USRE33963E - Solid rapidly released medicament preparations containing dihydropyridines, and processes for their preparation - Google Patents
Solid rapidly released medicament preparations containing dihydropyridines, and processes for their preparation Download PDFInfo
- Publication number
- USRE33963E USRE33963E US07/647,611 US64761191A USRE33963E US RE33963 E USRE33963 E US RE33963E US 64761191 A US64761191 A US 64761191A US RE33963 E USRE33963 E US RE33963E
- Authority
- US
- United States
- Prior art keywords
- weight
- solid
- parts
- nifedipine
- pvp
- 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
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
Definitions
- the present invention relates to certain novel special rapidly absorbable solid medicament preparations which contain dihydropyridines and polyvinylpyrrolidone, and to processes for their preparation.
- Nifedipine (dimethyl 1,4-dihydro-2,6-dimethyl-4-(o-nitrophenyl)-pyridine-3,5-dicarboxylate) is a known active compound from the substance class of the dihydropyridines, which affects the circulation (see British Patent Specification No. 1,173,862). Owing to its extreme sensitivity to light and its extremely low solubility in aqueous media, a number of difficulties occur in the pharmaceutical preparation of special medicaments, as is evident from numerous patent applications and patents for special formations of this active compound.
- U.S. Pat. No. 3,784,684 relates, for example, to special gelatine bitable capsules which contain nifedipine in dissolved form, in order advantageously to utilise the coronary action of nifedipine.
- British Patent Specification No. 1,456,618 describes and claims solid medicament preparations which are intended to ensure good bio-availability of the nifedipine.
- coprecipitates are prepared by dissolving nifedipine and PVP in organic solvents and subsequently evaporating the solvent to obtain a glassy mass (see DEOS (German Published Specification) No. 2,822,882).
- nifedipine and PVP inorganic solvents
- evaporation of the organic solvent can be carried out industrially only at great expense, since the PVP mass binds the organic solvent strongly and becomes very viscous shortly before drying.
- a voluminous foamy mass is formed which is very viscous shortly before the end of the drying procedure, can no longer be stirred, and is difficult to process further.
- auxiliaries which may be chosen are very limited, in particular for the production of tablets, because PVP simultaneously acts as a binder, and the disintegration of the tablets or capsules is hindered by the presence of large amounts of PVP (30-100 mg per tablet or capsule).
- Nimodipine (1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine 3-methoxyethyl ester 5-isopropyl ester) is likewise a known dihydropyridine with a cerebral action (see DOS (German Published Specification) No. 2,815,578). This compound also is difficult to process to give pharmaceutical preparation forms, owing to its physico-chemical properties. Nimodipine has, for example, a substantially poorer solubility than nifedipine in aqueous media.
- the present invention relates to new solid rapidly released preparations containing dihydropyridines, and processes for their preparation, which no longer have these disadvantages of the preparations known hitherto.
- rapidly absorbable, solid medicament preparations with a uniform active compound content comprising 1 part by weight of dihydropyridine as active compound, 2.0 to 6.0 parts by weight of PVP having a mean molecular weight of 15,000 to 50,000, and absorptive excipients consisting of from 3.5 to 15 parts by weight of cellulose, 0.25 to 4.0 parts by weight of starch and 0.25 to 4.0 parts by weight of crosslinked insoluble PVPP, and comprising if appropriate, further formulation auxiliaries and/or excipients.
- PVPP cross-linked insoluble polyvinylpyrrolidone
- Polyplasdone XL® from GAF Corp., New York, N.Y. USA or KOLLIDONE CL® from BASF, Ludwigshafen, Germany.
- These solid medicament preparations are prepared by a process in which 1 part by weight of dihydropyridine and 2 to 6 parts by weight of PVP are dissolved in a small amount of organic solvent in which the two solid constituents are just soluble, and this solution is granulated with 4 to 23 parts by weight, preferably with 5.25 to 17 parts by weight, of the abovementioned excipients, and these granules are then processed further, if desired, with further formulation auxiliaries and/or excipients to give solid medicament preparations.
