CA2346062C - Coated medicament forms with controlled active substance release - Google Patents
Coated medicament forms with controlled active substance release Download PDFInfo
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- CA2346062C CA2346062C CA002346062A CA2346062A CA2346062C CA 2346062 C CA2346062 C CA 2346062C CA 002346062 A CA002346062 A CA 002346062A CA 2346062 A CA2346062 A CA 2346062A CA 2346062 C CA2346062 C CA 2346062C
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- meth
- acid
- acrylate
- acrylic
- methacrylic acid
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Classifications
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- 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
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
Abstract
The invention relates to a pharmaceutical preparation consisting of: (a) a core containing an active substance, optionally an excipient and common pharmaceutical additives in addition to the salt of an inorganic acid whose proportion in the weight of the core ranges from 2.5 to 97 % by weight and (b) and outer film coating consisting of one or more (meth)acrylate copolymers and optionally common pharmaceutical adjuvants, wherein 40 to 100 % by weight of the (meth)acrylat e copolymers consist of 93 to 98 % by weight of radically polymerized C1- to C4-alkylesters of acrylic or methacrylic acid and 7 to 2 % by weight of (meth)acrylate monomers with a quaternary ammonium group in the alkyl radical and that may be optionally present in a mixture consisting of 1 to 60 % by weight of one or more additional (meth)acrylate copolymers different from the above-mentioned (meth)acrylate copolymers, consisting of 85 to 100 % by weight of a radically polymerized C1- to C4-alkylesters of acrylic orethacrylic aci d and optionally and optionally up to 15 % by weight of additional (meth)acrylate monomers with basic groups or acid groups in the alkyl radica l.
Description
COATED MEDICAMENT FORMS WITH CONTROLLED ACTIVE SUBSTANCE RELEASE
Field of the Invention The invention relates to the art of coated pharmaceutical forms with controlled active principle release.
Backqround of the Invention European Patent Application 0463877 describes pharmaceutical compositions with delayed active principle release, comprising a core with a pharmaceutical active principle and a single-layer coating film of a hydrophobic salt and a water-insoluble copolymer of ethyl acrylate, methyl methacrylate and trimethylammoniumethyl methacrylate chloride. The hydrophobic salt can be, for example, Ca or Mg stearate. Sigmoidal release curves are obtained.
European Patent Applications 0225085, 0122077 and 0123470 describe the use of organic salts in pharmaceutical cores provided with various coatings from organic solutions. Substantially sigmoidal release characteristics are found.
European Patent Application 0436370 describes pharmaceutical compositions with delayed active principle release comprising a core with a pharmaceutical active principle and an organic acid and an outer coating film which was applied by aqueous spraying and is a copolymer of ethyl acrylate, methyl methacrylate and trimethylammoniumethyl methacrylate chloride. Sigmoidal release curves are obtained in this case also. The use of organic acids in the salt form is not considered in any of the cited documents.
Field of the Invention The invention relates to the art of coated pharmaceutical forms with controlled active principle release.
Backqround of the Invention European Patent Application 0463877 describes pharmaceutical compositions with delayed active principle release, comprising a core with a pharmaceutical active principle and a single-layer coating film of a hydrophobic salt and a water-insoluble copolymer of ethyl acrylate, methyl methacrylate and trimethylammoniumethyl methacrylate chloride. The hydrophobic salt can be, for example, Ca or Mg stearate. Sigmoidal release curves are obtained.
European Patent Applications 0225085, 0122077 and 0123470 describe the use of organic salts in pharmaceutical cores provided with various coatings from organic solutions. Substantially sigmoidal release characteristics are found.
European Patent Application 0436370 describes pharmaceutical compositions with delayed active principle release comprising a core with a pharmaceutical active principle and an organic acid and an outer coating film which was applied by aqueous spraying and is a copolymer of ethyl acrylate, methyl methacrylate and trimethylammoniumethyl methacrylate chloride. Sigmoidal release curves are obtained in this case also. The use of organic acids in the salt form is not considered in any of the cited documents.
Summary of the Invention It was regarded as an object to improve the pharmaceutical preparations known from European Patent Applications 0463877 and 0436370. Among the objectives in this regard it was hoped to obtain, even with relatively small layer thicknesses, sigmoidal release curves that otherwise can only be achieved with larger applications of coating mater-ial.i Accordingly, as an aspect of the invention there is provided a pharmaceutical formulation comprising (a) a core containing an active principle, if necessary a substrate and common pharmaceutical additives, and the salt of an organic acid, whose proportion of the core weight corresponds to 2.5 to 97.5 wt%, and (b) an outer coating film, which comprises one or more (meth)acrylate copolymers and, if necessary, common pharmaceutical adjuvants, wherein 40 to 100 wt% of the (meth)acrylate copolymers comprise 93 to 98 wt% of radically polymerized Cl to C4 alkyl esters of acrylic or methacrylic acid and 7 to 2 wt% of (meth)acrylate nionomers with a quaternary ammonium group in the alkyl rad.ical and if necessary can be present in a rriixture with I to 60 wt% of one or more further (meth)acrylate copolymers, which are different from the above-mentioned (meth)acrylate cppolymers, and which are composed of 85 to 100 wt% of radically polymerized Cl to C4 alkyl esters of acrylic or methacrylic acid and if necessary up to 15 wt% of further (meth)acrylate monomers with basic groups or acid groups in the alkyl radical.
3.
Detailed Description Cores (a) In the simplest case, the core can be composed mereEy of the active principle and the salt of the organic acid. Usually it additionally contains a substrate such as a nonpareil and pharmaceutical adjuvants such as highly disperse silica gel or polyvinylpyrrolidone (PVP).
Thus core (a) comprises = up to 97.5 to 2.5, preferably 80 to 5 wt% of active principle = 2.5 to 97.5, preferably 5 to 80, especially 10 to 50 wt% of one or more salts of organic acid = 0 to 95, preferably 10 to 50 wt% of pharmaceutical adjuvants = 0 to 95, preferably 10 to 50 wt% of a substrate The cores can be manufactured by techniques such as direct pressing, extrusion and followed by forming to rounded shape, moist or dry granulation or direct pelleting (for example on plates) or by binding of powders (powder layering) on spheruies (nonpareils.) free of active principle or on particles containing active principle.
The pharmaceutical adjuvants included in addition to the active principle can be, for example, binders such as cellulose and derivatives thereof, polyvinylpyrrolidone (PVP), gelatins, (meth)acrylates, starches and derivatives thereof or sugar.
I I
P-:tIAY. r7. 2001 4: J 2PM 4 YV,~. ~f E 1 u iCA 02346062 2001 03 30 ~ ~
F NO. 0256 P. 6/22 The cores can be homogeneous or can have a layered structure, wherein the active principle is preferably contained in the outer layer.
Salts of organic acids The salts of organic acids used must be toxicologicaNy safe and usable in pharmaceuticals. Alkali salts (ammonium, lithium, sodium, potassium) are preferred_ The preferred type depends on the special formulation; besides the inventive functionality, however, the pharmacological effects of the ions must also be considered. Preferred are salts of weak organic acids such as citric acid, fumaric acid, formic acid, acetic acid, maleit: acid, tartaric acid, glutaric acid or lactic acid.
