Use of N-vinyllactam-or-N-vinylamine-containing copolymers...

Details Use of N-vinyllactam-or-N-vinylamine-containing copolymers... Use of N-vinyllactam-or-N-vinylamine-containing copolymers...

1999-04-01

2002-08-20

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Matrices

C424S484000, C424S487000, C424S401000, C424S422000, C514S772000, C514S772200, C514S772300, C514S772400

Reexamination Certificate

active

06436440

ABSTRACT:

The use of N-vinyllactam- or N-vinylamine-containing copolymers as matrix for producing solid pharmaceutical and cosmetic presentations.
The present invention relates to the use of N-vinyllactam- or N-vinylamine-containing copolymers as matrix for producing solid pharmaceutical and cosmetic presentations.
Oral drug forms with a delayed release of active ingredient (slow-release drug forms) are becoming increasingly important. The latter is associated advantageously with improved patient compliance owing to a reduced frequency of intake, a reduction in side effects owing to the avoidance of plasma level peaks, more uniform levels of the medicinal substance in the blood, and the avoidance of local irritation.
Besides coated slow-release forms, i.e. formulation of cores containing medicinal substance and coated with a film which is insoluble in water but semipermeable or contains pores through which the medicinal substance diffuses, it is also possible to achieve control and prolongation of release by embedding the medicinal substance in a matrix.
Embedding the medicinal substance in a matrix offers the particular advantages of simple and low-cost production and high drug safety because dose dumping effects (e.g. the occurrence of high plasma concentrations due to incorrect intake—for example chewing instead of swallowing coated tablets) cannot occur.
The ancillary substances which are usually employed for this, such as hydroxypropylcellulose, hydroxypropylmethylcellulose, alginic acid or alginates, and xanthan, have technical disadvantages on use, however. These derive, on the one hand, from the release of medicinal substance being dependent on the pH or ionic strength and, on the other hand, from the unsatisfactory direct tabletability because, owing to the small binding effect and the poor flow properties of the abovementioned polymers, the resulting compacts frequently have only low hardness or are inhomogeneous.
Since some of the abovementioned ancillary substances are products of natural origin or refined products of natural origin, there may be variations in batch conformity and thus an unfavorable effect on the performance of the pharmaceutical preparation.
DE-A-25 14 100 describes copolymers of vinylpyrrolidone and long-chain alkyl (meth)acrylates, and terpolymers of vinylpyrrolidone, vinyl acetate and long-chain alkyl (meth)acrylates for use as emulsifiers for emulsions of the water-in-oil (W/O) type.
DE-A-38 10 343 describes a process for producing solid slow-release pharmaceutical forms which contain as binder an N-vinylpyrrolidone-containing water-soluble polymer, wherein the pharmaceutical active ingredient, the polymeric binder and, where appropriate, other pharmaceutical ancillary substances are mixed below the glass transition temperature of the binder, and this mixture is compressed above the glass transition temperature of the binder but below the decomposition temperature of the active ingredient to pharmaceutical forms and removed from the mold with the form at a temperature below the glass transition temperature of the binder.
DE-A-25 28 068 describes crosslinked, water-soluble hydrophilic gels consisting, inter alia, of N-vinylpyrrolidone-containing copolymers with various water-insoluble monomers. Water-insoluble monomers which are mentioned are alkyl acrylates and alkyl methacrylates, alkyl having up to 18 C atoms. The polymerization is carried out in bulk or in solution, the active ingredient being present in the reaction medium during the polymerization.
WO 89/06957 describes uncrosslinked copolymers of hydrophilic monomers such as N-vinylpyrrolidone, acrylic acid, methacrylic acid (and their lower esters and hydroxyalkyl esters) and unsaturated linear or branched esters of acrylic acid or methacrylic acid as hydrophobic component for use as binders for active ingredients which are to undergo delayed release. The molar ratio of the monomers is from 1:1.2 to 1:0.8 in the case of N-vinylpyrrolidone/methyl methacrylate.
