WO1991001722A1 - Diltiazem containing pharmaceutical compositions - Google Patents
Diltiazem containing pharmaceutical compositions Download PDFInfo
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- WO1991001722A1 WO1991001722A1 PCT/SE1990/000500 SE9000500W WO9101722A1 WO 1991001722 A1 WO1991001722 A1 WO 1991001722A1 SE 9000500 W SE9000500 W SE 9000500W WO 9101722 A1 WO9101722 A1 WO 9101722A1
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- diltiazem
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- coated
- pharmaceutical composition
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
Definitions
- the present invention relates to pharmaceut cal compositions containing di ltiazem, which compositions can be administered once or twice da ly and sti ll provide an adequate therapeuti- cally acti e serum level.
- the object of the present invention is to obtain a possibi lity of ad inistering di ltiazem once or twice a day (24 hrs).
- Di ltiazem is a benz oth i az i ne derivative with coronary and other smooth muscle calciu ⁇ i channel blocking activity. It is a potent vasodilator primari ly used in the treatment of angina pectoris and arterial hypertension.
- the recommended dosage is individu ⁇ al. Starting with 60 mg three times a day the dosage can be in ⁇ creased to 240 mg a day (given in divided doses 4 times dai ly) at one or two days interval unti l optimum response is obtained.
- di ltiazem 3 chloric acid addition salt is highly stable and light insensi ⁇ tive. Diltiazem is absorbed rapidly and completely. T-max oc ⁇ curs after 2-4 hrs when peak levels of 60-150 ng/ml are reached after an oral dose of 120 mg. Di ltiazem appears to be extensi ⁇ vely fi rst-pass metabolized showing an absolute bi oavai Labi I ity of about 40%. The half-life of di ltiazem ranges from 3-6 hrs ith an average of 2.7-3.0 hrs.
- Di ltiazem is present on the market in the form of tablets con ⁇ taining 60 mg of di ltiazem, which are to be administered three to four times dai ly.
- the tablet gives a rapid onset and di ltia ⁇ zem can be analysed in blood serum already after 15 min after ad inistration.
- Di ltiazem is present in the form of base and different acid ad- dition salts, such as di ltiazem ascorbate, p. 148-150 C (sub ⁇ limation); di ltiazem bensoate, m.p. 91-94 C; di ltiazem fumarate (2:1) m.p. 180-186 (sublimation); di ltiazem hydroch lori de , m.p. 205-215°C (sublimation); di ltiazem lactate, m.p. 82-86°C; dil- tiazem succinate, m.p.
- These salts have different solubi lities of from 18 g/l (bensoate) of water at 21°C to 650 g/l (sulphate) com ⁇ pared with the pure base which has a solubi lity of 0.22 g/l of water at 21°C.
- the base melts at 101-109°C.
- the variation in bioavai Labi I ity is dependent on the amount of coating material, as well as the relationship between anionic polymer and ethyl cellulose.
- FIG. 1 shows the mean values for 8 subjects.
- FIG. 2 shows a graph over the plasma concentration of desace ⁇ ty L-di Iti azem, mean values for 8 subjects.
- the bi oava i Labi I ity of MR is compared to an aqueous solution of di ltiazem in a single dose administration (60 mg di ltiazem)
- the bi oava i labi I ity of MR expressed as area under the curve (AUC) in a graph over the concentration in plasma is only about 70 % of that of an aqueous solution.
- the bio- avai lability of the multiple unit dose granule formulation increases and becomes equivalent to the bioavai labi lity of the prior art diltiazem tablet, when the MR is administered once a day (180 mg) and the ' latter is administered three times a day (3x60 mg).
- the MR is administered once a day (180 mg) and the ' latter is administered three times a day (3x60 mg).
- 25 % of the granules are uncoated granules and 75 % of the granules are coated granules.
- FIG. 3 shows the mean value graph for the composition of the present invention (MR) and the prior art diltiazem tablet. As evident therefrom the bi oavai labi I iti es are equal. It is also evident that the mu Ltip le-unit-dose granule formulation pro ⁇ vides a more even plasma level than the tablet does.
