nce the rate of rel ease drops to a level which may not be satisfactory relatively quickly. One method which has been proposed to alleviate this problem is to control the geometry of the device. One such device is described in USP 3924622. The geometry is such that as the diffusion path length increases there is an increase in the area of the carrier comprising the active which is exposed to the aqueous medium.
Another method by which this problem may be alleviated is the utilisation of carrier materials which alter their geometry when exposed to water. The most common class of carriers which have been proposed are water sweliabie materials. They are advantageous in that the initial release of active is effectively slowed as the materials swells and presents the active with a diffusion path length which is more nearly constant. A particular example of a material which has been proposed for use are the water swellable cross-linked polyethylene oxide) hydrogels which are described in British Patent Applications 2047093 and 2047094. These disclosures suggest that the hydrogels can be utilised in a variety of geometries for example as hollow or blank cylinders, spheres, CA 02059855 2000-09-22 . . .. .... .. .. . .. ....:
CONTROLLED RELEASE COMPOSITIQN~
This invention relates to compositions designed to release an active ingredient into an aqueous medium in a controlled manner.
A considerable number of proposals to use carriers especially polymeric carriers in the formulation of controlled release compositions exist in the art. In their simplest form these compositions release their active contents at a rate which is proportional to t~~ where t is the time elapsed since the device was exposed to the aqueous medium. This is essentially due to the increase in the diffusion path length which the active material must traverse before being released with time.
Such devi ces are not i deal si nce the rate of rel ease drops to a level which may not be satisfactory relatively quickly. One method which has been proposed to alleviate this problem is to control the geometry of the device. One such device is described in USP 3924622. The geometry is such that as the diffusion path length increases there is an increase in the area of the carrier comprising the active which is exposed to the aqueous medium.
Another method by which this problem may be alleviated is the utilisation of carrier materials which alter their geometry when exposed to water. The most common class of carriers which have been proposed are water sweliabie materials. They are advantageous in that the initial release of active is effectively slowed as the materials swells and presents the active with a diffusion path length which is more nearly constant. A particular example of a material which has been proposed for use are the water swellable cross-linked polyethylene oxide) hydrogels which are described in British Patent Applications 2047093 and 2047094. These disclosures suggest that the hydrogels can be utilised in a variety of geometries for example as hollow or blank cylinders, spheres, CA 02059855 2000-09-22 . . .. .... .. .. . .. ....:
2 _ tablets or slabs. Hollow devices especially hollow cylindrical devices are clearly attractive insofar as the diffusion path length cannot exceed the thickness of the cylinder wall.
However, such devices are disadvantageous insofar as they may be difficult to fabricate and in that ideally the ends of the cylinders will be closed so as to prevent release from the interior walls thus complicating the fabrication of the device still further. It will be appreciated that there remains a need to provide controlled release compositions which have improved release profiles and are reasonably simple to produce.
The present invention comprises a controlled release composition designed for administration in non-divisible form comprising an active ingredient and a water s'wellable carrier therefor the controlled release of the active ingredient being achieved as a result of swelling of the carrier, the composition having a crenellated surface.
The nature of the crenellations may vary, in particular according to the basic shape of the composition. Thus, for example, where the composition is spherical the surface may be dimpled so as to be similar to that of a golf ball.
Alternatively, the crenellations may be provided as pimples upon the surface of the sphere. Where the composition takes the shape of a cylinder or a slab, the crenellations may conveniently take the form of ridges or furrows running for convenience parallel to the longitudinal axis of the cylinder or slab. The crenellations may be arranged in a regular fashion or an irregular one. For example the ridges or furrows may be arranged so as to lie parallel or they may be at;an angle to one another; they may be continuous or they may not. The crenellations will preferably have a depth which is significant in relation to the thickness of the device. In the preferred embodiments the entire surface of the composition will be crenellated and the depth of the crenellations will be such that the ratio of maximum dimension of the device to the minimum ~~~9~~~
However, such devices are disadvantageous insofar as they may be difficult to fabricate and in that ideally the ends of the cylinders will be closed so as to prevent release from the interior walls thus complicating the fabrication of the device still further. It will be appreciated that there remains a need to provide controlled release compositions which have improved release profiles and are reasonably simple to produce.
The present invention comprises a controlled release composition designed for administration in non-divisible form comprising an active ingredient and a water s'wellable carrier therefor the controlled release of the active ingredient being achieved as a result of swelling of the carrier, the composition having a crenellated surface.
The nature of the crenellations may vary, in particular according to the basic shape of the composition. Thus, for example, where the composition is spherical the surface may be dimpled so as to be similar to that of a golf ball.
Alternatively, the crenellations may be provided as pimples upon the surface of the sphere. Where the composition takes the shape of a cylinder or a slab, the crenellations may conveniently take the form of ridges or furrows running for convenience parallel to the longitudinal axis of the cylinder or slab. The crenellations may be arranged in a regular fashion or an irregular one. For example the ridges or furrows may be arranged so as to lie parallel or they may be at;an angle to one another; they may be continuous or they may not. The crenellations will preferably have a depth which is significant in relation to the thickness of the device. In the preferred embodiments the entire surface of the composition will be crenellated and the depth of the crenellations will be such that the ratio of maximum dimension of the device to the minimum ~~~9~~~
dimension measured in at least one direction will be at least 2:1. The crenellations will preferably be arranged and of such a shape as to i ncrease the external surface area of the devi ce by a factor of at least 15% or even at least 25% compared to a composition containing the same quantity of carrier but having a smooth surface and the same basic shape.