Particularly suitable are sodium succinate, sodiuni citrate and sodium acetate.
The use of acetic acid in the form of sodium acetate offers the advantage that processing can be achieved with a solid rather than with a liquid, The type of acid controls the steepness of the acitive principle release curve, especially in the case of sigmoidal release curves.
In the inventive formulations, the salts are present as the outer layer of the core, bound by binders. They are applied by spraying from solution or by application of powder witti simultaneous supply of binder solution.
Variations are also possible in individual cases, however, in which the active principle is applied in a mixture with the salts or a masking layer is applied 1V~At. ~?. 2 U1 4 F F:};: ,.LFI ~ CA 02346062 2001-03-30 ~ l256 P. J~
2 ' ~ +vi +J 1 Y U. V V J .D. I~ / 2 2-Wp 00/19984 PCTlEP99/07179 between the active principle layer and the salt layer. Finaily, the salt of the organic acid can also be applied on the core, so that it forms the outer layer.
The proportion of the salts of the organic acid(s) in the core weight amounts to 2.5 wt lo to 97.5 wt%, preferably 5 to 80 wt%, especially 10 to 50 wt%.
Outer coating film (b) The outer coating film comprises one or more (rneth)acrylate copolymers and if necessary common pharmaceutical adjuvants such as plasticizers, pigments, pore-forming agents, wetting agents, release agents, etc.
The principle of the invention is based on a suspected interaction between the salt of an organic acid and a (meth)acrylate copolymer comprising 93 to 98 wt% of Cl to C4 alkyl esters of acrylic or methacrylic acid and 7 to 2 wt% of (meth)acrylate monomers with a quaternary amrnonium group in the alkyl radical. in order to ensure this interaction, the said (meth)acrylate copolymers must comprise at least 40 wt% of the structure of the coating, in order to achieve the desired interaction, Such (meth)acrylate monomers are commercially available and have long been used for delayed-release coatings.
They are practically insoluble in water. They cari be used alone or in mixtures with other (meth)acrylate copolymers. If sigmoidal active principle release characteristics are to be obtained, coating (b) miust comprise at least 80, Cti~ ~ iCA 02346062 2001-03-30 7 14~AY. 17. 2001 4 .G ~,~ ~P~I UV;~BE~ L,. ... ~~~ ~~~9 i~
~256 P. 8122 preferably 90 or 100 wt% of the said copolymer type.
Preferred Cl to C4 alkyl esters of acrylic or methacrylic acid are methyl, acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate and methyl methacrylate.
2-Trimethylammoniumethyl methacrylate chloride is especially preferred as the (meth)acrylate monomer containing quaternary ammonium groups.
An appropriate copolymer can be formed, for example, from 50 to 70 wt% of methyl methacrylate, 20 to 40 wt% of ethyl acrylate and 7 to 2 wt% of trimethylammoniumethyl methacrylate chloride.
A preferred copolymer contains 65 wt !o of methyl methacrylate, 30 wt% of ethyl acrylate and 5 wt% of 2-trimethylammniumethyl methacrylate chloride (EUDRAGITQ3 RS).
.', Mixtures of (meth)acrXlate copolymers The mixture of the above-mentioned copolymers with further (meth)acrylate copolymers makes it possible to establish individual active principle release profiles. As exampies; it is also possible to obtain, instead of sigmoidal curves, profiles with immediate release, continuous release profiles or profiles of zeroth order or first order. Depending on the active principle requirement, profiles intermediate between the said types can also be achieved.
MAY. 17. 2001 4.5 Ll PI~ ~'~7E y ~t l CA 02346062 2001-03-30 ~.G Nf i, 0256 P.
WO 00l19984 PCT/EP99/07179 According to the invention, outer coating film (b) therefore can a mixture of the (meth)acrylate copolymers which comprise 93 to 98 wt% of Cl to C4 alkyl esters of acrylic or methacrylic acid and 7 to 2 wt% of (meth)acrylate monomers with a quaternary ammonium group in the alkyl radical and which are present in a proportion of at least 40 wt% with 1 to 60 wt%, preferably 40 to 60 wt% of one or more, preferably one, further (meth)acrylate copolymer or copolymers, which is or are composed of 85 to 100 wt% of Cl to C4 alkyl esters of acrylic or methacrylic acid and if neces-jary up to 15 wt% of further (meth)acrylate monomers with functional basic groups or acid groups in the alkyl radical. When the content of basic groups or acid groups in the alkyl radical exceeds 15 wt%, the interactions among the components are influenced in an undesired or hardly foreseeable manner.
A suitable (meth)acrylate copolymer for such a mixture can be composed, for example, of 85 to less than 93 wt% of Cl to G4 alkyl esters of acrylic or methacrylic acid and more than 7 to 15 wt% of (meth)acrylate monomers with a quaternary ammonium group in the alkyl radical. Such (meth)acrylate monomers are commercially available and have long been used for delayed-release coatings.
A copolymer which specifically is suitable contains, for example, 60 wt% of methyl methacrylate, 30 wt% of ethyl acrylate and 10 wt% of 2-trimethylammoniumethyl methacrylate chloride (EiURRAGITO RL).
Another suitable (meth)acrylate copolymer for a niixture comprises 95 to 100 wt% of Cl to C4 alkyl esters of acrylic or methacrylic acid and 0 to 5 wt% of 1Vi~~. ~ ~. 2001 ~ = 5 ~ 11~~ ~ir' 1 BE ~j~ 1 LCA 02346062 2001 03-30 )f~
WO 00/19984 PCTIEp99/07179 acrylic or methacrylic acid. Such (meth)acrylate monomers are commercially available.
Synthesis of (meth)acrylate copolymers in gener~31 The (rneth)acry{ate copolymers are obtained in ways known in themselves by radical bulk, solution, bead or emulsion polymerization. They can exist in the 4i form of extruded granules, ground powder, solution or dispersion.
Coatings The polymer application depends on the size anci surface area of the cores, on the solubility of the active principles and on the dlesired release profile.
It ranges between 5 and 80 wt% relative to the core, preferably between 10 and 60%.
The coatings can be applied in multiple layers or as a mixture. Mixtures of the polymers make it possible to establish weli-defined slopes in the second phase of the release profile. The content of quaternary amrnonium groups in the coating controls the permeability and thus the diffusion rate of dissolved substances (McGinity, Ed., Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, Marcel Dekker, Inc., Chapter 4, pp. 208-216). The release rate becomes faster as the proportion of hydrophilic, quaternary ammonium groups is increased. In this way there is achieved an adiditional capability for controi of active principle dosage in the second phase of the release profile.
%7~~, 17, L ~ U 1 4 :53P1~ 1iV'lx~E?" ~ 02346062 2001-03-30 ~ ~ u ~ Il 0256 P. 11/22 wO 00119984 pCT/EP99/07179 Further additives These are used mainly as processing aids and are intended to ensure a reliable and reproducible manufacturing process as well as long shelf Vife.
