Solid dosage form with polymeric binder

Details Solid dosage form with polymeric binder Solid dosage form with polymeric binder

1999-09-14

2001-09-04

Travers, Russell (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic nonactive ingredient containing other...

Aftertreated solid synthetic organic polymer

C514S772200, C424S465000, C424S476000, C424S482000

Reexamination Certificate

active

06284803

ABSTRACT:

The invention relates to solid dosage forms comprising at least one polymeric binder and at least one active ingredient and, where appropriate, conventional additives and to a process for producing the solid dosage form.
Solid dosage forms comprising physiologically tolerated polymers as binders are becoming increasingly important, especially for dosage forms with delayed release of active ingredient. Thus, EP-A 609 961 describes solid dosage forms based on physiologically tolerated copolymers, which have a core/shell structure of various copolymers in order to achieve uniform release of active ingredient.
WO 89/06957 describes pharmaceutical formulations with controlled release of active ingredient in which the N-vinylpyrrolidone/alkyl (meth)acrylate copolymer employed as binder makes it possible, because of its large swelling capacity of from 50% to 250%, to delay release of active ingredient.
U.S. Pat. No. 3,900,559 describes active ingredient compositions with delayed release of active ingredient based on crosslinked copolymers, which comprise, inter alia, N-vinyllactams and (meth)acrylates, in particular (meth)acrylates of di- and polyols, as comonomers. In this case, the active ingredient is preferably introduced by impregnating the polymer with a solution of the active ingredient or by polymerizing the monomers in the presence of the dissolved active ingredient.
In order to achieve delayed release of active ingredient, in U.S. Pat. No. 4,248,855 the polymers which are employed as binders and contain acid groups are dissolved, a solution of a salt-forming active ingredient is added, and the active ingredient/polymer salt is formulated for pharmaceutical use. In order to achieve adequate solubility, the binder contains at least 75% by weight of hydrophilic monomers; in turn, at least 10% by weight of these are monomers containing acid groups in order to make it possible to bind the active ingredient in the form of its salt.
The prior art solid dosage forms mentioned have the disadvantage that the introduction of the active ingredient and/or its release take place by diffusion. Moreover, the release is coupled to the great swelling capacity of the binder, and thus depends on the diffusion characteristics of the particular active ingredient in the particular binder. The introduction of the active ingredient and/or the production of the solid dosage form requires elaborate or multistage processes in order to achieve the desired delayed release. In addition, the conventional processes for producing solid pharmaceutical dosage forms, especially tablets, are carried out batchwise and comprise a plurality of stages.
A considerably simpler continuous process for producing solid pharmaceutical dosage forms, in which an active ingredient-containing, solvent-free melt of a polymeric binder is extruded, and the extrudate is shaped to the required dosage form, for example in a calender with molding rolls, is disclosed in EP-A 240 904, EP-A 240 906, EP-A 337 256 and EP-A 358 105 (melt extrusion).
EP-A 240 904 mentions as polymeric binders polyvinylpyrrolidone or copolymers of N-vinylpyrrolidone with, inter alia, vinyl esters, unsaturated carboxylic acids, including acrylic acid and methacrylic acid, their amides and their esters with C
1
-C
12
-alkanols. In the examples, vinylpyrrolidone/vinyl acetate copolymers are employed. The N-vinylpyrrolidone/vinyl acetate copolymers have, just like the N-vinylcaprolactam polymers and copolymers disclosed in DE 197 53 300.0, a very favorable profile of properties as binders for producing solid dosage forms by compression at elevated temperature and, in particular, by melt extrusion, but they have the disadvantage that they release the active ingredient relatively rapidly.
