Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-07-27
2003-12-09
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S489000, C424S490000, C424S493000, C424S494000
Reexamination Certificate
active
06660298
ABSTRACT:
TECHNICAL FIELD
By addition of an acidulent and a water dispersible polymer, a sufficient degree of solubility for paroxetine hydrochloride amorphous in aqueous solution can be achieved to permit a practical wet granulation method to be performed. These formulations are particularly useful for preparing capsules and tablets.
BACKGROUND ART
Wet granulation is the oldest and most conventional method of making tablets. This highly versatile process has been extensively reviewed by Record (
Int. J Pharm. Prod Dev
., 1:32-39, 1980), Kristensen and Schaefer (
Drug Dev. Ind. Pharm
., 13 (4 and 5):803-872, 1987) and Capes (
Handbook of powder Technology
, J. C. Williams and T. Allen, Eds., Elsevier, Amsterdam, 1980).
Pharmaceutical Dosage Forms: Tablets
, Volume 1, H. A. Lieberman, L. Lachman and J. B. Schwartz, Eds., 1989, lists some advantages of the wet granulation method. These are improvement in the cohesiveness and compressibility of powders, enhancement of the flow properties of the drug and/or excipients, improvement in the content uniformity of the blend, especially with low dose drugs, and improvement in the aesthetic elegance of the formulation by preventing problems such as non-uniform color distribution and/or color migration. Wet granulation has some disadvantages, such as the need for large number of processing steps which are time-consuming, the need for a number of pieces of expensive equipment, and slightly larger material losses. However, the superior quality of the final product and the versatility of the process normally outweighs these disadvantages.
One of the major parameters that needs to be controlled in wet granulation is the amount of granulating fluid used, so that the mass to be granulated and encapsulated or tabletted is merely moist and not wet or pasty. The amount of granulating fluid required to achieve this end depends on the total mass of filler, the amount of filler in the formulation and the solvent absorbing capacity of the filler. The active ingredient in the formulation must be sufficiently soluble in the granulating fluid to permit use of a quantity of fluid appropriate for the physical characteristics of the granulation formulation while supplying the requisite amount of drug.
Paroxetine HCl, the subject of the herein application, is used in the treatment of depression, pre-menstrual syndrome, social aversion disorder, premature ejaculation and other human and veterinarian conditions and diseases. Paroxetine HCl has been reported to be only slightly soluble in water (6 to 12 mg/ml). An amorphous form of paroxetine HCl has now been found to be soluble up to 75 mg/ml at room temperature. Even at this concentration, the wet formulation process would be less than conveniently feasible, as the quantity of solvent required to obtain a composition of desired strength would be too great to result in a tablet or capsule of reasonable size. This problem cannot be solved by granulating the paroxetine hydrochloride along with the filler (rather than dissolving it in the granulating fluid) because this would result in conversion of the amorphous form to the thermodynamically more stable crystalline form; a form with lower solubility that is less desirable.
It has now been found that the solubility of paroxetine hydrochloride can be increased sufficiently in a suitable granulation solvent to make the wet granulation process feasible.
DISCLOSURE OF THE INVENTION
The invention is directed to a method of formulating paroxetine hydrochloride using a wet granulation process and the resultant thereof, wherein the paroxetine hydrochloride retains its amorphous form and can readily be formulated into tablets and capsules. It has been found possible to solubilize amorphous paroxetine hydrochloride at a level of approximately 300 mg/ml which permits successful application of the wet granulation techniques.
Thus, in one aspect, the invention is directed to a method to prepare a formulation of paroxetine hydrochloride suitable for tabletting or encapsulation which method comprises sizing a dried mixture of at least one filler and an aqueous solution of paroxetine hydrochloride, which solution further comprises the combination of at least one water dispersible polymer and at least one acidulent, said combination present in sufficient concentration to solubilize the paroxetine hydrochloride to a level sufficient to provide a ratio of granulation solvent and filler that is satisfactory for tabletting and encapsulation. In another aspect, the invention is directed to wet granulation formulations prepared by the method of the invention and tablets and capsules prepared from them. The invention is also directed to methods to use the invention formulations.
In still another aspect, the invention is directed to a method to solubilize paroxetine HCl in aqueous solvents.
In still another aspect, the invention is directed to a method to formulate amorphous paroxetine hydrochloride into a wet granulated formulation wherein the process avoids any formation of crystalline forms, such as the hemihydrate.
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Kristensen and Schaefer. (1987).Drug Dev Ind Pharm13(4-5):.
Record. (1980).Int J Pharm Prod Dev1:32-39.
Kota Venkata R.
Ronsen Bruce
Sadhale Yogesh
Morrison & Foerster / LLP
Page Thurman K.
Pentech Pharmaceuticals, Inc.
Tran S.
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