They can influence the permeability of the coatings, a property that can be used if necessary as an additional control parameter.
- Plasticizers Substances that are suitable as plasticizers usually have a molecular weight of between 100 and 20,000 and contain, in the molecule, one or more hydrophilic groups such as hydroxyl, ester or amino groups. Examples of suitable plasticizers are citric acid alkyl esters, glycerol esters, phthalic acid esters, sebacic acid esters, sucrose esters, sorbitan esters, dibutyl sebacate and polyethylene glycols 4000 to 20,000. Preferred plasticizers are triethyl citrate and acetyltriethyl citrate.
Are usually esters and liquid at room temperature:
citrates, phthalates, sebacates, castor oil - Antiadhesive agents These substances, which usually have lipophilic properties, are added to the spray suspensions and prevent agglomeration of the cores during film formation. Preferred are talc, ground silica gel or nonionic emulsifiers with an HLB value of between 3 and 8. The proportions irange between 3 and 100 wt%
relative to the polymer.
li MAY. 1 17. 2 0 0 l 4 = 5 3 P IVi u"NA il DY ~~ U 1 ia 02346062 2001-03-30 ~ Q
14 ~ J, C 2 5 6 r 2/22 wo 00/19984 PCTiEP99/07179 - As examples of further additives there can be added, in ways known in themselves, stabilizers, dyes, antioxidants, wettirig agents, pore-forming agents, pigments, brighteners, etc. _ Apnlication of the film coating Application process takes place by spray application from organic solution, or aqueous dispersions by melting or by direct powder application. In this connection it is critical for execution that uniform, pore-free coatings be formed.
Application processes according to the prior art can be found in, for example, Bauer, Lehmann, Osterwaid, Rothgan, "Coated Pharmaceutical Forms", Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, Chapter 7, pp. 165-196..
Properties, required tests and specifications relevant for application are listed in pharmacopeias.
Details can be found in common textbooks, such as:
~..
- Voigt, R. (1984): Textbook of Pharmaceutical Technology; Verlag Chemie Weinheim - Beerfield Beach/Florida - Basel.
- Sucker, H., Fuchs, P., Speiser, P.: Pharmaceutical Technology; Georg Thieme Verlag, Stuttgart (1991), especially Chapters.15 and 16, pp. 626-642.
- Gennaro, A.R. (Editor), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania (1985), Chapter 88, pp. 1567-1573.
~lA~. 17. ~QQl ~J~~1~ vU111~J~~ iICA 02346062 2001 03 30N i Ci 2 5 6 L 13/22 - List, P.H. (1982): Science of Pharmaceutical Forms, Wissenschaftliche Verlagsgesellschaft mbH Stuttgart.
Active arinc-ples (bioloqicallv active substances}
The pharmaceuticals used within the meaning of the invention are intended for administration in the human or animal body in order ~..
1. to cure, alleviate, prevent or detect diseases, injuries, body damage or pathological conditi.ons, 2_ to allow the nature, condition or functions of the body or mental conditions to be discerned, 3. to replace active principles or body fluids clenerated by the human or animal body, 4, to combat, eliminate or render harmless pathogens, parasites or substances foreign to the body or 5, to influence the nature, condition or functicins of the body or mental conditions.
Common pharmaceuticals can be found in reference works such as the Red List or the Merck Index.
li MAY. 17. 200! 't = 5 J P1i 51~1~kp P, , ~j I CA 02346062 .2001-03-30 J f~ NO.
0256 P. 14/22 According to the invention there can be used all active principles that satisfy the desired therapeutic effect within the meaning of the definition given hereinabove and that have adequate thermal stability.
Without claiming completeness, important examples (groups and individual substances) are the following:
analgesics, antiallergics, antiarrhythmics antibiotics, chemotherapeutics, antidiabetics, antidotes, antiepileptics, antihypertensives, antihypotensives, anticoagulants, antimycotics, antiphlogistics, beta receptor blockers, caicium antagonists and ACE inhibitors, broncholyticslantiasthmatics, cholinergics, corticosteroids (internal), dermatics, diuretics, enzyme inhibitors, enzyme preparations and transport proteins, expectorants, geriatrics, gout remedies, flu medicines, hormones and their inhibitors, hypnotics/sedatives, cardiacs, lipid-lowering drugs, parathyroid hormones/calcium metabolism regulators, psychopharmaceuticals, sex hormones and their inhibitors, spasmolytics, sympatholytics, sympathomimetics, vitamins, wound medications, cytostatics.
Preferred active principles for slow release of active principles are:
nifedipine. diltiazem, theophylline, diclofenec sodium, ketoprofen, ibuprofen, indomethacin, diltianzem, ambroxol, terbutaline, vincamine, propranolol, pentoxifylline, codeine, morphine, etilefrin, carbamazepine or the therapeutically used salts thereof.
,{L A1='iP~ ~t Y, 17. 200 l 4: F~}! 'i S1~i1~;~~ t~'I. CA 02346062 2001 03 30 v~; 1VO. 0256 P. 15/22 WO 0019984 pCTlEP99107179 Application forms and further embodiments In principle the described pharmaceutical forms can be administered directly by oral application. In the case of multiparticulate forms (multi unit dosage forms), however, further processing steps are performed subsequently.
The coated forms prepared according to the invention can be filled as individual doses into gelatin capsules and bags (sachets) or into appropriate multi-dose containers with dispensing device. Ingestion takes place in solid form or as a suspension in liquids.
By pressing there are obtained from granulates, if necessary after mixing in further adjuvants, tablets that disintegrate after ingestion and release the retarded subunits. Also conceivable is the embedding of agglomerates in polyethylene glycol or lipids for preparation of suppositories or vaginal pharmaceutical forms, In addition, coatings (b) can also be combined with or coated by prior art coatings. Suitable for this purpose are in particular (meth)acrylate copolymers which contain 10 to 60 wt% of methacrylic acid groups and otherwise are composed of, for example, methyl methacrylate and/or ethyl acrylate (EUDRAGIT type L or 5). In this way taste-masking properties or formulations for selective releases in the colon can be additionatiy achieved in combination with the inventive formulations.
MAY. 17. 2001 4 = 5 4 M E { 'J U j ~,CA 02346062 2001-03-30 V C. 0256 P. 16/22 EXAMPL.ES
Cooolyrners used Copolymer 1:
65 wt lo of methyl methacrylate, 30 wt% o1f ethyl acrylate and 5 wt% of trimethylarnmoniumethyl methacrylate chloride (EUDRAGIT@ RS).
..._, Copolymer 2:
60 wt% of methyl methacrylate, 30 wt% of ethyl acrylate and 10 wt% of trimethylammoniumethyl methacrylate chloride (EUDRAGIT RL).
Copolymer 3:
30 wt% of ethyl acrylate, 69 wt% of inethyl methacrylate and 1 wt% of methacrylic acid (EUDRAGITO NE 30D).