- MR composition of the present invention
- Granules containing 85 % by weight of diltiazem hydrochloride were prepared by mixing the diltiazem hydroch Lor de (425 g) with mi crocrysta 11 ne cellulose, Avicel , 15 % by weight (75 g), moistening the mixture and granulate the same by passing it through an extruder (NICASYSTEM) and drying same.
- the granules were then coated in a fluidized bed coater with a mixture of ethyl cellulose (75 % by weight) and hydroxypropy I methylcellu- lose phtalate (HP 55) (25 % by weight) dissolved in methylene chlori de/ethano I.
- the coating shows no substantial pH depen ⁇ dency as evident from an in vitro study.
- FIG. 4 shows the release rate of three dif ⁇ ferent mu Ltip le-unit-compos it ons containing coated particles only, when these are coated with different amounts of coating material (25/75 HP/EC).
- FIG. 5 shows the release obtained when using different ratios of anionic polymer to ethyl cellulose. As evident there exists a typical threshold value between 27 and 28 % anionic polymer present in the coating mixture.
- FIG. 6 sho s the release rate dependency of the ratio between the an- ionic polymer and ethyl cellulose. Mu Itip le-un t-dose granule formulations were prepared contain ⁇ ing
- Granules consisting of di ltiazem lactate, 425 g, Avicel PH101, 70g, and sodium lauryl sulphate, 5 g, were prepared in accord- ance with Ex. 1 above. The granules were coated with a mixture of ethyl cellulose and HP 55 (75:25) in an amount of 40 g per 500 g of granulated cores.
- FIG. 7 shows the release rate depen ⁇ dency of the ratio between the anionic polymer and ethyl cellu ⁇ lose, as well as the influence of different amounts of coating material of one selected ratio of polymers.
- PH101 , 75 g were prepared in accordance with Ex. 1. The granu- les were coated as given in Ex. 2.
- Granules consisting of di ltiazem benzoate, 425 g, Avicel PH101, 65 g, and sodium lau ry Isu Iphate , 10g, were prepared in accordance with Ex. 1 above. The granules were coated as given in Ex. 2 using 50 g of polymer mixture per 500 g of cores, and a ratio of 40:60 HP55/ethyl cellulose. The release rates of different ratios of anionic polymer and ethyl cellulose when using 30 g of coating material per 500g of granules. EXAMPLE 5
- PH101, 75 g were prepared in accordance with Ex. 1 above.
- the granules were coated using a polymer mixture of Eudragit L100 dissolvable at pH 5.5 and ethyl cellulose in a ratio of 26:7 dissolved in methylene ch lori de/ethano I .
- the granules were coated using 0 g of polymer mixture per 500 g of cores.
- FIG. 9 shows the release rate of- such a coated material after preexpo- sure for 2 hr ⁇ in an artificial gastric juice pH 1.2.
- FIG. 10 shows the pH dependency of the multiple-unit-dose com ⁇ position given in Example 1. As evident therefrom the pH de ⁇ pendency is rather weak for one individual coating composition.
- FIG. 11 shows a simulated absorption of di ltiazem hydroch lor i de after administration of 1) a multiple-unit-dose composition ac ⁇ cording to example 1, administered twice a day using 180 mg each time, and 2) a prior art diltiazem hydroch lor de tablet, administered 3 times a day using 120 mg each time. Simulation is based upon the previous in vivo results obtained and relates to continous administration - multiple dose.
- the acid solution, and the buffer solution, respectively used in the release tests were as follows:
- the acidic solution was an artificial gastric juice without en ⁇ zymes, pH 1.2 in accordance with USP Standards and consists of 175 mis of concentrated HCl (35%), and 50 g of NaCl, diluted to 25000 mis.
- the phosphate used in accordance with said Standard having a pH of 6.8 consists of 170.125 g of KH-PO,, and 23 g of NaOH, di ⁇ luted to 25000 is using distilled water.
- Cardize tablets consists, in accordance with the declaration, of 60 mg diltiazem hydroch lori de, eth lcellulose, hydroxypro- pylmethyl cellulose, lactose, magnesium stearate, D S C Yellow, FD S C Yellow, acetylated onog lyceride, and other constitu ⁇ ents.
