WO1989002738A1 - Sustained-release nifedipine formulation - Google Patents

Sustained-release nifedipine formulation Download PDF

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Publication number
WO1989002738A1
WO1989002738A1 PCT/GB1988/000779 GB8800779W WO8902738A1 WO 1989002738 A1 WO1989002738 A1 WO 1989002738A1 GB 8800779 W GB8800779 W GB 8800779W WO 8902738 A1 WO8902738 A1 WO 8902738A1
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WO
Grant status
Application
Patent type
Prior art keywords
parts
formulation
coating
nifedipine
core
Prior art date
Application number
PCT/GB1988/000779
Other languages
French (fr)
Inventor
Brian William Barry
Bryan Arthur Mulley
Peter York
Original Assignee
Aps Research 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

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5036Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5026Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Abstract

A sustained-release nifedipine (4-(2'-nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine) formulation comprising sufficient granules to provide a predetermined dose or number of doses of nifedipine, each of said granules having a diameter of between 0.5 and 2.5 mm and comprising: (a) a core comprising 100 parts of nifedipine and from 50 to 800 parts of hydroxypropylmethyl cellulose; and (b) a coating covering substantially the whole surface of the core and comprising 100 parts of a water insoluble but water swellable acrylic polymer and from 20 to 70 parts of a water soluble hydroxylated cellulose derivative, the weight of the coating being from 2 to 25 % of the weight of the core. A method for preparing the formulation is also provided.

Description

SUSTAINED-RELEASE NIFEDIPINE FORMULATION

This invention relates to a sustained-release formulation containing nifedipine and, most preferably, to such a formulation which will provide sustained- release of the nifedipine over a period of about twelve hours. A method for preparing the sustained-release formulation is also provided.

Some medical conditions are best treated by administration of a pharmaceutical which is formulated to allow the active substance or ingredient to act as quickly as possible. Such a formulation may comprise an injectable solution or a readily dissolvable tablet or capsule. This type of formulation is useful, for instance, for treating acute pain, such as headaches, or pain associated with sudden trauma, such as an accident.

Other medical conditions are best treated by administration of a pharmaceutical in such a way as to sustain its action over an extended period of time. This type of administration is useful, for example, for treating chronic pain, such as that associated with rheumatic or arthritic conditions,or for the treatment of a chronic cardiovascular condition. It can be achieved by repeated administration of an immediate-release tablet or capsule at frequent intervals, for instance every four hours. However, this is generally inconvenient, especially during the night, when it is often necessary to awaken a patient to administer the tablet or capsule.

It has previously been proposed to produce a formulation which will release the active substance therein at a controlled rate such that the amount available in the body to treat the condition is maintained at a relatively constant level over an extended period of time. A particularly suitable period is twelve hours, since such a formulation need only be taken twice a day to maintain an effective treatment of the condition. Such formulations are generally known as "sustained-release formulations." Many sustained-release formulations are already known, but there is no generally applicable method by which such formulations can be designed. Each formulation is dependent on the particular active substance incorporated therein. In designing a formulation, it is generally necessary to take into account many factors, including the rates of absorption and clearance of the active substance, the interaction of the active substance with the excipients and/or coatings to be used in the formulation, the solubility of the excipients and/or coatings, and the effects on the bioavailability of the active substance which may be caused by the excipients and/or coatings. It is, however, not possible readily to predict whether any particular formulation will provide the desired sustained-release, and it is generally found necessary to carry out considerable experimentation to produce a sustained-release formulation having the desired properties.

Nifedipine is the generic name for 4-(2'- nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1 ,4- dihydropyridine. It is a vasodilator known to be useful for the treatment of hypertension and angina pectoris. Nifedipine is practically insoluble in water and has proved difficult to formulate effectively for oral administration. British Patent No. 1,173,862 relates to nifedipine itself and describes preparations thereof, optionally in admixture with an inert liquid or solid diluent or carrier, in the form of tablets and pills. These preparations have the disadvantage of a very slow and unpredictable rate of absorption from the gastrointestinal tract. U.S. Patent No. 3,784,684 describes oral- release capsules which are prepared by dissolving nifedipine using a solubilising agent and enclosing the solution in a capsule. The capsules provide a very rapid release of the nifedipine in a form which is readily absorbable by the body. However, liquid preparations in capsules are much more inconvenient to produce than solid preparations. Further, because of the low solubility of nifedipine, a large amount of the solubilising agent is required and so the unit doses, and thus the capsules containing them, are inevitably large. This is obviously a disadvantage with preparations intended for oral administration.