- organic solvents C 1 -C 3 -alkanols; C 1 -C 2 -dialkyl ketones; and chlorinated alkanes having 1-2 carbon atoms.
- organic solvents include ethanol, acetone, methylene chloride and chloroform, and in particular mixtures of these solvents. They are preferably employed in an amount of 2 to 20, in particular of 8 to 16, parts by weight, relative to the dihydropyridine.
- a .[.power.]. .Iadd.powder .Iaddend.mixture of 4 to 12 parts by weight of cellulose, 0.25 to 2.0 parts by weight of starch and 1 to 3 parts by weight of crosslinked insoluble PVPP is particularly suitable as the said adsorptive excipient.
- Preferred preparations according to the present invention are those in which the relative standard deviation of the active compound content is at most 2.5% and 50% of the active compound is released in less than 30 minutes; especially those in which the active compound is nifedipine 50% of which is released in less than 15 minutes.
- solid medicament preparations tablets, pills, dragees, granules, powders, capsules and sachets.
- the granules obtained by the process according to the invention and consisting of the powder mixture wetted with active compound/PVP solution can, without problems, be dried, sieved, processed further, mixed with other auxiliaries and excipients and pressed to give tablets.
- tablets were prepared, according to Examples A to F, by conventional methods in which a solid coprecipitate of nifedipine and PVP was first prepared by evaporating off the solvent, and these solid granules were then mixed with customary auxiliaries and excipients, and processed further to give solid tablets.
- the coprecipitate of nifedipine and PVP or of nimodipine and PVP was not isolated but was granulated as a solution with a mixture of solid excipients, and these granules were then pressed in the customary manner to give tablets.
- Example 1 The mixtures of Examples A to F and Example 1 relative to the preparation of 10,000 tablets each. Examples 2 to 4 account for 15,000 tablets each.
- coprecipitates prepared in the same manner as in A were brought, via an oscillating sieve, to a maximum particle size of 0.8 mm in the case of Example B or 0.6 mm in the case of Example C, and were then processed further, in the same manner as in Example A, to give tablets.
- coprecipitate prepared analogously to Example A was comminuted by means of a hammer mill and then processed further, as in Example A, to give tablets.
- a coprecipitate prepared analogously to Example E was mixed directly with the mixture of cellulose and starch, was granulated with the starch paste (that is to say in an aqueous medium), and was then pressed to give tablets, analogously to Example E. Although the tablets prepared in this manner possessed an improved content uniformity, they gave unsatisfactory release values.
- nifedipine and 400 g of PVP 25 were dissolved in 1,800 of methylene chloride.
- 1,050 g of cellulose, 200 g of starch and 100 g of insoluble PVPP were mixed in the dry state and granulated with the nifedipine/PVP solution.
- the moist granules obtained were dried and sieved, 145 g of insoluble PVPP, 200 g of starch and 4 g of magnesium stearate were then added, the ingredients were mixed, and this mixture was pressed to give tablets of 220 mg. These tablets were distinguished by a very good content uniformity and advantageous release.
- Example 2 Analogously to Example 1, 150 g of nifedipine and 600 g of PVP 25 were dissolved in 1,800 g of methylene chloride, and this solution was granulated directly with a mixture of 1,575 g of microcrystalline cellulose ("Avicel") and 600 g of corn starch. After the granules had been dried and sieved, they were mixed with 6 g of magnesium stearate and 369 g of insoluble PVPP, and the mixture was pressed to give tablets weighing 220 mg.
- Avicel microcrystalline cellulose
- Example 2 Analogously to Example 2, 150 g of nifedipine and 600 g of PVP 25 were dissolved in 2,200 g of methylene chloride. The solution was granulated for granulating a mixture of 1,575 g of microcrystalline cellulose 600 g of corn starch and 300 g of insoluble PVPP. After the granules had been dried and sieved, they were mixed with 6 g of magnesium stearate and 69 g of insoluble PVPP, and the mixture was pressed to give tablets weighing 220 mg.