Prevaration of coated theophylline preparations The preparation of the active-principle-containing pellet cores is achieved in a manner known in itself in a conventional sugar-coating pan by the sprinkling process. In this process the substrate cores (noripareils) are rotated in the pan and built up to pellets with the powder mixture (sprinkling) while continuous humidification is performed with the binder solution (spraying, nozzle diameter 1 mm, spraying pressure 0.5 bar, spraying spee(J 3 to 6 g/min). Thereafter the product is dried in the drying cabinet (24 hours ait 40 C) and the needed particle-size fraction is collected by sieving.
MAY. 17. 2 001 4 :54H S~ABEY ~GI!CA02346062 2001õ03-30Nu. 0256 h. 17/22 Wo 00/19984 PCT/Ep99107179 Nonpareils (0.5 to 0.6 mm) were used as substraites in ail examples. Thereon there was applied theophylline as the active principle as well as various proportions of the respective organic acid salt being used. As pharmaceutical adjuvants there were used a polyvinylpyrrolidone (Kollidon 25) in, and highly disperse silica gel (Aerosil 200) or sucrose. The sprinkling time ranged between 77 and 142 minutes at pan speeds of 40 rpm.
.~, The coating is applied by known techniques in a fluidized-bed apparatus.
Aqueous dispersions with a copolymer content oif 30 wt% were used. In addition, triethyl citrate was used as plasticizer aind talc as release agent.
Measurement of the theophylline release Determination of the active principle release was performed in a manner known in itself from the European Pharmacopeia in a paddle apparatus at a speed of 100 rpm in purified water or phosphate buffer of pH 6.8. The quantity of active principle released was determined photometrically. The measurement period was adapted to the adjusted release profile and ranged between 10 and 24 hours, with measurements every 1 or 2 hours as the case may be. After completion of the determination, the test liquid containing the remaining pellet residues was homogenized and the quantity of active principle present therein was used as 100% reference value for the calculation.
MAY. 17. L~~l ~=~~P1~~ 5~~ABD~l lf~ J~CA 02346062 2001 03 30J~ 3. U25 6 P.
Exa~ 1:
Release curve of the influence of various proportions (21, 32 and 43 wt%) of sodium acetate in theophyllinelsodium acetate cores with a coating application of 30 wt% of copolymer 1.
Example 2:
Release curve of the influence of various layer thicknesses (20, 30 and 40 wt%) of copolymer 1 on theophylline/sodium aceitate cores.
Example 3:
Comparison of the release of theophylline from ttieophylline/sodium succinate (Na succinate) and theophylline/succinic acid preparations with 42 and 60 wt%
coating applications of copolymer 1.
Example 4:
Release curve of the influence of various layer thicknesses (10, 20, 30 and 40 wt%) of a mixture (1:1) of copolymer 1 and copollymer 2 on theophylline/sodium acetate cores.
Example 5:
Release curve of the influence of various layer thicknesses (10, 20, 30 and 40 wt%) of a mixture (1:1) of copolymer 1 and copoUymer 3 on theophylline/sodium acetate cores.
MAY. 17. 2001 4:54P1dI S'4ti'ABEY O~,, IIa 02346062 2001-03-30'0 NC. G256 F.
wo 00/19984 PCT/EP99/07179 The recipes for Examples 1 to 5 are summarized in the following table (all values in g):
Example 1 2 3 4 5 CORES
1) Sprinkling mixture Nonpareils 700 700 700 700 700 Theophylline 901/675/450 675 420 675 675 ~,. Na acetate 450/675/901 575 - 675 675 Na-succinatel 960 / 700 succinic acid Kollidon 25 42 42 43 / 35 42 42 Aerosi1200 7 7 7l6 7 7 2) Binder solution Kollidon 30 20 20 - 20 20 Sucrose - - 276 / E17 - -Ethanol - - 135 / 28 - -Water 380 380 430 / fi5 380 380 CORES +
COATINGS
Quantity of 500 500 500 500 500 coated cores Copolymer 1 500 333/500/667 1005 83/167/250/ 83/167/250/
dispersion, 333 333 30%
Copolymer 2 - - 125/167/250/ -dispersion, 333 30%
Copolymer 3 - - - - 831167/2501 dispersion, 333 30%
Triethyl citrate 30 27140/53 38 10/20130/40 10/20/30/40 Talc 75 50/751100 159 25/501751100 25/50/75/100 Water 670 447/670/893 1179- 225/447/670/ 225/447/670/
Detailed Description Cores (a) In the simplest case, the core can be composed mereEy of the active principle and the salt of the organic acid. Usually it additionally contains a substrate such as a nonpareil and pharmaceutical adjuvants such as highly disperse silica gel or polyvinylpyrrolidone (PVP).
Thus core (a) comprises = up to 97.5 to 2.5, preferably 80 to 5 wt% of active principle = 2.5 to 97.5, preferably 5 to 80, especially 10 to 50 wt% of one or more salts of organic acid = 0 to 95, preferably 10 to 50 wt% of pharmaceutical adjuvants = 0 to 95, preferably 10 to 50 wt% of a substrate The cores can be manufactured by techniques such as direct pressing, extrusion and followed by forming to rounded shape, moist or dry granulation or direct pelleting (for example on plates) or by binding of powders (powder layering) on spheruies (nonpareils.) free of active principle or on particles containing active principle.
The pharmaceutical adjuvants included in addition to the active principle can be, for example, binders such as cellulose and derivatives thereof, polyvinylpyrrolidone (PVP), gelatins, (meth)acrylates, starches and derivatives thereof or sugar.
I I
P-:tIAY. r7. 2001 4: J 2PM 4 YV,~. ~f E 1 u iCA 02346062 2001 03 30 ~ ~
F NO. 0256 P. 6/22 The cores can be homogeneous or can have a layered structure, wherein the active principle is preferably contained in the outer layer.
Salts of organic acids The salts of organic acids used must be toxicologicaNy safe and usable in pharmaceuticals. Alkali salts (ammonium, lithium, sodium, potassium) are preferred_ The preferred type depends on the special formulation; besides the inventive functionality, however, the pharmacological effects of the ions must also be considered. Preferred are salts of weak organic acids such as citric acid, fumaric acid, formic acid, acetic acid, maleit: acid, tartaric acid, glutaric acid or lactic acid.
Particularly suitable are sodium succinate, sodiuni citrate and sodium acetate.
The use of acetic acid in the form of sodium acetate offers the advantage that processing can be achieved with a solid rather than with a liquid, The type of acid controls the steepness of the acitive principle release curve, especially in the case of sigmoidal release curves.
In the inventive formulations, the salts are present as the outer layer of the core, bound by binders. They are applied by spraying from solution or by application of powder witti simultaneous supply of binder solution.
Variations are also possible in individual cases, however, in which the active principle is applied in a mixture with the salts or a masking layer is applied 1V~At. ~?. 2 U1 4 F F:};: ,.LFI ~ CA 02346062 2001-03-30 ~ l256 P. J~
2 ' ~ +vi +J 1 Y U. V V J .D. I~ / 2 2-Wp 00/19984 PCTlEP99/07179 between the active principle layer and the salt layer. Finaily, the salt of the organic acid can also be applied on the core, so that it forms the outer layer.