European Patent Application No. 0001247 relates to pharmaceutical preparations for oral administration which comprise either a solution of nifedipine in polyethylene glycol or a non-crystalline dispersion of nifedipine in polyvinylpyrrolidone. These preparations are said to be stable and to present nifedipine in a form which is easily and rapidly absorbable by the body.

British Patent No. 1,579,818 describes various solid pharmaceutical preparations containing nifedipine. These include preparations which comprise a mixture of nifedipine and one or more of methyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose, optionally together with other components. The preparations are produced by a method which involves dissolving the ingredients in an organic solvent, which is then extracted leaving a solid composition or a powdery solid composition. The resulting preparations show a rapid release of the nifedipine and are said to show the same high bioavailability within the body as the previously mentioned liquid preparations. There is no teaching or suggestion that the preparations could be formulated with a coating for achieving sustained-release properties.

A sustained-release formulation containing nifedipine is currently marketed in the United Kingdom under the name Adalat Retard (a registered, trade mark).

However, this formulation does not provide as good a sustained-release as is desirable. There is therefore a need for an improved sustained-release nifedipine formulation and particularly one having good sustained- release over a period of twelve hours. The present invention is based on the discovery of such an improved sustained-release formulation.

According to the present invention there is provided a sustained-release nifedipine formulation comprising sufficient granules to provide a predetermined dose or number of doses of nifedipine, each of said granules having a diameter of between 0.5 and 2.5 mm and comprising: a) a core comprising 100 parts of nifedipine and from 50 to 800 parts of hydroxypropylmethyl cellulose; and b) a coating covering substantially the whole surface of the core and comprising 100 parts of a water insoluble but water swellable acrylic polymer and from 20 to 70 parts of a water soluble hydroxylated cellulose derivative, the weight of the coating being from 2 to 20% of the weight of the core.

The invention further provides a method for preparing a sustained-release formulation and which comprises: i) mixing nifedipine with hydroxypropylmethyl cellulose; ii) forming the mixture into core particles comprising 100 parts of nifedipine and from 50 to 800 parts of hydroxypropylmethyl cellulose; iii) forming a solution comprising 100 parts of a water insoluble but water swellable acrylic polymer and from 20 to 70 parts of a water soluble hydroxylated cellulose derivative; and iv) coating the said core particles with the said solution to form granules having a diameter of between 0.5 and 2.5 mm.

In the following description, all parts and percentages are by weight unless otherwise indicated. It will be appreciated that to some extent the diameter of the granules, the composition of the core and the composition and amount of coating will depend on the time over which the formulation is designed to work. Generally, however, each of the granules will have a diameter of between 0.5 and 2.0 mm, preferably between 0.7 and 1.2 mm. For every 100 parts of nifedipine present in the core, there will be from 50 to 800 parts of hydroxypropylmethyl cellulose. The core most preferably contains from 60 to 400 parts of hydroxypropylmethyl cellulose, more particularly from 80 to 150 parts. For every 100 parts of the water insoluble but water swellable acrylic polymer present in the coating, there will preferably be from 20 to 70 parts of the water-soluble hydroxylated cellulose derivative. The weight of the coating will usually be from 2 to 25% of the weight of the core.

For a formulation designed to provide sustained-release over a period of 24 hours, the granule diameter is preferably between 1.5 and 2.0 mm, the coating preferably contains 20 to 70 parts of the water soluble hydroxylated cellulose derivative, and the weight of the coating is from approximately 5 to 25% of the weight of the core.

For a formulation designed to provide sustained-release over a period of 12 hours, the granule diameter is between 0.7 and 1.2 mm, the coating preferably contains 20 to 70 parts of the water soluble hydroxylated cellulose derivative, and the weight of the coating is preferably between 5 and 15% of the weight of the core.

In addition to nifedipine and hydroxypropylmethyl cellulose, the core also preferably contains a bulking agent such as microcrystalline cellulose. This is a well known form of cellulose which is partially depolymerised. A particularly suitable microcrystalline cellulose is sold under the name Avicel (a registered trade mark). However, other conventional bulking agents may also be used, as will be readily apparent to those skilled in the art.