EP-A-0 054 279 and EP-A-0 409 383 describe the use of water-insoluble, uncrosslinked copolymers of N-vinylpyrrolidone and linear alkyl esters of (meth)acrylic acid in preparations for transdermal administration (ointments, gels) of nitroglycerine or estrogens.
It is an object of the present invention to find polymers which are suitable as matrix for producing solid pharmaceutical and cosmetic preparations with controlled release of active ingredient.
We have found that this object is achieved by using copolymers comprising
a) 50 to 99% by weight of at least one N-vinyllactam or N-vinylamine selected from the group consisting of N-vinylpyrrolidone, N-vinylpiperidone, N-vinylcaprolactam, N-vinylimidazole and methylated N-vinylimidazole or N-vinylformamide and
b) 1 to 50% by weight of at least one monomer selected from the group of
b
1
) C
14
-C
30
-alkyl esters of monoethylenically unsaturated C
3
-C
8
-carboxylic acids;
b
2
) N—C
8
-C
30
-alkyl-substituted amides of monoethylenically unsaturated C
3
-C
8
-carboxylic acids;
b
3
) N,N—C
8
-C
30
-dialkyl-substituted amides of monoethylenically unsaturated C
3
-C
8
-carboxylic acids;
b
4
) vinyl esters of aliphatic C
8
-C
30
-carboxylic acids;
b
5
) C
8
-C
30
-alkyl vinyl ethers
as matrix for producing solid pharmaceutical and cosmetic presentations.
The following polymerizable comonomers may be mentioned as hydrophilic components a):
N-vinyllactams and N-vinylamines, in particular N-vinylpyrrolidone, N-vinylpiperidone, N-vinylcaprolactam, N-vinylimidazole, N-vinyl-2-methylimidazole, N-vinyl-4-methylimidazole and N-vinyl formamide.
Preferred hydrophilic components are N-vinylpyrrolidone, N-vinylimidazole and N-vinylcaprolactam, particularly preferably N-vinylpyrrolidone.
The proportion of hydrophilic monomer units a) in the copolymer is in the range from 50 to 99% by weight, preferably 60 to 99% by weight, particularly preferably in the range from 65 to 98% by weight.
The following polymerizable comonomers may be mentioned as hydrophobic components b):
esters of monoethylenically unsaturated C
3
-C
8
-carboxylic acids with a C
14
-C
30
-alcohol, preferably a C
14
-C
22
-alcohol, particularly preferably with a C
14
-C
18
-alcohol.
Monoethylenically unsaturated carboxylic acids with 3 to 8 C atoms mean, for example, acrylic acid, methacrylic acid, dimethylacrylic acid, ethacrylic acid, maleic acid, citraconic acid, methylenemalonic acid, allylacetic acid, vinylacetic acid, crotonic acid, fumaric acid, mesaconic acid and itaconic acid.
Preferably used from this group of carboxylic acids are acrylic acid, methacrylic acid, maleic acid or mixtures of said carboxylic acids, in particular acrylic acid.
Particularly important in this connection are acrylic and methacrylic esters with fatty alcohols of a chain length of from 14 to 22 carbon atoms.
The following may be mentioned here as preferred: myristyl acrylate, cetyl acrylate, stearyl acrylate, oleyl acrylate, behenyl acrylate, myristyl methacrylate, cetyl methacrylate, stearyl methacrylate, oleyl methacrylate, behenyl methacrylate, with the C
14
-C
18
-alkyl esters of acrylic acid being particularly preferred from this group.
Further hydrophobic comonomers b) which can be employed are N—C
8
-C
30
-alkyl- or N,N—C
8
-C
30
-dialkyl-substituted amides of monoethylenically unsaturated C
3
-C
8
-carboxylic acids, the alkyl radicals being aliphatic or cycloaliphatic alkyl radicals with 8 to 30, preferably 8 to 22, particularly preferably 12 to 18, carbon atoms.
The amidated monoethylenically unsaturated carboxylic acids with 3 to 8 C atoms can, as mentioned above, be, for example, acrylic acid, methacrylic acid, dimethylacrylic acid, ethacrylic acid, maleic acid, citraconic acid, methylenemalonic acid, allylacetic acid, vinylacetic acid, crotonic acid, fumaric acid, mesaconic acid and itaconic acid.
Likewise preferably used from this group of carboxylic acids are acrylic acid, methacrylic acid, maleic acid or mixtures of said carboxylic acids.
Examples of preferred amidated comonomers are N-octylacrylamide, N-2-ethylhexylacrylamide, N-nonylacrylamide, N-

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