Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2001-07-30
2003-06-10
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S453000, C424S452000, C424S462000, C264S004100, C264S004330
Reexamination Certificate
active
06576255
ABSTRACT:
This application is a 371 of PCT/EP00/11922 filed Nov. 29, 2000.
The invention relates to a process for manufacturing molded articles by means of injection molding, to the molded articles themselves and to their use for pharmaceutical purposes.
Prior Art
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. Solubility of the (meth)acrylate copolymer, which for example comprises equal proportions of methyl methacrylate and dimethylaminoethyl methacrylate, is achieved by stirring it in the form of powder with particle sizes smaller than 0.25 mm in water while simultaneously adding an acid. An insoluble copolymer, such as one of methyl methacrylate and ethyl acrylate (70:30) is used as binder. 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 and water in less than two minutes.
European Patent 0704207 A2 describes thermoplastic plastics for pharmaceutical coatings that are soluble in gastric fluid. They are copolymers of 16 to 40 wt % of acrylic or methacrylic acid, 30 to 80 wt % of methyl acrylate and 0 to 40 wt % of other alkyl esters of acrylic acid and/or methacrylic acid.
In the example, corresponding copolymers are melted at 160° C. and mixed after addition of 6 wt % of glycerol monostearate. The mixture is crushed and ground to a powder. The powder is filled into the tab of an injection-molding die and injected at 170° C. under a pressure of 150 bar through a 0.5 mm wide aperture into the mold cavity. After cooling there are obtained bubble-free, slightly opaque, thin-walled pharmaceutical capsules. Special measures for removal of low-boiling constituents immediately before processing by injection molding are not disclosed.
Object and Achievement
The object was considered to be to provide a process with which the known (meth)acrylate copolymers containing monomers with tertiary ammonium groups can be processed in the injection-molding process. In this way molded articles are supposed to be obtained that have properties of solubility in gastric fluid and that meet stringent mechanical requirements, and so can be used, for example, as capsules (locking capsules) which function as receptacles for pharmaceutical active principles.
A process for making molded articles by means of injection molding with the process steps of
a) melting of a (meth)acrylate copolymer, which is composed of 30 to 80 wt % of radical-polymerized C1 to C4 alkyl esters of acrylic or methacrylic acid and 70 to 20 wt % of (meth)acrylate monomers with a tertiary ammonium group in the alkyl residue,
wherein the (meth)acrylate copolymer is present in a mixture with 1 to 70 wt % of a plasticizer and a desiccant in the ratio of 1:1 to 1:20,
wherein the plasticizer is present in a content of at least 1 wt %,
and a release agent is present in a content of 0.05 to 5 wt % and
further standard additives or adjuvants and if necessary a pharmaceutical active principle can also be present in the mixture, and before the mixture is melted it has a content of more than 0.5 wt % of low-boiling constituents with a vapor pressure of at least 1.9 bar at 120° C.
b) degassing of the mixture in the thermoplastic condition at temperatures of at least 120° C., whereby the content of low-boiling constituents with a vapor pressure of at least 1.9 bar at 120° C. is lowered to at most 0.5 wt %
c) injection of the melted and degassed mixture into the mold cavity of an injection-molding die, wherein the mold cavity has a temperature which lies at least 10° C. below the glass transition temperature of the (meth)acrylate copolymer, cooling of the melt mixture and removal of the obtained molded article from the mold.
By means of the inventive process it is possible to obtain novel injection-molded articles that meet the requirements of high mechanical strength and high thermal stability.
Operation of the Invention
The inventive process for manufacture of molded articles by means of injection molding is divided into process steps a), b) and c).
Process Step a)
Melting of a (meth)acrylate copolymer, which is composed of 30 to 80 wt % of radical-polymerized C1 to C4 alkyl esters of acrylic or methacrylic acid and 70 to 20 wt % of (meth)acrylate monomers with a tertiary ammonium group in the alkyl residue, wherein the (meth)acrylate copolymer is present in a mixture with 1 to 70 wt % of a plasticizer and a desiccant in the ratio of 1:1 to 1:20, preferably 1:1 to 1:10, particularly preferably 1:1 to 1:4, wherein the plasticizer content is present in a content of at least 1 wt %, a release agent is present in a content of 0.05 to 5 wt %, preferably 0.1 to 3 wt % and further standard additives or adjuvants and if necessary a pharmaceutical active principle can also be present in the mixture, and before the mixture is melted it has a content of more than 0.5 wt % of low-boiling constituents with a vapor pressure of at least 1.9 bar at 120° C.
Melting of the copolymer, which has the form of granules or powder, takes place preferably in an extruder at a temperature of 80 to 250° C.
The (Meth)Acrylate Copolymer
The (meth)acrylate copolymer is composed of 30 to 80 wt % of radical-polymerized C1 to C4 alkyl esters of acrylic or methacrylic acid and 70 to 20 wt % of (meth)acrylate monomers with a tertiary ammonium group in the alkyl residue.
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. In particular, there can be cited 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. Dimethylaminoethyl methacrylate is particularly preferred.
The content of monomers with tertiary ammonium groups in the copolymer can be advantageously between 20 and 70 wt %, preferably between 40 and 60 wt %. The proportions of the C1 to C4 alkyl esters of acrylic or methacrylic acid is 70 to 30 wt %. Examples are methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate.
A suitable (meth)acrylate copolymer with tertiary amino groups can be formed, for example, from 20 to 30 wt % of methyl methacrylate, 20 to 30 wt % of butyl methacrylate and 60 to 40 wt % of dimethylaminoethyl methacrylate.
A specifically suitable commercial (meth)acrylate copolymer with tertiary amino groups is formed, for example, from 25 wt % of methyl methacrylate, 25 wt % of butyl methacrylate and 50 wt % of dimethylaminoethyl methacrylate (EUDRAGIT® E100).
The copolymers are obtained in ways known in themselves by radical bulk, solution, bead or emulsion polymerization. Before processing, their particle sizes must be reduced to the inventive range by suitable grinding, drying or spraying processes. This can be achieved by simple crushing of extruded and cooled strand for granules or by hot face cutting.
The use of powders can be advantageous in particular for mixing with other powders or liquids. Suitable apparatus for preparing powders are familiar to those skilled in the art. Examples are air-jet mills, rod mills and fan-type mills. If necessary, appropriate sieving steps can be included. A suitable mill for industrial-scale large quantities is, for example, a counter-jet mill (Multi No. 4200), which is operated with about 6 bar gauge pressure.
The average particle size of the powder form can be determined as follows:
By air-jet sieving for simple separation of the ground product into a few fractions. This method is somewhat less precise in this measurement range than are the alternatives. At least 70%, preferably 90% of the particles relative to th
Assmus Manfred
Beckert Thomas
Fuchs Wolfgang
Hoess Werner
Petereit Hans-Ulrich
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Page Thurman K.
Roehm GmbH & Co. KG
Tran S.
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