The core may also contain a diluent, such as lactose. A capillary-active agent, such as sodium carboxymethylcellulose, which is sold under the name Ac-Di-Sol (a registered trade mark), may additionally be included. These components are used in conventional amounts. If desired, the formulation of this invention may also contain colouring agents, sweetening agents and flavouring agents.

The coating preferably comprises about 30 parts of the hydroxylated cellulose derivative. If too much is present, the coating may become too sticky and the rate of release may become too high. If too little is present, the rate of release may be too low. A particularly suitable hydroxylated cellulose derivative is hydroxypropylmethyl cellulose having a degree of substitution of 28 to 30% of methoxy groups and 7 to 12% of hydroxy groups. However, other equivalent materials such as hydroxypropyl, hydroxyethyl or hydroxymethyl celluloses can be used.

The acrylic polymer component of the coating is preferably neutral and may comprise a homopolymer or a copoly er, for instance of acrylic acid esters or methacrylic acid esters. Preferably, the acrylic polymer is provided as an aqueous dispersion. A particularly suitable acrylic polymer is sold under the name Eudragit (a registered trade mark), which comprises a copolymer of acrylic and methacrylic acid esters and which is usually supplied as an aqueous dispersion containing approximately 30% solids. The formulation of this invention can be prepared in the following manner. The nifedipine is micronised (to increase its surface area and thereby improve dissolution) and then blended with the hydroxypropylmethyl cellulose and any other constituents of the core, such as a bulking agent, a diluent and a capillary-active agent. Alternatively, the nifedipine and the hydroxypropylmethyl cellulose may be mixed and then micronised, prior to blending with the other constituents. The blending is conveniently performed by mixing the components together with some water to produce a slightly cohesive product. This is then extruded, chopped into suitable lengths, spheronised and dried to form the core particles of the formulation. The particles may then be sieved. The coating is prepared by forming a solution of the hydroxylated cellulose derivative and mixing it with a dispersion of the acrylic polymer. The aqueous mixture is then used to coat the dried core particles, and the coated particles are subsequently dried to produce the granules. Preferably, the coated granules are then sieved to ensure that they are in the correct size range.

The resulting granules may be supplied loose with a means for dispensing a measured amount of granules, for instance to be sprinkled on food. Alternatively, the granules may be provided in sachets containing measured amounts. More preferably, however, the granules are placed in measured amounts in readily soluble capsules. The capsule may be any of those already known in the art, and may, for instance, comprise a thin gelatin skin. Preferably, the capsule contains sufficient granules to provide a dose of 10, 20 or 40 mg of nifedipine. The granules may, if desired, be formed into tablets using conventional tabletting machinery, although it should be recognised that normal tabletting processes would be likely to damage at least some of the coated granules.

It has surprisingly been found that by the above set out selection of the materials for the core and the coating, the relative amounts of the components, and the size of the granules, it is possible to produce a sustained-release nifedipine formulation which shows effective sustained-release over any desired period and, in particular, over a twelve hour period. While not wishing to be limited by any mechanism, the inventors believe that the sustained-release properties shown by the formulation are achieved as follows. Upon being administered orally, the contents of the core of each granule is thought to dissolve quickly. It is the polymeric coating around the core which limits the subsequent release of the components of the core and hence produces the controlled sustained-release shown by the formulation.

One embodiment of the present invention will now be described, by way of example only, with reference to the accompanying drawing. Figure 1 shows the comparative in vitro dissolution profiles of a previously known formulation (Adalat Retard) and the formulation of the present invention (Apsipine 30/5).

Example

The formulation described below (designated Apsipine 30/5) was developed using the 0SAT system developed by the inventors at the University of Bradford ' The formulation was prepared from the following Core

Nifedipine 10% w/w

Hydroxypropylmethyl cellulose 10% w/w (Pharmacoat 603)

Avicel PH 101 39% w/w

Lactose 39% w/w

Ac-Di-Sol 2% w/w

Water q.s

Coating

Eudragit NE30D 5 parts

Hydroxypropylmethyl cellulose

(Pharmacoat 603) 1.5 parts

Core - Micronised nifedipine and the hydroxypropylmethyl cellulose, Avicel, lactose and Ac- Di-Sol were mixed together by doubling up in a dry blender. Water was added in portions until a slightly cohesive product was formed. The cohesive product was passed through an extruder and the extruded material was chopped to produce slugs having a diameter of about 1mm and a length- of 2 to 3 mm. The slugs were spheronised by passage through a spheroniser, and the particles thus formed were dried to constant weight at 60 C. The dried particles were sieved to separate those having diameters between 0.7 and 1.5 mm.

