WO1999001129A1 - Process for preparing controlled-release dihydropyridine compositions - Google Patents

Process for preparing controlled-release dihydropyridine compositions Download PDF

Info

Publication number
WO1999001129A1
WO1999001129A1 PCT/EP1998/003982 EP9803982W WO9901129A1 WO 1999001129 A1 WO1999001129 A1 WO 1999001129A1 EP 9803982 W EP9803982 W EP 9803982W WO 9901129 A1 WO9901129 A1 WO 9901129A1
Authority
WO
WIPO (PCT)
Prior art keywords
controlled
pharmaceutical composition
release
formulation
calcium channel
Prior art date
Application number
PCT/EP1998/003982
Other languages
English (en)
French (fr)
Inventor
Giancarlo Santus
Cristina Macelloni
Romano Rivolta
Aldo Mancini
Original Assignee
Recordati S.A. Chemical And Pharmaceutical Company
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Recordati S.A. Chemical And Pharmaceutical Company filed Critical Recordati S.A. Chemical And Pharmaceutical Company
Priority to AU83396/98A priority Critical patent/AU8339698A/en
Publication of WO1999001129A1 publication Critical patent/WO1999001129A1/en

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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—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 having two or more different coatings optionally including drug-containing subcoatings with drug-free core

Definitions

  • the invention relates to a procedure for the preparation of controlled-release pharmaceutical compositions for suspension in liquids, suitable for the administration of dihydropyridine calcium channel antagonist compounds and compositions obtained by such process.
  • Nifedipine and other dihydropyridine calcium channel antagonist compounds such as, for example, amlodipine, lacidipine, nicardipine, lercanidipine, and nitrendipine, are compounds known to be extremely useful in the treatment of hypertension and coronary disease. Only a few of these dihydropyridine calcium channel antagonist compounds are available in dosage forms suitable for once-daily administration, either because they possess a sufficiently long in vivo metabolic half-life (for example amlodipine) or because of inherent pharmacodynamic characteristics (for example lercanidipine).
  • dihydropyridine calcium channel antagonist compounds such as nifedipine, nicardipine, and nimodipine
  • nifedipine has a short half-life which, when fast-release formulations are administered, can require three or more daily doses in order to maintain therapeutically effective levels of drug in a subject's bloodstream.
  • nifedipine due to their low solubility, sensitivity to light, and low bioavailability, there also exists another serious problem posed by the immediate-release, liquid or soft-gelatin-capsule formulations normally used to administer these drugs.
  • the problem can be minimized or eliminated when formulations designed to control (i.e., slow) the release of the drug are administered.
  • U.S. Patent 5,252,337 describes the preparation of microcapsules for the controlled release of nifedipine or other dihydropyridine calcium channel antagonist compounds.
  • EP 526,862 describes bioadhesive preparations for the administration of drugs comprised of a high-density material to improve the bioavailability of nifedipine and other active ingredients.
  • EP 385,582 describes nifedipine compositions having a particular particle size.
  • U.S. patent 5,108,757 describes tablets obtained from a granulate which was sprayed with a solution of nifedipine together with a wetting and release-retarding agent.
  • these formulations provide for safe (i.e., controlled-release) administration of dihydropyridine calcium channel antagonist compounds.
  • the mode and timing of administration of these formulations also create problems of compliance and dosage flexibility, which, given the predominantly elderly population which typically takes dihydropyridine calcium channel antagonist compounds for hypertension and other coronary diseases, are significant disadvantages.
  • the administration of solid dosage forms to elderly subjects or subjects who have had a stroke can involve compliance problems because these dosage forms are difficult to swallow. Swallowing problems can be significantly reduced when liquids are administered.
  • existing liquid formulations of dihydropyridine calcium channel antagonist compounds such as, for example, nifedipine drops, do not permit a controlled-release administration of the drug.
  • U.S. Patent 5,296,236 describes a formulation consisting of microgranules containing active ingredient dispersed in a solid form, such microgranules being coated with a series of film-forming materials capable of modulating the release of the active ingredient and preserving the active ingredient's stability after the microgranules have been suspended in an aqueous vehicle.
