WO1994005262A1 - Composition sous forme de matrice a liberation prolongee - Google Patents

Composition sous forme de matrice a liberation prolongee Download PDF

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Publication number
WO1994005262A1
WO1994005262A1 PCT/AU1993/000462 AU9300462W WO9405262A1 WO 1994005262 A1 WO1994005262 A1 WO 1994005262A1 AU 9300462 W AU9300462 W AU 9300462W WO 9405262 A1 WO9405262 A1 WO 9405262A1
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WO
WIPO (PCT)
Prior art keywords
core element
approximately
core
weight
total weight
Prior art date
Application number
PCT/AU1993/000462
Other languages
English (en)
Inventor
Angelo Mario Morella
Eugene Anthony Quinn
David John Willoughby
Original Assignee
F.H. Faulding & Co. Limited
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 F.H. Faulding & Co. Limited filed Critical F.H. Faulding & Co. Limited
Priority to AU48094/93A priority Critical patent/AU4809493A/en
Publication of WO1994005262A1 publication Critical patent/WO1994005262A1/fr

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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
    • A61K9/48—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
    • 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

Definitions

  • the present invention relates to sustained release pharmaceutical microparticle compositions in particular sustained release pharmaceutical microparticle compositions including an active ingredient of very low solubility in water, and to a method of preparing same.
  • active ingredients of very low solubility include the dihydropyridine compounds which are used as cardiovascular agents. Difficulties often occur in the pharmaceutical formulation of these potent active compounds due to their very low solubility, which can result in erratic and/or poor absorption of the drug from pharmaceutical dosage forms.
  • One such technique of enhancing drug absorption is to formulate a solid dispersion or co-precipitate system. This technique is well known and is extensively discussed in the article "Pharmaceutical Applications of Solid Dispersion Systems" by Win Loung Chiou and Sidney Riegelman. J. of Pharm. Sci. Vol. 60, No. 9, September
  • Solid Dispersion or Co-Precipitate refers to the dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by the melting (fusion), solvent, or melting-solvent method and is hereinafter simply referred to as a "matrix" .
  • Solid dispersions may also be called solid-state dispersions.
  • a sustained release matrix pharmaceutical microparticle composition including a core element including an active ingredient of very low solubility; and at least two polymers in a matrix therewith; and optionally an enteric coating over the core element.
  • matrix as used herein we mean that the active ingredient is in a solid dispersion or co-precipiate with a polymer.
  • microparticle composition as used herein we mean pellets or granules. Preferably the microparticle composition is in the form of pellets.
  • sustained release as used herein we mean at least a two fold reduction in dosing frequency as compared to drug presented as a conventional dosage form (e.g. as a solution or a prompt drug-releasing, conventional dosage form).
  • a conventional dosage form e.g. as a solution or a prompt drug-releasing, conventional dosage form.
  • active ingredient of very low solubility as used herein we mean pharmaceutically active, orally acceptable ingredients having an aqueous solubility of
  • bioavailability as used herein we mean the extent to which the active drug ingredient is absorbed from the microparticle composition and which reaches the general circulation intact.
  • the active ingredient of very low solubility may be selected from the group consisting of dihydropyridines for example Nifedipine, Nitrendipine, Nisoldipine, Nimodipine, Nicardipine, Darodipine, Isradipine, Niludipine, Amlodipine, Felodipine, Lacidipine, BBR-2160, Cronidipine, Diperdine, Mepirodipine, Nilvadipine, Oxodipine, Sangandipine, Clinidipine, Manidipine, Benidipine, pharmaceutically acceptable isomers and salts thereof and mixtures thereof.
  • the active ingredient in the final composition is preferably in crystalline form.
  • the active ingredient may be present in the core element in any suitable effective amount.
  • the amount of active ingredient is dependent on the potency of the active ingredient and on the desired dosage strength and volume of a unit dose of the drug product.
  • the active ingredient may be present in amounts of approximately 0.1 to 99%, preferably 1 to 95% by weight, based on the total weight of the core element.
  • the active ingredient may preferably be a dihydropyridine compound, more preferably nifedipine.
  • the compound nifedipine may be present in amounts of approximately 5 to 70% by weight, preferably 15 to 50% by weight, based on the total weight of the core element.