The proportion of the salts of the organic acid(s) in the core weight amounts to 2.5 wt lo to 97.5 wt%, preferably 5 to 80 wt%, especially 10 to 50 wt%.
Outer coating film (b) The outer coating film comprises one or more (rneth)acrylate copolymers and if necessary common pharmaceutical adjuvants such as plasticizers, pigments, pore-forming agents, wetting agents, release agents, etc.
The principle of the invention is based on a suspected interaction between the salt of an organic acid and a (meth)acrylate copolymer comprising 93 to 98 wt% of Cl to C4 alkyl esters of acrylic or methacrylic acid and 7 to 2 wt% of (meth)acrylate monomers with a quaternary amrnonium group in the alkyl radical. in order to ensure this interaction, the said (meth)acrylate copolymers must comprise at least 40 wt% of the structure of the coating, in order to achieve the desired interaction, Such (meth)acrylate monomers are commercially available and have long been used for delayed-release coatings.
They are practically insoluble in water. They cari be used alone or in mixtures with other (meth)acrylate copolymers. If sigmoidal active principle release characteristics are to be obtained, coating (b) miust comprise at least 80, Cti~ ~ iCA 02346062 2001-03-30 7 14~AY. 17. 2001 4 .G ~,~ ~P~I UV;~BE~ L,. ... ~~~ ~~~9 i~
~256 P. 8122 preferably 90 or 100 wt% of the said copolymer type.
Preferred Cl to C4 alkyl esters of acrylic or methacrylic acid are methyl, acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate and methyl methacrylate.
2-Trimethylammoniumethyl methacrylate chloride is especially preferred as the (meth)acrylate monomer containing quaternary ammonium groups.
An appropriate copolymer can be formed, for example, from 50 to 70 wt% of methyl methacrylate, 20 to 40 wt% of ethyl acrylate and 7 to 2 wt% of trimethylammoniumethyl methacrylate chloride.
A preferred copolymer contains 65 wt !o of methyl methacrylate, 30 wt% of ethyl acrylate and 5 wt% of 2-trimethylammniumethyl methacrylate chloride (EUDRAGITQ3 RS).
.', Mixtures of (meth)acrXlate copolymers The mixture of the above-mentioned copolymers with further (meth)acrylate copolymers makes it possible to establish individual active principle release profiles. As exampies; it is also possible to obtain, instead of sigmoidal curves, profiles with immediate release, continuous release profiles or profiles of zeroth order or first order. Depending on the active principle requirement, profiles intermediate between the said types can also be achieved.
MAY. 17. 2001 4.5 Ll PI~ ~'~7E y ~t l CA 02346062 2001-03-30 ~.G Nf i, 0256 P.
WO 00l19984 PCT/EP99/07179 According to the invention, outer coating film (b) therefore can a mixture of the (meth)acrylate copolymers which comprise 93 to 98 wt% of Cl to C4 alkyl esters of acrylic or methacrylic acid and 7 to 2 wt% of (meth)acrylate monomers with a quaternary ammonium group in the alkyl radical and which are present in a proportion of at least 40 wt% with 1 to 60 wt%, preferably 40 to 60 wt% of one or more, preferably one, further (meth)acrylate copolymer or copolymers, which is or are composed of 85 to 100 wt% of Cl to C4 alkyl esters of acrylic or methacrylic acid and if neces-jary up to 15 wt% of further (meth)acrylate monomers with functional basic groups or acid groups in the alkyl radical. When the content of basic groups or acid groups in the alkyl radical exceeds 15 wt%, the interactions among the components are influenced in an undesired or hardly foreseeable manner.
A suitable (meth)acrylate copolymer for such a mixture can be composed, for example, of 85 to less than 93 wt% of Cl to G4 alkyl esters of acrylic or methacrylic acid and more than 7 to 15 wt% of (meth)acrylate monomers with a quaternary ammonium group in the alkyl radical. Such (meth)acrylate monomers are commercially available and have long been used for delayed-release coatings.
A copolymer which specifically is suitable contains, for example, 60 wt% of methyl methacrylate, 30 wt% of ethyl acrylate and 10 wt% of 2-trimethylammoniumethyl methacrylate chloride (EiURRAGITO RL).
Another suitable (meth)acrylate copolymer for a niixture comprises 95 to 100 wt% of Cl to C4 alkyl esters of acrylic or methacrylic acid and 0 to 5 wt% of 1Vi~~. ~ ~. 2001 ~ = 5 ~ 11~~ ~ir' 1 BE ~j~ 1 LCA 02346062 2001 03-30 )f~
WO 00/19984 PCTIEp99/07179 acrylic or methacrylic acid. Such (meth)acrylate monomers are commercially available.
Synthesis of (meth)acrylate copolymers in gener~31 The (rneth)acry{ate copolymers are obtained in ways known in themselves by radical bulk, solution, bead or emulsion polymerization. They can exist in the 4i form of extruded granules, ground powder, solution or dispersion.
Coatings The polymer application depends on the size anci surface area of the cores, on the solubility of the active principles and on the dlesired release profile.
It ranges between 5 and 80 wt% relative to the core, preferably between 10 and 60%.
The coatings can be applied in multiple layers or as a mixture. Mixtures of the polymers make it possible to establish weli-defined slopes in the second phase of the release profile. The content of quaternary amrnonium groups in the coating controls the permeability and thus the diffusion rate of dissolved substances (McGinity, Ed., Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, Marcel Dekker, Inc., Chapter 4, pp. 208-216). The release rate becomes faster as the proportion of hydrophilic, quaternary ammonium groups is increased. In this way there is achieved an adiditional capability for controi of active principle dosage in the second phase of the release profile.
%7~~, 17, L ~ U 1 4 :53P1~ 1iV'lx~E?" ~ 02346062 2001-03-30 ~ ~ u ~ Il 0256 P. 11/22 wO 00119984 pCT/EP99/07179 Further additives These are used mainly as processing aids and are intended to ensure a reliable and reproducible manufacturing process as well as long shelf Vife.
They can influence the permeability of the coatings, a property that can be used if necessary as an additional control parameter.
- Plasticizers Substances that are suitable as plasticizers usually have a molecular weight of between 100 and 20,000 and contain, in the molecule, one or more hydrophilic groups such as hydroxyl, ester or amino groups. Examples of suitable plasticizers are citric acid alkyl esters, glycerol esters, phthalic acid esters, sebacic acid esters, sucrose esters, sorbitan esters, dibutyl sebacate and polyethylene glycols 4000 to 20,000. Preferred plasticizers are triethyl citrate and acetyltriethyl citrate.