  • U.S. Patent 5,296,236 also teaches that the active ingredient of the composition must be intimately mixed and granulated together with the excipients which make up the microgranules. This method, particularly in the case of active ingredients that possess poor stability, can lead to reactions which degrade the active ingredient. Furthermore, when the active ingredients are to be administered in low-dosages, maximizing the yield of the industrial manufacturing process becomes important.
  • a solution and/or suspension of an active ingredient can be applied to an inert microgranular nucleus which has been previously screened to the required size. This avoids the need to regranulate the microgranule fractions which are outside the desired dimensional limits, thus improving production yield. Furthermore, the method is particularly beneficial in the case of low-dose and poor-chemical-stability active ingredients. This is because it is during the regranulation step required by the processes of the prior art that active ingredients are most often, and most easily, degraded.
  • nifedipine plasma levels obtained by administering a controlled-release liquid suspension prepared according to the method of preparation of the present invention are comparable with those obtained by administering the controlled-release solid preparations already available in the market.
  • the present invention provides a novel procedure for the preparation of slow-release pharmaceutical compositions suitable for the oral administration of dihydropyridine calcium channel antagonist compounds, in particular nifedipine, and the pharmaceutical composition prepared by such process.
  • This procedure entails an initial coating of a microgranule consisting solely of excipients with active ingredient dissolved or suspended in an appropriate solvent, followed by one or more successive coatings of the resulting active ingredient- coated microgranules with layers of film-forming materials capable of controlling the release rate of the active ingredient after administration to a subject.
  • the microgranules coated as described above can then be combined with common vehicles suitable for the preparation of oral liquid suspensions.
  • microgranules of the invention are suitable for preparing suspensions for reconstitution immediately before use, as well as suspensions remaining stable throughout the period after reconstitution and before administration.
  • the microgranules of the invention can be used to prepare ready-to-use suspensions which do not require reconstitution.
  • Figure 1 is a graph which shows the steady-state plasma levels of nifedipine (Cone. (ng/mL)) obtained by administering FORMULATION A (diamonds) or B (circles) either on an empty stomach (dotted lines) or after food intake (solid lines) over time
  • a controlled-release pharmaceutical composition is a composition that can either maintain constant plasma levels of active agent after administration of the composition, or which can prolong therapeutic blood levels of active agent for an extended period of time relative to conventional, fast release compositions.
  • the invention provides a process for the preparation of a controlled-release pharmaceutical composition according to the invention for the administration of dihydropyridine calcium channel antagonist compounds, which is suitable for suspension and administration in liquids.
  • the process comprises the following steps: a)granulating excipients to provide microgranules having diameters ranging from 50 to 500 mm, preferably from 125 to 315 ⁇ m, said microgranules having a substantially spherical shape; b) applying a first coating layer uniformly to the surface of said microgranules, said coating layer comprising a dihydropyridine calcium channel antagonist compound; c)applying a second coating layer over said first coating layer to form a pH insensitive barrier, said second coating layer being capable of controlling the release rate of said dihydropyridine calcium channel antagonist compound; d) applying at least two successive coating layers comprised of alternating hydrophilic and lipophilic layers over said second coating layer, said hydrophilic and lipophilic layers being capable of controlling the release rate of said dihydropyridine calcium channel antagonist compound.