  • Nifedipine is a cardiovascular drug and is a potent relaxant of arterial smooth muscle. It dilates both the main coronary arteries and arterials both in normal and in ischaemic myocardioregions. Nifedipine is also a potent inhibitor of coronary artery spasm. Nifedipine is thus indicated in the long-term management of angina pectoris due to coronary heart disease. The usual dose is one 10 mg capsule three times daily but up to two capsules four times daily may be taken.
  • the benefits of a sustained release microparticle composition including nifedipine are thus obvious.
  • the polymeric component of the sustained release matrix pharmaceutical composition may include, in addition to the active ingredient, a polymer which is at least partially water-soluble (water-soluble polymer); and a polymer which is substantially insoluble at acidic pH but at least partially soluble at a less acidic to basic pH (enteric polymer) .
  • the water-soluble polymer may be selected from the group consisting of polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol and mixtures thereof.
  • Polyethylene glycols or Macrogols of intermediate molecular weights (4000-12000) have been found to be suitable.
  • the polyethylene glycol sold under the trade designation PEG 6000 has been found to be suitable.
  • the water-soluble polymer may be present in the core element in amounts of from approximately 10 to 80%, preferably 15 to 60% by weight, based on the total weight of the core element.
  • the enteric polymer when present, may be selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methyl- cellulose phthalate (HPMCP) , polyvinyl acetate phthalate, methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, shellac, cellulose acetate trimellitate and mixtures thereof.
  • Particularly preferred enteric polymers include synthetic or semi-synthetic resins bearing carboxyl groups.
  • HP50 or HP55 have been found to be suitable.
  • the enteric polymer may be present in the core element in an amount of from 0 to approximately 50% by weight, preferably 0.1 to 20% by weight, more preferably 0.5 to 10% by weight, based on the total weight of the core element.
  • a sustained release pharmaceutical microparticle composition including a core element including approximately 1 to approximately 95% by weight based on the total weight of the core element of a pharmaceutically active ingredient of very low solubility; and approximately 5 to approximately 99% by weight of a polymeric component in a matrix therewith including a water-soluble polymer; and an enteric polymer; and optionally an enteric coating over the core element.
  • the core element may further include other compounding ingredients including plasticisers and fillers. Accordingly, in a preferred aspect, the core element may further include
  • a plasticiser selected from the group consisting of diethyl phthalate, triethyl citrate, triethyl acetyl citrate, triacetin, tributyl citrate, glycerol or mixtures thereof; optionally
  • a filler selected from the group consisting of insoluble materials such as silicon dioxide, titanium dioxide, talc, alumina, starch, kaolin, polacrilin potassium, powdered cellulose, and microcrystalline cellulose and mixtures thereof; and optionally 0 to approximately 50% by weight, preferably 5 to
  • a water-insoluble polymer selected from any suitable pharmaceutically acceptable polymer substantially insoluble independent of pH.
  • the polymer may be selected from the group consisting of ethylcellulose, acrylic and/or methacrylic ester polymers or mixtures thereof and the like may be used. Polymers or copolymers of acrylates or methacrylates having a low quaternary ammonium content may be used.
  • the acrylic acid ethyl ester: methacrylic acid ester (1:1) copolymer has been found to be suitable.
  • the core element may further include 0 to approximately 20% by weight, preferably 1 to 10% by weight of at least one surfactant selected from docusate sodium lecithin, polyoxethylene, sorbitan fatty acids (e.g. tweens) and sorbitan esters (e.g. spans).
  • the surfactant sold under the trade designation Cremaphore RH410 has been found to be suitable.
  • the core element of the pharmaceutical microparticle composition according to the present invention may include a core seed.
  • the size and amount of the core seed may vary substantially from approximately lOO ⁇ m to 1700 ⁇ m depending upon the amount of active ingredient to be included. Accordingly, the core seeds may vary from approximately 5 to 99% by weight, preferably 10 to 70% by weight based on the total weight of the core element, depending on the potency • of the active ingredient.
  • the core seed may be of such a diameter to provide a final core element having a diameter of approximately 200 to 2000 ⁇ m.
  • the core seed may be of any suitable type.
