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WO1992007553A1 - Coating or matrix material for medicaments - Google Patents

Coating or matrix material for medicaments Download PDF

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Publication number
WO1992007553A1
WO1992007553A1 PCT/EP1991/002046 EP9102046W WO9207553A1 WO 1992007553 A1 WO1992007553 A1 WO 1992007553A1 EP 9102046 W EP9102046 W EP 9102046W WO 9207553 A1 WO9207553 A1 WO 9207553A1
Authority
WO
WIPO (PCT)
Prior art keywords
carboxy groups
copolymer
meth
alkyl
coating
Prior art date
Application number
PCT/EP1991/002046
Other languages
French (fr)
Inventor
Renaat Daniel Kinget
Rita Maria Rosa Peeters
Original Assignee
K.U. Leuven Research & Development
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
Priority claimed from NL9002331A external-priority patent/NL9002331A/en
Application filed by K.U. Leuven Research & Development filed Critical K.U. Leuven Research & Development
Publication of WO1992007553A1 publication Critical patent/WO1992007553A1/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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/14—Esterification

Definitions

  • This invention relates to a coating or matrix material for medicaments which is resistent to gastric juice and will disintegrate only within the large intestine (co ⁇ lon) . Further, it relates to a method of preparing such a coating or matrix material and to medicaments provided with a coating or matrix of that material.
  • medicaments for oral administration are provided with a coating or matrix of a material which is resistent to gastric juice but will disolve or disintegrate in the juice of the small intestine, thus allowing the active ingredient to pass the stomach without any hindrance and to be released only in the small intestine to excercise its activity.
  • Materials of this type are commonly indicated as gastric-resistent coating or matrix materials or "enteric coating matrix materials". Suitable examples thereof are: methacrylate polymers and copolymers, cellulose derivatives esterified with polybasic acids, and polyvinyl acetate-phthalate.
  • a medicament with a coating or matrix which can withstand gastric as well as enteric environments and which will release the active ingredient only when the medicament has reached the large intestine and in particular the colon.
  • This may be suitable in treating special colon diseases such as Crohm's disease and several types of colon cancer but also to reach a higher efficacy of medicaments such as corticosteroides, laxatives, vermicides and the like, thus allowing smaller doses to be sufficient.
  • Most of the cited coating and matrix materials are unsuitable for this purpose, however, because they will dissolve or disintegrate already in the small intestine. It has been suggested already to coat medicaments with polymers which have been cross-linked with azoaromatic groups.
  • the invention provides a coating or matrix material for medicaments which comprises a copolymer of
  • the copolymers meant herein are composed of acrylic acid or methacrylic acid units and of alkyl acrylate, hy ⁇ droxyalkyl acrylate, alkyl methacrylate or hydroxyalkyl methacrylate units, in random or ordered sequences.
  • the alkyl groups will have 1-5 and preferably 1-3 carbon atoms whereas the hydroxyalkyl groups will have 1-5 and preferably 2-4 carbon atoms.
  • Suitable examples are copolymers of metha- crylic acid and methyl methacrylate, copolymers of methacry- lie acid and ethyl methacrylate as well as copolymers of methacrylic acid and methyl acrylate.
  • They should satisfy the condition that the ratio of free carboxy groups to esterified carboxy groups is between 1:4.5 and 1:3.
  • the invented coating or matrix material may be prepared in general in several ways. Thus, it is possible that preparation is effected by copoly erisation of (meth)- acrylic acid and alkyl or hydroxyalkyl (meth)acrylate in such proportions that the ratio of free carboxy groups to esterified carboxy groups in the end product is between 1:4.4 and 1:3.
  • Such a copolymerisation may be effected conventionally as an emulsion polymerisation.
  • Another option which is preferred at the moment comprises starting with a copolymer of (meth)acrylic acid and alkyl or hydroxyalkyl (meth)acrylate wherein the ratio of free carboxy group to esterified carboxy groups has a value between 1:1 and 1:3, and partially esterifying the free carboxy groups therein until the ratio of free carboxy groups to esterified carboxy groups is between 1:4.5 and 1:3.
  • Esterification may be effected with alkyl groups or hydroxyalkyl groups, alkyl groups having 1-3 carbon atoms and hydroxyalkyl groups having 2-4 carbon atoms being again preferred.
  • Any suitable agent for introducing alkyl or hydroxyalkyl groups may be used as an esterification agent.
  • Diazomethane is a preferred agent for the introduction of methyl groups.
  • the invented copolymer may be used as a coating material for medicaments by spraying a solution of that copolymer in an organic solvent onto the medicament which may have the form of a fine powder, a granulate or tablets or which may be contained in gelatin capsules. After removal of the solvent by drying, the polymer remains as a coating layer at the surface of the medicament.