- the amounts of the ingredients besides diltiazem are not ⁇ Q given but the ingredients are given in the order they are pre ⁇ sent as to amount.
- ethyl cellulose is present in the same or larger amount compared to hydroxy propyl methyl ce I lulose.
Abstract
The present invention relates to a pharmaceutical composition containing diltiazem as a therapeutically active ingredient and to be administered in the form of a multiple-unit-dose granule formulation once and/or twice a day, wherein a diltiazem acid addition salt is administered partly in the form of an uncoated multiple-unit-dose granule, and partly in the form of a multiple-unit-dose granule being coated with a mixture of ethyl cellulose and an anionic polymer which dissolves at a pH of above 5.0 and whereby said composition releases and whereby the coating mixture contains 20-40 parts per weight of anionic polymer in relation to 80-60 parts per weight of ethyl cellulose.
Description
DILTIAZEM CONTAINING PHARMACEUTICAL COMPOSITIONS.
DESCRIPTION
Techn cal field
The present invention relates to pharmaceut cal compositions containing di ltiazem, which compositions can be administered once or twice da ly and sti ll provide an adequate therapeuti- cally acti e serum level.
The object of the present invention is to obtain a possibi lity of ad inistering di ltiazem once or twice a day (24 hrs).
Background of the invention
Di ltiazem is a benz oth i az i ne derivative with coronary and other smooth muscle calciuπi channel blocking activity. It is a potent vasodilator primari ly used in the treatment of angina pectoris and arterial hypertension. The recommended dosage is individu¬ al. Starting with 60 mg three times a day the dosage can be in¬ creased to 240 mg a day (given in divided doses 4 times dai ly) at one or two days interval unti l optimum response is obtained. Di Itiazem, cis-(+)-3-acetyloxy)-5-|-2-dimethylamino)ethyl j -Σ^- dihydro^-^-methoxyphenyD-I^S-benzot iazepine^CSl-D-one has a pK of 7.7 and is highly Lipophi lic. Diltiazem -as its hydro-
3 chloric acid addition salt is highly stable and light insensi¬ tive. Diltiazem is absorbed rapidly and completely. T-max oc¬ curs after 2-4 hrs when peak levels of 60-150 ng/ml are reached after an oral dose of 120 mg. Di ltiazem appears to be extensi¬ vely fi rst-pass metabolized showing an absolute bi oavai Labi I ity of about 40%. The half-life of di ltiazem ranges from 3-6 hrs ith an average of 2.7-3.0 hrs.
Di ltiazem is present on the market in the form of tablets con¬ taining 60 mg of di ltiazem, which are to be administered three to four times dai ly. The tablet gives a rapid onset and di ltia¬ zem can be analysed in blood serum already after 15 min after ad inistration.
Di ltiazem is present in the form of base and different acid ad-
dition salts, such as di ltiazem ascorbate, p. 148-150 C (sub¬ limation); di ltiazem bensoate, m.p. 91-94 C; di ltiazem fumarate (2:1) m.p. 180-186 (sublimation); di ltiazem hydroch lori de , m.p. 205-215°C (sublimation); di ltiazem lactate, m.p. 82-86°C; dil- tiazem succinate, m.p. about 85 C (somewhat amorphous); di ltia¬ zem sulphate, m.p. 130-135 C; diltiazem maleate; di ltiazem suc- cinate (2:1), m.p. 133-138°C; diltiazem maleate (2:1), m.p. 136-142°C (65%); diltiazem adipate; di ltiazem laurate; diltia¬ zem glutarate. These salts have different solubi lities of from 18 g/l (bensoate) of water at 21°C to 650 g/l (sulphate) com¬ pared with the pure base which has a solubi lity of 0.22 g/l of water at 21°C. The base melts at 101-109°C.
In order to reduce the number of administrations of drugs there is a general demand for products which can be administered 1-2 times a day.