  • the microgranular controlled-release pharmaceutical composition according to the invention is combined with a vehicle system, which vehicle system can be made up of: a)a dry mixture of suspending agents and sweeteners, which when combined with the microgranular controlled-release pharmaceutical composition results in a dry formulation which can be reconstituted by the patient immediately before administration; b)a dry mixture of suspending agents, sweeteners and preservatives, which when combined with the microgranular controlled-release pharmaceutical composition results in a formulation that can be reconstituted with water by the patient and stored as a liquid suspension, where the liquid suspension maintains controlled- release properties during storage.
  • vehicle system can be made up of: a)a dry mixture of suspending agents and sweeteners, which when combined with the microgranular controlled-release pharmaceutical composition results in a dry formulation which can be reconstituted by the patient immediately before administration; b)a dry mixture of suspending agents, sweeteners and preservatives, which when combined with the microgranular controlled-release pharmaceutical composition results in a formulation that can be reconstituted with water by the patient and
  • the controlled-release properties of the microgranular controlled-release pharmaceutical composition is stable in aqueous solution, and upon reconstitution can be used for immediate administration as well as subsequent administration, until such time as administration is terminated or the liquid suspension has been consumed; or c)an aqueous solution of suspending agents, sweeteners, and preservatives, where the coated controlled-release microgranules are suspended during manufacture and maintain their controlled-release properties during storage and use, i.e., for at least two years.
  • kits comprising at least a pharmaceutical composition according to the invention, preferably in form of dry formulation or in form of suspension, and optionally at least a liquid for the reconstitution of the liquid formulation before administration, said reconstitution being easy to be prepared by the patient.
  • the kit according to the invention can comprise the pharmaceutical composition in dry formulation or in form of suspension presented as multidose bottle, single-dose package, single dose bottle or ready-to-use suspension.
  • suspension is in form of single-dose packages, they are preferably paper, aluminum or polyethylene packages.
  • the present invention also relates to an effective amount of the pharmaceutical composition according to the invention for use in therapy, preferably for the treatment of cardiovascular disease.
  • the present invention further relates to the use of dihydropyridine calcium channel antagonist compound for the manufacture of a controlled-release pharmaceutical composition for the treatment of cardiovascular disease.
  • the excipients used for obtaining the microgranules to be coated with active ingredient can be chosen from those commonly used in a wet mixture, such as lactose, dibasic calcium phosphate, microcrystalline cellulose, starch, talc, sugars, polyvinylpyrrolidone, gelatin, a polyvinylpyrrolidone-vinylacetate copolymer and the like.
  • lactose dibasic calcium phosphate
  • microcrystalline cellulose starch
  • talc sugars
  • polyvinylpyrrolidone gelatin
  • a polyvinylpyrrolidone-vinylacetate copolymer and the like.
  • the addition of compounds such as polyethylene glycol (PEG), and in particular PEG 6000 can useful in the preparation of the microgranular nucleus.
  • the mixing liquid to be used for wet granulation may be water or a solvent miscible with water such as, for example, ethyl alcohol, or other alcohols used in the pharmaceutical industry or any mixture thereof with water.
  • An active ingredient such as nifedipine, or other dihydropyridine calcium channel antagonist compounds can be dissolved in a suitable solvent such as acetone or ethanol, or can be suspended in a mixture of an organic solvent and water.
  • Dihydropyridine calcium channel antagonist compounds are known in the art, and are defined herein as those compounds which comprise a dihydropyridine structural nucleus and possess the property of antagonizing, i.e., blocking, calcium ion channels when administered to mammals.
  • Such compounds include nifedipine, amlodipine, lacidipine, nicardipine, isradipine, felodipine, nimodipine, lercanidipine, and nitrendipine, and the like.
  • dihydropyridine compounds and their properties, are described, e.g., in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Ed., J.G. Hardman, L.E. Limbird, P.B. Molinoff, R.W. Ruddon, and A.G. Gilman, Eds., Chapter 32, pp. 767-772, 1996.
  • binding compounds such as hydroxypropylcellulose, hydroxypropylmethylcellulose or polyethylene glycols can be useful to layer the active ingredient on the microgranular excipient nucleus.
