Process for producing solid dosage forms

Details Process for producing solid dosage forms Process for producing solid dosage forms

1999-10-13

2002-07-23

Vargot, Mathieu D. (Department: 1732)

Plastic and nonmetallic article shaping or treating: processes

Forming articles by uniting randomly associated particles

Utilizing diverse solid particles

C264S211000

Reexamination Certificate

active

06423256

ABSTRACT:

The invention relates to a process for producing solid dosage forms, in particular solid pharmaceutical dosage forms.
A continuous process for producing solid pharmaceutical forms has been known for some time and entails extruding an active ingredient-containing, solvent-free melt of a polymeric binder, and shaping this extrudate to the required drug form, for example in a calendar 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. Employed as polymeric binder are, in particular, polymers of N-vinylpyrrolidone or copolymers thereof, e.g. with vinyl acetate.
The known process has the disadvantage that polymeric binders with a K value of more than 75, in particular homo- or copolymers of vinylpyrrolidone, cannot be processed because they show crosslinking, discoloration or decomposition at the required temperatures and/or residence times in the extruder. Ancillary substances customary in pharmaceutical technology, such as polyvinylpyrrolidone with a K value of 90, have therefore not been usable to date for producing dosage forms by extrusion. The use of polymeric binders with high K values is of interest for producing solid solutions which permit slow release of active ingredient.
It is an object of the present invention to provide a process for producing solid dosage forms by shaping a plastic mixture which allows high molecular weight polymeric binders to be used.
We have found that this object is achieved by controlling the temperature and the shear energy input during the process.
The present invention therefore relates to a process for producing solid dosage forms, in which (i) a plastic mixture of at least one pharmacologically acceptable polymeric binder with a K value of more than 75, at least one pharmaceutical active ingredient and, where appropriate, conventional pharmaceutical additives is prepared and (ii) the plastic mixture is shaped to the required dosage form, with step (i) being carried out under conditions of temperature and shear energy input such that the reduction in molecular weight of the polymeric binder, expressed as the difference in the K value, is less than 15, preferably less than 10.
Dosage forms mean in this connection all forms suitable for use as drug products, plant treatment products, animal feed products and human food products 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 animal or human food products.
The dosage forms obtainable according to the invention generally comprise:
a) from 0.1 to 90% by weight, in particular 0.1 to 60% by weight (based on the total weight of the dosage form) of an active ingredient,
b) from 10 to 99.9% by weight, in particular 40 to 99% by weight, of a polymeric binder and
c) where appropriate additives.
The polymeric binder has a K value of more than 75, in particular more than 80, preferably more than 85 and particularly preferably 90-200. The K values are determined by the method of H. Fikentscher, Cellulose-Chemie, volume 13, (1932) 58-64 and 71-74, in aqueous solution or in an organic solvent at 25° C., at concentrations which are between 0.1% and 5% depending on the K value range. The K value of water-soluble polymers is generally determined in aqueous solution. If the polymer is not completely soluble in water, solvents such as THF, acetone, alcohols, e.g. ethanol, are employed.
Step (i) in the process according to the invention is carried out under conditions of temperature and shear energy input such that the reduction in molecular weight of the polymeric binder, expressed as difference in the K value, is less than 15, preferably less than 10. The skilled worker is able easily to establish suitable process parameters on the basis of simple tests. For this purpose, the K value of the polymeric binder in the resulting dosage form is determined and compared with the K value of the polymeric binder employed. The process parameters can be varied so that, while the mixing is adequate, the reduction in molecular weight of the polymeric binder is minimized.
Suitable binders are polymers, copolymers, cellulose derivatives and starch derivatives, for example:
polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone (NVP) and vinyl acetate or vinyl propionate, copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate, polyvinyl alcohol, poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates), polyacrylates and polymethacrylates (Eudragit types), copolymers of methyl methacrylate and acrylic acid, polyacrylamides, polyethylene glycols, polyvinylformamide (where appropriate partially or completely hydrolyzed), cellulose esters, cellulose ethers, in particular methylcellulose and ethylcellulose, hydroxyalkylcelluloses, in particular hydroxypropylcellulose, hydroxyalkylalkylcelluloses, in particular hydroxypropylethylcellulose, cellulose phthalates, in particular cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, and mannans, in particular galactomannans. Of these, polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl esters, poly(hydroxy alkylacrylates), poly(hydroxyalkyl methacrylates), polyacrylates, polymethacrylates, alkylcelluloses and hydroxyalkylcelluloses are particularly preferred.
Homo- or copolymers of vinylpyrrolidone, in particular those with at least 1% by weight, preferably at least 10% by weight, particularly preferably at least 25% by weight and, in particular, at least 50% by weight of vinylpyrrolidone units, are preferred. Suitable comonomers are vinyl esters of aliphatic C
2
-C
24
-carboxylic acids, such as vinyl acetate or vinyl propionate; C
1
-C
24
-alkyl(meth)acrylates, such as methyl methacrylate, ethyl acrylate, stearyl(meth)acrylate; vinyl ethers, such as methyl vinyl ether. Hydrophobic comonomers are generally preferred.
The polymeric binder must soften in the complete mixture of all the components in the range from 70 to 300° C., preferably 80 to 250° C., to form a plastic mixture. The glass transition temperature of the mixture must therefore be below 250° C., preferably below 200° C.
In preferred embodiments, the glass transition temperature is reduced by adding pharmacologically acceptable plasticizing ancillary substances. The amount of plasticizer is generally from 0.5 to 30, preferably 0.5 to 15, % of the total weight of the mixture.
Examples of such plasticizers are:
long-chain alcohols, ethylene glycol, propylene glycol, glycerol, trimethylolpropane, triethylene glycol, butandiols, pentanols, such as pentaerythritol, hexanols, polyethylene glycols, polypropylene glycols, polyethylene/propylene glycols, silicones, aromatic carboxylic esters (e.g. dialkyl phthalates, trimellitic esters, benzoic esters, terephthalic esters) or aliphatic dicarboxylic esters (e.g. dialkyl adipates, sebacic esters, azelaic esters, citric and tartaric esters), fatty acid esters such as glycerol monoacetate, glycerol diacetate or glycerol triacetate or sodium diethyl sulfosuccinate, of which polyethylene glycols and polyethylene/propylene glycols are preferred.
The use of a plasticizer reduces the softening point of the polymeric binder. The formation of the plastic mixture and the shaping can take place at lower temperatures, which limits the reduction in molecular weight.
In preferred embodiments, the plastic mixture also contains pharmaceutically acceptable antioxidants. These can be used in an amount of from 0.001 to 10%, preferably 0.01 to 5%, of the total weight of the mixture. Examples of suitable antioxidants are gallic esters, ascorbyl palmitate, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, nordihydroguajaretic acid, 2,6-di-tert-butyl-4-methylphenol, alkali metal or alkaline earth metal sulfites or bisulfites and mixtures thereof.
The additional use of antioxidants makes it possible to limit further the reducti

Affiliated with

Also associated with

Rating

Process for producing solid dosage forms does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for producing solid dosage forms, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for producing solid dosage forms will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2850863