Description of the present invention
It has now surprisingly turned out that it is possible to meet this demand by means of the present i nventi on* whi ch is charac¬ terized in that a di ltiazem acid addition salt is administered partly in the form of an uncoated multiple-unit-dose granule, and partly in the form of a mult ple-unit-dose granule being coated with a mixture of ethyl cellulose and an anionic polymer which dissolves at a pH of above 5.0 and whereby said composi¬ tion releases diltiazem in a release test according to US Phar- acopea Standards, USP XXI (apparatus 2, 100 rp ) in an amount of 10-40 % by weight at pH 1.2 within 2 hrs, and in an amount of 30-60 % by weight at pH 6.8 within 4 hrs (6 hrs of total ex- posure), and in an amount of 50-80 % by weight at pH 6.8 within 8 hrs (10 hrs of total exposure) and more than 70 % by weight at pH 6.8 after 15 hrs, and whereby the coating mixture con¬ tains 20-40 parts per weight of anionic polymer in relation to 80-60 parts per weight of ethyl cellulose, whereby preferably the coating mixture contains 20-27 parts per weight of anionic polymer and 80-73 parts per weight of ethyl cellulose when the di ltiazem hydroch lor de, and di ltiazem laktate are concerned.
A standard mult ple-unit-dose granule (MR) formulation of di l¬ tiazem hydroch lori de , the granules being coated with a mixture of an anionic polymer and ethyl cellulose, wi ll show a bio- avai labi lity of only about 51-69 % compared to the di ltiazem hydroc lor i de tablet formulation found on the market, when said granules are administered once a day single dose containing 120 mg of di ltiazem. The variation in bioavai Labi I ity is dependent on the amount of coating material, as well as the relationship between anionic polymer and ethyl cellulose.
FIG. 1 shows the mean values for 8 subjects.
Also when the main metabolite of di ltiazem, viz. desacety Idi L- tiaze , is studied, the same magnitude of reduction in bio- avai lability is seen. The metabolite present in blood serum shows a bi oava i Labi I ity of 45-60 % compared to the situation when the di ltiazem tablet i s being administered.
' FIG. 2 shows a graph over the plasma concentration of desace¬ ty L-di Iti azem, mean values for 8 subjects.
The mere sustained release of di ltiazem from a pharmaceutical composition wi ll thus not improve bi oavai L abi I ity over the prior art.
In the case where the bi oava i Labi I ity of MR is compared to an aqueous solution of di ltiazem in a single dose administration (60 mg di ltiazem) the bi oava i labi I ity of MR expressed as area under the curve (AUC) in a graph over the concentration in plasma is only about 70 % of that of an aqueous solution.
However, when the multiple-unit-dose granule formulation con¬ sists of a combination of uncoated granules and coated gra- nules, as such granules given below in the Examples, the bio- avai lability of the multiple unit dose granule formulation (MR) increases and becomes equivalent to the bioavai labi lity of the
prior art diltiazem tablet, when the MR is administered once a day (180 mg) and the'latter is administered three times a day (3x60 mg). Hereby 25 % of the granules are uncoated granules and 75 % of the granules are coated granules.
FIG. 3 shows the mean value graph for the composition of the present invention (MR) and the prior art diltiazem tablet. As evident therefrom the bi oavai labi I iti es are equal. It is also evident that the mu Ltip le-unit-dose granule formulation pro¬ vides a more even plasma level than the tablet does.
EXAMPLE 1
Granules containing 85 % by weight of diltiazem hydrochloride were prepared by mixing the diltiazem hydroch Lor de (425 g) with mi crocrysta 11 ne cellulose, Avicel , 15 % by weight (75 g), moistening the mixture and granulate the same by passing it through an extruder (NICASYSTEM) and drying same. The granules were then coated in a fluidized bed coater with a mixture of ethyl cellulose (75 % by weight) and hydroxypropy I methylcellu- lose phtalate (HP 55) (25 % by weight) dissolved in methylene chlori de/ethano I. The coating shows no substantial pH depen¬ dency as evident from an in vitro study.
