Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2001-08-28
2003-11-11
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S464000, C424S465000, C424S466000, C424S489000, C424S493000, C424S494000, C424S497000
Reexamination Certificate
active
06645523
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a paroxetine compositions, especially pharmaceutical formulations and dosage forms, and to processes of manufacturing the same.
2. Description of the Related Arts
U.S. Pat. No. 4,007,196 describes certain compounds that possess anti-depressant activity. One specific compound mentioned in this patent is known as paroxetine and is represented by the following formula:
Paroxetine has been approved for treating, inter alia, depression in humans and is being marketed around the world under such brand names as Paxil® (SmithKline Beecham) and Seroxat. Dosage forms thus far include immediate release tablets, extended release tablets, capsules and suspensions. The active substance in all commercial forms thus far has been paroxetine hydrochloride and specifically with regard to tablets and other solid forms the active has been paroxetine hydrochloride hemihydrate as disclosed in U.S. Pat. No. 4,721,723 and EP 223403.
WO 95/16448 reports that all commercial paroxetine hydrochloride hemihydrate tablets were, at least up until that time, made using a wet granulation process. Further, the commercial tablets exhibited a color change; i.e., these tablets often developed a pink hue that is highly undesirable. This was apparently masked in the commercial product by a colored outer coat layer. The point of the PCT publication is that the pink hue formation can be avoided by carrying out tableting in the absence of water, i.e. by conventional dry granulation and direct compression. The PCT publication does not mention what the coloring compound(s) are or their route of formation. But, subsequent documents reveal that the coloration problem involves the formation of a coloring impurity identified below as the compound of formula A.
Since the publication of WO95/16448, it appears that the brand name paroxetine hydrochloride hemihydrate product in Europe, at least, was changed to a dosage form made by a dry granulation technique in accordance with the teachings in the PCT publication.
It would be advantageous to find a paroxetine composition that does not suffer from coloration or that is less prone to coloration regardless of how the composition is made. Further, it would be desirable to make a paroxetine composition with the aid of water, such as by wet granulation, that nonetheless was not prone to the above-mentioned coloration problems.
In particular, the application of an aqueous granulation process for industrial scale production is desirable in that such a process provides uniform distribution of the active substance within the bulk granulate composition so that the dose uniformity of tablets or capsules is more easily assured. This is especially true in the case of unit dosage forms containing a low dose of a potent active agent. Here, paroxetine is normally used in 20 to 40 mg per tablet and thus its uniformity in large scale production could be of concern. Water is a very suitable solvent for the granulation process because it is non-toxic and non-flammable. Thus, it would be desirable to find a way to use an aqueous granulation process for the industrial scale production of paroxetine final forms that would also avoid or limit the occurrence of the color forming impurities.
U.S. Pat. No. 5,874,447 describes paroxetine sulfonate salts, including paroxetine methane sulfonate also known as paroxetine mesylate. These sulfonate salts have advantageous properties in comparison to the known salts, including the hydrochloride salts. For example, the sulfonate salts have high water solubility and good thermal stability, making them useful in forming a commercial paroxetine dosage form. The U.S. Pat. No. 5,874,447 patent discloses that tablets can be made by any known method including a dry technique (direct compression, dry granulation) or a wet technique (wet granulation). However, no discussion appears in the U.S. Pat. No. 5,874,447 patent regarding the paroxetine hydrochloride coloring problem.
SUMMARY OF THE INVENTION
Now, it has surprisingly been discovered that solid paroxetine compositions including granulates and dosage forms made therefrom, can be made more stable against coloration, even if made with the aid of water such as by an aqueous granulation process, by controlling the pH of the composition to 6.5 or less. Further, it appears that paroxetine sulfonate salts are less prone to coloration problems than paroxetine hydrochloride salts, even if made with the assistance of water. Studies by the present inventors reveal that the impurity A is a dimer formed from the paroxetine free base in an aqueous alkaline environment. Oxygen is also apparently needed to allow the dimer reaction to proceed. Given the discovery that coloring impurity A is formed in the presence of water, it is understandable in hindsight how carrying out a dry process as suggested in WO95/16448 would help to minimize and/or avoid coloration; i.e. the required aqueous medium for forming the dimeric impurity is missing thereby inhibiting its formation. Having elucidated the source of the coloring problem, the present invention provides a novel solution thereto by keeping the pH of the composition to 6.5 or less. Alternatively, the present invention unexpectedly solves the coloring problem by switching the paroxetine salt from hydrochloride to sulfonate and thereby allowing the use of water in the preparation of paroxetine granules without incurring any substantial coloration.
Thus, in a first aspect of the invention, there is provided a solid paroxetine composition comprising a paroxetine salt and an excipient wherein said composition has a pH of 6.5 or less, as is hereinafter defined. The paroxetine salt is preferably a paroxetine sulfonate salt such as paroxetine methane sulfonate or a paroxetine hydrochloride salt. The excipients generally include a binder or diluent such as calcium phosphate or microcrystalline cellulose as well as a disintegrant and lubricant. The composition can be an intermediate form or a final dosage form such as a tablet or capsule. In one embodiment, a tablet is made that does not need a taste masking coating to avoid the usual bitter taste associated with paroxetine compositions.
A second aspect of the present invention relates to paroxetine solid dosage forms comprising a paroxetine sulfonate salt as a pharmaceutically active agent and having been made with the aid of water. The solid dosage form can be a tablet, pellet or capsule form, etc., and contains a pharmaceutically effective amount of paroxetine sulfonate, e.g. for treating depression, obsessive-compulsive disorder, or panic attack, etc. Preferably the excipients are selected so that the composition has a pH of 6.5 or less. Further, the composition is normally dried to a sufficient extent that the total content of added water remaining is 2.0 wt % or less, preferably 1.3 wt % or less, and more preferably 1.0 wt % or less. Generally, the composition does not contain any decolorization agent as an excipient. Even though an aqueous process is used, the dosage form of the present invention exhibits no, or substantially no, formation of a pink or other colored hue.
A third aspect of the invention provides for a granulate formed by mixing water, paroxetine sulfonate salt, and at least one excipient and drying the resulting mixture. Typically the water and paroxetine sulfonate salt are provided together as an aqueous solution and added to the powdered or dry excipient(s), although this is not required. In some embodiments, the excipient(s) may be pre-blended and granulated such as by a dry granulation technique before being contacted with a concentrated aqueous paroxetine sulfonate salt solution. The mixture is dried to form a granulate to which additional excipients may be added, if desired. The granulate can be formed into other conventional dosage forms such as tablets, capsules, sachets, pellets, etc. The composition is preferably selected as described above for the dosage forms, namely with a pH of 6.5 or less and with an added water content o
Lemmens Jacobus M.
Peters Theodorus H. A.
Picha Frantisek
Platteeuw Johannes J.
van Dalen Frans
Oh Simon J.
Page Thurman K.
Synthon BCT Technologies, LLC
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