  • the copolymer is mixed with the medicament in such a way that it will form a matrix having the medicament embedded therein. In both cases, the medicament will be released as soon as the copolymer has passed the stomach and has reached the colon after oral administration.
  • the copolymer is used as a coating material for medicaments
  • several variants are possible which may lead to a controlled release of medicament in the colon or in other parts of the gastro-intestinal tract.
  • various degrees of delay can be obtained by varying the solubility characteristics of the coating layer, simply by blending copolymers having different values for the ratio of free carboxy groups to esterified carboxy groups.
  • Fur- ther it is possible to provide different parts or particles of the medicament with coating layers of varying thickness so as to result into a phased or gradual release.
  • the requi ⁇ red thickness can be determined by routine experiments but it should be noted that a thickness of at least 10 ⁇ m is normally needed for providing sufficient mechanical strength.
  • the coating layer may consist as a whole of a copolymer according to the invention, but as an alternative, this copolymer may form a "window" in an inert coating layer or it may lend temporary strength to a coating layer which is weak in itself.
  • the copolymer-coated medicament may be provided with a conventional gastric-resistent coa ⁇ ting layer and may optionally have an active ingredient between the two coating layers; in that way, it is possible to ensure release of a medicament in the stomach and/or in the small intestine, and release of a medicament in the colon as well.
  • the material coated with a coating layer may be a solid or an aqueous or semi-aqueous liquid, provided that this material does not affect or deteriorate the copo ⁇ lymer.
  • the starting material of this example was a commer ⁇ cially available copolymer of methacrylic acid and methyl methacrylate, having about 30% of methacrylic acid units (the ratio of free carboxy groups to esterified carboxy groups being 1:2.3).
  • the acid number was 185 (calculated as mg of KOH per gram of dry solids) .
  • 10 grams of this copolymer were suspended in 25 ml of ether. 50 ml of an ethereal solution of diazomethane (concentration 0.425 M) was added thereto and the mixture was stirred at room temperature for 5 minutes. The resulting product was filtered off, dried in the air and completely dried at 50°C in vacuo. This product had an acid number of 120 which corresponds to a value of 1:3.5 for the ratio of free carboxy groups to esterified carboxy groups.
  • a solution of the resulting copolymer in acetone was cast onto a glass plate and dried thereon to obtain a film product.
  • Pieces of the isolated film were introduced in glass tubes containing buffer solutions of different pH values (ranging from pH 7 to pH 8) .
  • the time period necessa ⁇ ry for the film to dissolve was measured.
  • the copolymer having an acid number of 120 did not dissolve after staying 4 hours in a medium of pH 7 but had been dissolved after 2 hours stay in a medium of pH 7.4.
  • the copolymer having an acid number of 100 did not dissolve after staying 4 hours at pH 7 or pH 7.4 but had been dissolved after 2 hours stay at pH 8.
  • Pieces of the isolated film were introduced as a membrane between the donor compartment and the acceptor compartment of a series of diffusion cells.
  • Both compart ⁇ ments of each cell contained an electrolyte of certain pH (ranging from pH 7 to pH 8 for the whole series of cells) and caffe ⁇ n had been added as a marker to each donor com ⁇ partment.
  • the progression of caffe ⁇ n concentration within the acceptor compartment of each cell was measured spectrop- hotometrically during a period of several hours.
  • a sudden increase of the caffe ⁇ n concentration as measured was regar ⁇ ded as indicating the disintegration of the film used as a membrane. 5
  • the film from copolymer of acid number 120 disinte ⁇ grated after 13 hours at pH 7, after 144 minutes at pH 7.5, and after 50 minutes at pH 8.
  • Gelatin capsules were filled with pellets of Amber- lite IR-120-P (Sigma, USA) ion exchanger which had been marked with [ ⁇ In] indium chloride and a small amount of [1- 15 14 C] cholylglycine. Thereafter, the capsules were coated with a film of methylated copolymer.
  • the capsules were orally administered to test persons and their course through the body was scintigraphi- cally monitored with the aid of a gamma-ray camera and an 20 image screen. The time needed by the capsules to reach the colon without disintegration was measured.
  • Capsules having a coating layer of 2.1 mg/cm 2 from copolymer of acid number 100 reached the colon without disintegration after 300 minutes (one test person) and disintegrated after 600 minutes (detection of radio active C0 2 in the person's breath and visual observation on the image screen) .
  • Capsules having a coating layer of 5.3 mg/cm 2 from copolymer of acid number 100 also reached the colon after 300 minutes (one test person) but did not disintegrate.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