- nifedipine and 600 g of PVP 25 were dissolved in 2,100 g of methylene chloride. This solution was used for granulating a mixture of 1,575 g of microcrystalline cellulose, 600 g of corn starch and 150 g of insoluble PVPP. After the granules had been dried and sieved, they were mixed with 66 g of magnesium stearate and 219 g of insoluble PVPP, and the mixture was pressed to give tablets weighing 220 mg.
- nifedipine 1 kg of nifedipine and 4 kg of PVP 25 were dissolved in 7 kg of acetone.
- the solution was used for granulating a mixture of 10.5 kg of microcrystalline cellulose ("Avicel"), 2 kg of starch and 1 kg of insoluble PVPP.
- the mass was dried in vacuo, sieved, and mixed with 1.46 kg of insoluble PVPP, 2 kg of starch and 0.04 kg of magnesium stearate.
- the mixture was pressed to give tablets weighing 220 mg and having a diameter of 9 mm.
- 20 kg of tablets were sprayed with a suspension of 0.3 kg of hydroxypropylmethylcellulose, 0.1 kg of polyethylene glycol 4000, 0.09 kg of titanium dioxide and 0.01 kg of red iron oxide in 6.17 kg of water.
- nimodipine 0.6 kg of nimodipine and 1.5 kg of PVP 25 were dissolved in 1.4 kg of acetone. The solution was used for granulating a mixture of 2.85 kg of microcrystalline cellulose, 0.150 kg of starch and 0.6 kg of insoluble PVPP. The mass was dried in vacuo, sieved, and mixed with 0.288 kg of insoluble PVPP, 0.566 kg of starch and 0.011 kg of magnesium stearate. The mixture was pressed to give tablets weighing 330 mg and having a diameter of 10 mm.
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
TABLE __________________________________________________________________________ Examples according to Examples according to known methods the invention Example No. A B C D E F 1 2 3 4 __________________________________________________________________________ Standard deviation 1.7% 1.0% 1.1% 1.7% -- -- 1.0% 0.7% 0.7% 0.8% of the tablet weights Deviation of the 8.86- 8.04- 8.75- 8.44- 10.01- 9.55- 10.03- 10.30- 10.49- 9.98- nifedipine con- 10.12 10.32 10.15 9.65 10.83 10.03 10.31 10.55 10.81 10.53 tent in mg in individual tablets (10 tablets) Standard deviation 4.1% 6.7% 5.1% 4.7% 2.4% 1.8% 1.0% 0.774% 1.088% 1.413% of the nifedipine content per tablet Nifedipine release* appr. appr. appr. appr. <10' 30'-40' <5' <10' <10' <10' 50% released after 10' 10' 10' 10' (minutes) __________________________________________________________________________ *The release test is effected according to the USP Paddle method.