  • the solution and/or suspension of the active ingredient is then applied onto the microgranular excipient nucleus using a spray system in a fluid-bed apparatus such as those described in the Examples below.
  • the compounds suitable for the first film-coating layer which is applied directly on the active ingredient, is intended to form a barrier insensitive to pH changes, and can include derivatives of cellulose, acrylic or methacrylic polymers to which plasticizers can be added, such as diethyl phthalate, triethylcitrate, dibutyl sebacate, vegetable oils and the like.
  • the compounds suitable for the second coating layer can be hydrophilic derivatives of cellulose, in particular cellulose acetophthalate or hydroxypropylmethylcellulose phthalate, and acrylic and methacrylic polymers.
  • Plasticizers can optionally be added to the second, hydrophilic coating layer, such as diethyl phthalate, triethylcitrate, dibutyl sebacate, vegetable oils and the like.
  • the compounds suitable for the third coating layer, which has lipophilic characteristics include fatty compounds such as mono-, di- or triglycerides of fatty acids having a chain with 6 to 36 carbon atoms, carnauba wax, beeswax, candelilla wax, fatty alcohols and fatty acids. These can be applied either in solution using chlorinated solvents or in the melted state, which allows application without the use of solvents.
  • the compounds making up the second coating layer can also be used for the third coating layer.
  • the active-ingredient containing microgranules coated according to the above described methods can be combined with a vehicle to form a mixture of the two granulates which can be suspended in water, i.e., reconstituted, at the time of administration.
  • the vehicle can also be made up of a mixture of excipients which permit a ready-to-use suspension to be produced.
  • the constituent elements of the vehicle include: - suspending and structuring agents such as cellulose esters and ethers, microcrystalline cellulose, alginic acid derivatives, polyvinylpyrrolidone derivatives, natural gums, and the like;
  • sugars such as saccharose, sorbitol, xylitol, dextrose and the like;
  • - buffering compounds such as citric acid and sodium citrate, glycine and hydrochloric acid, sodium and potassium phosphates, and the like;
  • bacteriostats such as the esters of p-hydroxybenzoic acid, sorbic acid and its salts and the like;
  • the dosage form to be delivered ready for use also includes water or mixtures of water and co-solvents miscible with water such as glycols, alcohols and glycerin.
  • EXAMPLE 1 Preparation of basic placebo nucleus (placebo microgranules) A mixture made up of 4050 g of micronized lactose and 450 g of polyvinylpyrrolidone (PVP K 30) was mixed for 5 minutes. A 0.8 mm Glatt nozzle set for a flow rate of 20 g/minute was then fitted onto the cover of a Fielder high-speed kneader/granulator (Nitro-Fielder Mayflower, Eastleigh Hampshire, England).
  • PVP K 30 polyvinylpyrrolidone
  • EXAMPLE 2 Application of nicardipine on placebo microgranulate 1200 g of a 10% (w/w) suspension of nicardipine dispersed in a 50/50 mixture of ethanol/water was applied onto 2400 g of a placebo microgranulate prepared in accordance with Example 1. The suspension was immediately sprayed using a 7-inch Wurster insert in a Glatt GPCG-3 fluid-bed apparatus (Glatt GmbH, Binzen Lorrach, Germany).. After the application of nicardipine, the microgranulate was coated with a film of ethylcellulose followed by a film of waxy material and finally a film of cellulose acetophthalate.
  • EXAMPLE 3 Application of nifedipine on placebo microgranulate 1233 g of a solution of micronized nifedipine dissolved in 11% acetone (w/w) was applied to 2400 g of a placebo microgranulate prepared according to Example 1. The application was performed spraying the nifedipine solution by means of a 1.2-mm nozzle in a Glatt GPCG-3 fluid-bed apparatus equipped with a 7-inch Wurster film-coating insert. The working conditions included: air flow-rate 23-28 nrVhour, inlet air temperature 40-45°C, atomizing pressure 1 bar, outlet air temperature 30-37°C, product temperature 34-40°C, pump flow-rate 8-14 g/min.
  • EXAMPLE 4 Coating of nifedipine microgranulate with ethylcellulose 735 g of a solution having the following composition: ethylcellulose N22 3.0% diethyl phthalate 1.0% polyethylene glycol 400 0.1 % 95% ethanol 95.9% was sprayed onto 1500 g of a microgranulate coated with nifedipine according to Examples 1 and 3.
  • the film-coating was performed using a GPCG-3 fluid-bed apparatus with a 6-inch Wurster insert, into which air heated to a temperature of 55°C was blown at a pressure of 2 bars and a flow-rate of 11 g/minute using a nozzle.