  • a sugar sphere or an active core seed may be used.
  • the core element may further include other carriers or excipients, stabilizing agents and colorants.
  • the enteric coating may be formed from an enteric polymer as described above.
  • a hydroxypropyl methyl cellulose phthalate coating such as that sold under the trade designation HP50 or HP55 has been found to be suitable.
  • the enteric coating may further include a plasticiser.
  • the enteric coating may include approximately 40 to 100% by weight, preferably 70 to 95% by weight, based on the total weight of the enteric coating, of at least one enteric polymer,
  • the enteric coating may comprise from approximately 2 to 20% by weight, preferably approximately 4 to 10% by weight, of the pharmaceutical microcapsule composition.
  • the pharmaceutical microparticle composition may have the following formulation
  • Percentage ranges for the components of the pharmaceutical microparticle composition (percentages W/W) :
  • the core element may comprise a single or a plurality of core layers.
  • the core element comprises a single layer.
  • a sustained release matrix pharmaceutical microparticle composition including a core element comprising a single layer including approximately 1 to approximately 95% by weight based on the core element of a pharmaceutically active ingredient of very low solubility; and approximately 5 to approximately 99% by weight of a polymeric component in a matrix therewith including at least one water-soluble polymer; and at least one enteric polymer; and optionally an enteric coating over the core element.
  • the pharmaceutical microparticle composition may have the following formulation:
  • Percentage ranges for the components of the pharmaceutical microparticle composition (percentages W/W) :
  • Nifedipine (5-70) (10-40) PEG 6000 (10-80) (15-60) Sugar spheres (10-80) (15-60) HP 50 (0.1-50) (0.5-20) Diethylphthalate (0-10) (0-1)
  • the core element comprises a plurality of core layers.
  • a sustained release pharmaceutical microparticle composition including a core element including a plurality of core layers, wherein the core element includes approximately 1 to approximately 95% by weight based on the total weight of the core element of a pharmaceutically active ingredient of very low solublity; and approximately 5 to approximately 99% by weight based on the total weight of the core element of a polymeric component in a matrix therewith, wherein at least one core layer includes a water-soluble polymer: and an enteric polymer in a matrix therewith; and optionally an enteric coating over the core element.
  • the outer core layer of the core element comprises the two polymers in matrix therewith.
  • the pharmaceutically active ingredient may be present in the outer core layer in any suitable effective amount.
  • the amount of active ingredient is dependent on the potency of the active ingredient and on the desired dosage strength and volume of a unit dose of the drug product.
  • the active ingredient may be present in amounts of approximately 0.1 to 95% by weight, based on the total weight of the outer core layer.
  • the active ingredient may preferably be a dihydropyridine compound.
  • the compound may be present in amounts of approximately 5 to 70% by weight, preferably 10 to 60% by weight, based on the total weight of the outer core layer.
  • the water-soluble polymer may be selected from the list of polymers as previously described.
  • the polyethylene glycol sold under the trade designation PEG 6000 has been found to be suitable.
  • the water-soluble polymer may be present in the outer core layer in amounts of from approximately 10 to 80%, preferably 15 to 60% by weight, more preferably 30 to 50% by weight, based on the total weight of the outer core layer.
  • the enteric polymer may be selected from the list of polymers previously described.
  • the hydroxypropyl methyl cellulose phthalates sold under the trade designation HP50 or HP55 have been found to be suitable.
  • the enteric polymer may be present in the outer core layer in an amount of up to approximately 50% by weight, preferably 1 to 20% by weight, more preferably 2 to 15% by weight, based on the total weight of the outer core layer.
  • a sustained release matrix pharmaceutical microparticle composition including a core element including approximately 1 to 95% by weight based on the total weight of the core element of a dihydropyridine compound; a core seed; approximately 20 to 90% by weight based on the total weight of the inner core layer of a water-soluble polymer in a matrix therewith; and approximately 30 to 80% by weight based on the total weight of the outer core layer, of a water-soluble polymer; and approximately 2 to 20% by weight based on the total weight of the outer core layer, of an enteric polymer in a matrix therewith, and optionally an enteric coating over the core element.
  • the pharmaceutical microparticle composition may include a plurality of core layers.
