Method for producing solid dosing forms

Details Method for producing solid dosing forms Method for producing solid dosing forms

2000-05-31

2003-03-04

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S474000, C424S484000, C424S486000, C424S489000, C514S772100

Reexamination Certificate

active

06528089

ABSTRACT:

The invention relates to a process for producing solid dosage forms by mixing at least one polymeric binder, at least one active ingredient and, where appropriate, conventional additives to form a plastic mixture, and shaping the mixture. The invention particularly relates to a process for producing solid pharmaceutical dosage forms.
Classical processes for producing solid pharmaceutical forms, especially tablets, are carried out batchwise and comprise a plurality of stages. Pharmaceutical granules represent an important intermediate therefor. Thus, for example, it is evident from Bauer, Frömmig and Fuhrer, Pharmazeutische Technologie, Georg-Thieme-Verlag, pages 292 et seq., that drug forms can be obtained from the melt by dry granulation. The possibility of producing solidified melt granules either by melting and shock solidification, by casting and comminuting or by prilling in spray towers is described. One problem with these processes is the accurate shaping which is necessary for producing drugs. Irregular particles or fragments are produced, so that the resulting shape by no means corresponds to customary drug forms, and granules therefore have only little importance as a drug form on their own. Production of desired solid drug forms requires the use of further process steps such as compression in tabletting machines. This is time-consuming and costly. A considerably simpler continuous process for producing solid pharmaceutical forms has been known for some time and entails extruding a solvent-free melt of a polymeric binder containing active ingredients, in shaping the extrudate to the required drug form, for example in a calender with molding rolls, see EP-A-240 904, EP-A-240 906, EP-A-337 256 and EP-A-358 105 (melt extrusion). It is possible in this way to achieve specific shaping. The polymeric binders employed are, in particular, polymers of N-vinylpyrrolidone or copolymers thereof, eg. with vinyl acetate.
Dosage forms based on such polymers have the disadvantage that they release the active ingredient relatively rapidly. It is therefore impossible to produce slow-release dosage forms without taking additional measures, such as applying a coating which controls their release.
It is an object of the present invention to provide dosage forms which can be produced by melt extrusion and are able to release the active ingredient slowly.
We have found that this object is achieved by using as polymeric binder a copolymer of an N-vinyllactam and a copolymerizable monomer having a hydrophobic radical.
The present invention therefore relates to a process for producing solid dosage forms by mixing at least one polymeric binder, at least one active ingredient and, where appropriate, conventional additives to form a plastic mixture, and shaping, wherein the polymeric binder used is a copolymer of an N-vinyllactam of the formula I:
where n is 1, 2 or 3, and at least one copolymerizable monomer having a hydrophobic radical.
The process according to the invention makes it possible to produce solid dosage forms with slow release (sustained release) of the active ingredient in a simple and low-cost manner.
Dosage forms mean herein all forms which are suitable for use as drugs, plant treatment compositions, human and animal foods and for delivering fragrances and perfume oils. These include, for example, tablets of any shape, pellets, granules, but also larger forms such as cubes, blocks (bricks) or cylindrical forms, which can be used, in particular, as human or animal foods.
The dosage forms obtainable according to the invention generally comprise:
a) 0.1-90% by weight, in particular 0.1-60% by weight (based on the total weight of the dosage form), of an active ingredient,
b) 10-99.9% by weight, in particular 40-99.9% by weight, of a polymeric binder and
c) where appropriate additives.
