Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2003-03-27
2004-02-24
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C562S595000, C424S451000, C424S452000, C424S464000, C424S465000, C424S468000, C424S489000
Reexamination Certificate
active
06696496
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to low water-soluble venlafaxine salts, especially venlafaxine maleate, 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-methoxyphenyl) 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 different batches.
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 0 797 991 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.
WO99/22724 also discloses encapsulated venlafaxine hydrochloride extended release dosage forms. These formulations differ from those in U.S. Pat. No. 6,274,171 and EP 0 797 991 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 discloses 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 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 low water-soluble venlafaxine salts. Unlike venlafaxine hydrochloride, the low water-soluble salts of the present invention are more easily formulated into extended release formulations including hydrogel tablets. Thus, a first aspect of the present invention relates to a low water-soluble venlafaxine salt. Such salts exhibit lower water-solubility relative to venlafaxine hydrochloride and preferably 380 mg/ml or less.
A preferred low water-soluble venlafaxine salt is venlafaxine maleate. Accordingly, a second aspect of the invention relates to a venlafaxine maleate 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 hydrogenmaleate anhydrate.
Another aspect of the present invention relates to a pharmaceutical composition comprising an effective amount of venlafaxine maleate 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 maleate is provided in a hydrogel tablet. The hydrogel tablet preferably provides sufficient extended release so that the tablet is a once daily dosage form.
An additional aspect of the present invention relates to a pharmaceutical composition comprising a low water-soluble venlafaxine salt and a hydrophilic matrix material. Such a composition includes finished hydrogel tablets as well as tabletting powder blends and other intermediates in making a final dosage form. The hydrogel tablet exhibits extended release such that no more than twice daily dosing and preferably once daily dosing can be achieved.
A further aspect of the invention relates to the use of a low water-soluble venlafaxine salt, and in particular venlafaxine maleate, in treating venlafaxine-treatable 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 a low water-soluble venlafaxine salt such as venlafaxine maleate. The low water-soluble salt is typically administered as an oral composition such as a tablet or capsule and is preferably administered once daily.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is based on the surprising discovery that various salts of venlafaxine are low water-soluble relative to the water solubility of venlafaxine hydrochloride. As used herein “low water-soluble” venlafaxine salt means that the salt exhibits a water solubility that is less than two thirds the water solubility of venlafaxine hydrochloride, preferably less than half, more preferably one third and more preferably less than one quarter the water solubility of venlafaxine hydrochloride. In absolute values, a low water-soluble salt of venlafaxine preferably has a water solubility of 380 mg/ml or less, preferably 200 mg/ml or less, more preferably 150 mg/ml or less.
Such low water soluble salts include venlafaxine maleate compounds and venlafaxine benzenesulfonate (besylate) compounds and is expected to also include venlafaxine fumarate compounds, but is not limited thereto. Any salt of venl
Keltjens Rolf
Oosterbaan Marinus J. M.
Buscher Mark R.
Page Thurman K.
Sheikh Humera N.
Synthon BV
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