Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-06-27
2001-11-20
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S468000, C514S772400
Reexamination Certificate
active
06319520
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a new solid controlled-release pharmaceutical composition obtained by thermoforming, in the hot state, a mixture based on polymer(s) belonging to the polymethacrylate family and medicinal active ingredient(s).
Numerous pharmaceutical compositions intended for the controlled release of pharmaceutical active ingredients have been proposed and produced, for administration by the oral, buccal, sublingual, ocular, rectal, vaginal and/or parenteral routes. The objectives of those new compositions were essentially:
to reduce the frequency of administration of the medicaments,
to obtain relatively constant levels of active ingredient in the target medium or biological site,
to obtain release profiles matching the pharmacological activity of the medicaments.
The principle most commonly employed for controlling release is to incorporate the active ingredient(s), together with excipients, which most often are polymeric in nature, in matrices.
Whatever the matrix compositions envisaged, their production is beset by specific problems of manufacture:
a manufacturing process that is complex and composed of several steps,
problems of stability of the active ingredient during the manufacturing process and in relation to the excipients used,
problems in the fine control of the rate of release of the active ingredient(s), which is often variable over time and dependent for example on the particle size of the batches of polymers with compression processes,
a manufacturing process that allows a pharmaceutical form to be obtained which is essentially suited to just one route of administration,
difficulty in achieving reproducibility of the batches due to the multiplicity of steps.
The present invention is an alternative thereto that, by using techniques of thermoforming, allows the difficulties of a general nature described hereinbefore to be overcome to obtain solid pharmaceutical compositions that allow the controlled release of medicinal active ingredient(s). It especially allows the number of steps in the production of final galenical forms to be reduced, thereby limiting the problems of reproducibility and the economic cost, as well as ensuring savings of time and space within a chain of production.
More especially, the invention is directed to a new application of polymethacrylates in the production of the said solid pharmaceutical compositions without addition of plasticiser and without addition of agents that modify the release of the active ingredient(s). The invention, as accomplished by the inventors, accordingly allows the number of products involved in a galenical formulation to be restricted, thereby limiting the problems of stocking and of supply, as well as the problems associated with management of the environment.
PRIOR ART DESCRIPTION
Thermoforming in the hot state relates especially to the techniques of extrusion, co-extrusion, injection and co-injection. These different techniques are well known in the field of plastics and have been widely used in the automobile and packaging sectors.
Because of their characteristics, and the physicochemical properties of the polymers that can be used for thermoforming, the said techniques, and especially simple extrusion, are increasingly being applied in the field of formulating active ingredients.
Various patents accordingly describe controlled-release pharmaceutical compositions which are obtained by extrusion of a mixture comprising at least one active ingredient, one or more extrudable and pharmaceutically acceptable polymers, one plasticiser and/or one retardant, the latter compound allowing the release of the active ingredient to be modified.
In particular, Patent Application WO 96/14058 claims a pharmaceutical composition including especially as therapeutic agent an opioid, which is dispersed in a matrix produced by extrusion. The matrix for extrusion therefore comprises an active ingredient, a hydrophobic material which can be mclted, such as an alkylcellulose or an acrylic or methacrylic polymer, and a hydrophobic material, such as a fatty acid or a fatty alcohol. The latter compound serves as retardant and allows the release of the said active ingredient to be slowed down and controlled. A plasticiser is added to the mixture for the purpose of reducing the extrusion temperature.
U.S. Pat. No. 5,102,668 describes a pharmaccutical composition for controlled release which is independent of the pH, the said composition being obtained by wet extrusion of polymers such as polymethacrylates, the said polymers being hydrophilic at low pH and hydrophobic at high pH. The polymethacrylate preferably used is Eudragit® E100. The extrudates thereby obtained must subsequently undergo a spheronisation step and then, advantageously, they are covered with a polymer film composed of Eudragit® NE 30 D. The association between the polymer comprising the extrudate and the polymer comprising the coating film allows the particular technical problem of that invention to be solved, namely control of the release of the active ingredient as a function of the pH of the dissolution medium.
Among the prior art there may also be mentioned the patent DE 41 38 513, which presents a process for the preparation of a controlled-release pharmaceutical composition by continuous extrusion of a mixture comprising at least one active ingredient, a polymethacrylate, and a polymer of N-vinylpyrrolidone and/or of hydroxyalkyl (methyl)cellulose. The latter compounds are used as plasticisers and play a role in regulating the controlled release of the active ingredient.
The article
Pharm. Res
. 1996, 13 (5), 804-808, also describes the hot extrusion of Eudragit® E 100, to which a plasticiser (at least 12% triethyl citrate) has been added, for obtaining films allowing the controlled release of active ingredients.
Similarly, the journals
J. Cont. Rel
. 1995, 36, 243-250 and
Drug Dev. Ind. Pharm
. 1994, 20, 1323-1339 report the use of Eudragit® RS PM, to which a plasticiser (triacetin) has been added, for obtaining granules by hot extrusion. The active ingredient release kinetics are rapid and the granules do not release all the active ingredient. The extrusion temperatures are located in the range from 130° C. to 140° C.
Those various documents therefore describe the application of the technique of simple extrusion for obtaining new pharmaceutical compositions. The techniques of injection and co-injection have been much less studied and principally concern solid pharmaceutical compositions wherein the matrix is based on cellulose derivatives, starch or polyethylene glycol.
Finally, with regard to the technique of co-extrusion, Patent Application FR 2 766 088 describes a process for the production of an article from which it is possible to manufacture controlled-release devices, the said process comprising carrying out co-extrusion of polymer and active ingredient, the polymer used being preferably an organosilicate compound capable of cross-linking in the presence or absence of a cross-linking agent.
DETAILED DESCRIPTION OF THE INVENTION
The present invention allows, in a simple and economical manner, a solid controlled-release pharmaceutical composition to be obtained directly, by simple mixture of one or more active ingredient(s) and of polymer(s) that have plastic properties and are pharmaceutically acceptable, without addition of plasticiser or retardant, the said mixture being thermoformed. The control of the release of active ingredient in the said composition is obtained solely by means of judicious selection of the plastic polymer(s) used and of the amount thereof relative to that of the active ingredient(s). Besides the fact that the pharmaceutical composition according to the invention is new, it allows galenical forms to be obtained that are easily adaptable to various active ingredients and to their best mode of administration and that ensure controlled and reproducible release of the said active ingredients.
One of the objects of the invention was to achieve a solid controlled-release pharmaceutical compositi
Briault Gilles
Pichon Gerald
Rolland Herve
Tharrault François
Wuthrich Patrick
Adir et Compagnie
Bennett Rachel M.
Page Thurman K.
Sage G. Patrick
The Firm of Hueschen and Sage
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