Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
2002-01-24
2004-06-22
Dees, José (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S401000, C424S451000, C424S452000, C424S464000
Reexamination Certificate
active
06752997
ABSTRACT:
FIELD OF THE INVENTION
This invention is directed to pharmaceutical compositions (including dosage forms) of a salt of valproic acid that (despite the hygroscopicity of the active ingredient) resists absorbing moisture from the environment and hence remains stable over a prolonged period of time. The invention encompasses the compositions, processes for producing the compositions, and methods of treating medical conditions using the compositions.
BACKGROUND OF THE INVENTION
Valproic acid and its pharmaceutically acceptable salts are useful for treating various forms of epilepsy as well as certain other disorders. Valproic acid is considered a first line therapy for treating petit mal, monoclonic seizures, generalized and partial motor seizures, absence and infantile spasms. Recently, valproic acid was also approved for the treatment of partial epilepsy, bipolar disorders (psychotic disorders) and migraine.
The effective blood concentrations of the drug generally range from 50 to 100 mg/ml. Because valproate salts, such as sodium valproate, have a short biological half life, the drug usually needs to be administered more than once (e.g. three times a day) to maintain an effective blood concentration. Since such a short dose interval reduces patient compliance, there have been many efforts to develop sustained release preparations of sodium valproate.
Although valproic acid or its salts have known utility as anti-convulsants, a number of problems are associated in formulating them in a solid form. According to the Merck Index, valproic acid is a liquid and therefore suffers from the difficulties attendant any liquid formulation; that is, it is inconvenient to use since the precise volume necessary to result in administration of the proper dose must be measured for each administration, and it is less easily portable than solid dosage forms. Efforts have been made to address the problems of administering valproic acid by converting it to its salt forms, which are solid. However, as disclosed in U.S. Pat. No. 4,301,176, the sodium salt of valproic acid is hygroscopic. Hygroscopicity interferes with and, in fact, has precluded production of a compressed tablet formulation, and thus is a serious disadvantage.
Various attempts have been made to formulate moisture-stable solid valproic acid and valproic acid salt formulations. U.S. Pat. No. 5,049,586 discloses conventional (immediate-release) formulations of valproic acid containing fillers, disintegrants, binders and lubricants. The lubricated granulate disclosed therein is said to be a dry, non-hygroscopic mixture which is said to be suitable for use in forming compressed tablets or for filling capsules. The formulation is asserted to be moisture stable and to need no protective coating. However, production of the tablets described in the '586 patent is disadvantageous because the production requires a wet granulation step and is more complicated compared to the procedure described in the present invention.
U.S. Pat. Nos. 5,017,613 and 5,185,159 disclose a pharmaceutical composition based on valproic acid and one of the pharmaceutically acceptable salts in the absence of any binder. According to the '613 and '159 patents, the granules for compression are formed directly by simply mixing with a suitable granulating solvent. Valproic acid is added slowly, either directly or by spraying, to the valproic acid salt, with the granular agglomeration occurring automatically in a few minutes. The granules thus obtained were passed through a screen for calibration. This operation could be carried out in an atmosphere of 55-60% relative humidity, without risk of any uptake of moisture. The compressibility of these granules was found to be very good and, moreover, the valproic acid acted as a lubricant.
Similarly EP 0 133 110 discloses an oral tablet pharmaceutical composition of approximately 25-35% by weight of valproic acid and about 65-75% by weight of sodium valproate. The granules for compression are formed directly by mixing suitable proportions of valproic acid and one of the pharmaceutically acceptable salts thereof in the absence of any binder or granulating solvent.
U.S. Pat. Nos. 4,988,731 and 5,212,326 disclose a highly stable non-hygroscopic, solid entity prepared from valproic acid and its salts, which is a single crystalline entity consisting of one molecule each of valproic acid or diethylacetic acid and sodium valproate salt. It was shown that the crystalline compound has equal or better physiological properties than either valproic acid or sodium valproate. Since the crystalline compound has far superior physical characteristics than either monomer from which it is made, it greatly facilitates the preparation of solid pharmaceutical dosage forms.
The methods disclosed in U.S. Pat. Nos. 5,017,613, 5,185,159, 4,988,731, 5,212,326 and EP 0 133 110 are disadvantageous since these methods require reaction between valproic acid and its salt to produce a new entity. Moreover the production of the new entity, according to U.S. Pat. Nos. 4,988,731 and 5,212,326, includes steps involving cooling and filtration which complicates the production of the new formed entity.
The production of the granules according to U.S. Pat. Nos. 5,017,613, 5,185,159 and EP 0 133 110 is disadvantageous. Since valproic acid is a viscous liquid which is hard to handle and the granules for compression are formed in the absence of a granulating solvent, this may lead to a technological difficulty in forming an homogeneous mixture of valproic acid and valproic acid salt.
Hasegawa et al. [Hasegawa, A. et al.,
YAKUZAIGAKU,
47: 86-92, 1987] describes a solid dispersion of water insoluble carriers and sodium valproate. This composition inhibits moisture absorption when a saturated fatty acid such as stearic acid or other organic acids such as citric acid, succinic acid or tartaric acid are employed. Although it was shown that these solid dispersions inhibit moisture uptake, such compositions are disadvantageous since relatively high concentrations of the acids are required (about 20% by weight of sodium valproate). Moreover, part of these reactions (especially the reaction with citric acid) are exothermic and require cooling of the mixture. In particular, the reaction of sodium valproate with citric acid is highly exothermic and leads to melting of the mixture, which is a serious disadvantage.
Other attempts have been made to develop controlled release pharmaceutical compositions of valproic acid and its salts and other derivatives. U.S. Pat. No. 4,913,906 discloses a controlled release dosage form of valproic acid, sodium valproate, valproamide and other derivatives of therapeutic value. The controlled release oral dosage form comprises a homogeneous admixture of an active ingredient and a physiologically acceptable polymer or a native protein. Although the formulations described were found to provide sustained release action, the production of the tablets requires that such dosage form should be performed in dry atmosphere cabinet, at less than 30% Relative Humidity (RH) which is a serious disadvantage, especially for commercial scale products.
None of these prior art references disclose a process for preparing a non-hygroscopic composition of a salt of valproic acid which can be produced under a variety of relative humidity conditions (including RH substantially higher than 30%) by combining a hygroscopic salt of valproic acid with a polymeric agent and a non-hygroscopic additive.
There is a widely recognized need for an effective formulation containing a solid valproic acid derivative, which is non-hygroscopic, simple to produce, lower in cost and yet suitable for treatment of epilepsy, psychotic disorders and migraine headaches as described in the present invention. There is an acute need for such a formulation that is a sustained release and/or an enteric coated formulation.
SUMMARY OF THE INVENTION
This invention is directed to processes for preparing pharmaceutical compositions comprising as an active ingredient a hygroscopic salt
Barder Maya
Friedman Michael
Golander Yechiel
Levitt Barrie
Moros Daniel A.
Darby & Darby
Dees Jose
George Konata M.
Taro Pharmaceuticals U.S.A. Inc.
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