Coating - The hydroxypropylmethyl cellulose was dissolved i hot water and cooled. The cooled solution was mixed with the Eudragit NE30D and the mixture was diluted with further water to produce a coating mixture containing 0.2 g solids per gram of mixture.

The sieved core particles were rotated in a small coating pan and the coating mixture was added in portions to the pan until the weight of solids in the added coating mixture was 5% of the weight of the core particles. After each portionwise addition of coating mixture, air was blown into the pan to assist in water removal. At the end of the addition of the coating mixture, the coated core particles were dried to constant weight and sieved to produce granules having a size between 0.8 and 1.2 mm.

Hard gelatin capsules were each filled with the granules, to produce a total dose of 20 mg of nifedipine per capsule. In vitro experiments were then carried out to determine the release properties of this formulation in comparison to Adalat Retard. The dissolution test used was the USP basket method, pH 6.8, flat-bottomed flask, temperature of 37°C, detector wavelength 238 nm, optical density of 3 mg/1 nifedipine solution = 0.171.

The results are shown in Figure 1. The release properties of the formulation of the present invention (designated Apsipine 30/5) and Adalat Retard were monitored for 10 hour From the resulting dissolution profiles of Figure 1 , it is clear that the formulation of the present invention shows rather faster initial release of the nifedipine, good subsequent sustaining release and increased total release after 10 hours. It will be appreciated from the above data that the formulation of the present invention provides a much improved sustained-release formulation compared with those previously available. It will be appreciated that the present invention has been described above by way of illustration only, and it will be clear that variations and alterations of detail may be made by the man skilled in the art without departing from the scope of the invention.

Claims

1. A sustained-release nifedipine formulation comprising sufficient granules to provide a predetermined dose or number of doses of nifedipine, each of said granules having a diameter of between 0.5 and 2.5 mm and comprising:
(a) a core comprising 100 parts of nifedipine and from 50 to 800 parts of hydroxypropylmethyl cellulose; and
(b) a coating covering substantially the whole surface of the core and comprising 100 parts of a water insoluble but water swellable acrylic polymer and from 20 to 70 parts of a water soluble hydroxylated cellulose derivative, the weight of the coating being from 2 to 25% of the weight of the core.
2. A formulation as claimed in claim 1 , which provides sustained-release over a period of 12 hours, wherein the diameter of the granules is between 0.7 and 1.2 mm, the coating contains from 20 to 70 parts of the water soluble hydroxylated cellulose derivative, and the weight of the coating is between 5 and 15% of the weight of the core.
3- A formulation as claimed in claim 1, which provides sustained-release over a period of 24 hours, wherein the diameter of the granules is between 1.5 and 2.0 mm, the coating contains from 20 to 70 parts of the water soluble hydroxylated cellulose derivative, and the weight of the coating is from 5 to 25% of the weight of the core.
4. A formulation as claimed in any one of the preceding claims, wherein said core contains from 80 to 150 parts of hydroxypropylmethyl cellulose.
5. A formulation as claimed in any one of the preceding claims, wherein said coating contains 30 parts of the hydroxylated cellulose derivative.
6. A formulation as claimed in any one of the preceding claims, wherein the hydroxylated cellulose derivative in the coating is hydroxypropylmethyl cellulose having a degree of substitution of 28 to 30% of methoxy groups and 7 to 12% of hydroxy group's.
7. A formulation as claimed in any one of the preceding claims, wherein the acrylic polymer in the coating is neutral.
8. A formulation as claimed in any one of the preceding claims, wherein said granules are contained within a capsule.
9. A method for preparing a sustained-release nifedipine formulation and which comprises: i) mixing nifedipine with hydroxypropylmethyl cellulose; ii) forming the mixture into core particles comprising 100 parts of nifedipine and from 50 to 800 parts of hydroxypropylmethyl cellulose; iii) forming a solution comprising 100 parts of a water insoluble but water swellable acrylic polymer and from 20 to 70 parts of a water soluble hydroxylated cellulose derivative; and iv) coating the said core particles with the said solution to form granules having a diameter of between 0.5 and 2.5 mm.
10. A method as claimed in claim 9, wherein the granules are sieved after formation.
PCT/GB1988/000779 1987-09-22 1988-09-22 Sustained-release nifedipine formulation WO1989002738A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
GB8722306A GB8722306D0 (en) 1987-09-22 1987-09-22 Sustained-release formulation
GB8722306 1987-09-22

