Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-10-19
2003-11-11
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
Reexamination Certificate
active
06645527
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to sustained release matrix preparations containing tramadol or a pharmaceutically acceptable salt thereof as the therapeutically active agent.
Sustained release preparations are known to those skilled in the art to achieve a slow release of a drug over an extended period of time, thereby extending the duration of drug action over that achieved by conventional delivery. Preferably such a preparation maintains a drug concentration in the blood within the therapeutic range for 12 hours or more.
An important aspect of the manufacture, regulatory review and approval of all dosage forms concerns their stability over extended periods of time. The stability data obtained with regard to a particular dosage form directly affects its shelf-life. The stability of a pharmaceutical dosage form is related to maintaining its physical, chemical, microbiological, therapeutic, and toxicological properties when stored, i.e., in a particular container and environment. Stability study requirements are covered, e.g., in the Good Manufacturing Practices (GMPs), the U.S.P., as well as in the regulatory requirements of the country where approval to market a dosage form is being sought. In the United States, a request to test, and eventually market, a drug or a drug formulation may be made via a New Drug Application (NDA), an Abbreviated New Drug Application (ANDA) or an Investigational New Drug Applications (IND).
The agents used in sustained release dosage formulations often present special problems with regard to their physical stability during storage. For example, waxes which have been used in such formulations are known to undergo physical alterations on prolonged standing. Precautions may be taken to stabilize waxes at the time of manufacture or to prevent the change from occurring. Fats and waxy materials when used in purified states are known to crystallize in unstable forms, causing unpredictable variations in availability rates during stability testing at the time of manufacture and during later storage.
It is known that certain strategies can be undertaken to obtain stabilized controlled release formulations in many cases, such as insuring that the individual agents are in a stable form before they are incorporated into the product, and that processing does not change this condition, retarding the instability by including additional additives, and inducing the individual agents of the dosage form to reach a stable state before the product is finally completed.
It is also recognized that the moisture content of the product can also influence the stability of the product. Changes in the hydration level of a polymeric film, such as the ethyl celluloses, can alter the rate of water permeation and drug availability. Also, binders such as acacia are known to become less soluble when exposed to moisture and heat. However, moisture content of a product can be controlled fairly successfully by controls in the processing method and proper packaging of the product.
Hydrophobic polymers such as certain cellulose derivatives, zein, acrylic resins, waxes, higher aliphatic alcohols, and polylactic and polyglycolic acids have been used in the prior art to develop controlled release dosage forms. Methods of using these polymers to develop controlled release dosage forms such as tablets, capsules, suppositories, spheroids, beads or microspheres are to overcoat the individual dosage units with these hydrophobic polymers. It is known in the prior art that these hydrophobic coatings can be applied either from a solution, suspension or dry. Since most of these polymers have a low solubility in water, they are usually applied by dissolving the polymer in an organic solvent and spraying the solution onto the individual drug forms (such as beads or tablets) and evaporating off the solvent.
The use of organic solvents in the preparation of hydrophobic coatings is considered undesirable because of inherent problems with regard to flammability, carcinogenicity, environmental concerns, and safety in general. It considered very desirable in the art, however, to provide a controlled release coating derived from aqueous dispersions of a hydrophobic material. Unfortunately, such formulations were prone to changes in dissolution characteristics upon storage, rendering such formulations unsuitable for oral sustained release dosage forms containing therapeutically active agents. Stabilized controlled release formulations which utilize ethyl cellulose as a controlled release coating are described in the assignee's previous U.S. Pat. Nos. 5,273,760 and 5,472,712, hereby incorporated by reference. Stabilized controlled release formulations which utilize one or more acrylic polymers as a controlled release coating are described in the assignee's previous U.S. Pat. Nos. 5,286,493; 5,580,578; and 5,639,476, hereby incorporated by reference.
Sustained release oral dosage forms in which the therapeutically active agent is incorporated into a matrix containing one or more hydrophobic and/or hydrophilic materials are also well known to those skilled in the art. In this regard, reference is made to U.S. Pat. No. 3,965,256 (Leslie) which is directed to slow release pharmaceutical compositions comprising a combination of a higher aliphatic alcohol and a hydrated hydroxy-alkyl cellulose; and U.S. Pat. Nos. 4,861,598 and 4,970,075 (Oshlack, et al.), wherein the release of therapuetically active agents from controlled release bases is extended by using a combination of a higher aliphatic alcohol and an acrylic resin as the base material.
Melt granulation techniques have also been suggested to provide controlled release formulations. Melt granulation usually involves mechanically working an active ingredient in particulate form with one or more suitable binders and/or pharmaceutically acceptable excipients in a mixer until one or more of the binders melts and adheres to the surface of the particulate, eventually building up granules. This technique has been utilized in the exemplification of sustained release oral tramadol dosage formulations, as set forth in the assignee's U.S. Pat. No. 5,591,452, hereby incorporated by reference.
PCT International Publication No. WO 92/06679, incorporated by reference, discloses melt granulating methods for producing pellets containing therapeutically active substances. The method includes mechanically working a mixture containing the active substance in cohesive form with a binder having a melting point of 40-100° C., while supplying sufficient energy to melt the binder and form “overmoist” spherical pellets and thereafter adding an additional cohesive substance while maintaining the mechanical working to finally produce dry pellets.
PCT International Publication No. WO 93/18753, incorporated by reference, also discloses another melt extrusion process for preparing sustained release pellets. This method includes pelletizing a mixture containing drug in finely divided form and a binder which includes one or more water-insoluble-wax-like binder substances with a melting point above 40° C. using a high shear mixer.
OBJECTS AND SUMMARY OF THE INVENTION
It is an object of the present invention to provide an oral sustained release solid dosage form of tramadol suitable for at least twelve-hourly (e.g. up to twenty-four hourly) administration for the treatment of pain.
It is an object of the present invention to provide sustained release tramadol formulations which provide a stable dissolution, even after exposure to accelerated storage conditions or to prolonged storage at room temperature.
It is an object of the present invention to provide a method of preparing a sustained release tablet which includes tramadol as the drug which tablet provides a stable dissolution profile of the drug when plated in an environment of use, despite exposure to accelerated storage conditions.
A further object of the present invention is to provide a stabilized sustained release tramadol formulation wherein the sustained release is provided via a matrix of a
Chasin Mark
Goldenheim Paul
Huang Hua-Pin
Oshlack Benjamin
Davidson Davidson & Kappel LLC
Euro-Celtique S.A.
Joynes Robert M.
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