The elevated portions of the crenellations will be such that they comprise at least 30% and preferably at least 50% by weight of the total weight of the composition. The preferred compositions thus provide a controlled release composition having a large surface area and in which the crenellations ensure that the diffusion path length for at least that proportion of the active contained in the elevated portions is substantially constant.
The compositions of this invention are conveniently and preferably useful in the administration of pharmaceutically active compounds in human or animal patients. They may be utilised as oral dosage forms, as subcutaneous implants or as a buccal, cervical, intrauterine, nasal, dermal inserts or artificial gland device. They find particular application as suppositories or pessaries. The compositions may be fabricated in the sizes and shapes which are conventional for these applications. In the preferred embodiments the devices will conveniently take the form of slabs or cylinders having a longitudinal axis which is longer than their other axes and a relatively small cross sectional area. The invention will hereinafter be described in relation to such devices although it will be appreciated that other configurations could be employed.
The invention is illustrated in the accompanying drawings in which:
Figure 1 is a cross-sectional view of a generally cylindrical device having four crenellations;
Figure 2 is a cross-sectional view of a generally cylindrical device having five crenellations; and Figure 3 is a cross-sectional view of a known hollow ~~~~~v~
_.
cylindrical device (which is 'included only for comparative purposes).
Figure 4 is a side elevation of a device having the cross section shown in Figure 1.
Figure 5 is a perspective view of the device shown in Figure 4.
Figure 6 is a side elevation of a device having the cross section shown in Figure 2.
Figure 7 is another side elevation of a device having the cross section shown in Figure 2.
Figure 8 is a perspective view of the device shown in Figures 6 and 7.
The cross-sectional area of the three devices is approximately equal, i.e. equal lengths of each cylindrical device will comprise equal amounts of material. The hollow cylindrical device of Figure 3 typically has an internal diameter of 7mm and an external diameter of lOmm. The device of Figure 1 has a maximum diameter A of 8.7mm, a minimum diameter B
of 3mm. The diameter of the crenellations C is 3mm. The radius D is 4.35mm. The device of Figure 2 has corresponding dimensions of 4mm (B>, 3mm (C> and 4.15mm (D>.
The number of crenellations may vary but will preferably be from 3 to 6. The shape of the crenellations may also vary.
They could be triangular, circular or even square. The crenellations will preferably be of equal size and will be spaced equiangularly around the axis of the composition. The upraised portion may have a greater width at its extremity than at its neck in which case the space between the crenellations may have a corresponding narrow neck and wide base. This latter construction may be particularly preferred in a further embodiment of the invention in which the space between crenellations is filled with a further composition which may be of therapeutic value. Tire space may be filled with other active materials optionally in admixture with a carrier or with another controlled release composition so as to provide a novel release profile of one or a combination of active materials.
The devices shown in figures 1 and 2 have a uniform cross section. It will be appreciated that this is not an essential feature of the devices of this invention. In practice the crenellations may spiral around the longitudinal axis of the cylinder or they may be interrupted and/or off-set against one another.
The devices of this preferred aspect of the invention need not have a cross-section whi ch i s perfectly cyl i ndri cal but may have ellipsoidal or in the extreme case a rectangular cross section.
In the preferred embodiments the devices have a solid cross section although devices having a hollow cross section may also be useful. However, those devices having a solid cross section are preferable especially insofar as they are relatively easy to fabricate compared to those having a hollow cross section, because they are relatively strong and because they offer a reduced overall cross-sectional area to the body.
The devices of this invention may be formed from any material which is known or has been proposed for use in the art of controlled release. The materials may conveniently be polymeric materials and in particular are preferably water swellable polymeric materials.
The carrier material should be one which can conveniently be fabricated in the crenellated shapes useful according to this invention. The fabrication may be carried out using any one of a vari ety of techni goes known i n the art whi ch are useful for a particular carrier. The composition should retain its mechanical integrity over the period during which the active is to be released. The water swellable materials may alter their shape somewhat during that period but should retain a crenellated shape.
In an especially preferred embodiment the compositions are formed from the polymers which are described in 6B 2047094, i.e.
they are polymeric carriers comprising residues which are cross linked through urethane groups and which comprise polyethylene oxide having a ratio of number average molecular weight to functionality greater than 1000 and wherein the polymeric material is a crystalline hydrogel in the dry form and exhibits syneresis in the wet form.
The compositions of this invention find particular application in the form of suppositories and pessaries far the administration of pharmaceuticals in humans. They may be used to provide release over a period of up to 48 hours although longer periods of release of from 3 and up to 10 days may be attainable and desirable in some instances. The crenellations in the surface of the compositions offer an additional advantage in that they can be removed from the body more readily than those having a smooth surface if desired. The crenellations may also facilitate the location of a cord on the composition which in use extends outside the body and can be used to pull the composition out of the body.
The compositions of this invention may conveniently be formulated by forming the water swellable material in the desired shape, immersing the farmed polymer in a solution of the active material, allowing the material to swell and subsequently drying the swollen polymer. Hgain the polymers of GB 2047093 and GB 2047094 are preferred because of the ease with which they can be formulated in this way.
~Je have di scavered that the devi ces of thi s i nvention whi ch are water swellable provide release profiles of active material which are more consistently reproducible than those offered by identical devices having a smooth surface when used in vivo, especially in humans. The crene~ilated surface appears to swell in a more reproducible manner when placed in an in vivo environment.
The present invention is of broad applicability in the formulation of active substances, particularly biologically active substances. Examples of classes of biologically active substances which may be incorporated in compositions of the _,_ present invention include pharmaceuticals, bacteriostats, viruscides, insecticides, herbicides, larvicides, fungicides, algaecides, nematocides, topical or dermatological agents, antifoulants, for marine growth prevention, enzymes and preservatives. Of particular interest are compositions of the present invention comprising, as biologically active substance, at least one pharmaceutical.