  • EXAMPLE 5 Coating with cellulose acetophthalate (hydrophilic coating) A hydrophilic coating of cellulose acetophthalate was applied onto 1250 g of film-coated granulate according to Example 4, using the same type of equipment and procedure. 300 ml of a solution having the following per-cent composition: cellulose acetophthalate 4.0 diethyl phthalate 1.0 isopropyl alcohol 23.7 acetone 71.3 was sprayed at a pressure of 2 bars and a flow rate of 8 to 10 g/min.
  • EXAMPLE 6 Coating with a waxy mixture (lipophilic coating)
  • the waxes were first melted in an oil bath at a temperature of 120°C and then applied maintaining the temperature at about 80°C with compressed air (pre-heated to 135°C) at a pressure of 3 bars by means of a coaxial nozzle which permitted mixing of melted waxes and compressed air.
  • a Glatt GPCG-3 apparatus with a 6-inch Wurster insert was used for this operation.
  • the sprayed waxes were equivalent to 3.8% by weight of the microgranulate after application of nifedipine. A spraying rate of 2.5 g/minute was used.
  • EXAMPLE 7 Final coating
  • 0.706 g of a slow-release microgranulate prepared according to Examples 3, 4, 5 and 7 was transferred into a compartment under the cap of a single-dose bottle (Bormioli) and was kept separate from the liquid contained in the bottle.
  • the composition of the single-dose liquid included 70% sorbitol 3500 mg, pineapple-lemon flavour 15 mg, citric acid 15 mg, sodium benzoate 10 mg, purified water q.s. to 8 ml. Before use, the contents of the cap compartment were put in contact with the liquid in the bottle by pressing on the cap compartment.
  • Each bottle contained 30 mg of nifedipine as a single-dose suspension.
  • a slow-release granulate prepared according to Examples 3, 4, 5 and 7, was dispersed in a suspension vehicle having the following composition: 70% sorbitol 67.50 g, glycerine 11.80 g, mannitol 4.00 g, citric acid 0.01 g, potassium sorbate 0.15 g, sodium lauryl sulphate 0.1 g, avicel CL 611 1.00 g, xanthan gum 0.12 g, titanium dioxide 0.50 g, 10% simethicone 0.10 g, orange flavour 0.15 g, water 26.68 g.
  • the suspension was prepared by dissolving mannitol in half a liter of water and then dispersing avicel CL 611 , glycerine, xanthan gum and half of the sorbitol in the solution.
  • Citric acid, potassium sorbate, sodium lauryl sulfate and simethicone were dissolved separately and titanium dioxide was dispersed in the solution.
  • the two suspensions were combined and the slow-release granulate and the remaining sorbitol were added to the combined suspensions. After mixing the orange flavor was added.
  • EXAMPLE 9 in vitro dissolution
  • the release properties of the microgranules coated with nifedipine and prepared according to Examples 1 , 3, 4, 5, 6 and 7 are shown below. Determinations were made using the "Paddle" apparatus II described by the U.S. Pharmacopoeia XXIII at page 1792, operating with 900 ml of water, at 50 revolutions per minute, at 37°C and in a pH gradient, to which 2% of TexaponTM N40 was added. The amount of active ingredient was determined by HPLC collecting 5 ml of the solution at pre-established times. The dissolution data are shown in Table 1. TABLE 1
  • bioavailability and pharmacokinetic profile of an exemplary formulation of the present invention were determined in "in vivo" single-dose and repeated-dose clinical studies, also evaluating the effect of food intake on changes in these parameters.
  • the reference compound was a controlled-release tablet which acted via an osmotic system (Procardia XL R 30 mg, also known as ADALAT-CRONO R ) (FORMULATION
  • C max (peak concentration) is the highest concentration reached by the drug in plasma after dosing
  • T max (peak time) is the time required to reach the level of C max ;
  • AUC M (area under the curve) is the total area under the time-concentration curve and represents a measure of the bioavailability of the drug
  • the graph shows that the controlled-release liquid-suspension formulation provides a constant pharmacokinetic profile which prevents the side effects associated with immediate-release formulations.
  • the formulation of the present invention can, therefore, be considered equivalent, with respect to pharmacological performance, to the best controlled-release solid formulations currently available (Procardia XL - FORMULATION B).
  • the formulation of the present invention ALSO possesses the benefits which are peculiar to liquid formulations, for example ease of swallowing and dosage flexibility, due to the ability to administer any desired volume of liquid suspension, as opposed to the relatively fixed dose in a solid dosage form.