Publications (1)

Publication Number Publication Date
WO1989002738A1 true true WO1989002738A1 (en) 1989-04-06

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1988/000779 WO1989002738A1 (en) 1987-09-22 1988-09-22 Sustained-release nifedipine formulation

Country Status (4)

Country Link
EP (1) EP0386023A1 (en)
JP (1) JPH03500288A (en)
GB (1) GB8722306D0 (en)
WO (1) WO1989002738A1 (en)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992001446A1 (en) * 1990-07-20 1992-02-06 Aps Research Limited Sustained-release formulations
EP0557244A1 (en) * 1992-02-17 1993-08-25 Siegfried Pharma AG Dosage forms having prolonged active-ingredient release
WO1994005262A1 (en) * 1992-09-10 1994-03-17 F.H. Faulding & Co. Limited Sustained release matrix composition
EP0599282A1 (en) * 1992-11-27 1994-06-01 BIOPROGRESS S.p.A. Pharmaceutical compositions containing ursodeoxycholic acid
US5439687A (en) * 1992-02-17 1995-08-08 Siegfried Pharma Ag Dosage forms having zero-order dihydropyridine calcium antagonist release
US5455046A (en) * 1993-09-09 1995-10-03 Edward Mendell Co., Inc. Sustained release heterodisperse hydrogel systems for insoluble drugs
US5594013A (en) * 1992-01-13 1997-01-14 Ethical Pharmaceuticals Limited Pharmaceutical compositions containing nifedipine and process for the preparation thereof
US5662933A (en) * 1993-09-09 1997-09-02 Edward Mendell Co., Inc. Controlled release formulation (albuterol)
US6048548A (en) * 1993-09-09 2000-04-11 Edward Mendell Co., Inc. Sustained release heterodisperse hydrogel systems-amorphous drugs
US6056977A (en) * 1997-10-15 2000-05-02 Edward Mendell Co., Inc. Once-a-day controlled release sulfonylurea formulation
US6093420A (en) * 1996-07-08 2000-07-25 Edward Mendell Co., Inc. Sustained release matrix for high-dose insoluble drugs
WO2002072064A2 (en) * 2001-03-09 2002-09-19 Dow Global Technologies Inc. Granular composition comprising an active compound and a cellulose ether and the use thereof
US6726930B1 (en) 1993-09-09 2004-04-27 Penwest Pharmaceuticals Co. Sustained release heterodisperse hydrogel systems for insoluble drugs
US9439851B2 (en) * 2004-03-25 2016-09-13 Sun Pharma Advanced Research Company Ltd. Gastric retention system

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0123470A1 (en) * 1983-04-21 1984-10-31 Elan Corporation P.L.C. Controlled absorption pharmaceutical composition
EP0142561A1 (en) * 1981-09-14 1985-05-29 Kanebo, Ltd. Long-acting nifedipine preparation
WO1986001717A1 (en) * 1984-09-14 1986-03-27 Pharmatec S.P.A. Controlled release nifedipine preparation
EP0255404A1 (en) * 1986-08-01 1988-02-03 APS Research Limited Sustained release ibuprofen formulation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0142561A1 (en) * 1981-09-14 1985-05-29 Kanebo, Ltd. Long-acting nifedipine preparation
EP0123470A1 (en) * 1983-04-21 1984-10-31 Elan Corporation P.L.C. Controlled absorption pharmaceutical composition
WO1986001717A1 (en) * 1984-09-14 1986-03-27 Pharmatec S.P.A. Controlled release nifedipine preparation
EP0255404A1 (en) * 1986-08-01 1988-02-03 APS Research Limited Sustained release ibuprofen formulation