The compositions of this invention thus find wide application in medical and surgical, including veterinary, contexts and in horticulture and agriculture as well as outside these areas.
There is no necessity for the active substance to be water soluble although it will often possess some degree of water solubility; all that is required is that it is soluble to an extent commensurate with its desired concentration (which, in the case of a biologically active substance, is related to this activity) in the controlled release composition of this invention in the water or organic solvent used to swell the polymeric carrier on incorporation of the active substance therein.
Specific classes of drug which may be utilised in a controlled release composition of the invention include abortifacients> hypnotics, sedatives, tranquilisers, anti-pyretics, anti-inflammatory agents, anti-histamines, anti-tussives, anti-convulsants, muscle relaxants, anti-tumour agents, for example those for the treatment of malignant neoplasia, local anaesthetics, anti-Parkinson agents, topical or dermatological agents, diuretics, for example those containing potassium, such as potassium iodide, preparations for the treatment of mental illness, for example preparations containing lithium for use in the treatment of manic depression, anti-spasmodics, anti-ulcer agents, preparations containing various substances for the treatment of infection by pathogens including anti-fungal agents, for example metronidazole, anti-parasitic agents and other anti-microbials, anti-malarials, ~05~ ~j _$_ cardiovascular agents, preparations containing hormones, for example androgenic, estrogenic and progestational hormones, notably steroids such as oestradiol, sympathomimetic agents, hypoglycaemic agents, contraceptives, nutritional agents, preparations containing enzymes of various types of activity, for example ehymotrypsin, preparations containing analgesics, for example aspirin, and agents with many other types of action including nematocides and other agents of veterinary application. Mixtures of active substances may be incorporated into the polymeric carrier.
The active substances may be incorporated into the polymer with this in dispersed form but is more preferably incorporated into the polymeric carrier after this has been formed into an appropriate physical format. Accordingly, the usual procedure for incorporation of the biologically active substance is for the polymer, in suitable physical form, to be swelled using a solution containing the substance or substances to be incorporated. This solution may often be aqueous but may incorporate organic solvents for example alcohols such as ethyl alcohol in order to solubilise the substance and also in view of the improved swelling characteristics of such mixtures, and in some instances a completely non-aqueous organic solvent such as chloroform, methyl benzoate, butyrolactone or benzyl alcohol may be used. After swelling and absorption of the active substance, the release composition may be dried to remove the solvent or alternatively may be used in the swollen form. It has been found that the swelling procedure, and in particular the proportion of swelling relative to the original volume ~ehich is allowed to take place, can have a quite significant effect upon the subsequent behaviour of the release composition in vivo, even though it may be dried before use. Preferably, therefore, the degree of swelling during incorporation of 'the biologically active substance lies between 50 parts per hundred and 700 parts per hundred of the original dry volume, particularly between 200 and 500 parts per hundred.
2~~~~
_ g _ Certain of the areas of pharmaceutical utility for compositions according to the present invention, such as the administration of hormones, drugs for the treatment of prophylaxis of various conditions, e.g. substances having activity against pathogenic micro-organisms, are particularly suited to vaginal or rectal administration of the active substance and pessaries are of especial interest in such contexts. The compositions may, however, be used for various localised application in other parts of the body such as the treatment of maladies of the mouth or eye, for example glaucoma. The compositions are also of interest for oral administration or in a topical patch to release a drug which can treat or be absorbed by 'the skin; and for use by implantation.
The concentration of active substance incorporated into the controlled release composition of this invention can range from very high to very low. Thus, if a liquid biologically active material, such as m-cresol which swells the polymer to more than 1 ,000 pph, were used al so to swel l the polymer, then the active species could comprise more than 90% by weight of the release composition. A liquid which swelled to 1,000 pph and contained 25% by weight of a drug could leave a loading of more than 70%
by weight of the drug in the dry polymer, and 30% by weight loadings would be commonly attainable. Much lower ioadings, e.g. 1.0% to 0.5% are also readily attainable.
Other uses for compositions of the present invention include the prevention of formation of slime such as algae in swimming pools by application of a slimicide (or algaecide) consequent upon the daytime temperature rise, and the inhibition of polymerisation through release of a polymerisation inhibitor in response to a temperature rise in stored polymerisable monomers. In these cases, the active substance absorbed in the swollen polyethylene oxide is a slimicide (or algaecide) and a polymerisation inhibitor respectively. Controlled release compositions of this invention, in dry form, are also of interest in relation to the beneficial effect on the storage to -stability of potentially unstable compounds by incorporation into a crystalline matrix.
The invention is illustrated by the following examples:
Example 1_ A crystalline poly (ethylene oxide) hydrogel according to the teachings of British Patents 2047093 and 2947094 was produced by reaction of One part by ereight of a poly (ethylene glycol) having a number average molecular weight of 4000 (purchased as pharmaceutical grade PEG 4000 from the !C. $r K. Greef Company) One part by weight of hexane triol 2.5 parts by weight of hexamethylene diisocyanate.
The reactants were polymerised in suitable moulds so as to produce a three separate solid polymers having the shapes i5 illustrated in Figures 1, 2 and 3.
The compositions were cut to equal lengths. The compositions were immersed in an aqueous solution of morphine containing 30 gms/litre of morphine sulphate BP for a period of 24 hours. The swollen polymers were removed and dried under vacuum at ambient temperatures.