It is an object of the present invention to provide solid dosage forms which make slow release of the active ingredient possible and can be produced straightforwardly and cost-effectively, e.g. by melt extrusion.
We have found that this object is achieved by using as binder a polymer of at least one N-vinyllactam, methyl methacrylate, at least one other copolymerizable monomer and, where appropriate, up to 9.9% by weight of at least one copolymerizable carboxylic acid.
The present invention therefore relates to a solid dosage form comprising at least one polymeric binder and at least one active ingredient and, where appropriate, conventional additives, wherein the polymeric binder comprises as copolymerized units
a) 15-83% by weight of at least one N-vinyllactam of the formula I
in which n is 1, 2 or 3,
b) 15-83% by weight of methyl methacrylate,
c) 2-70% by weight of at least one other monomer selected from vinyl esters of aliphatic C
1
-C
22
-carboxylic acids, esters of &agr;,&bgr;-ethylenically unsaturated C
3
-C
8
-mono- and dicarboxylic acids with C
1
-C
8
-alkanols, C
1
-C
4
-diols or di-(C
1
-C
4
)-alkylamino-C
l
-C
4
-alkanols, amides, nitriles and cyclic anhydrides of these carboxylic acids, and
d) 0-9.9% by weight of at least one &agr;,&bgr;-ethylenically unsaturated acid selected from C
3
-C
8
-mono- and -dicarboxylic acids, noncyclic anhydrides of these carboxylic acids, monoesters of the C
3
-C
8
-dicarboxylic acids, &agr;,&bgr;-ethylenically unsaturated sulfonic acids and the salts or quaternized products thereof,
where the amounts of the monomers add up to 100% by weight.
The polymer used as binder comprises preferably 25-75% by weight and particularly preferably 30-65% by weight of at least one N-vinyllactam of the formula I as copolymerized units. The binder may comprise a mixture of N-vinyllactams of the formula I, but the binder preferably comprises one N-vinyllactam, as copolymerized units. Preferred N-vinyllactams of the formula I are N-vinylpyrrolidone, N-vinylpiperidone and N-vinylcaprolactam; N-vinylpyrrolidone is particularly preferred. The binder comprises preferably 20-70% by weight and particularly preferably 20-55% by weight of methyl methacrylate as comonomer.
In addition, the polymeric binder comprises at least one other copolymerizable monomer (further monomer c)) in an amount of 2-70% by weight, preferably 5-55% by weight and particularly preferably 15-50% by weight, based on the total weight of the monomers. Particularly suitable as further monomer c) are vinyl esters of aliphatic C
1
-C
22
-carboxylic acids, such as vinyl formate, vinyl acetate, vinyl propionate, vinyl butyrate, vinyl valerate, vinyl caproate, vinyl octanoate, vinyl caprate, vinyl laurate, vinyl myristate and vinyl palmitate, with vinyl acetate being particularly preferred. Also suitable as further monomer c) are, for example, the esters of monoethylenically unsaturated carboxylic acids having 3 to 8 carbon atoms, such as acrylic acid, methacrylic acid, dimethacrylic acid, ethacrylic acid, maleic acid, citraconic acid, methylenemalonic acid, allylacetic acid, vinylacetic acid, crotonic acid, fumaric acid, mesaconic acid and itaconic acid, with C
1
-C
8
-alkanols, apart from methyl methacrylate, with C
1
-C
4
-diols, with mono- and di-C
1
-C
4
-alkylamino-C
l
-C
4
-alkanols, and the amides, mono- and di-C
1
-C
4
-alkylamides and nitriles of these carboxylic acids, e.g. methyl acrylate, ethyl acrylate, propyl acrylate, n-butyl acrylate, 2-ethylhexyl acrylate, ethyl methacrylate, propyl methacrylate, n-butyl methacrylate, 2-ethylhexyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxybutyl acrylate, hydroxyisobutyl acrylate, hydroxyethyl methacrylate, hydroxypropyl methacrylate, hydroxybutyl methacrylate, hydroxyisobutyl methacrylate, dimethyl maleate, diethyl maleate, dibutyl maleate, acrylamide, methacrylamide, N,N-dimethylacrylamide, N-tert-butylacrylamide, acrylonitrile, methacrylonitrile, dimethylaminoethyl acrylate, diethylaminoethyl acrylate, diethylaminoethyl methacrylate and the salts of the last-mentioned monomers with carboxylic acids or mineral acids or the quaternized products. It is, of course, also possible to employ mixtures of said monomers.
In addition, the polymeric binder may also comprise 0-9.9% by weight, in particular 0-7% by weight, pref

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