Different amounts of coating material were used for coating in order to be able to study different release profiles. Thus, 25, 35, and 50 g of polymer mixture were used per 500 g of granu¬ les, respectively. FIG. 4 shows the release rate of three dif¬ ferent mu Ltip le-unit-compos it ons containing coated particles only, when these are coated with different amounts of coating material (25/75 HP/EC). FIG. 5 shows the release obtained when using different ratios of anionic polymer to ethyl cellulose. As evident there exists a typical threshold value between 27 and 28 % anionic polymer present in the coating mixture. FIG. 6 sho s the release rate dependency of the ratio between the an- ionic polymer and ethyl cellulose.
Mu Itip le-un t-dose granule formulations were prepared contain¬ ing
(a) 100 % by weight of coated granules (spherical, diameter 0.5-1.5 mm) were packed in hard gelatine capsules and used for bioavai Labi lity tests, the results of which are shown in FIG. 1 , and
(b) 75 % by weight of coated granules (35 g of polymer mixture per 500 g of granules) together with 25 % by weight of uncoated granulated cores were packed in hard gelatine capsules (60 mg of di ltiazem'HCl in each, cf. FIG. 11 below).
EXAMPLE 2
D
Granules consisting of di ltiazem lactate, 425 g, Avicel PH101, 70g, and sodium lauryl sulphate, 5 g, were prepared in accord- ance with Ex. 1 above. The granules were coated with a mixture of ethyl cellulose and HP 55 (75:25) in an amount of 40 g per 500 g of granulated cores. FIG. 7 shows the release rate depen¬ dency of the ratio between the anionic polymer and ethyl cellu¬ lose, as well as the influence of different amounts of coating material of one selected ratio of polymers.
EXAMPLE 3 ft Granules consisting of di ltiazem ascorbate, 425 g, and Avicel
PH101 , 75 g, were prepared in accordance with Ex. 1. The granu- les were coated as given in Ex. 2.
EXAMPLE 4 p
Granules consisting of di ltiazem benzoate, 425 g, Avicel PH101, 65 g, and sodium lau ry Isu Iphate , 10g, were prepared in accordance with Ex. 1 above. The granules were coated as given in Ex. 2 using 50 g of polymer mixture per 500 g of cores, and a ratio of 40:60 HP55/ethyl cellulose. The release rates of different ratios of anionic polymer and ethyl cellulose when using 30 g of coating material per 500g of granules.
EXAMPLE 5
R Granules consisting of di ltiazem hydrochlori de, 425 g, Avicel
PH101, 75 g, were prepared in accordance with Ex. 1 above. The granules were coated using a polymer mixture of Eudragit L100 dissolvable at pH 5.5 and ethyl cellulose in a ratio of 26:7 dissolved in methylene ch lori de/ethano I . The granules were coated using 0 g of polymer mixture per 500 g of cores. FIG. 9 shows the release rate of- such a coated material after preexpo- sure for 2 hr^ε in an artificial gastric juice pH 1.2.
***-
The release profiles of the coated granules of Ex. 1-5 _i_rτ. v tro according to the standardized method of US Phar acopea USP XXI (apparatus 2, paddle, 100 rpm) and using standardized buffers of pH 1.2 and 6.8 (phosphate buffer) were determined.
FIG. 10 shows the pH dependency of the multiple-unit-dose com¬ position given in Example 1. As evident therefrom the pH de¬ pendency is rather weak for one individual coating composition.
FIG. 11 shows a simulated absorption of di ltiazem hydroch lor i de after administration of 1) a multiple-unit-dose composition ac¬ cording to example 1, administered twice a day using 180 mg each time, and 2) a prior art diltiazem hydroch lor de tablet, administered 3 times a day using 120 mg each time. Simulation is based upon the previous in vivo results obtained and relates to continous administration - multiple dose.
The acid solution, and the buffer solution, respectively used in the release tests were as follows:
The acidic solution was an artificial gastric juice without en¬ zymes, pH 1.2 in accordance with USP Standards and consists of 175 mis of concentrated HCl (35%), and 50 g of NaCl, diluted to 25000 mis.
The phosphate used in accordance with said Standard having a pH of 6.8 consists of 170.125 g of KH-PO,, and 23 g of NaOH, di¬ luted to 25000 is using distilled water.