The rel ease profi 1 a of these composi tions was determi ned i n a suitable pH 7.9 phosphate buffer using USP XX1 paddle method (a rotational speed of 50 rpm). Samples were withdrawn at appropriate time points and assayed in the ultraviolet spectrum at 210 nm. The results were as follows:
(1> Hollow Compositions (average of 3 results) Time (hours) % r"torphine Dissolved CV%
0.5 9.77 5.36 1.0 14.50 3.68 2.0 24.19 3.33 4.0 41.99 3.93 8.0 62.39 4.11 12.0 76.26 3.34 T'/Z = 5 hours 30 minutes.
~~5~~~:~
(2> Four Ribbed Composition (average of 6 results) Time (hours) % Morphine DissolvedCV%
0.5 33.93 2.72 1.0 40.18 1.76 2.0 52.13 1.97 4.0 72.55 1.67 8.0 90.02 1.29 12.0 90.42 1.15 T'/= s 1 hour 45 minutes.
(3> Five Ribbed Composition (average6 results) of Time (hours) % Morphine DissolvedC~l%a 0.5 27.40 5.91 1.0 33.42 3.98 2.0 44.25 2.69 4.0 61.53 2.14 8.0 79.81 2.45 12.0 88.53 2.01 ExamrJle 2 A second series o~F hollow compositions and 'Four ribbed compositions were prepared loaded with morphine sulphate and tested in the manner described in Example i. Each series comprised four suppositories made from different production batches of polymer. The results obtained are presented below.
(1> Hollo~aCompositions morphinesulphatedissolved - %
. Time (hours) 1 2 3 4 0.5 12.70 16.90 13.71 14.23 1.0 17.10 20.65 19.00 19.93 2.0 30.03 36.21 31.18 28.73 4.0 50.07 58.30 51.17 43.13 8.0 74.98 80.20 73.98 57.9$
12.0 86.88 89.87 82.29 67.67 (2> Four RibbedCompositions- %
morphine sulphate dissolved Time (hours) 1 2 3 4 0.5 33.93 31.92 25.10 21.96 1.0 40.18 39.35 34.08 32.97 2.0 52.13 51.84 50.06 50.25 4.0 72.55 72.60 73.31 74.52 8.0 90.02 90.33 90.07 92.05 12.0 95.42 96.21 95.88 96.75
The elevated portions of the crenellations will be such that they comprise at least 30% and preferably at least 50% by weight of the total weight of the composition. The preferred compositions thus provide a controlled release composition having a large surface area and in which the crenellations ensure that the diffusion path length for at least that proportion of the active contained in the elevated portions is substantially constant.
The compositions of this invention are conveniently and preferably useful in the administration of pharmaceutically active compounds in human or animal patients. They may be utilised as oral dosage forms, as subcutaneous implants or as a buccal, cervical, intrauterine, nasal, dermal inserts or artificial gland device. They find particular application as suppositories or pessaries. The compositions may be fabricated in the sizes and shapes which are conventional for these applications. In the preferred embodiments the devices will conveniently take the form of slabs or cylinders having a longitudinal axis which is longer than their other axes and a relatively small cross sectional area. The invention will hereinafter be described in relation to such devices although it will be appreciated that other configurations could be employed.
The invention is illustrated in the accompanying drawings in which:
Figure 1 is a cross-sectional view of a generally cylindrical device having four crenellations;
Figure 2 is a cross-sectional view of a generally cylindrical device having five crenellations; and Figure 3 is a cross-sectional view of a known hollow ~~~~~v~
_.
cylindrical device (which is 'included only for comparative purposes).
Figure 4 is a side elevation of a device having the cross section shown in Figure 1.
Figure 5 is a perspective view of the device shown in Figure 4.
Figure 6 is a side elevation of a device having the cross section shown in Figure 2.
Figure 7 is another side elevation of a device having the cross section shown in Figure 2.
Figure 8 is a perspective view of the device shown in Figures 6 and 7.
The cross-sectional area of the three devices is approximately equal, i.e. equal lengths of each cylindrical device will comprise equal amounts of material. The hollow cylindrical device of Figure 3 typically has an internal diameter of 7mm and an external diameter of lOmm. The device of Figure 1 has a maximum diameter A of 8.7mm, a minimum diameter B
of 3mm. The diameter of the crenellations C is 3mm. The radius D is 4.35mm. The device of Figure 2 has corresponding dimensions of 4mm (B>, 3mm (C> and 4.15mm (D>.
The number of crenellations may vary but will preferably be from 3 to 6. The shape of the crenellations may also vary.
They could be triangular, circular or even square. The crenellations will preferably be of equal size and will be spaced equiangularly around the axis of the composition. The upraised portion may have a greater width at its extremity than at its neck in which case the space between the crenellations may have a corresponding narrow neck and wide base. This latter construction may be particularly preferred in a further embodiment of the invention in which the space between crenellations is filled with a further composition which may be of therapeutic value. Tire space may be filled with other active materials optionally in admixture with a carrier or with another controlled release composition so as to provide a novel release profile of one or a combination of active materials.
The devices shown in figures 1 and 2 have a uniform cross section. It will be appreciated that this is not an essential feature of the devices of this invention. In practice the crenellations may spiral around the longitudinal axis of the cylinder or they may be interrupted and/or off-set against one another.
The devices of this preferred aspect of the invention need not have a cross-section whi ch i s perfectly cyl i ndri cal but may have ellipsoidal or in the extreme case a rectangular cross section.
In the preferred embodiments the devices have a solid cross section although devices having a hollow cross section may also be useful. However, those devices having a solid cross section are preferable especially insofar as they are relatively easy to fabricate compared to those having a hollow cross section, because they are relatively strong and because they offer a reduced overall cross-sectional area to the body.