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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
PCT/EP1998/003982 1997-07-01 1998-07-01 Process for preparing controlled-release dihydropyridine compositions WO1999001129A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU83396/98A AU8339698A (en) 1997-07-01 1998-07-01 Process for preparing controlled-release dihydropyridine compositions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI97A001547 1997-07-01
IT97MI001547A IT1292440B1 (it) 1997-07-01 1997-07-01 Procedimento per preparare una composizione farmaceutica a rilascio controllato di diidropiridine per sospensione in liquidi

Publications (1)

Publication Number Publication Date
WO1999001129A1 true WO1999001129A1 (en) 1999-01-14

Family

ID=11377467

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/003982 WO1999001129A1 (en) 1997-07-01 1998-07-01 Process for preparing controlled-release dihydropyridine compositions

Country Status (3)

Country Link
AU (1) AU8339698A (enrdf_load_stackoverflow)
IT (1) IT1292440B1 (enrdf_load_stackoverflow)
WO (1) WO1999001129A1 (enrdf_load_stackoverflow)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100315872B1 (ko) * 1999-03-08 2001-12-22 류덕희 디히드로피리딘 유도체를 포함하는 지속성 제제의 제조방법
US7510729B2 (en) 2002-03-14 2009-03-31 Basf Aktiengesellschaft Combination of polyvinyl acetate with water-insoluble, acid-insoluble, or alkali-insoluble polymers used for the production of film coatings with highly controlled release and high stability
US8728508B2 (en) 2002-12-20 2014-05-20 Coloplast A/S Hydrophilic coating and a method for the preparation thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4758437A (en) * 1981-12-23 1988-07-19 Yamanouchi Pharmaceutical Co., Ltd. Composition for long acting nicardipine preparation and process of producing the composition
WO1994005262A1 (en) * 1992-09-10 1994-03-17 F.H. Faulding & Co. Limited Sustained release matrix composition
US5296236A (en) * 1988-09-16 1994-03-22 Recordati S.A., Chemical And Pharmaceutical Company Controlled release therapeutic system for a liquid pharmaceutical formulations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4758437A (en) * 1981-12-23 1988-07-19 Yamanouchi Pharmaceutical Co., Ltd. Composition for long acting nicardipine preparation and process of producing the composition
US5296236A (en) * 1988-09-16 1994-03-22 Recordati S.A., Chemical And Pharmaceutical Company Controlled release therapeutic system for a liquid pharmaceutical formulations
WO1994005262A1 (en) * 1992-09-10 1994-03-17 F.H. Faulding & Co. Limited Sustained release matrix composition

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100315872B1 (ko) * 1999-03-08 2001-12-22 류덕희 디히드로피리딘 유도체를 포함하는 지속성 제제의 제조방법
US7510729B2 (en) 2002-03-14 2009-03-31 Basf Aktiengesellschaft Combination of polyvinyl acetate with water-insoluble, acid-insoluble, or alkali-insoluble polymers used for the production of film coatings with highly controlled release and high stability
US8728508B2 (en) 2002-12-20 2014-05-20 Coloplast A/S Hydrophilic coating and a method for the preparation thereof

Also Published As

Publication number Publication date
AU8339698A (en) 1999-01-25
ITMI971547A1 (it) 1999-01-01
IT1292440B1 (it) 1999-02-08
ITMI971547A0 (enrdf_load_stackoverflow) 1997-07-01

Similar Documents

Publication Publication Date Title
US5296236A (en) Controlled release therapeutic system for a liquid pharmaceutical formulations
US5674533A (en) Pharmaceutical composition for the controlled release of moguisteine in a liquid suspension
US5695784A (en) Flavor-masked pharmaceutical compositions
US5215755A (en) Rotogranulations and taste masking coatings for preparation of chewable pharmaceutical tablets
US6214386B1 (en) Prompt-release oral pharmaceutical compositions for extemporaneous suspensions
RU2328274C2 (ru) Препарат ламотриджин с контролируемым высвобождением
HU214590B (hu) Eljárás ellenőrzött hatóanyag-felszabadítású gyógyszerkészítmények előállítására
ES2189232T5 (es) Microgránulos de omeprazol protegidos gástricamente, procedimiento de obtención y preparaciones farmacéuticas
JPH0122245B2 (enrdf_load_stackoverflow)
PT88945B (pt) Processo para a preparacao de formas de dosagem farmaceuticas de libertacao controlada contendo um antagonista do calcio, tal como cloridrato de diltiazem
HU205712B (en) Process for producing pharmaceutical compositions with controlled release of active ingredient
US5320855A (en) Rotogranulations and taste masking coatings for preparation of chewable pharmaceutical tablets
JP2001172201A (ja) 経口投与形のための味をマスキングするコーティングとしてのフィルム被覆の使用、経口投与形及びその製造法
HUP0202338A2 (en) Pharmaceutical composition containing fenofibrate and preparation method
CN105007898A (zh) 难溶性药物的过饱和的稳定纳米颗粒
TW201204415A (en) Method for preparing pharmaceutical compositions intended for oral administration comprising one or more active ingredients and the compositions comprising same
JP2881442B2 (ja) ジルチアゼムの遅放出性無酸医薬製剤及びその製法
NZ232030A (en) Sustained release pharmaceutical pellet composition; theophylline compound core, coated to allow faster release rate in intestine
EP0216743B1 (fr) Nouvelles formes galéniques du vérapamil, leur fabrication et médicaments contenant ces nouvelles formes galéniques
HUT50632A (en) Process for producing pharmaceutical compositions with retarded active ingredient release, comprising dihydro-pyridine as active ingredient
WO1994005262A1 (en) Sustained release matrix composition
EP0862421B1 (en) Prompt-release pharmaceutical compositions
ES2852899T3 (es) Formulaciones estabilizadas de molindona
JP3221891B2 (ja) 咀嚼可能な製薬錠剤調製のための回転造粒及び味覚遮蔽被覆加工
KR0133531B1 (ko) 액체 약제 제형용 서방성 치료 시스템

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HR HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: KR

NENP Non-entry into the national phase

Ref country code: CA

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase