Coating and excipient agent for oral or dermal dosage forms

Details Coating and excipient agent for oral or dermal dosage forms Coating and excipient agent for oral or dermal dosage forms

2001-01-23

2003-09-23

Yoon, Tae H (Department: 1714)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Processes of preparing a desired or intentional composition...

C523S202000, C523S200000, C523S332000, C106S217600, C106S287250, C106S400000, C424S474000

Reexamination Certificate

active

06624210

ABSTRACT:

The invention relates to a coating and binding agent for oral and dermal pharmaceutical forms, comprising a (meth)acrylate copolymer, plasticizer and emulsifier.
PRIOR ART
The use of (meth)acrylate copolymers in pharmaceutical coatings has been known for decades. (Meth)acrylate copolymers containing monomer units with tertiary amino groups are'suitable, for example, for pharmaceutical coatings which mask the taste and which dissolve in the gastric fluid and thus permit rapid release of active principle. Such polymers can be processed very effectively in the form of organic solutions. Unfortunately organic solvents suffer from several disadvantages, in that, for example, they pollute the environment and are toxic and readily flammable. Thus efforts already began years ago, wherever possible, to replace organic solutions by aqueous dispersions or to permit processing without any addition of solvent whatsoever (such as processing in the melt).
U.S. Pat. No. 4,705,695 describes a process for coating pharmaceutical formulations with an aqueous coating agent containing a water-soluble (meth)acrylate copolymer with tertiary amino groups as well as a water-insoluble, neutral polymer as binder. The solubility of the (meth)acrylate copolymer comprising, for example, equal proportions of methyl methacrylate and dimethylaminoethyl methacrylate is achieved by stirring the powder form with particle sizes smaller than 0.25 mm into water while simultaneously adding an acid. As the binder there is used an insoluble copolymer comprising, for example, methyl methacrylate and ethyl acrylate (70:30). The preparation of the coating solution is relatively complex. Because of the acid content, the coating has an unpleasant taste. Corresponding films dissolve both in synthetic gastric fluid as well as in water in less than two minutes. European Patent 181515 B describes a process for preparation of an aqueous coating agent dispersion and the use thereof for coating of pharmaceuticals. For this purpose there is used a (meth)acrylate copolymer containing quaternary ammonium groups, which copolymer swells but is not soluble in water. The copolymer can comprise, for example, methyl methacrylate, ethyl acrylate and 2-trimethylammonium ethyl methacrylate chloride (60:30:10). It is preferably used in the form of finely ground powder in the particle-size range smaller than 200 &mgr;m. Particle sizes smaller than 20 to 50 &mgr;m can be used, but are less suitable because of the dust generation tendency. The powder dissolves in water at elevated temperature after prolonged stirring. Dispersion is promoted by the addition of plasticizers. Addition of emulsifiers is said to be unnecessary.
European Patent Application 0727205 A describes thermoplastically processable coating and binding agents for pharmaceutical forms. Therein there is described among other possibilities the solvent-free processing to meltable pharmaceutical formulations of (meth)acrylate copolymers containing monomer units with tertiary amino groups, by means of addition of incompatible fluidizing agents such as glycol monostearate.
OBJECT AND ACHIEVEMENT
In contrast to (meth)acrylate copolymers containing monomer units with quaternary amino groups, heretofore it has not been possible, without addition of acids, to convert to stable aqueous solutions or dispersions (meth)acrylate copolymers which contain monomer units with tertiary amino groups. In addition, further additives such as neutral (meth)acrylate copolymers are usually necessary in order to obtain formulations that can be sprayed at all.
Coatings according to U.S. Pat. No. 4,705,695 cited in the introduction also have the disadvantage that they are expensive to prepare, have a bitter taste and can be prepared only by relatively complex means. Since such formulations already dissolve rapidly in pure water, they are unsuitable as taste-masking coatings.
One object of the present invention was seen as providing a formulation and a process for preparation of a coating and binding agent for pharmaceutical forms containing (meth)acrylate copolymers which monomer units with tertiary amino groups, which process permits simple wet or dry further processing. In this connection the formulations should be suitable in particular for preparation of taste-masking coatings and therefore should be less soluble in water than in synthetic gastric fluid. The aqueous formulations should be readily processable, especially by spray application. Furthermore, the formulations should also be suitable for dry processing, in order to provide a further alternative to the meltable pharmaceutical formulations according to European Patent Application 0727205 A.
Surprisingly it has been found that the object is achieved by a process for preparation of a coating and binding agent for oral or dermal pharmaceutical forms comprising
(a) 35 to 98 wt % of a copolymer comprising radical-polymerized C1 to C4 esters of acrylic or methacrylic acid and further (meth)acrylate monomers containing functional tertiary ammonium groups and
(b) 1 to 50 wt % of a plasticizer as well as
(c) 1 to 15 wt % of an emulsifier with an HLB value of at least 14,
wherein components (a), (b) and (c) are intermixed with each other with or without addition of water and possibly with addition of a pharmaceutical active principle and further common fillers, and the coating and binding agent is prepared by melting, casting, doctoring or spraying,
characterized in that
the copolymer (a) is introduced in powder form with a mean particle size of 1 to 40 &mgr;m.
The surprisingly good processability of the formulation is due to the provision of copolymer (a) in powder form with extremely small particle size, and was not foreseeable. Copolymer (a) in this powder form is new and is also claimed. Furthermore, the invention is based on the knowledge that components (a), (b) and (c) must be present in well-defined ratios in order to achieve the stated object. It is assumed that the advantageous effects are due to mutual interactions of the components with each other during the preparation process. The coating and binding agents which are also part of the invention are therefore characterized by the preparation process.
Since the advantageous effects are also achieved without use of water or solvents, the components can also be processed in dry form. It is suspected that under these conditions constituents (a) and (b) and (c) aggregate with each other in advantageous manner under the effect of heat.
The layers or coatings that can be prepared from the powder are insoluble or difficultly soluble in water. The layer transformed to film remains impervious in the neutral environment of the mouth, but in synthetic gastric fluid it dissolves rapidly and releases the encapsulated or embedded active principle very rapidly in the desired manner.
OPERATION OF THE INVENTION
Component (a)
Copolymers (a) comprise substantially or completely radical-polymerized C1 to C4 esters of acrylic or methacrylic acid and further (meth)acrylate monomers containing functional tertiary ammonium groups.
Suitable monomers with functional tertiary ammonium groups are listed in U.S. Pat. No. 4,705,695, column 3, line 64 to column 4, line 13. Worth special mention are dimethylaminoethyl acrylate, 2-dimethylaminopropyl acrylate, dimethylaminopropyl methacrylate, dimethylaminobenzyl acrylate, dimethylaminobenzyl methacrylate, (3-dimethylamino-2,2-dimethyl)propyl acrylate, dimethylamino-2,2-dimethyl)propyl methacrylate, (3-diethylamino-2,2-dimethyl)propyl acrylate and diethylamino-2,2-dimethyl)propyl methacrylate. Especially preferred is dimethylaminoethyl methacrylate.
The content of monomers with tertiary ammonium groups in the copolymer can range advantageously between 30 and 70 wt %, preferably between 40 and 60 wt %. The proportion of the C1 to C4 esters of acrylic or methacrylic acid is 70 to 30 wt %. Examples of such esters are methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate.
A (meth)acrylate copolymer with tertiary amino grou

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