  • the composition of the core layers may differ in the concentration or nature of the active ingredients therein. For example use of active ingredients of differing crystal size in adjacent layers is preferred. This may extend the period of sustained release even further.
  • the inner layer and outer core layer of the core element may be present in any suitable amounts in the pharmaceutical microparticle composition.
  • the inner core layer (including sugar seeds where present) may comprise from approximately 40 to 95% by weight, preferably 50 to 85% by weight, of the pharmaceutical microparticle composition.
  • the outer core layer may comprise from approximately 5 to 60% by weight, preferably 15 to 50% by weight, of the pharmaceutical microparticle composition. Accordingly, the pharmaceutical matrix microcapsule composition may have the following formula:
  • the components of the core element other than the core seed when present, may be provided in the form of a solution, dispersion or suspension.
  • the solvent or solvents may be present in amounts of from approximately 25 to 97% by weight, preferably 85 to 97% by weight, based on the total weight of the core formulation.
  • the solvent for the core formulation may be a solvent such as methanol, ethanol, methylene chloride, acetone, isopropanol and mixtures thereof. Methanol, methylene chloride or a mixture thereof is preferred.
  • a method for preparing a sustained release pharmaceutical microparticle composition providing a core seed; a core formulation including an active ingredient of very low solubility; at least two polymers capable of forming a matrix with the active ingredient; and a solvent therefor; introducing the core seed into a fluidised bed coater, a centrifugal granulator or spheronizer; and spraying the core formulation onto the core seed to form a matrix core element; and drying the core element.
  • the core seed may include a sugar sphere.
  • the active ingredient may be a dihydropyridine compound, preferably nifedipine.
  • the method may further include providing a core layer formulation including at least one active ingredient of very low solubility; at least two polymers including a water-soluble polymer; and optionally an enteric polymer; and a solvent therefor; introducing the core seed into a fluidised bed coater, a centrifugal granulator or spheronizer; and spraying successive layers onto the core seed to form the matrix core element wherein at least one layer includes the core layer formulation.
  • the method may further include providing a sustained release pharmaceutical microparticle; and an enteric coating formulation including an enteric polymer; optionally a plasticiser; and a solvent therefor introducing the microparticle into a fluidised bed coater, a centrifugal granulator or spheronizer; and spraying the enteric coating formulation onto the microparticle to form a sustained release microcapsule.
  • an enteric coating formulation including an enteric polymer; optionally a plasticiser; and a solvent therefor introducing the microparticle into a fluidised bed coater, a centrifugal granulator or spheronizer; and spraying the enteric coating formulation onto the microparticle to form a sustained release microcapsule.
  • the sustained release core element and sustained release microcapsules may be subjected to a drying step.
  • the drying step may be conducted in a fluidised bed or drying oven.
  • Spray coating of core elements may be undertaken utilizing bottom or Wurster, top or tangentially located spray nozzles.
  • a bottom spray nozzle may reside proximate to the base of the fluidised bed facing upwards while a top spraying nozzle is located above the contents of the bed and facing downwards.
  • the spray nozzle may reside in the mid-section of the fluidised bed and be oriented such as to spray tangentially to the rotating core elements.
  • the sustained release matrix pharmaceutical microparticle composition according to the present invention may include a plurality of microparticles.
  • the sustained release pharmaceutical composition may be provided in any suitable unit dosage form.
  • An encapsulated form may be used.
  • the pharmaceutical microparticle composition may be provided in a pellet or tabletted pellet form.
  • a tablet may be formed by compression of the pellets optionally with the addition of suitable excipients.
  • the sustained release pharmaceutical microparticle composition may be in multi-pellet encapsulated, sprinkle, sachet or tabletted forms.
  • the sustained release pharmaceutical microparticle composition may be administered under a similar dosage regimen to that used in the prior art. However, it is preferred that the pellet composition be administered less frequently.
  • the multi-pellet encapsulated form may for example be administered once every 12 hours, preferably once every 24 hours.
  • the sustained release pharmaceutical pellet composition incorporating the dihydropyridine compound may provide effective vasodilation with once daily administration.
  • Versatility of dosing may be achieved with 20 to 90 mg or any other dose strength of capsules required.