The devices of this invention may be formed from any material which is known or has been proposed for use in the art of controlled release. The materials may conveniently be polymeric materials and in particular are preferably water swellable polymeric materials.
The carrier material should be one which can conveniently be fabricated in the crenellated shapes useful according to this invention. The fabrication may be carried out using any one of a vari ety of techni goes known i n the art whi ch are useful for a particular carrier. The composition should retain its mechanical integrity over the period during which the active is to be released. The water swellable materials may alter their shape somewhat during that period but should retain a crenellated shape.
In an especially preferred embodiment the compositions are formed from the polymers which are described in 6B 2047094, i.e.
they are polymeric carriers comprising residues which are cross linked through urethane groups and which comprise polyethylene oxide having a ratio of number average molecular weight to functionality greater than 1000 and wherein the polymeric material is a crystalline hydrogel in the dry form and exhibits syneresis in the wet form.
The compositions of this invention find particular application in the form of suppositories and pessaries far the administration of pharmaceuticals in humans. They may be used to provide release over a period of up to 48 hours although longer periods of release of from 3 and up to 10 days may be attainable and desirable in some instances. The crenellations in the surface of the compositions offer an additional advantage in that they can be removed from the body more readily than those having a smooth surface if desired. The crenellations may also facilitate the location of a cord on the composition which in use extends outside the body and can be used to pull the composition out of the body.
The compositions of this invention may conveniently be formulated by forming the water swellable material in the desired shape, immersing the farmed polymer in a solution of the active material, allowing the material to swell and subsequently drying the swollen polymer. Hgain the polymers of GB 2047093 and GB 2047094 are preferred because of the ease with which they can be formulated in this way.
~Je have di scavered that the devi ces of thi s i nvention whi ch are water swellable provide release profiles of active material which are more consistently reproducible than those offered by identical devices having a smooth surface when used in vivo, especially in humans. The crene~ilated surface appears to swell in a more reproducible manner when placed in an in vivo environment.
The present invention is of broad applicability in the formulation of active substances, particularly biologically active substances. Examples of classes of biologically active substances which may be incorporated in compositions of the _,_ present invention include pharmaceuticals, bacteriostats, viruscides, insecticides, herbicides, larvicides, fungicides, algaecides, nematocides, topical or dermatological agents, antifoulants, for marine growth prevention, enzymes and preservatives. Of particular interest are compositions of the present invention comprising, as biologically active substance, at least one pharmaceutical.
The compositions of this invention thus find wide application in medical and surgical, including veterinary, contexts and in horticulture and agriculture as well as outside these areas.
There is no necessity for the active substance to be water soluble although it will often possess some degree of water solubility; all that is required is that it is soluble to an extent commensurate with its desired concentration (which, in the case of a biologically active substance, is related to this activity) in the controlled release composition of this invention in the water or organic solvent used to swell the polymeric carrier on incorporation of the active substance therein.
Specific classes of drug which may be utilised in a controlled release composition of the invention include abortifacients> hypnotics, sedatives, tranquilisers, anti-pyretics, anti-inflammatory agents, anti-histamines, anti-tussives, anti-convulsants, muscle relaxants, anti-tumour agents, for example those for the treatment of malignant neoplasia, local anaesthetics, anti-Parkinson agents, topical or dermatological agents, diuretics, for example those containing potassium, such as potassium iodide, preparations for the treatment of mental illness, for example preparations containing lithium for use in the treatment of manic depression, anti-spasmodics, anti-ulcer agents, preparations containing various substances for the treatment of infection by pathogens including anti-fungal agents, for example metronidazole, anti-parasitic agents and other anti-microbials, anti-malarials, ~05~ ~j _$_ cardiovascular agents, preparations containing hormones, for example androgenic, estrogenic and progestational hormones, notably steroids such as oestradiol, sympathomimetic agents, hypoglycaemic agents, contraceptives, nutritional agents, preparations containing enzymes of various types of activity, for example ehymotrypsin, preparations containing analgesics, for example aspirin, and agents with many other types of action including nematocides and other agents of veterinary application. Mixtures of active substances may be incorporated into the polymeric carrier.
The active substances may be incorporated into the polymer with this in dispersed form but is more preferably incorporated into the polymeric carrier after this has been formed into an appropriate physical format. Accordingly, the usual procedure for incorporation of the biologically active substance is for the polymer, in suitable physical form, to be swelled using a solution containing the substance or substances to be incorporated. This solution may often be aqueous but may incorporate organic solvents for example alcohols such as ethyl alcohol in order to solubilise the substance and also in view of the improved swelling characteristics of such mixtures, and in some instances a completely non-aqueous organic solvent such as chloroform, methyl benzoate, butyrolactone or benzyl alcohol may be used. After swelling and absorption of the active substance, the release composition may be dried to remove the solvent or alternatively may be used in the swollen form. It has been found that the swelling procedure, and in particular the proportion of swelling relative to the original volume ~ehich is allowed to take place, can have a quite significant effect upon the subsequent behaviour of the release composition in vivo, even though it may be dried before use. Preferably, therefore, the degree of swelling during incorporation of 'the biologically active substance lies between 50 parts per hundred and 700 parts per hundred of the original dry volume, particularly between 200 and 500 parts per hundred.
2~~~~
_ g _ Certain of the areas of pharmaceutical utility for compositions according to the present invention, such as the administration of hormones, drugs for the treatment of prophylaxis of various conditions, e.g. substances having activity against pathogenic micro-organisms, are particularly suited to vaginal or rectal administration of the active substance and pessaries are of especial interest in such contexts. The compositions may, however, be used for various localised application in other parts of the body such as the treatment of maladies of the mouth or eye, for example glaucoma. The compositions are also of interest for oral administration or in a topical patch to release a drug which can treat or be absorbed by 'the skin; and for use by implantation.
The concentration of active substance incorporated into the controlled release composition of this invention can range from very high to very low. Thus, if a liquid biologically active material, such as m-cresol which swells the polymer to more than 1 ,000 pph, were used al so to swel l the polymer, then the active species could comprise more than 90% by weight of the release composition. A liquid which swelled to 1,000 pph and contained 25% by weight of a drug could leave a loading of more than 70%
by weight of the drug in the dry polymer, and 30% by weight loadings would be commonly attainable. Much lower ioadings, e.g. 1.0% to 0.5% are also readily attainable.
Other uses for compositions of the present invention include the prevention of formation of slime such as algae in swimming pools by application of a slimicide (or algaecide) consequent upon the daytime temperature rise, and the inhibition of polymerisation through release of a polymerisation inhibitor in response to a temperature rise in stored polymerisable monomers. In these cases, the active substance absorbed in the swollen polyethylene oxide is a slimicide (or algaecide) and a polymerisation inhibitor respectively. Controlled release compositions of this invention, in dry form, are also of interest in relation to the beneficial effect on the storage to -stability of potentially unstable compounds by incorporation into a crystalline matrix.
The invention is illustrated by the following examples:
Example 1_ A crystalline poly (ethylene oxide) hydrogel according to the teachings of British Patents 2047093 and 2947094 was produced by reaction of One part by ereight of a poly (ethylene glycol) having a number average molecular weight of 4000 (purchased as pharmaceutical grade PEG 4000 from the !C. $r K. Greef Company) One part by weight of hexane triol 2.5 parts by weight of hexamethylene diisocyanate.
The reactants were polymerised in suitable moulds so as to produce a three separate solid polymers having the shapes i5 illustrated in Figures 1, 2 and 3.
The compositions were cut to equal lengths. The compositions were immersed in an aqueous solution of morphine containing 30 gms/litre of morphine sulphate BP for a period of 24 hours. The swollen polymers were removed and dried under vacuum at ambient temperatures.
The rel ease profi 1 a of these composi tions was determi ned i n a suitable pH 7.9 phosphate buffer using USP XX1 paddle method (a rotational speed of 50 rpm). Samples were withdrawn at appropriate time points and assayed in the ultraviolet spectrum at 210 nm. The results were as follows:
(1> Hollow Compositions (average of 3 results) Time (hours) % r"torphine Dissolved CV%
0.5 9.77 5.36 1.0 14.50 3.68 2.0 24.19 3.33 4.0 41.99 3.93 8.0 62.39 4.11 12.0 76.26 3.34 T'/Z = 5 hours 30 minutes.
~~5~~~:~
(2> Four Ribbed Composition (average of 6 results) Time (hours) % Morphine DissolvedCV%
0.5 33.93 2.72 1.0 40.18 1.76 2.0 52.13 1.97 4.0 72.55 1.67 8.0 90.02 1.29 12.0 90.42 1.15 T'/= s 1 hour 45 minutes.
(3> Five Ribbed Composition (average6 results) of Time (hours) % Morphine DissolvedC~l%a 0.5 27.40 5.91 1.0 33.42 3.98 2.0 44.25 2.69 4.0 61.53 2.14 8.0 79.81 2.45 12.0 88.53 2.01 ExamrJle 2 A second series o~F hollow compositions and 'Four ribbed compositions were prepared loaded with morphine sulphate and tested in the manner described in Example i. Each series comprised four suppositories made from different production batches of polymer. The results obtained are presented below.
(1> Hollo~aCompositions morphinesulphatedissolved - %
. Time (hours) 1 2 3 4 0.5 12.70 16.90 13.71 14.23 1.0 17.10 20.65 19.00 19.93 2.0 30.03 36.21 31.18 28.73 4.0 50.07 58.30 51.17 43.13 8.0 74.98 80.20 73.98 57.9$
12.0 86.88 89.87 82.29 67.67 (2> Four RibbedCompositions- %
morphine sulphate dissolved Time (hours) 1 2 3 4 0.5 33.93 31.92 25.10 21.96 1.0 40.18 39.35 34.08 32.97 2.0 52.13 51.84 50.06 50.25 4.0 72.55 72.60 73.31 74.52 8.0 90.02 90.33 90.07 92.05 12.0 95.42 96.21 95.88 96.75
Claims (12)
1. A controlled release composition designed for administration in non-divisible form comprising an active ingredient and a water swellable carrier therefor the controlled release of the active ingredient being achieved as a result of swelling of the carrier, the composition having a crenellated surface.
2. A composition according to claim 1, in which the carrier is a polymeric material comprising residues which are cross-linked through urethane groups and which comprise polyethylene oxide having a ratio of number average molecular weight to functionality of greater than 1000 and wherein the polymeric material is a crystalline hydrogel in the dry form and exhibits syneresis in the wet form.
3. A composition according to claim 1 or 2, in which the crenellations take the form of a series of furrows and ridges running in the direction of the longitudinal axis of a cylinder.
4. A composition according to claim 3, in which the surface of the composition comprises from 3 to 6 crenellations.
5. A composition according to claim 4, in which the surface comprises 4 crenellations.
6. A composition according to claim 4, in which the surface comprises 5 crenellations.
7. A composition according to any one of claims 4 to 6 characterised in that the crenellations are of equal size and are spaced equiangularly.
8. A composition according to any one of claims 1 to 7 characterised in that the device has an external surface area which is at least 15% greater than that of a device formed from the same quantity of material having a smooth exterior surface.