A coating or matrix material for medicaments, comprising a copolymer of (meth)acrylic acid and alkyl or hydroxyalkyl (meth)acrylate, will have the property of being resistent to gastric juice and dissolving or disintegrating only in the colon if the ratio of free carboxy groups to esterified carboxy groups in the copolymer is between 1:4.5 and 1:3 (the limiting values excluded). Such copolymers may be prepared either by direct copolymerisation of monomers in such proportions that a copolymer having the specified ratio is obtained, or else by starting with a copolymer having a ratio between 1:1 and 1:3 and partially esterifying the free carboxy groups therein to reach the specified ratio.

Description

Coating or matrix material for medicaments
This invention relates to a coating or matrix material for medicaments which is resistent to gastric juice and will disintegrate only within the large intestine (co¬ lon) . Further, it relates to a method of preparing such a coating or matrix material and to medicaments provided with a coating or matrix of that material.
In many cases, it is desirable to coat a medicament in such a way that the active ingredient is only released after a predetermined time interval or after reaching a certain location within the body. Thus, many medicaments for oral administration are provided with a coating or matrix of a material which is resistent to gastric juice but will disolve or disintegrate in the juice of the small intestine, thus allowing the active ingredient to pass the stomach without any hindrance and to be released only in the small intestine to excercise its activity. Materials of this type are commonly indicated as gastric-resistent coating or matrix materials or "enteric coating matrix materials". Suitable examples thereof are: methacrylate polymers and copolymers, cellulose derivatives esterified with polybasic acids, and polyvinyl acetate-phthalate.
In some cases, it is desired to provide a medicament with a coating or matrix which can withstand gastric as well as enteric environments and which will release the active ingredient only when the medicament has reached the large intestine and in particular the colon. This may be suitable in treating special colon diseases such as Crohm's disease and several types of colon cancer but also to reach a higher efficacy of medicaments such as corticosteroides, laxatives, vermicides and the like, thus allowing smaller doses to be sufficient. Most of the cited coating and matrix materials are unsuitable for this purpose, however, because they will dissolve or disintegrate already in the small intestine. It has been suggested already to coat medicaments with polymers which have been cross-linked with azoaromatic groups. Such polymers would protect the medicament against absorption within the stomach and the small intestine but would release the medicament in the colon as a result of disintegration through activity of the microflora present therein. Reported data show, however, that large individual differences are existing in practice (Saffran et al, Scien¬ ce, 1986, 233, 1081).
In accordance with the invention, it has been found that certain copolymers of (meth)acrylic acid and alkyl or hydroxyalkyl (meth)aerylate will fulfill the object in view because they are resistent to gastric juice and will dissol¬ ve or disintegrate only in an environment of pH above 7 such as prevailing in the colon. A precondition is that the ratio of free carboxy groups to esterified carboxy groups in the copolymer is between 1:4.5 and 1:3, the limiting values of this range being excluded. The copolymer has become insolu¬ ble in any intestinal juice at a value of 1:4.5 for said ratio and the copolymer will dissolve or disintegrate alrea¬ dy prior to reaching the colon at a value of 1:3.
It has to be noted that several copolymers of (meth)acrylic acid and alkyl (meth)acrylate, suitable for use as gastric-resistent coating or matrix material for medicaments, are already known in the art and commercially available. However, the available copolymers of this type have a value of 1:1 or 1:2.3 for the ratio of free carboxy groups to esterified carboxy groups and will start to disin¬ tegrate already in the small intestine at pH 6, and pH 7 respectively, thus rendering them unsuitable for the purpo¬ ses of the invention.
So, the invention provides a coating or matrix material for medicaments which comprises a copolymer of
(meth)acrylic acid and alkyl or hydroxyalkyl (meth)aerylate wherein the ratio of free carboxy groups to esterified carboxy groups is between 1:4.5 and 1:3, the limiting values of this range being excluded. The copolymers meant herein are composed of acrylic acid or methacrylic acid units and of alkyl acrylate, hy¬ droxyalkyl acrylate, alkyl methacrylate or hydroxyalkyl methacrylate units, in random or ordered sequences. The alkyl groups will have 1-5 and preferably 1-3 carbon atoms whereas the hydroxyalkyl groups will have 1-5 and preferably 2-4 carbon atoms. Suitable examples are copolymers of metha- crylic acid and methyl methacrylate, copolymers of methacry- lie acid and ethyl methacrylate as well as copolymers of methacrylic acid and methyl acrylate. However, they should satisfy the condition that the ratio of free carboxy groups to esterified carboxy groups is between 1:4.5 and 1:3. The invented coating or matrix material may be prepared in general in several ways. Thus, it is possible that preparation is effected by copoly erisation of (meth)- acrylic acid and alkyl or hydroxyalkyl (meth)acrylate in such proportions that the ratio of free carboxy groups to esterified carboxy groups in the end product is between 1:4.4 and 1:3. Such a copolymerisation may be effected conventionally as an emulsion polymerisation.
Another option which is preferred at the moment comprises starting with a copolymer of (meth)acrylic acid and alkyl or hydroxyalkyl (meth)acrylate wherein the ratio of free carboxy group to esterified carboxy groups has a value between 1:1 and 1:3, and partially esterifying the free carboxy groups therein until the ratio of free carboxy groups to esterified carboxy groups is between 1:4.5 and 1:3. Esterification may be effected with alkyl groups or hydroxyalkyl groups, alkyl groups having 1-3 carbon atoms and hydroxyalkyl groups having 2-4 carbon atoms being again preferred. Any suitable agent for introducing alkyl or hydroxyalkyl groups may be used as an esterification agent. Diazomethane is a preferred agent for the introduction of methyl groups.
The invented copolymer may be used as a coating material for medicaments by spraying a solution of that copolymer in an organic solvent onto the medicament which may have the form of a fine powder, a granulate or tablets or which may be contained in gelatin capsules. After removal of the solvent by drying, the polymer remains as a coating layer at the surface of the medicament. In another utilisation, the copolymer is mixed with the medicament in such a way that it will form a matrix having the medicament embedded therein. In both cases, the medicament will be released as soon as the copolymer has passed the stomach and has reached the colon after oral administration.
In the case that the copolymer is used as a coating material for medicaments, several variants are possible which may lead to a controlled release of medicament in the colon or in other parts of the gastro-intestinal tract. Thus, various degrees of delay can be obtained by varying the solubility characteristics of the coating layer, simply by blending copolymers having different values for the ratio of free carboxy groups to esterified carboxy groups. Fur- ther, it is possible to provide different parts or particles of the medicament with coating layers of varying thickness so as to result into a phased or gradual release. The requi¬ red thickness can be determined by routine experiments but it should be noted that a thickness of at least 10 μm is normally needed for providing sufficient mechanical strength. The coating layer may consist as a whole of a copolymer according to the invention, but as an alternative, this copolymer may form a "window" in an inert coating layer or it may lend temporary strength to a coating layer which is weak in itself. Further, the copolymer-coated medicament may be provided with a conventional gastric-resistent coa¬ ting layer and may optionally have an active ingredient between the two coating layers; in that way, it is possible to ensure release of a medicament in the stomach and/or in the small intestine, and release of a medicament in the colon as well. The material coated with a coating layer may be a solid or an aqueous or semi-aqueous liquid, provided that this material does not affect or deteriorate the copo¬ lymer. Example a) Preparation of a suitable copolymer by methylation.
The starting material of this example was a commer¬ cially available copolymer of methacrylic acid and methyl methacrylate, having about 30% of methacrylic acid units (the ratio of free carboxy groups to esterified carboxy groups being 1:2.3). The acid number was 185 (calculated as mg of KOH per gram of dry solids) . 10 grams of this copolymer were suspended in 25 ml of ether. 50 ml of an ethereal solution of diazomethane (concentration 0.425 M) was added thereto and the mixture was stirred at room temperature for 5 minutes. The resulting product was filtered off, dried in the air and completely dried at 50°C in vacuo. This product had an acid number of 120 which corresponds to a value of 1:3.5 for the ratio of free carboxy groups to esterified carboxy groups.
In a similar way, a product having an acid number of 100, corresponding to a value of 1:4 for the ratio of free to esterified carboxy groups, was obtained from 10 grams of starting copolymer and 38 ml of diazomethane solution, b) Solubility in vitro.
A solution of the resulting copolymer in acetone was cast onto a glass plate and dried thereon to obtain a film product. Pieces of the isolated film were introduced in glass tubes containing buffer solutions of different pH values (ranging from pH 7 to pH 8) . The time period necessa¬ ry for the film to dissolve was measured. The copolymer having an acid number of 120 did not dissolve after staying 4 hours in a medium of pH 7 but had been dissolved after 2 hours stay in a medium of pH 7.4. The copolymer having an acid number of 100 did not dissolve after staying 4 hours at pH 7 or pH 7.4 but had been dissolved after 2 hours stay at pH 8. c) Disintegration of the copolymer in vitro
Pieces of the isolated film were introduced as a membrane between the donor compartment and the acceptor compartment of a series of diffusion cells. Both compart¬ ments of each cell contained an electrolyte of certain pH (ranging from pH 7 to pH 8 for the whole series of cells) and caffeϊn had been added as a marker to each donor com¬ partment. The progression of caffeϊn concentration within the acceptor compartment of each cell was measured spectrop- hotometrically during a period of several hours. A sudden increase of the caffeϊn concentration as measured was regar¬ ded as indicating the disintegration of the film used as a membrane. 5 The film from copolymer of acid number 120 disinte¬ grated after 13 hours at pH 7, after 144 minutes at pH 7.5, and after 50 minutes at pH 8.
The film from copolymer of acid number 100 disinte¬ grated after 12 hours at pH 7.5 and after 200 minutes at pH 0 8. d) Behaviour in vivo.
Gelatin capsules were filled with pellets of Amber- lite IR-120-P (Sigma, USA) ion exchanger which had been marked with [ ιIn] indium chloride and a small amount of [1- 15 14C] cholylglycine. Thereafter, the capsules were coated with a film of methylated copolymer.
The capsules were orally administered to test persons and their course through the body was scintigraphi- cally monitored with the aid of a gamma-ray camera and an 20 image screen. The time needed by the capsules to reach the colon without disintegration was measured.
Moreover, a breath test on radio-active C02 was carried out. If the coating layer of the capsule disintegra¬ tes after a certain residence time in the colon, the con- 25 tents of the capsule will be released and radio-active cholylglycine will be metabolised by the intestinal flora whereupon [14C] C02 is breathed out. During the breath test, C0 was captured by hyamine dissolved in ethanol. The con¬ centration of [1 C] C02 in the hyamine solution was determi- 30 ned with a Packard counter.
Capsules having a coating layer from copolymer of acid number 120 reached the colon after 300 minutes (average of 6 test persons) and radio-active C02 was measured in the test persons1 breath after 70 minutes residence time in the 35 colon, which indicates a disintegration of the coating layer.
Capsules having a coating layer of 2.1 mg/cm2 from copolymer of acid number 100 reached the colon without disintegration after 300 minutes (one test person) and disintegrated after 600 minutes (detection of radio active C02 in the person's breath and visual observation on the image screen) . Capsules having a coating layer of 5.3 mg/cm2 from copolymer of acid number 100 also reached the colon after 300 minutes (one test person) but did not disintegrate.
The conclusion from these tests must be that the copolymer of acid number 120 (ratio 1:3.5) is suitable for the purposes of the invention whereas the copolymer of acid number 100 is substantially unsuitable for such purposes.

Claims

C L A I M S
1. A coating or matrix material for medicaments, said material comprising a copolymer of (meth)acrylic acid and alkyl or hydroxyalkyl (meth)acrylate wherein the ratio of free carboxy groups to esterified carboxygroups is be- tween 1:4.5 and 1:3, the limiting values of this range being excluded.
2. A coating or matrix material as claimed in claim 1, characterized in that the alkyl or hydroxy alkyl (meth)- acrylate in said copolymer is a C1-3 alkyl or a C.4 hydroxy- alkyl (meth)acrylate.
3. A method of preparing a coating or matrix materi¬ al for medicaments, characterized by preparing a copolymer of (meth)acrylic acid and alkyl or hydroxyalkyl (meth)acryl¬ ate wherein the ratio of free carboxy groups to esterified carboxy groups is between 1:4.5 and 1:3, the limiting values of this range being excluded.
4. A method as claimed in claim 3, characterized in that the preparation is effected by copolymerisation of (meth)acrylic acid and alkyl or hydroxyalkyl (meth)acrylate in such proportions that the ratio of free carboxy groups to esterified carboxy groups in the end product is between 1:4.5 and 1:3.
5. A method as claimed in claim 3, characterized by starting with a copolymer of (meth)acrylic acid and alkyl or hydroxyalkyl (meth)acrylate which has a value between 1:1 and 1:3 for its ratio of free carboxy groups to esterified carboxy groups, and partially esterifying the free carboxy groups therein until the ratio of free carboxy groups to esterified carboxy groups is between 1:4.5 and 1:3.
6. A method as claimed in claim 5, characterized in that esterification is effected by introducing C^ alkyl or C2. hydroxyalkyl groups.
7. A method as claimed in claim 5, characterized in that esterification is effected by introducing methyl groups with the aid of diazomethane. 3
8. A medicament provided with a coating or matrix of a material as claimed in claim 1.
PCT/EP1991/002046 1990-10-24 1991-10-24 Coating or matrix material for medicaments WO1992007553A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
NL9002331A NL9002331A (en) 1990-10-24 1990-10-24 Delivery of medicaments to the colon - by providing acrylic coating stable to gastric juice, used for treatment of colon diseases, laxatives, corticosteroid(s), vermicides, etc.
NL9002331 1990-10-24
NL9002336A NL9002336A (en) 1990-10-24 1990-10-25 COATING OR MATRIX MATERIAL FOR MEDICINES.
NL9002336 1990-10-25

Publications (1)

Publication Number Publication Date
WO1992007553A1 true WO1992007553A1 (en) 1992-05-14

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Country Status (3)