*■> Cardize tablets consists, in accordance with the declaration, of 60 mg diltiazem hydroch lori de, eth lcellulose, hydroxypro- pylmethyl cellulose, lactose, magnesium stearate, D S C Yellow, FD S C Yellow, acetylated onog lyceride, and other constitu¬ ents. The amounts of the ingredients besides diltiazem are not ■ Q given but the ingredients are given in the order they are pre¬ sent as to amount. Thus, e.g., ethyl cellulose is present in the same or larger amount compared to hydroxy propyl methyl ce I lulose.
5
0
5
0
5
Claims
1. A pharmaceutical composition containing diltiazem as a the- rapeutically active ingredient and to be administered in the form of a multiple-unit-dose granule formulation once and/or twice a day, characterized in that a diltiazem acid addition salt is administered partly in the form of an uncoated multip¬ le-unit-dose granule, and partly in the form of a multiple- unit-dose granule being coated with a mixture of. ethyl cellu¬ lose and an anionic polymer which dissolves at a pH of above 5.0 and whereby said composition releases and whereby the coat¬ ing mixture contains 20-40 parts per weight of anionic polymer in relation to 80-60 parts per weight of ethyl cellulose.
2. A pharmaceutical composition according to claim 1, wherein the composition releases diltiazem in a release test according to US Pharmacopea Standards, USP XXI (apparatus 2, paddle, 100 rpm) in an amount of 10-40 % by weight at pH 1.2 within 2 hrs, and in an amount of 30-60 % by weight at pH 6.8 within 4 hrs (6 hrs of total exposure), and in an amount of 50-80 % by weight ' at pH 6.8 within 8 hrs (10 hrs of total exposure) * and more than 70 % by weight at pH 6.8 after 15 hrs.
3. A pharmaceutical composition according to claim 1, wherein the granules comprises 50-95% by weight, preferably 80-90 % by weight of diltiazem.
4. A pharmaceutical composition according to claims 1-3, where¬ in the coated granules are coated with a mixture of ethyl cel¬ lulose and hydroxypropyI ethy Ice I lu lose phtalate.
5. A pharmaceutical composition according to claims 1-4, where¬ in the coating material is at least 25 g per 500 g of coated granules, preferably 25-50 g per 500 g of coated granules.
6. A pharmaceutical composition according to any of the pre- ceeding daims, wherein 10-30 % by weight of the mu It ip Le-unit- dose granules are uncoated, and 70-90 % by weight of the mul- tip le-uni t-dose granules are coated.
7. A pharmaceutical composition according to any of the pre- ceeding claims, wherein the ratio between anionic polymer and ethyl cellulose is 20-30:80-70, preferably 22-27:78-73 when diltiazem hydrochlori de is used as active therapeutic agent.
The present invention relates to a pharmaceutical composition containing diltiazem as a therapeuti ca I ly active ingredient and to be administered in the form of a multiple-unit-dose granule formulation once and/or twice a day, wherein a di ltiazem -acid addition salt is administered partly in the form of an uncoated multiple-unit-dose granule, and partly in the form of a multip¬ le-unit-dose granule being coated with a mixture of ethyl cel¬ lulose and an anionic polymer which dissolves at a pH of above 5.0 and whereby said composition releases and whereby the coat¬ ing mixture contains 20-40 parts per weight of anionic polymer in relation to 80-60 parts per weight of ethyl cellulose. (FIG. 3)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8902699-1 | 1989-08-09 | ||
| SE8902699A SE8902699D0 (en) | 1989-08-09 | 1989-08-09 | DILTIAZEM CONTAINING PHARMACEUTICAL COMPOSITIOS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1991001722A1 true WO1991001722A1 (en) | 1991-02-21 |
Family
ID=20376653
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SE1990/000500 WO1991001722A1 (en) | 1989-08-09 | 1990-07-23 | Diltiazem containing pharmaceutical compositions |