9. A composition according to any one of claims 1 to 7, characterized in that the device has an external surface area which is at least 25% greater than that of a device formed from the same quantity of material having a smooth exterior surface.
10. A composition according to any one of claims 4 to 9 which is useful as a suppository in humans.
11. A composition according to any one of claims 4 to 9 which is useful as a pessary in humans.
12. A composition according to any one of claims 4 to 11 in which the active material is morphines or a derivative thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9101502.4 | 1991-01-23 | ||
| GB919101502A GB9101502D0 (en) | 1991-01-23 | 1991-01-23 | Controlled release compositions |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2059855A1 CA2059855A1 (en) | 1992-07-24 |
| CA2059855C true CA2059855C (en) | 2002-03-05 |
Family
ID=10688907
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002059855A Expired - Lifetime CA2059855C (en) | 1991-01-23 | 1992-01-22 | Controlled release compositions |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US5352455A (en) |
| JP (1) | JP3296579B2 (en) |
| KR (1) | KR0123625Y1 (en) |
| CA (1) | CA2059855C (en) |
| DE (1) | DE9200765U1 (en) |
| ES (1) | ES1021151Y (en) |
| FR (1) | FR2671726B3 (en) |
| GB (2) | GB9101502D0 (en) |
| PT (1) | PT100047B (en) |
| ZA (1) | ZA92477B (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5342624A (en) * | 1989-02-16 | 1994-08-30 | British Technology Group Ltd. | Dispensing device |
| GB2254002B (en) * | 1991-01-16 | 1995-03-22 | Controlled Therapeutics | Retrievable pessary |
| GB9612370D0 (en) * | 1996-06-13 | 1996-08-14 | Whitehall Lab Ltd | A novel suppository |
| DE19734538C1 (en) * | 1997-07-30 | 1998-12-24 | Jenapharm Gmbh | Bioadhesive tablet |
| DE19814014A1 (en) * | 1997-12-19 | 1999-09-30 | Krewel Meuselbach Gmbh | Medicinal plant dry extracts |
| US6720356B2 (en) * | 2001-04-20 | 2004-04-13 | Spencer Feldman | Magnesium di-potassium EDTA complex and method of administration |
| US20040234602A1 (en) | 2001-09-21 | 2004-11-25 | Gina Fischer | Polymer release system |
| US20040253310A1 (en) | 2001-09-21 | 2004-12-16 | Gina Fischer | Morphine polymer release system |
| ES2360102T3 (en) | 2003-03-26 | 2011-05-31 | Egalet A/S | SYSTEM FOR CONTROLLED RELEASE OF MORPHINE. |
| EP1802357B2 (en) * | 2004-10-01 | 2013-09-18 | Menicon Singapore Pte Ltd. | Method for sterilising contact lens with package solution |
| AU2008258596B2 (en) | 2007-06-04 | 2013-02-14 | Egalet Ltd | Controlled release pharmaceutical compositions for prolonged effect |
| NZ594207A (en) | 2009-02-06 | 2013-03-28 | Egalet Ltd | Immediate release composition resistant to abuse by intake of alcohol |
| EP2445487A2 (en) | 2009-06-24 | 2012-05-02 | Egalet Ltd. | Controlled release formulations |
| EP2877161A1 (en) | 2012-07-06 | 2015-06-03 | Egalet Ltd. | Abuse deterrent pharmaceutical compositions for controlled release |
| USD765828S1 (en) | 2015-02-19 | 2016-09-06 | Crossford International, Llc | Chemical tablet |
Family Cites Families (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3114371A (en) * | 1960-03-11 | 1963-12-17 | Joseph F Montague | Suppository |
| GB1142325A (en) * | 1965-05-14 | 1969-02-05 | Higham Stanley Russell | Means for administering drugs |
| GB1154318A (en) * | 1965-10-21 | 1969-06-04 | Higham Stanley Russell | Improvements in Vitamin B12 Compositions |
| CH502891A (en) * | 1967-11-21 | 1971-02-15 | Ciba Geigy Ag | Technical, notched tablet |
| DE1814142A1 (en) * | 1967-12-13 | 1969-07-31 | Lokomotivbau Elektrotech | Device for vapor deposition in a vacuum of large areas |
| US3927194A (en) * | 1972-12-06 | 1975-12-16 | Ives Lab Inc | Tablet formulation |
| DE2401361C3 (en) * | 1974-01-11 | 1978-06-08 | Abbott Laboratories, Chicago, Ill. (V.St.A.) | Drug carrier anchor to remain in body cavities |
| US4218433A (en) * | 1977-03-03 | 1980-08-19 | Nippon Kayaku Kabushiki Kaisha | Constant-rate eluting tablet and method of producing same |
| AU537741B2 (en) * | 1979-03-21 | 1984-07-12 | British Technology Group Limited | Controlled release compositions |
| US5079009A (en) * | 1979-03-21 | 1992-01-07 | National Research Development Corporation | Controlled release compositions including polyethylene oxide with urethane cross-linking |
| US4258027A (en) * | 1979-03-26 | 1981-03-24 | Mead Johnson & Company | Multi-fractionable tablet structure |
| US4353887A (en) * | 1979-08-16 | 1982-10-12 | Ciba-Geigy Corporation | Divisible tablet having controlled and delayed release of the active substance |
| US4454309A (en) * | 1980-11-12 | 1984-06-12 | Tyndale Plains-Hunter, Ltd. | Polyurethane polyene compositions |
| ZA813205B (en) * | 1980-12-05 | 1983-03-30 | Smith Kline French Lab | Dosage units |
