Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-03-08
2003-12-02
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S400000, C424S484000, C424S489000
Reexamination Certificate
active
06656507
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to an aqueous dispersion suitable for the production of binders and coatings for solid oral drugs, containing as the solid portion, a polymer mixture A) consisting of a polymethacrylate copolymer and an alkali salt of carboxymethylcellulose and B) the customary added ingredients. The invention also relates to the applications of the dispersion.
2. Description of the Background
Water-soluble nonionic polysaccharide derivatives, for example, hydroxypropylmethylcellulose (HPMC), are routinely used for the granulation of tablet mixtures and for simple coating of solid drugs. Less often, soluble ionic polysaccharides, for example, sodium carboxymethylcellulose (Na—CMC), are used. However, both polymers form coatings that quickly dissolve in water and have a high permeability. Therefore, the protective and insulating effect in drugs is limited. The binding ability of these materials for pigments is also limited, so that the covering power of coatings for strongly colored cores is not sufficient. Furthermore, hydrophilic, strongly swelling polymers tend to form clumps when stirred in water, which must be avoided by means of special dissolution methods.
DE 4,021,678 A1 describes a method for the production of small formed pieces containing etofibrate, and controlled release of active ingredients by mixture of the active ingredients with a physiologically neutral colloid that is insoluble in water and one that is soluble or swells in water, and subsequent extrusion. The colloids that are insoluble in water and are water-soluble or capable of swelling can be used in a ratio of 1:10 to 90:1. Etofibrate can, for example, be mixed together with a polymethacrylic acid ester with quaternary ammonium groups (EUDRAGIT® RS) and sodium carboxymethylcellulose in the ratio 2:1. The goal is to achieve a release which is as constant as possible over a period of 4-6 h.
EP 0 793 959 describes formulations with controlled release of active ingredients that are coated with a substance that is insoluble in water and a polymer capable of swelling, that has no basic groups. In the long list of substances that can potentially be used, polymethacrylate copolymers with quaternary ammonium groups (EUDRAGIT® RS) are named among the substances that are insoluble in water. Sodium carboxymethylcellulose is listed among the substances that are capable of swelling. No concrete indication of combining these two polymers is present in the disclosure of the publication.
SUMMARY OF THE INVENTION
Accordingly, one object of the invention is to provide a coating and binder for solid oral drugs that, on one hand releases active ingredients for drugs quickly and without affecting the pH value, and on the other hand, which makes possible a good insulating effect in thin coatings, as well as high pigment binding ability and reliable protection of flavor.
Another object of the invention is to provide an aqueous polymer dispersion for drug formulations which, as an applied coating, is not impeded by swelling and adhesion.
Briefly, these objects and other objects of the invention as hereinafter will become more readily apparent can be attained by an aqueous dispersion for the production of binders or coatings for solid oral drugs having a water content of 90-40 wt. % and a solids portion of 10-60 wt. %, whereby said solids portion is composed of:
(A) 10-99 wt. % of a polymer mixture consisting of:
(a) 75-99 wt. % of a polymethacrylate copolymer consisting of 98-85 wt. % of alkyl (meth)acrylate monomers with C
1
-C
4
alkyl residues and 2-15 wt. % of alkyl (meth)acrylate monomers with a quaternary ammonium group in the alkyl residue, and (b) 25-1 wt. % of an alkali salt of carboxymethylcellulose having a weight average molecular weight of less than 150,000, and
(B) 90-1 wt. % of at least one substance normally added to pharmaceutical formulations.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The polymer mixture A consisting of components (a) and (b) in the stated quantity ratio is decisive for the properties of the coatings and binders for solid oral drugs which are produced from the dispersion. In the process, it is indispensable for the two components to be present in an aqueous medium, because the advantageous effects cannot be achieved when an organic solution is used (see Comparison Example 19). It is presumed that polymers (a) and (b) aggregate with one another in an advantageous manner in the aqueous phase either first in the dispersion itself or during the application of the dispersion, or during the evaporation of the water. Surprisingly, by increasing the quantity of component (b), there is an increase in tensile strength of the coated product, but a reduction of elongation at break. The binders or coatings that can be produced from the dispersion have a good mechanical strength (see Example 10), but disintegrate, as desired, very quickly in artificial gastric juice. The release of the active ingredients is practically constant and independent of the pH. In fact, disintegration of the prepared pharmaceutical coatings occurs in less than 30 min for a polymer coating of 2 mg/cm
2
in artificial gastric juice. The protection of flavor is very reliable (see Example 9), and the pigment binding ability is high (see Example 8).
Water Content and Particle Size
The water content of the dispersion is in the customary range of 90-40 wt. %, preferably 80-50 wt. %. The average particle size of the particulate matter in the dispersion is in the range of 50-500 nm.
Polymer Mixtures A
Component (a)
A portion of polymer mixture A consisting of components (a) and (b), to a large extent insoluble in water, is formed by a (meth)acrylate copolymer (a) that consist of up to 98-85 wt. %, preferably up to 96-88 wt. %, of alkyl (meth)acrylate monomers with C
1
-C
4
alkyl residues, and up to 2-15 wt. %, preferably up to 4-12 wt. % of alkyl (meth)acrylate monomers having a quaternary ammonium group in the alkyl residue.
Suitable alkyl (meth)acrylate monomers having C
1
-C
4
alkyl residues include methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate, and methyl methacrylate. The copolymer contains 20-40 wt. %, especially 25-35 wt % ethyl acrylate and 50-70 wt. %, especially 55-70 wt. % methyl methacrylate.
Suitable alkyl (meth)acrylate monomers having quaternary ammonium groups can be found, for example, in EP 0 181 515. Disclosed Examples include acryl and methacryloxytrimethylammonium chloride or the methosulfate, benzyldimethylammonium methyl methacrylate chloride, diethylmethylammonium ethyl acrylate and methacrylate methosulfate, N-trimethylammonium propyl methacrylamide chloride and N-trimethylammonium 2,2-dimethylpropyl-1-methacrylate chloride. 2-Trimethyl ammonium methyl methacrylate chloride is specially preferred.
Preferably, the (meth)acrylate copolymer having quaternary ammonium groups corresponding to component (a), can be composed of 65 or 60 wt. % methyl methacrylate, 30 wt. % ethyl acrylate and 5 or 10 wt. % 2-trimethylammonium methyl methacrylate chloride (EUDRAGIT® RS or RL).
The copolymers (a) are obtained by known techniques such as radical, solution, bead, or emulsion polymerization. They can be present as an extruded granulate, ground or spray-dried powder, or as a dispersion, for example, with 30 wt. % solid material.
Component (b)
The water-soluble component (b) of polymer mixture A consisting of components (a) and (b) is formed by alkali salts of carboxymethylcellulose having a molecular weight (weight average) of less than 150,000, preferably 5,000-100,000, especially preferably, 7,000-70,000. If the molecular weight of component (b) is 150,000 or more, there may be a thickening of the batch may occur, so that it can practically no longer be processed. Suitable alkali salts include lithium, sodium and potassium, as well as ammonium salts. Preferably, sodium salts are used. The viscosity of a 2% solution in water at 20° C. is usually in the range of 1-200 mPas, preferably 2-60 mPas. Preferably such types are used which
Goelz Silke
Petereit Hans-Ulrich
Weisbrod Wolfgang
Joynes Robert M.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Page Thurman K.
Roehm GmbH & Co. KG
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