  • a method of treating cardiovascular related conditions in patients requiring such treatment which method includes administering to a patient an effective amount of a sustained release pharmaceutical microparticle composition including a core element including a dihydropyridine; and at least two polymers in a matrix therewith; and optionally an enteric coating over the core element.
  • the method of treatment according to this aspect of the present invention is particularly applicable to the treatment of Hypertension and/or Angina pectoris due to coronary heart disease, particularly Angina pectoris related to coronary artery spasm, utilising for example nifedipine.
  • the sustained release pharmaceutical microparticle composition is provided in a unit dosage form and administration occurs at intervals of approximately 12 to 24 hours.
  • Finished cores are between 600 - 850 ⁇ m with potency of 14%, yield 1000 g.
  • Finished cores are between 600 - 850 ⁇ m with potency of 14%, yield 933 g.
  • Examples 1 to 3 illustrate how the ratio of polymers may be varied to the desired release profile.
  • Finished cores are between 600 - 850 ⁇ m with potency of 24%, yield 420 g.
  • Example 4 uses a different enteric polymer to Examples 1 to 3.
  • Finished cores are between 500 - 710 ⁇ m with potency of
  • Finished cores are between 710 - 1000 ⁇ m with potency of 22% and yield of 460 g.
  • the cores produced from Example 6 was enteric coated using the following process.
  • Each formulation included 60 mg equivalent to nifedipine and was dissolved in 900 mL at pH of 6.8 with surfactant and an orthophosphate buffer.
  • the apparatus used is baskets. Sampling is carried out using a 0.45 ⁇ m filter and samples were determined using a UV spectrophotometer at a wavelength of 340 nm. The results are provided in Figures 1 to 7.
  • Comparison A is not in accordance with the invention and comprises an uncoated core where micronised nifedipine is layered onto sugar spheres.
  • the formulation comprises
  • Comparison B is the existing commercially available sustained release product Procardia XL, 60 mg extended release tablets by Pfizer.

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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compositions à microparticules à libération prolongée, comprenant un noyau contenant un principe actif de très faible solubilité et au moins deux polymères. Le noyau est éventuellement enrobé d'une pellicule entérique et comprend des dihydropyridines, en particulier la nifédipine, comme principe actif. On prépare ces compositions en pulvérisant une granule centrale avec la formulation du noyau dans un dispositif d'enrobage à lit fluidisé, un granulateur centrifuge ou un sphéronisateur, et en faisant sécher la composition. Ces compositions conviennent au traitement d'états cardiovasculaires.
PCT/AU1993/000462 1992-09-10 1993-09-09 Composition sous forme de matrice a liberation prolongee WO1994005262A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU48094/93A AU4809493A (en) 1992-09-10 1993-09-09 Sustained release matrix composition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPL460292 1992-09-10
AUPL4602 1992-09-10

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WO1994005262A1 true WO1994005262A1 (fr) 1994-03-17

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Cited By (19)

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WO1999001129A1 (fr) * 1997-07-01 1999-01-14 Recordati S.A. Chemical And Pharmaceutical Company Procede permettant de preparer des compositions de dihydropyridine a liberation controlee
US5958459A (en) * 1991-12-24 1999-09-28 Purdue Pharma L.P. Opioid formulations having extended controlled released
US5968551A (en) * 1991-12-24 1999-10-19 Purdue Pharma L.P. Orally administrable opioid formulations having extended duration of effect
US6110494A (en) * 1997-01-03 2000-08-29 Elan Corporation, Plc Cisapride mini-tablet formulations
