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WO1992007553A1 - Matiere d'enrobage ou matricielle pour medicaments - Google Patents

Matiere d'enrobage ou matricielle pour 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
English (en)
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/nl
Application filed by K.U. Leuven Research & Development filed Critical K.U. Leuven Research & Development
Publication of WO1992007553A1 publication Critical patent/WO1992007553A1/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
    • A61K9/4891—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.

Landscapes

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

Abstract

Matière d'enrobage ou matricielle pour médicaments comprenant un copolymère d'acide (méth)acrylique et d'alkyle ou hydroxyalkyle (méth)acrylate, présentant la propriété d'être résistant au suc gastrique et de se dissoudre ou de se désintégrer uniquement dans le colon si le rapport entre les groupes carboxy libres et les groupes carboxy estérifiés dans le copolymère se situe entre 1:4,5 et 1:3 (les valeurs limite étant exclues). On peut préparer lesdits copolymères soit par copolymérisation directe de monomères dans des proportions telles qu'un copolymère ayant le rapport spécifié est obtenu, ou encore en partant d'un copolymère ayant un rapport compris entre 1:1 et 1:3 et en estérifiant partiellement les groupes carboxy libres qu'il contient afin d'atteindre le rapport spécifié.
PCT/EP1991/002046 1990-10-24 1991-10-24 Matiere d'enrobage ou matricielle pour medicaments WO1992007553A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
NL9002331 1990-10-24
NL9002331A NL9002331A (nl) 1990-10-24 1990-10-24 Bekledings- of matrixmateriaal voor geneesmiddelen.
NL9002336 1990-10-25
NL9002336A NL9002336A (nl) 1990-10-24 1990-10-25 Bekledings- of matrixmateriaal voor geneesmiddelen.

Publications (1)

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

Family

ID=26646764

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1991/002046 WO1992007553A1 (fr) 1990-10-24 1991-10-24 Matiere d'enrobage ou matricielle pour medicaments

Country Status (3)

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

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995011032A1 (fr) * 1993-10-19 1995-04-27 The Procter & Gamble Company Forme galenique de sene
WO1996014344A1 (fr) * 1994-11-02 1996-05-17 Zeneca Limited Modificateur rheologique pour revetements a base de solvant
EP0779361A2 (fr) 1995-12-15 1997-06-18 F. Hoffmann-La Roche Ag Forme tronquée de la protéine inhibitrice kappa B, production récombinante et utilisation
EP1195394A1 (fr) * 2000-10-04 2002-04-10 Basf Aktiengesellschaft Polymères et copolymères à base d'hydroxyacrylates ou hydroxymethacrylates, leur préparation et leur utilisation pour les formes posologiques en pharmacie

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

Citations (7)

* Cited by examiner, † Cited by third party
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 (de) * 1968-09-03 1970-04-30 Banker Dr Gilbert S Arzneimittelzubereitung
WO1983000435A1 (fr) * 1981-07-31 1983-02-17 Rhodes, John Compositions pharmaceutiques administrables oralement
EP0143608A2 (fr) * 1983-11-25 1985-06-05 Ciba Specialty Chemicals Water Treatments Limited Production et utilisation de billes polymères
EP0143935B1 (fr) * 1983-10-04 1989-08-16 RB Kunststoffpatent-Verwertungs AG Polymére thermoplastique et articles fabriqués à partir d'un polymère thermoplastique
EP0383967A1 (fr) * 1989-02-17 1990-08-29 Dojin Iyaku-Kako Co., Ltd. Composition de Diclofénac sodium à libération soutenue

Patent Citations (7)

* Cited by examiner, † Cited by third party
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 (de) * 1968-09-03 1970-04-30 Banker Dr Gilbert S Arzneimittelzubereitung
WO1983000435A1 (fr) * 1981-07-31 1983-02-17 Rhodes, John Compositions pharmaceutiques administrables oralement
EP0143935B1 (fr) * 1983-10-04 1989-08-16 RB Kunststoffpatent-Verwertungs AG Polymére thermoplastique et articles fabriqués à partir d'un polymère thermoplastique
EP0143608A2 (fr) * 1983-11-25 1985-06-05 Ciba Specialty Chemicals Water Treatments Limited Production et utilisation de billes polymères
EP0383967A1 (fr) * 1989-02-17 1990-08-29 Dojin Iyaku-Kako Co., Ltd. Composition de Diclofénac sodium à libération soutenue

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEM. ZENTRALBLATT vol. 50, no. 1864, 1965, I. UTSUMI: 'SCHUTZ]BERZ]GE' see abstract *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995011032A1 (fr) * 1993-10-19 1995-04-27 The Procter & Gamble Company Forme galenique de sene
US5514663A (en) * 1993-10-19 1996-05-07 The Procter & Gamble Company Senna dosage form
WO1996014344A1 (fr) * 1994-11-02 1996-05-17 Zeneca Limited Modificateur rheologique pour revetements a base de solvant
US6117935A (en) * 1994-11-02 2000-09-12 Zeneca Limited Rheology modifier for solvent-based coatings
EP0779361A2 (fr) 1995-12-15 1997-06-18 F. Hoffmann-La Roche Ag Forme tronquée de la protéine inhibitrice kappa B, production récombinante et utilisation
EP1195394A1 (fr) * 2000-10-04 2002-04-10 Basf Aktiengesellschaft Polymères et copolymères à base d'hydroxyacrylates ou hydroxymethacrylates, leur préparation et leur utilisation pour les formes posologiques en pharmacie
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

Also Published As

Publication number Publication date
NL9002336A (nl) 1992-05-18
AU8852391A (en) 1992-05-26

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