Are usually esters and liquid at room temperature:
citrates, phthalates, sebacates, castor oil - Antiadhesive agents These substances, which usually have lipophilic properties, are added to the spray suspensions and prevent agglomeration of the cores during film formation. Preferred are talc, ground silica gel or nonionic emulsifiers with an HLB value of between 3 and 8. The proportions irange between 3 and 100 wt%
relative to the polymer.
li MAY. 1 17. 2 0 0 l 4 = 5 3 P IVi u"NA il DY ~~ U 1 ia 02346062 2001-03-30 ~ Q
14 ~ J, C 2 5 6 r 2/22 wo 00/19984 PCTiEP99/07179 - As examples of further additives there can be added, in ways known in themselves, stabilizers, dyes, antioxidants, wettirig agents, pore-forming agents, pigments, brighteners, etc. _ Apnlication of the film coating Application process takes place by spray application from organic solution, or aqueous dispersions by melting or by direct powder application. In this connection it is critical for execution that uniform, pore-free coatings be formed.
Application processes according to the prior art can be found in, for example, Bauer, Lehmann, Osterwaid, Rothgan, "Coated Pharmaceutical Forms", Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, Chapter 7, pp. 165-196..
Properties, required tests and specifications relevant for application are listed in pharmacopeias.
Details can be found in common textbooks, such as:
~..
- Voigt, R. (1984): Textbook of Pharmaceutical Technology; Verlag Chemie Weinheim - Beerfield Beach/Florida - Basel.
- Sucker, H., Fuchs, P., Speiser, P.: Pharmaceutical Technology; Georg Thieme Verlag, Stuttgart (1991), especially Chapters.15 and 16, pp. 626-642.
- Gennaro, A.R. (Editor), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania (1985), Chapter 88, pp. 1567-1573.
~lA~. 17. ~QQl ~J~~1~ vU111~J~~ iICA 02346062 2001 03 30N i Ci 2 5 6 L 13/22 - List, P.H. (1982): Science of Pharmaceutical Forms, Wissenschaftliche Verlagsgesellschaft mbH Stuttgart.
Active arinc-ples (bioloqicallv active substances}
The pharmaceuticals used within the meaning of the invention are intended for administration in the human or animal body in order ~..
1. to cure, alleviate, prevent or detect diseases, injuries, body damage or pathological conditi.ons, 2_ to allow the nature, condition or functions of the body or mental conditions to be discerned, 3. to replace active principles or body fluids clenerated by the human or animal body, 4, to combat, eliminate or render harmless pathogens, parasites or substances foreign to the body or 5, to influence the nature, condition or functicins of the body or mental conditions.
Common pharmaceuticals can be found in reference works such as the Red List or the Merck Index.
li MAY. 17. 200! 't = 5 J P1i 51~1~kp P, , ~j I CA 02346062 .2001-03-30 J f~ NO.
0256 P. 14/22 According to the invention there can be used all active principles that satisfy the desired therapeutic effect within the meaning of the definition given hereinabove and that have adequate thermal stability.
Without claiming completeness, important examples (groups and individual substances) are the following:
analgesics, antiallergics, antiarrhythmics antibiotics, chemotherapeutics, antidiabetics, antidotes, antiepileptics, antihypertensives, antihypotensives, anticoagulants, antimycotics, antiphlogistics, beta receptor blockers, caicium antagonists and ACE inhibitors, broncholyticslantiasthmatics, cholinergics, corticosteroids (internal), dermatics, diuretics, enzyme inhibitors, enzyme preparations and transport proteins, expectorants, geriatrics, gout remedies, flu medicines, hormones and their inhibitors, hypnotics/sedatives, cardiacs, lipid-lowering drugs, parathyroid hormones/calcium metabolism regulators, psychopharmaceuticals, sex hormones and their inhibitors, spasmolytics, sympatholytics, sympathomimetics, vitamins, wound medications, cytostatics.
Preferred active principles for slow release of active principles are:
nifedipine. diltiazem, theophylline, diclofenec sodium, ketoprofen, ibuprofen, indomethacin, diltianzem, ambroxol, terbutaline, vincamine, propranolol, pentoxifylline, codeine, morphine, etilefrin, carbamazepine or the therapeutically used salts thereof.
,{L A1='iP~ ~t Y, 17. 200 l 4: F~}! 'i S1~i1~;~~ t~'I. CA 02346062 2001 03 30 v~; 1VO. 0256 P. 15/22 WO 0019984 pCTlEP99107179 Application forms and further embodiments In principle the described pharmaceutical forms can be administered directly by oral application. In the case of multiparticulate forms (multi unit dosage forms), however, further processing steps are performed subsequently.
The coated forms prepared according to the invention can be filled as individual doses into gelatin capsules and bags (sachets) or into appropriate multi-dose containers with dispensing device. Ingestion takes place in solid form or as a suspension in liquids.
By pressing there are obtained from granulates, if necessary after mixing in further adjuvants, tablets that disintegrate after ingestion and release the retarded subunits. Also conceivable is the embedding of agglomerates in polyethylene glycol or lipids for preparation of suppositories or vaginal pharmaceutical forms, In addition, coatings (b) can also be combined with or coated by prior art coatings. Suitable for this purpose are in particular (meth)acrylate copolymers which contain 10 to 60 wt% of methacrylic acid groups and otherwise are composed of, for example, methyl methacrylate and/or ethyl acrylate (EUDRAGIT type L or 5). In this way taste-masking properties or formulations for selective releases in the colon can be additionatiy achieved in combination with the inventive formulations.
MAY. 17. 2001 4 = 5 4 M E { 'J U j ~,CA 02346062 2001-03-30 V C. 0256 P. 16/22 EXAMPL.ES
Cooolyrners used Copolymer 1:
65 wt lo of methyl methacrylate, 30 wt% o1f ethyl acrylate and 5 wt% of trimethylarnmoniumethyl methacrylate chloride (EUDRAGIT@ RS).
..._, Copolymer 2:
60 wt% of methyl methacrylate, 30 wt% of ethyl acrylate and 10 wt% of trimethylammoniumethyl methacrylate chloride (EUDRAGIT RL).
Copolymer 3:
30 wt% of ethyl acrylate, 69 wt% of inethyl methacrylate and 1 wt% of methacrylic acid (EUDRAGITO NE 30D).
Prevaration of coated theophylline preparations The preparation of the active-principle-containing pellet cores is achieved in a manner known in itself in a conventional sugar-coating pan by the sprinkling process. In this process the substrate cores (noripareils) are rotated in the pan and built up to pellets with the powder mixture (sprinkling) while continuous humidification is performed with the binder solution (spraying, nozzle diameter 1 mm, spraying pressure 0.5 bar, spraying spee(J 3 to 6 g/min). Thereafter the product is dried in the drying cabinet (24 hours ait 40 C) and the needed particle-size fraction is collected by sieving.
MAY. 17. 2 001 4 :54H S~ABEY ~GI!CA02346062 2001õ03-30Nu. 0256 h. 17/22 Wo 00/19984 PCT/Ep99107179 Nonpareils (0.5 to 0.6 mm) were used as substraites in ail examples. Thereon there was applied theophylline as the active principle as well as various proportions of the respective organic acid salt being used. As pharmaceutical adjuvants there were used a polyvinylpyrrolidone (Kollidon 25) in, and highly disperse silica gel (Aerosil 200) or sucrose. The sprinkling time ranged between 77 and 142 minutes at pan speeds of 40 rpm.