US6399096B1 (en) 1995-09-22 2002-06-04 Euro-Celtique S.A. Pharmaceutical formulation
WO2010053337A2 (fr) * 2008-11-10 2010-05-14 (주)아모레퍼시픽 Particule a liberation lente et procede de production associe
US8142811B2 (en) 2000-10-30 2012-03-27 Purdue Pharma L.P. Controlled release hydrocodone formulations
US8268791B2 (en) 2004-08-25 2012-09-18 Aegis Therapeutics, Llc. Alkylglycoside compositions for drug administration
US8440631B2 (en) 2008-12-22 2013-05-14 Aegis Therapeutics, Llc Compositions for drug administration
US8551468B2 (en) 2004-08-25 2013-10-08 Aegis Therapeutics Llc Absorption enhancers for intranasal interferon administration
US8895546B2 (en) 2009-03-27 2014-11-25 Hale Biopharma Ventures, Llc Administration of benzodiazepine compositions
US8975273B2 (en) 1999-10-29 2015-03-10 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9655894B2 (en) 2001-05-02 2017-05-23 Purdue Pharma L.P. Once-A day oxycodone formulations
US9895444B2 (en) 2004-08-25 2018-02-20 Aegis Therapeutics, Llc Compositions for drug administration
US10046025B2 (en) 2006-06-23 2018-08-14 Aegis Therapeutics, Llc Stabilizing alkylglycoside compositions and methods thereof
US10179130B2 (en) 1999-10-29 2019-01-15 Purdue Pharma L.P. Controlled release hydrocodone formulations
US10265402B2 (en) 2004-08-25 2019-04-23 Aegis Therapeutics, Llc Absorption enhancers for drug administration
US10682414B2 (en) 2018-02-06 2020-06-16 Aegis Therapeutics, Llc Intranasal epinephrine formulations and methods for the treatment of disease
US11241414B2 (en) 2008-03-28 2022-02-08 Neurelis, Inc. Administration of benzodiazepine compositions

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JPS6248618A (ja) * 1985-08-27 1987-03-03 Zeria Shinyaku Kogyo Kk 徐放性製剤およびその製造法
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AU6820787A (en) * 1987-01-09 1988-07-14 Elan Corporation, Plc Sustained release capsule or tablet formulation
WO1989002738A1 (fr) * 1987-09-22 1989-04-06 Aps Research Limited Preparation de nifedipine a liberation soutenue
EP0387782A2 (fr) * 1989-03-14 1990-09-19 Egis Gyogyszergyar Préparations pharmaceutiques solides et leurs procédés de fabrication
JPH03169814A (ja) * 1989-11-29 1991-07-23 Nippon Yakuhin Kogyo Kk ニフェジピン持続性製剤の製造法
DD295550A5 (de) * 1987-11-26 1991-11-07 Univ Halle Wittenberg Verfahren zur herstellung einer nifedipin-arzneiform mit gleichmaessig verzoegerter wirkstofffreisetzung
WO1993013773A1 (fr) * 1992-01-13 1993-07-22 Ethical Pharmaceuticals Limited Compositions pharmaceutiques contenant de la nifedipine et leurs procedes de preparation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1579818A (en) * 1977-06-07 1980-11-26 Yamanouchi Pharma Co Ltd Nifedipine-containing solid preparation composition
US4740365A (en) * 1984-04-09 1988-04-26 Toyo Boseki Kabushiki Kaisha Sustained-release preparation applicable to mucous membrane in oral cavity
JPS6117510A (ja) * 1984-07-03 1986-01-25 Toyobo Co Ltd 口腔粘膜適用徐放性ニフエジピン製剤
AU4959485A (en) * 1984-09-14 1986-04-08 Pharmatec S.P.A. Controlled release nifedipine preparation
AU5828486A (en) * 1985-06-11 1986-12-18 Euro-Celtique S.A. Oral pharmaceutical composition
JPS6248618A (ja) * 1985-08-27 1987-03-03 Zeria Shinyaku Kogyo Kk 徐放性製剤およびその製造法
EP0220760A2 (fr) * 1985-10-15 1987-05-06 EURAND ITALIA S.p.A. Procédé de préparation de formulations de nifédipine sous forme solide à effet retardé et leurs formulations ainsi obtenues
AU6820787A (en) * 1987-01-09 1988-07-14 Elan Corporation, Plc Sustained release capsule or tablet formulation
WO1989002738A1 (fr) * 1987-09-22 1989-04-06 Aps Research Limited Preparation de nifedipine a liberation soutenue
DD295550A5 (de) * 1987-11-26 1991-11-07 Univ Halle Wittenberg Verfahren zur herstellung einer nifedipin-arzneiform mit gleichmaessig verzoegerter wirkstofffreisetzung
EP0387782A2 (fr) * 1989-03-14 1990-09-19 Egis Gyogyszergyar Préparations pharmaceutiques solides et leurs procédés de fabrication
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