Claims (8)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/647,611 USRE33963E (en) | 1981-10-29 | 1991-01-28 | Solid rapidly released medicament preparations containing dihydropyridines, and processes for their preparation |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE3142853 | 1981-10-29 | ||
DE19813142853 DE3142853A1 (en) | 1981-10-29 | 1981-10-29 | Solid pharmaceutical compositions containing nifedipine and process for their production |
DE19823205399 DE3205399A1 (en) | 1982-02-16 | 1982-02-16 | Solid, rapid-release pharmaceutical compositions with dihydropyridines and process for their production |
DE3205399 | 1982-02-16 | ||
US07/647,611 USRE33963E (en) | 1981-10-29 | 1991-01-28 | Solid rapidly released medicament preparations containing dihydropyridines, and processes for their preparation |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US06728123 Continuation | 1985-04-29 | ||
US06/864,677 Reissue US4882144A (en) | 1981-10-29 | 1986-05-19 | Solid, rapidly released medicament preparations containing dihydropyridines, and processes for their preparation |
Publications (1)
Publication Number | Publication Date |
---|---|
USRE33963E true USRE33963E (en) | 1992-06-16 |
Family
ID=27189648
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US07/647,611 Expired - Lifetime USRE33963E (en) | 1981-10-29 | 1991-01-28 | Solid rapidly released medicament preparations containing dihydropyridines, and processes for their preparation |
Country Status (1)
Country | Link |
---|---|
US (1) | USRE33963E (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5266581A (en) * | 1984-07-04 | 1993-11-30 | Bayer Aktiengesellschaft | Solid composition containing dihydropyridine, PVP and PVPP |
WO1994023700A1 (en) * | 1993-04-22 | 1994-10-27 | Rijksuniversiteit Gent Laboratorium Voor Farmaceutische Technologie | High release solid preparation, preparation and use thereof |
US5478848A (en) * | 1994-01-26 | 1995-12-26 | Bayer Corporation | Inhibition of arthritis by L-type calcium channel antagonists nimodipine, nisoldipine and nifedipine |
US5543099A (en) * | 1994-09-29 | 1996-08-06 | Hallmark Pharmaceutical, Inc. | Process to manufacture micronized nifedipine granules for sustained release medicaments |
US20060257470A1 (en) * | 2002-10-09 | 2006-11-16 | Abbott Gmbh & Co. Kg | Method for producing solid galenic formulations using a crosslinked non-thermoplastic carrier |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4216155A (en) * | 1977-07-15 | 1980-08-05 | Ciba-Geigy Corporation | Process for the preparation of novel benzopyrane derivatives |
US4412986A (en) * | 1977-06-07 | 1983-11-01 | Yamanouchi Pharmaceutical Co. Ltd. | Nifedipine-containing solid preparation composition |
-
1991
- 1991-01-28 US US07/647,611 patent/USRE33963E/en not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4412986A (en) * | 1977-06-07 | 1983-11-01 | Yamanouchi Pharmaceutical Co. Ltd. | Nifedipine-containing solid preparation composition |
US4216155A (en) * | 1977-07-15 | 1980-08-05 | Ciba-Geigy Corporation | Process for the preparation of novel benzopyrane derivatives |
Non-Patent Citations (8)
Title |
---|
Chemical Abstracts, vol. 83 (1975), #209407w; Kramer et al. |
Chemical Abstracts, vol. 83 (1975), 209407w; Kramer et al. * |
Chemical Abstracts, vol. 90 (1979), #109987m; Kawata et al. |
Chemical Abstracts, vol. 90 (1979), 109987m; Kawata et al. * |
Chemical Abstracts, vol. 93 (1980), #53922d; Sugimoto et al. |
Chemical Abstracts, vol. 93 (1980), 53922d; Sugimoto et al. * |
Chemical Abstracts, vol. 96 (1982), #205448f; Hegasy et al. |
Chemical Abstracts, vol. 96 (1982), 205448f; Hegasy et al. * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5266581A (en) * | 1984-07-04 | 1993-11-30 | Bayer Aktiengesellschaft | Solid composition containing dihydropyridine, PVP and PVPP |
WO1994023700A1 (en) * | 1993-04-22 | 1994-10-27 | Rijksuniversiteit Gent Laboratorium Voor Farmaceutische Technologie | High release solid preparation, preparation and use thereof |
US5478848A (en) * | 1994-01-26 | 1995-12-26 | Bayer Corporation | Inhibition of arthritis by L-type calcium channel antagonists nimodipine, nisoldipine and nifedipine |
US5543099A (en) * | 1994-09-29 | 1996-08-06 | Hallmark Pharmaceutical, Inc. | Process to manufacture micronized nifedipine granules for sustained release medicaments |
US20060257470A1 (en) * | 2002-10-09 | 2006-11-16 | Abbott Gmbh & Co. Kg | Method for producing solid galenic formulations using a crosslinked non-thermoplastic carrier |
US7846477B2 (en) | 2002-10-09 | 2010-12-07 | Abbott Gmbh & Co. Kg | Method for producing solid galenic formulations using a crosslinked non-thermoplastic carrier |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4882144A (en) | Solid, rapidly released medicament preparations containing dihydropyridines, and processes for their preparation | |
CA1280976C (en) | Process for the preparation of solid nifedipine formulations of high bioavailability and with sustained effect, and formulations thusobtained | |
CA1146866A (en) | Process for the production of sustained release pharmaceutical composition of solid medical material | |
US5015479A (en) | Sustained release capsule or tablet formulation comprising a pharmaceutically acceptable dihydropyridine | |
US5972373A (en) | Taste masking pharmaceutical composition for oral administration | |
US5972381A (en) | Solid solution of an antifungal agent with enhanced bioavailability | |
EP0001247A1 (en) | Pharmaceutical preparation containing nifedipine and a method for producing the same. | |
US6383517B1 (en) | Process for preparing solid formulations of lipid-regulating agents with enhanced dissolution and absorption | |
KR920006908B1 (en) | Process for preparing solid medicament preparation containing dihydropyridines | |
JP2000514057A (en) | Solid solution of antifungal agent with enhanced bioavailability | |
JP3110794B2 (en) | Preparation containing 1,4-dihydropyridine derivative | |
US5445830A (en) | Highly absorbable pharmaceutical composition | |
CA2216277C (en) | Controlled release pharmaceutical compositions for the oral administration containing nifedipine as active substance | |
EP0371471A1 (en) | Readily absorbable drug formulation of NB-818 | |
WO1989002738A1 (en) | Sustained-release nifedipine formulation | |
USRE33963E (en) | Solid rapidly released medicament preparations containing dihydropyridines, and processes for their preparation | |
US20020076444A1 (en) | Novel method for obtaining microspheres and resulting products | |
EP0410422B1 (en) | A highly absorbable pharmaceutical composition | |
JPH0338248B2 (en) | ||
US5266581A (en) | Solid composition containing dihydropyridine, PVP and PVPP | |
US8062664B2 (en) | Process for preparing formulations of lipid-regulating drugs | |
JPH04159222A (en) | Production of solid preparation for oral administration | |
KR880001558B1 (en) | Processes for the production of solid rapidly released medicament preparations containing dihydropyridines | |
EP0487335A1 (en) | Pharmaceutical dosage forms of dihydropyridines | |
JP5134818B2 (en) | Method for the manufacture of lipid controlled drug formulations |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FPAY | Fee payment |
Year of fee payment: 4 |
|
FEPP | Fee payment procedure |
Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
FPAY | Fee payment |
Year of fee payment: 8 |
|
FEPP | Fee payment procedure |
Free format text: PAYER NUMBER DE-ASSIGNED (ORIGINAL EVENT CODE: RMPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
FPAY | Fee payment |
Year of fee payment: 12 |
|
AS | Assignment |
Owner name: BAYER HEALTHCARE AG, GERMANY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BAYER AKTIENGESELLSCHAFT;REEL/FRAME:016182/0190 Effective date: 20050307 |
|
AS | Assignment |
Owner name: BAYER SCHERING PHARMA AKTIENGESELLSCHAFT, GERMANY Free format text: CHANGE OF NAME;ASSIGNOR:BAYER HEALTHCARE AG;REEL/FRAME:023148/0924 Effective date: 20090109 |
|
AS | Assignment |
Owner name: BAYER SCHERING PHARMA AKTIENGESELLSCHAFT, GERMANY Free format text: A CHANGE OF NAME WAS RECORDED ON AUGUST 28, 2009 AT REEL/FRAME 023148/0924. THE ADDRESS SHOULD ALSO HAVE BEEN CHANGE FROM LEVERKUSEN GERMANY 51368 TO BERLIN, GERMANY 13353;ASSIGNOR:BAYER SCHERING PHARMA AKTIENGESELLSCHAFT;REEL/FRAME:024973/0737 Effective date: 20090105 |