.~, The coating is applied by known techniques in a fluidized-bed apparatus.
Aqueous dispersions with a copolymer content oif 30 wt% were used. In addition, triethyl citrate was used as plasticizer aind talc as release agent.
Measurement of the theophylline release Determination of the active principle release was performed in a manner known in itself from the European Pharmacopeia in a paddle apparatus at a speed of 100 rpm in purified water or phosphate buffer of pH 6.8. The quantity of active principle released was determined photometrically. The measurement period was adapted to the adjusted release profile and ranged between 10 and 24 hours, with measurements every 1 or 2 hours as the case may be. After completion of the determination, the test liquid containing the remaining pellet residues was homogenized and the quantity of active principle present therein was used as 100% reference value for the calculation.
MAY. 17. L~~l ~=~~P1~~ 5~~ABD~l lf~ J~CA 02346062 2001 03 30J~ 3. U25 6 P.
Exa~ 1:
Release curve of the influence of various proportions (21, 32 and 43 wt%) of sodium acetate in theophyllinelsodium acetate cores with a coating application of 30 wt% of copolymer 1.
Example 2:
Release curve of the influence of various layer thicknesses (20, 30 and 40 wt%) of copolymer 1 on theophylline/sodium aceitate cores.
Example 3:
Comparison of the release of theophylline from ttieophylline/sodium succinate (Na succinate) and theophylline/succinic acid preparations with 42 and 60 wt%
coating applications of copolymer 1.
Example 4:
Release curve of the influence of various layer thicknesses (10, 20, 30 and 40 wt%) of a mixture (1:1) of copolymer 1 and copollymer 2 on theophylline/sodium acetate cores.
Example 5:
Release curve of the influence of various layer thicknesses (10, 20, 30 and 40 wt%) of a mixture (1:1) of copolymer 1 and copoUymer 3 on theophylline/sodium acetate cores.
MAY. 17. 2001 4:54P1dI S'4ti'ABEY O~,, IIa 02346062 2001-03-30'0 NC. G256 F.
wo 00/19984 PCT/EP99/07179 The recipes for Examples 1 to 5 are summarized in the following table (all values in g):
Example 1 2 3 4 5 CORES
1) Sprinkling mixture Nonpareils 700 700 700 700 700 Theophylline 901/675/450 675 420 675 675 ~,. Na acetate 450/675/901 575 - 675 675 Na-succinatel 960 / 700 succinic acid Kollidon 25 42 42 43 / 35 42 42 Aerosi1200 7 7 7l6 7 7 2) Binder solution Kollidon 30 20 20 - 20 20 Sucrose - - 276 / E17 - -Ethanol - - 135 / 28 - -Water 380 380 430 / fi5 380 380 CORES +
COATINGS
Quantity of 500 500 500 500 500 coated cores Copolymer 1 500 333/500/667 1005 83/167/250/ 83/167/250/
dispersion, 333 333 30%
Copolymer 2 - - 125/167/250/ -dispersion, 333 30%
Copolymer 3 - - - - 831167/2501 dispersion, 333 30%
Triethyl citrate 30 27140/53 38 10/20130/40 10/20/30/40 Talc 75 50/751100 159 25/501751100 25/50/75/100 Water 670 447/670/893 1179- 225/447/670/ 225/447/670/
Claims (9)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical formulation comprising (a) a core containing an active principle, optionally a substrate and common pharmaceutical additives, and the salt of an organic acid, whose proportion of the core weight corresponds to 2.5 to 97.5 wt%, and (b) an outer coating film, which comprises one or more (meth)acrylate copolymers and, optionally, common pharmaceutical adjuvants, wherein 40 to 100 wt% of the (meth)acrylate copolymers comprise 93 to 98 wt% of radically polymerized C1 to C4 alkyl esters of acrylic or methacrylic acid and 7 to 2 wt% of (meth)acrylate monomers with a quaternary ammonium group in the alkyl radical and, optionally is present in a mixture with 1 to 60 wt% of one or more further (meth)acrylate copolymers which are different from the above-mentioned (meth)acrylate copolymers and which are composed of 85 to 100 wt% of radically polymerized C1 to C4 alkyl esters of acrylic or methacrylic acid and up to 15 wt% of further (meth)acrylate monomers with basic groups or acid groups in the alkyl radical.
2. A formulation according to claim 1, wherein the (meth)acrylate copolymer component of the outer coating film (b) is a mixture of 99 to 40 wt% of a (meth)acrylate copolymer comprising 93 to 98 wt% of C1 to C4 alkyl esters of acrylic or methacrylic acid and 7 to 2 wt% of (meth)acrylate monomers with a quaternary ammonium group in the alkyl radical, and 1 to 60 wt% of a (meth)acrylate copolymer which is composed of 85 to less than 92 wt% of C1 to C4 alkyl esters of acrylic or methacrylic acid and more than 7 to 15 wt% of (meth)acrylate monomers with a quaternary ammonium group in the alkyl radical.
3. A formulation according to claim 1, wherein the (meth)acrylate copolymer component of the outer coating film (b) is a mixture of 99 to 40 wt% of a (meth)acrylate copolymer comprising 93 to 98 wt% of C1 to C4 alkyl esters of acrylic or methacrylic acid and 7 to 2 wt% of (meth)acrylate monomers with a quaternary ammonium group in the alkyl radical, and 1 to 60 wt% of a (meth)acrylate copolymer which is composed of 95 to 100 wt% of C1 to C4 alkyl esters of acrylic or methacrylic acid and 0 to 5 wt% of acrylic or methacrylic acid.
4. A formulation according to any one of claims 1 to 3, wherein trimethylammoniumethyl methacrylate chloride is used as the (meth)acrylate monomer with a quaternary ammonium group in the alkyl radical.
5. A formulation according to any one of claims 1 to 4, wherein ammonium, lithium, sodium or potassium salts of citric acid, fumaric acid, formic acid, acetic acid, maleic acid, succinic acid, tartaric acid, glutaric acid or lactic acid are used as the salt of the organic acid.
6. A formulation according to any one of claims 1 to 5, wherein said formulation is pressed into tablets.
7. A formulation according to any one of claims 1 to 5, wherein said formulation is encapsulated by a gelatin capsule.
8. A formulation according to any one of claims 1 to 6, wherein said formulation is additionally encapsulated with a (meth)acrylate copolymer which contains 10 to 60 wt% of methacrylic acid radicals.