Country Status (2)
| Country | Link |
|---|---|
| SE (1) | SE8902699D0 (en) |
| WO (1) | WO1991001722A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0514814A1 (en) * | 1991-05-20 | 1992-11-25 | Hoechst Marion Roussel, Inc. | Diltiazem formulation |
| US5286497A (en) * | 1991-05-20 | 1994-02-15 | Carderm Capital L.P. | Diltiazem formulation |
| WO1994022431A1 (en) * | 1993-03-30 | 1994-10-13 | Pharmacia Ab | Controlled release preparation containing a salt of morphine |
| US5601845A (en) * | 1991-08-12 | 1997-02-11 | Euro-Celtique, S.A. | Pharmaceutical spheroid formulation |
| US6214385B1 (en) | 1995-01-05 | 2001-04-10 | Grant W. Heinicke | Controlled absorption diltiazem pharmaceutical formulation |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4173626A (en) * | 1978-12-11 | 1979-11-06 | Merck & Co., Inc. | Sustained release indomethacin |
| US4765990A (en) * | 1981-09-14 | 1988-08-23 | Kanebo, Ltd | Sustained-release nifedipine preparation |
| EP0282698A1 (en) * | 1987-02-20 | 1988-09-21 | International Trade Managers Limited | Process for the preparation of a retarding formulation containing diltiazem for a single daily dose |
| EP0318398A1 (en) * | 1987-11-26 | 1989-05-31 | Ethypharm | Diltiazem sustained release form and medicament thereof |
-
1989
- 1989-08-09 SE SE8902699A patent/SE8902699D0/en unknown
-
1990
- 1990-07-23 WO PCT/SE1990/000500 patent/WO1991001722A1/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4173626A (en) * | 1978-12-11 | 1979-11-06 | Merck & Co., Inc. | Sustained release indomethacin |
| US4765990A (en) * | 1981-09-14 | 1988-08-23 | Kanebo, Ltd | Sustained-release nifedipine preparation |
| EP0282698A1 (en) * | 1987-02-20 | 1988-09-21 | International Trade Managers Limited | Process for the preparation of a retarding formulation containing diltiazem for a single daily dose |
| EP0318398A1 (en) * | 1987-11-26 | 1989-05-31 | Ethypharm | Diltiazem sustained release form and medicament thereof |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0514814A1 (en) * | 1991-05-20 | 1992-11-25 | Hoechst Marion Roussel, Inc. | Diltiazem formulation |
| US5286497A (en) * | 1991-05-20 | 1994-02-15 | Carderm Capital L.P. | Diltiazem formulation |
| AU653223B2 (en) * | 1991-05-20 | 1994-09-22 | Aventisub Ii Inc. | Diltiazem formulation |
| KR100244010B1 (en) * | 1991-05-20 | 2000-03-02 | 스티븐 엘. 네스비트 | Diltiazem formulation |
| US5439689A (en) * | 1991-05-20 | 1995-08-08 | Carderm Capital L.P. | Diltiazem formulation |
| US5470584A (en) * | 1991-05-20 | 1995-11-28 | Carderm Capital L.P. | Diltiazem formulation |
| US5670172A (en) * | 1991-08-12 | 1997-09-23 | Euro-Celtique, S.A. | Pharmaceutical spheroid formulation |
| US5601845A (en) * | 1991-08-12 | 1997-02-11 | Euro-Celtique, S.A. | Pharmaceutical spheroid formulation |
| US5614218A (en) * | 1993-03-30 | 1997-03-25 | Pharmacia & Upjohn Aktiebolag | Controlled release preparation |
| AU680891B2 (en) * | 1993-03-30 | 1997-08-14 | Pharmacia Ab | Controlled release preparation containing a salt of morphine |
| WO1994022431A1 (en) * | 1993-03-30 | 1994-10-13 | Pharmacia Ab | Controlled release preparation containing a salt of morphine |
| AU680891C (en) * | 1993-03-30 | 2002-01-03 | Pharmacia Ab | Controlled release preparation containing a salt of morphine |
| CN1104891C (en) * | 1993-03-30 | 2003-04-09 | 法马西雅公司 | Controlled release preparation containing a salt of morphine |
| US6214385B1 (en) | 1995-01-05 | 2001-04-10 | Grant W. Heinicke | Controlled absorption diltiazem pharmaceutical formulation |
Also Published As
| Publication number | Publication date |
|---|---|
| SE8902699D0 (en) | 1989-08-09 |
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