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992001446A1 (en) * 1990-07-20 1992-02-06 Aps Research Limited Sustained-release formulations
US5594013A (en) * 1992-01-13 1997-01-14 Ethical Pharmaceuticals Limited Pharmaceutical compositions containing nifedipine and process for the preparation thereof
EP0557244A1 (en) * 1992-02-17 1993-08-25 Siegfried Pharma AG Dosage forms having prolonged active-ingredient release
US5439687A (en) * 1992-02-17 1995-08-08 Siegfried Pharma Ag Dosage forms having zero-order dihydropyridine calcium antagonist release
WO1994005262A1 (en) * 1992-09-10 1994-03-17 F.H. Faulding & Co. Limited Sustained release matrix composition
EP0599282A1 (en) * 1992-11-27 1994-06-01 BIOPROGRESS S.p.A. Pharmaceutical compositions containing ursodeoxycholic acid
US6136343A (en) * 1993-09-09 2000-10-24 Edward Mendell Co., Inc. Sustained release heterodisperse hydrogel systems for insoluble drugs
US5554387A (en) * 1993-09-09 1996-09-10 Edward Mendell Co., Ltd. Sustained release heterodisperse hydrogel systems for insoluble drugs
US5512297A (en) * 1993-09-09 1996-04-30 Edward Mendell Co., Inc. Sustained release heterodisperse hydrogel systems for insoluble drugs
US5662933A (en) * 1993-09-09 1997-09-02 Edward Mendell Co., Inc. Controlled release formulation (albuterol)
US5667801A (en) * 1993-09-09 1997-09-16 Edward Mendell Co., Inc. Sustained release heterodisperse hydrogel systems for insoluble drugs
US5846563A (en) * 1993-09-09 1998-12-08 Edward Mendell Co., Inc. Sustained release heterodisperse hydrogel systems for insoluble drugs
US5958456A (en) * 1993-09-09 1999-09-28 Edward Mendell Co., Inc. Controlled release formulation (albuterol)
US5455046A (en) * 1993-09-09 1995-10-03 Edward Mendell Co., Inc. Sustained release heterodisperse hydrogel systems for insoluble drugs
US6726930B1 (en) 1993-09-09 2004-04-27 Penwest Pharmaceuticals Co. Sustained release heterodisperse hydrogel systems for insoluble drugs
US6245356B1 (en) 1993-09-09 2001-06-12 Edward Mendell Co., Inc. Sustained release heterodisperse hydrogel systems-amorphous drugs
US6048548A (en) * 1993-09-09 2000-04-11 Edward Mendell Co., Inc. Sustained release heterodisperse hydrogel systems-amorphous drugs
US6245355B1 (en) 1996-07-08 2001-06-12 Edward Mendell Co., Inc. Sustained release matrix for high-dose insoluble drugs
US6093420A (en) * 1996-07-08 2000-07-25 Edward Mendell Co., Inc. Sustained release matrix for high-dose insoluble drugs
US6689386B2 (en) 1996-07-08 2004-02-10 Penwest Pharmaceuticals Co. Sustained release matrix for high-dose insoluble drugs
US6537578B1 (en) 1997-10-15 2003-03-25 Penwest Pharmaceuticals Co. Once-a-day controlled release sulfonylurea formulation
US6056977A (en) * 1997-10-15 2000-05-02 Edward Mendell Co., Inc. Once-a-day controlled release sulfonylurea formulation
US6875793B2 (en) 1997-10-15 2005-04-05 Penwest Pharmaceuticals Co. Once-a-day controlled release sulfonylurea formulation
WO2002072064A2 (en) * 2001-03-09 2002-09-19 Dow Global Technologies Inc. Granular composition comprising an active compound and a cellulose ether and the use thereof
WO2002072064A3 (en) * 2001-03-09 2003-03-06 Dow Global Technologies Inc Granular composition comprising an active compound and a cellulose ether and the use thereof
US9439851B2 (en) * 2004-03-25 2016-09-13 Sun Pharma Advanced Research Company Ltd. Gastric retention system

Also Published As

Publication number Publication date Type
EP0386023A1 (en) 1990-09-12 application
GB8722306D0 (en) 1987-10-28 grant
JPH03500288A (en) 1991-01-24 application

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