Venlafaxine besylate

Details Venlafaxine besylate Venlafaxine besylate

2003-03-27

2004-04-06

Davis, Brian (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S360000, C514S653000

Reexamination Certificate

active

06717015

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a novel acid addition salt of venlafaxine, namely venlafaxine besylate, various forms thereof, and the use of the same in pharmaceutical compositions for treating depression and other conditions.
Venlafaxine is the common name for the compound 1-[2-(dimethylamino)-1-(4-metboxyphenyl) ethyl]cyclohexanol, having the structure shown below.
U.S. Pat. No. 4,535,186 describes a class of hydroxycycloalkanephenethyl amines as being useful antidepressants and exemplifies the compound now known as venlafaxine hydrochloride as one of the suitable species. Venlafaxine hydrochloride is approved for sale in various countries including the United States of America. It is available as an immediate release tablet and as an extended release capsule, under the brand name EFFEXOR® (Wyeth Ayerst) and EFFEXOR XR® (Wyeth Ayerst), respectively.
Venlafaxine has been the subject of various research endeavors. For example, U.S. Pat. No. 5,043,466 describes a process for making cyclohexanol derivatives in a specified solvent composition. Example 3 of this patent shows the synthesis of venlafaxine as the hydrochloride salt thereof.
U.S. Pat. No. 6,274,171 and related EP 0 797 991A1 disclose encapsulated extended release formulations for venlafaxine hydrochloride. These patents indicate that commercial venlafaxine hydrochloride tablets were administered two or three times daily, but that due to variations in the drug concentration in the patient's blood plasma caused by such a dosing regimen, unwanted side effects, especially nausea and vomiting were common. A once daily, encapsulated extended release dosage form is disclosed that provides a flattened drug plasma profile and reduces these side effects. The encapsulated dosage form is taught to comprise spheroids of venlafaxine hydrochloride, microcrystalline cellulose, and hydroxypropylmethylcellulose (HPMC). These spheroids are coated with a mixture of ethyl cellulose and HPMC. By providing an appropriate amount of the coating, the desired blood plasma profile can be obtained. An acceptable batch of coated spheroids will meet the following in vitro dissolution profile:
Average % venlafaxine
Time (hours)
hydrochloride released
2
<30
4
30-55
8
55-80
12
65-90
24
>80
using USP Apparatus 1 (basket) at 100 rpm in purified water at 37° C. The coated spheroids can be from a single batch or represent a blend of batches having different dissolution profiles.
U.S. Pat. No. 6,274,171 and EP 0 797 991 also state that forming an extended release dosage form of venlafaxine hydrochloride was difficult in part due to the high water solubility of the hydrochloride salt. In fact, these patents disclose that “[n]umerous attempts to produce extended release tablets by hydrogel technology proved to be fruitless because the compressed tablets were either physically unstable (poor compressibility or capping problems) or dissolved too rapidly in dissolution studies.” See U.S. Pat. No. 6,274,171 at column 4, lines 60-65 and EP 0 797 991A1 at page 3 lines 35-37. Unlike the encapsulated extended release formulations described in these patents, a hydrogel extended release venlafaxine hydrochloride tablet is taught to typically exhibit a dissolution profile wherein 40%-50% is released at 2 hours, 60%-70% is released at 4 hours, and 85%-100% is released at 8 hours.
WO 99/22724 also discloses encapsulated venlafaxine hydrochloride extended release dosage forms. These formulations differ from those in U.S. Pat. No. 6,274,171 and EP 0 797 991A1 in that the spheroid is substantially free of HPMC. Apparently HPMC can be omitted from the spheroid when smaller amounts of venlafaxine hydrochloride are employed.
U.S. Pat. No. 6,197,828 and WO00/32556 disclose the use of individual (+) and (−) enantiomers, respectively, of venlafaxine as well as metabolites thereof. While the commercial venlafaxine hydrochloride is a racemate, these patents teach that various side effects may be reduced by using one isomer substantially without the presence of the other.
Although venlafaxine hydrochloride provides good pharmaceutical activity, it would be beneficial to find other forms of venlafaxine. In particular, venlafaxine forms that are easier to handle would be advantageous. Venlafaxine hydrochloride is relatively aggressive towards handling equipment and is irritating to the skin, etc. of human personnel that handle the pure active. A venlafaxine form that is less aggressive and less irritating would be desirable. It is further desirable to provide a venlafaxine form that can be easily formulated into various dosage forms including hydrogel extended release tablets.
SUMMARY OF THE INVENTION
The present invention is based on the discovery of a new form of venlafaxine, namely venlafaxine besylate. Accordingly, a first aspect of the invention relates to a venlafaxine besylate compound. The compound can be isolated and/or purified or it can be part of a composition. The compound can be in solid form including crystalline forms but is not limited thereto. A preferred compound is crystalline venlafaxine besylate monohydrate.
Another aspect of the present invention relates to a pharmaceutical composition comprising an effective amount of venlafaxine besylate and a pharmaceutically acceptable excipient. The composition can be an immediate release dosage form or an extended release dosage form and embraces tablets as well as pellets/beads/spheroids or other encapsulated forms. In one embodiment, the venlafaxine besylate is provided in a hydrogel tablet. The hydrogel tablet preferably provides sufficient extended release so that the tablet is a once daily dosage form. In another preferred embodiment, the extended release composition uses a lipophilic matrix and is conveniently made by a hot melt granulation technique.
A further aspect of the invention relates to the use of venlafaxine besylate in treating venlafaxine-treatable diseases or conditions and/or in making medicaments for treating such diseases or conditions. Hence the invention provides a method for treating a venlafaxine-treatable disease or condition, which comprises administering to a patient in need thereof an effective amount of venlafaxine besylate. The venlafaxine besylate is typically administered as an oral composition such as a tablet or capsule and is preferably administered once daily.
Another aspect of the present invention relates to a process of making a venlafaxine besylate formulation that comprises mixing venlafaxine besylate and a molten fusible carrier to form a partially melted mass; and cooling the partially melted mass to form a solidified product. The solidified product is typically a granulate and can be converted to a tablet or pellet.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is based on the surprising discovery that venlafaxine besylate, i.e. venlafaxine benzenesulfonate, has advantageous properties in comparison to venlafaxine hydrochloride. First, venlafaxine besylate is much less water soluble than venlafaxine hydrochloride. For example, venlafaxine besylate monohydrate exhibits a solubility of about 25 mg/ml in water and less than 30 mg/ml in 0.1 N HCl at ambient conditions. In contrast, venlafaxine hydrochloride exhibits a water solubility of about 570 mg/ml at ambient conditions. This reduced solubility can be advantageous in formulating an extended release dosage form. In addition, venlafaxine besylate is less aggressive, less irritating, and easier to handle than venlafaxine hydrochloride. The besylate salt can be formed into a powder that is less irritating to the personnel handling the material than the hydrochloride salt and that can be readily transported by mechanical apparatus and compressed into a tablet. Generally, venlafaxine besylate powder has a higher bulk density and a higher tapped density (e.g., 500 tap) than venlafaxine hydrochloride. Additionally, venlafaxine besylate has a relatively lower melting point which can be advantageous in certain formulating techniques such as hot melt

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