The copolymer used as binder comprises as hydrophobic comonomer in particular units of a compound of the formula II:
where R
1
is a hydrogen atom or a methyl group, X is O, NH or NR
2
, R
2
is C
1
-C
30
-alkyl, and R
3
is C
8
-C
30
-alkyl, C
8
-C
30
-cycloalkyl or C
8
-C
30
-alkenyl. The comonomer thus comprises (meth)acrylic esters or (meth)acrylamides having a hydrophobic C
8
-C
30
-alkyl, C
8
-C
30
-cycloalkyl or C
8
-C
30
-alkenyl group. R
2
is preferably C
1
-C
18
-alkyl and R
3
is C
8
-C
18
-alkyl or C
8
-C
18
-alkenyl.
Examples of suitable acrylic and methacrylic esters are octyl acrylate, 2-ethylhexyl acrylate, nonyl acrylate, decyl acrylate, lauryl acrylate, myristyl acrylate, cetyl acrylate, stearyl acrylate, oleyl acrylate, behenyl acrylate, hexyl methacrylate, octyl methacrylate, nonyl methacrylate, decyl methacrylate, lauryl methacrylate, myristyl methacrylate, cetyl methacrylate, stearyl methacrylate, oleyl methacrylate, behenyl methacrylate and tert-butylcyclohexyl acrylate.
Examples of acrylamides and methacrylamides which can be used are N-stearylacrylamide, N-stearylmethacrylamide, N-octylacrylamide, N,N-dioctylacrylamide, N,N-dioctylmethacrylamide, N-cetylacrylamide, N-cetylmethacrylamide, N-dodecylacrylamide, N-dodecylmethacrylamide, N-myristylacrylamide and 2-ethylhexylacrylamide.
Particularly preferred copolymers comprise ethylhexyl, lauryl, myristyl, cetyl, stearyl, oleyl or behenyl acrylate or methacrylate units.
The polymeric binder may also comprise as monomer having a hydrophobic radical a vinyl ester of an aliphatic C
8
-C
30
-carboxylic acid, in particular a C
8
-C
18
-carboxylic acid. It is possible to use, for example, the vinyl esters of decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid and behenic acid.
It is, of course, also possible for the polymeric binder to comprise any desired mixtures of said monomer units.
The polymeric binder contains 50-99 mol %, preferably 70-99 mol %, and particularly preferably 90-99 mol %, of N-vinyllactam units. It contains 1-50 mol %, preferably 1-30 mol %, and in particular 1-10 mol %, of units of monomer having the hydrophobic radical.
In addition, the polymeric binder may contain units of other copolymerizable monomers (other comonomers) in an amount of 0.5 to 48% by weight, preferably 0.5 to 20% by weight, and particularly preferably 0.5 to 10% by weight. Other suitable comonomers are, in particular, monoethylenically unsaturated carboxylic acids having 3 to 8 carbon atoms, such as acrylic acid, methacrylic acid, dimethyl acrylic acid, ethacrylic acid, maleic acid, citraconic acid, methylenemalonic acid, allylacetic acid, vinylacetic acid, croton acid, fumaric acid, mesaconic acid and itaconic acid, and the monoesters of said dicarboxylic acids with C
1
-C
18
-alkanols. Acrylic acid, methacrylic acid, maleic acid or mixtures of said carboxylic acids are preferred. The monoethylenically unsaturated carboxylic acids can be employed in the form of the free acid and, where available, of the anhydrides or in partially or completely neutralized form. The neutralization is preferably carried out with alkali metal or alkaline earth metal bases, ammonia or amines, e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, magnesium oxide, calcium hydroxide, calcium oxide, gaseous or aqueous ammonia, triethylamine, ethanolamine, diethanolamine, morpholine, diethylenetriamine or tetraethylenepentamine.
Further examples of suitable comonomers are the esters of the abovementioned carboxylic acids with C
1
-C
6
-alkanols, C
1
-C
4
-diols, mono- and di-C
1
-C
4
-alkylamino-C
1
-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, methyl methacrylate, ethyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxybutyl acrylate, hydroxyethyl methacrylate, hydroxypropyl methacrylate, hydroxyisobutyl acrylate, hydroxyisobutyl methacrylate, monomethyl maleate, dimethyl maleate, monoethyl maleate, diethyl maleate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, acrylamide, methacrylamide, N,N-dimethylacrylamide, N-tert-butylacrylamide, acrylonitrile, methacrylonitril

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