Country Link
AU (1) AU8852391A (en)
NL (1) NL9002336A (en)
WO (1) WO1992007553A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995011032A1 (en) * 1993-10-19 1995-04-27 The Procter & Gamble Company Senna dosage form
WO1996014344A1 (en) * 1994-11-02 1996-05-17 Zeneca Limited Rheology modifier for solvent-based coatings
EP0779361A2 (en) 1995-12-15 1997-06-18 F. Hoffmann-La Roche Ag Truncated form of inhibitory kappa B protein (1kB), recombinant production and uses thereof
EP1195394A1 (en) * 2000-10-04 2002-04-10 Basf Aktiengesellschaft (Co-)Polymers of hydroxyalkyl(meth)acrylates, process for their preparation and their use in pharmaceutical dosage forms

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5330759A (en) * 1992-08-26 1994-07-19 Sterling Winthrop Inc. Enteric coated soft capsules and method of preparation thereof

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GB907309A (en) * 1959-02-18 1962-10-03 Abbott Lab Water permeable tablet coating and method of application
GB1159236A (en) * 1967-03-07 1969-07-23 Nattermann A & Cie Improvements relating to Soft-Gelatine Capsules and their Production
DE1944693A1 (en) * 1968-09-03 1970-04-30 Banker Dr Gilbert S Drug preparation
WO1983000435A1 (en) * 1981-07-31 1983-02-17 Rhodes, John Orally administrable pharmaceutical compositions
EP0143608A2 (en) * 1983-11-25 1985-06-05 Ciba Specialty Chemicals Water Treatments Limited Manufacture and use of polymeric beads
EP0143935B1 (en) * 1983-10-04 1989-08-16 RB Kunststoffpatent-Verwertungs AG Thermoplastic polymer and articles made of a thermoplastic polymer
EP0383967A1 (en) * 1989-02-17 1990-08-29 Dojin Iyaku-Kako Co., Ltd. Long acting diclofenac sodium preparation

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Publication number Priority date Publication date Assignee Title
GB907309A (en) * 1959-02-18 1962-10-03 Abbott Lab Water permeable tablet coating and method of application
GB1159236A (en) * 1967-03-07 1969-07-23 Nattermann A & Cie Improvements relating to Soft-Gelatine Capsules and their Production
DE1944693A1 (en) * 1968-09-03 1970-04-30 Banker Dr Gilbert S Drug preparation
WO1983000435A1 (en) * 1981-07-31 1983-02-17 Rhodes, John Orally administrable pharmaceutical compositions
EP0143935B1 (en) * 1983-10-04 1989-08-16 RB Kunststoffpatent-Verwertungs AG Thermoplastic polymer and articles made of a thermoplastic polymer
EP0143608A2 (en) * 1983-11-25 1985-06-05 Ciba Specialty Chemicals Water Treatments Limited Manufacture and use of polymeric beads
EP0383967A1 (en) * 1989-02-17 1990-08-29 Dojin Iyaku-Kako Co., Ltd. Long acting diclofenac sodium preparation

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995011032A1 (en) * 1993-10-19 1995-04-27 The Procter & Gamble Company Senna dosage form
US5514663A (en) * 1993-10-19 1996-05-07 The Procter & Gamble Company Senna dosage form
WO1996014344A1 (en) * 1994-11-02 1996-05-17 Zeneca Limited Rheology modifier for solvent-based coatings
US6117935A (en) * 1994-11-02 2000-09-12 Zeneca Limited Rheology modifier for solvent-based coatings
EP0779361A2 (en) 1995-12-15 1997-06-18 F. Hoffmann-La Roche Ag Truncated form of inhibitory kappa B protein (1kB), recombinant production and uses thereof
EP1195394A1 (en) * 2000-10-04 2002-04-10 Basf Aktiengesellschaft (Co-)Polymers of hydroxyalkyl(meth)acrylates, process for their preparation and their use in pharmaceutical dosage forms
US7049360B2 (en) 2000-10-04 2006-05-23 Basf Aktienegesellschaft Water-soluble or water-dispersible (co) polymers of hydroxyalkyl (meth) acrylates, a process for their preparation, and their use as coating agent, binder and/or film-forming excipient pharmaceutical dosage forms

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