9. A formulation according to any one of claims 1 to 8, wherein the salt of the organic acid forms the outer layer of the core.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19845358.2 | 1998-10-02 | ||
| DE19845358A DE19845358A1 (en) | 1998-10-02 | 1998-10-02 | Coated drug forms with controlled drug delivery |
| PCT/EP1999/007179 WO2000019984A2 (en) | 1998-10-02 | 1999-09-28 | Coated medicament forms with controlled active substance release |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2346062A1 CA2346062A1 (en) | 2000-04-13 |
| CA2346062C true CA2346062C (en) | 2008-09-16 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002346062A Expired - Fee Related CA2346062C (en) | 1998-10-02 | 1999-09-28 | Coated medicament forms with controlled active substance release |
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| US (1) | US6878387B1 (en) |
| EP (1) | EP1117387B1 (en) |
| JP (1) | JP4615124B2 (en) |
| KR (1) | KR100657779B1 (en) |
| CN (1) | CN1182840C (en) |
| AT (1) | ATE286724T1 (en) |
| AU (1) | AU6197499A (en) |
| BR (1) | BR9913104B1 (en) |
| CA (1) | CA2346062C (en) |
| DE (2) | DE19845358A1 (en) |
| ES (1) | ES2234303T3 (en) |
| HK (1) | HK1058152A1 (en) |
| MX (1) | MXPA01003392A (en) |
| PL (1) | PL193899B1 (en) |
| SK (1) | SK285295B6 (en) |
| WO (1) | WO2000019984A2 (en) |
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| US10722473B2 (en) | 2018-11-19 | 2020-07-28 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2470599A1 (en) * | 1979-12-07 | 1981-06-12 | Panoz Donald | IMPROVEMENTS IN PROCESSES FOR THE PREPARATION OF GALENIC SHAPES WITH DELAYED ACTION AND PROGRAMMED RELEASE AND GALENIC FORMS OF MEDICAMENTS THUS OBTAINED |
| DE3124090A1 (en) | 1981-06-19 | 1983-01-05 | Dr. Karl Thomae Gmbh, 7950 Biberach | NEW ORAL DIPYRIDAMOL FORMS |
| IE55745B1 (en) * | 1983-04-06 | 1991-01-02 | Elan Corp Plc | Sustained absorption pharmaceutical composition |
| PH18946A (en) * | 1983-04-21 | 1985-11-14 | Elan Corp Plc | Controlled absorption pharmaceutical composition |
| SE457505B (en) | 1984-01-10 | 1989-01-09 | Lejus Medical Ab | LAMINATED ORAL PHARMACEUTICAL COMPOSITION AND PROCEDURES FOR ITS PREPARATION |
| JPS62114910A (en) * | 1985-11-13 | 1987-05-26 | エラン コ−ポレ−シヨン ピ− エル シ− | Absorption-controlled medicine |
| US5292522A (en) * | 1989-06-20 | 1994-03-08 | Rohm Gmbh | Aqueous film coating agent for solid medicaments |
| JPH0674206B2 (en) * | 1989-12-28 | 1994-09-21 | 田辺製薬株式会社 | Controlled release formulation and process for producing |
| JP2558396B2 (en) * | 1990-06-28 | 1996-11-27 | 田辺製薬株式会社 | Controlled release formulation |
| ES2149250T3 (en) * | 1993-04-23 | 2000-11-01 | Novartis Ag | DEVICE FOR THE ADMINISTRATION OF MEDICINES WITH CONTROLLED RELEASE. |
| EP0640341A1 (en) * | 1993-08-27 | 1995-03-01 | Mitsui Toatsu Chemicals, Incorporated | Sustained release pharmaceutical composition and process for producing same |
| AUPN969796A0 (en) * | 1996-05-07 | 1996-05-30 | F.H. Faulding & Co. Limited | Taste masked liquid suspensions |
| DE19626045C2 (en) * | 1996-06-28 | 1998-12-03 | Klinge Co Chem Pharm Fab | A stable dosage form for oral administration containing omeprazole as the active ingredient and methods of making the same |
| US5948440A (en) * | 1997-12-17 | 1999-09-07 | Ranbaxy Laboratories Limited | Modified release matrix formulation of cefaclor and cephalexin |
| US6159504A (en) * | 1999-01-11 | 2000-12-12 | Kitii Corporation, Ltd. | Core substance-containing calcium microparticles and methods for producing the same |
| JP2001139471A (en) * | 2000-11-20 | 2001-05-22 | Kyoto Pharmaceutical Industries Ltd | Flavoring oral medicinal composition |
-
1998
- 1998-10-02 DE DE19845358A patent/DE19845358A1/en not_active Withdrawn
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1999
- 1999-09-28 CN CNB998106801A patent/CN1182840C/en not_active Expired - Fee Related
- 1999-09-28 BR BRPI9913104-8A patent/BR9913104B1/en not_active IP Right Cessation
- 1999-09-28 KR KR1020017004111A patent/KR100657779B1/en not_active IP Right Cessation
- 1999-09-28 JP JP2000573346A patent/JP4615124B2/en not_active Expired - Fee Related
- 1999-09-28 MX MXPA01003392A patent/MXPA01003392A/en active IP Right Grant
- 1999-09-28 AT AT99948881T patent/ATE286724T1/en active
- 1999-09-28 SK SK426-2001A patent/SK285295B6/en not_active IP Right Cessation
- 1999-09-28 CA CA002346062A patent/CA2346062C/en not_active Expired - Fee Related
- 1999-09-28 EP EP99948881A patent/EP1117387B1/en not_active Expired - Lifetime
- 1999-09-28 ES ES99948881T patent/ES2234303T3/en not_active Expired - Lifetime
- 1999-09-28 DE DE59911452T patent/DE59911452D1/en not_active Expired - Lifetime
- 1999-09-28 PL PL99347780A patent/PL193899B1/en unknown
- 1999-09-28 AU AU61974/99A patent/AU6197499A/en not_active Abandoned
- 1999-09-28 US US09/787,438 patent/US6878387B1/en not_active Expired - Lifetime
- 1999-09-28 WO PCT/EP1999/007179 patent/WO2000019984A2/en active IP Right Grant
-
2004
- 2004-02-13 HK HK04101002A patent/HK1058152A1/en not_active IP Right Cessation
Also Published As
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|---|---|
| CA2346062A1 (en) | 2000-04-13 |
| DE59911452D1 (en) | 2005-02-17 |
| KR100657779B1 (en) | 2006-12-21 |
| KR20010075502A (en) | 2001-08-09 |
| MXPA01003392A (en) | 2003-07-21 |
| SK285295B6 (en) | 2006-10-05 |
| BR9913104A (en) | 2001-05-08 |
| PL347780A1 (en) | 2002-04-22 |
| EP1117387B1 (en) | 2005-01-12 |
| ATE286724T1 (en) | 2005-01-15 |
| BR9913104B1 (en) | 2010-11-30 |
| JP4615124B2 (en) | 2011-01-19 |
| WO2000019984A2 (en) | 2000-04-13 |
| HK1058152A1 (en) | 2004-05-07 |
| AU6197499A (en) | 2000-04-26 |
| ES2234303T3 (en) | 2005-06-16 |
| JP2002526401A (en) | 2002-08-20 |
| CN1446083A (en) | 2003-10-01 |
| EP1117387A2 (en) | 2001-07-25 |
| PL193899B1 (en) | 2007-03-30 |
| US6878387B1 (en) | 2005-04-12 |
| DE19845358A1 (en) | 2000-04-06 |
| CN1182840C (en) | 2005-01-05 |
| SK4262001A3 (en) | 2002-10-08 |
| WO2000019984A3 (en) | 2000-07-20 |
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| MKLA | Lapsed |
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