| GB2090535B (en) * | 1981-01-06 | 1984-09-19 | Osman Mohammad Fekry | Medical inserts |
| US4503031A (en) * | 1982-12-17 | 1985-03-05 | Glassman Jacob A | Super-fast-starting-sustained release tablet |
| GB2150938B (en) * | 1983-12-05 | 1987-04-23 | Tyndale Plains Hunter Limited | Hydrophilic polyurethane acrylate compositions |
| US4769027A (en) * | 1984-08-15 | 1988-09-06 | Burroughs Wellcome Co. | Delivery system |
| EP0202159B1 (en) * | 1985-05-10 | 1991-07-03 | Merck & Co. Inc. | Drug delivery device which can be retained in the stomach for a controlled period of time |
| US4767627A (en) * | 1985-05-29 | 1988-08-30 | Merck & Co., Inc. | Drug delivery device which can be retained in the stomach for a controlled period of time |
| DE3532692A1 (en) * | 1985-09-13 | 1987-03-19 | Boehringer Mannheim Gmbh | METHOD FOR PRODUCING TABLETS FROM PELLETS |
| DE3545090C1 (en) * | 1985-12-19 | 1987-06-25 | Capsoid Pharma Gmbh | Process for the production of individually dosed dosage forms |
| US4824677A (en) * | 1986-12-18 | 1989-04-25 | The Unjohn Company | Grooved tablet for fractional dosing of sustained release medication |
| KR900700071A (en) * | 1987-12-17 | 1990-08-11 | 로버어트 에이 아미테이지 | Tri-scored Drug Tablets |
| US4837111A (en) * | 1988-03-21 | 1989-06-06 | Alza Corporation | Dosage form for dispensing drug for human therapy |
| US5009896A (en) * | 1989-10-04 | 1991-04-23 | Akzo N.V. | Multi-fractionable tablet structure |
-
1991
- 1991-01-23 GB GB919101502A patent/GB9101502D0/en active Pending
-
1992
- 1992-01-17 US US07/821,946 patent/US5352455A/en not_active Expired - Lifetime
- 1992-01-22 FR FR9200685A patent/FR2671726B3/en not_active Expired - Lifetime
- 1992-01-22 CA CA002059855A patent/CA2059855C/en not_active Expired - Lifetime
- 1992-01-22 GB GB9201355A patent/GB2252043B/en not_active Expired - Lifetime
- 1992-01-23 ZA ZA92477A patent/ZA92477B/en unknown
- 1992-01-23 PT PT100047A patent/PT100047B/en not_active IP Right Cessation
- 1992-01-23 JP JP01032092A patent/JP3296579B2/en not_active Expired - Fee Related
- 1992-01-23 KR KR92000909U patent/KR0123625Y1/en not_active IP Right Cessation
- 1992-01-23 ES ES19929200208U patent/ES1021151Y/en not_active Expired - Fee Related
- 1992-01-23 DE DE9200765U patent/DE9200765U1/de not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| KR920014773U (en) | 1992-08-14 |
| FR2671726B3 (en) | 1992-12-18 |
| DE9200765U1 (en) | 1992-04-16 |
| ES1021151Y (en) | 1993-03-16 |
| CA2059855A1 (en) | 1992-07-24 |
| US5352455A (en) | 1994-10-04 |
| JP3296579B2 (en) | 2002-07-02 |
| PT100047A (en) | 1993-02-26 |
| KR0123625Y1 (en) | 1998-08-17 |
| JPH04295418A (en) | 1992-10-20 |
| ES1021151U (en) | 1992-10-16 |
| PT100047B (en) | 1995-07-18 |
| FR2671726A3 (en) | 1992-07-24 |
| GB2252043B (en) | 1994-10-12 |
| GB9101502D0 (en) | 1991-03-06 |
| GB2252043A (en) | 1992-07-29 |
| ZA92477B (en) | 1992-10-28 |
| GB9201355D0 (en) | 1992-03-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2059855C (en) | Controlled release compositions | |
| EP0016652B1 (en) | Composition for the controlled release of an active substance and process for its preparation | |
| AU598938B2 (en) | A generic zero order controlled drug delivery system | |
| CA1047403A (en) | Process for making a monolithic drug delivery device | |
| CA1236357A (en) | Disposable spermicide-releasing diaphragm | |
| US4351337A (en) | Biodegradable, implantable drug delivery device, and process for preparing and using the same | |
| Graham et al. | Hydrogels for controlled drug delivery | |
| EP0132384B1 (en) | Controlled release device | |
| AU2003301669B2 (en) | Method and system for intravesicular delivery of the therapeutic agents | |
| US4235988A (en) | Delivery means for biologically active agents | |
| CA1085726A (en) | Polyoxyalkylene-polyurethane medicament delivery means | |
| US4769013A (en) | Bio-effecting medical material and device | |
| AU736940B2 (en) | Hydrogel composites and superporous hydrogel composites having fast swelling, high mechanical strength, and superabsorbent properties | |
| PT93170B (en) | METHOD FOR PREPARING DISTRIBUTING DEVICES IN CAPSULES CONTAINING AN ACTIVE INGREDIENT | |
| JPH0735327B2 (en) | Modified release formulation | |
| DE2528068A1 (en) | WATER-INSOLUBLE HYDROPHILIC COPOLYMERS | |
| US5017382A (en) | Controlled release compositions (II) | |
| US5079009A (en) | Controlled release compositions including polyethylene oxide with urethane cross-linking | |
| CA1242394A (en) | Controlled release device | |
| EP0164569B1 (en) | A medicine-releasing agent | |
| WO1995017171A1 (en) | Delivery device for delayed release of an active containing a solubilising agent |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |