Stable pharmaceutical formulation

Details Stable pharmaceutical formulation Stable pharmaceutical formulation

1999-07-21

2003-02-25

Solola, Taofiq (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S517000, C424S465000, C424S491000

Reexamination Certificate

active

06525084

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a novel granulate and a novel oral solid dosage formulation comprising an active ingredient and one or more carriers. Moreover the invention relates to a wet granulation method for preparing the granulate as well as a wet granulation method for preparing the oral solid dosage form.
BACKGROUND OF THE INVENTION
High shear mixers are widely used in the pharmaceutical industry for blending and granulation (cf. Handbook of pharmaceutical granulation technology, chapter 7, “Drugs and the pharmaceutical sciences”, vol. 81, 1997). Blending and wet massing is accomplished by high mechanical agitation by an impellar and chopper. High shear mixers have applications other than wet granulation, as it can be used for melt granulation and pelletization. When melt granulation or pelletization is performed, energy for melting the binder is supplied by agitation of the impellar and external heating of the bowl.
Compounds of Formula I
wherein R is hydrogen or C
1-6
alkyl; or a pharmaceutically acceptable salt thereof, are described in i.a. U.S. Pat. No. 5,280,040. This patent describes the preparation of these compounds, as well as their use for reducing or preventing bone loss. The preparation of pharmaceutical compositions is also described.
Centchroman, which is 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-pyrrolidin-1-yl)ethoxy)phenyl]-7-methoxychroman, is a non-steroidal compound known to have antiestrogenic activity. It is in use in India as an oral contraceptive (see, for example, Salman et al., U.S. Pat. No. 4,447,622; Singh et al., Acta Endocrinal (Copenh) 126 (1992), 444-450; Grubb, Curr Opin Obstet Gynecol 3 (1991), 491-495; Sankaran et al., Contraception 9 (1974), 279-289; Indian Patent Specification No. 129187). Centchroman has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra et al., Int J Cancer 43 (1989), 781-783. Recently, centchroman as a racemate has been found as a potent cholesterol lowering pharmaceutical agent expressed by a significant decrease of the serum concentrations (S. D. Bain et al., J Min Bon Res 9 (1994), S 394).
Levormeloxifene, (−)-3R,4R -trans-7-methoxy-2,2-dimethyl-3-phenyl4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane, is a particular preferred compound from this series of 3,4-diarylchromans. Levormeloxifene may be used in human and veterinary medicine for the regulation of bone metabolism. It may be used, for example, in the treatment of patients suffering from bone loss due to osteoporosis (including post-menopausal osteoporosis and glucocorticoid-related osteoporosis), Paget's disease, hyperparathyroidism, hypercalcemia of malignancy and other conditions characterized by excessive rates of bone resorption and/or decreased rates of bone formation.
The 3,4-diarylchromans are prepared according to known methods, such as those disclosed in U.S. Pat. No. 3,340,276 to Carney et al., U.S. Pat. No. 3,822,287 to Bolger, and Ray et al., J Med Chem 19 (1976), 276-279, the contents of which are incorporated herein by reference. Conversion of the cis isomer to the trans configuration by means of an organometallic base-catalyzed rearrangement is disclosed in U.S. Pat. No. 3,822,287. The optically active d- and I-enantiomers may be prepared as disclosed by Salman et al. in U.S. Pat. No. 4,447,622 (incorporated herein by reference) by forming an optically active acid salt which is subjected to alkaline hydrolysis to produce the desired enantiomer. The resolvation of (±)-3,4-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane in its optical antipodes is described in U.S. Pat. No. 4,447,622 incorporated herein by reference. Example 1 of U.S. Pat. No.4,447,622 describes the preparation of the minus enantiomer, shown by formula II:
(In this specification, the compound of formula II is referred to as levormeloxifene.) In example 2 of U.S. Pat. No. 4,447,622, levormeloxifene is obtained as the free base and the hydrochloride salt.
The compounds of formula I may be administered as pharmaceutically acceptable salts. A particularly useful pharmaceutically acceptable salt of levormeloxifene is the hydrogen fumarate salt. This salt form is prepared by dissolving fumaric acid and (−)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane in a common solvent such as e.g. methanol, and crystallizing the resulting salt from the solution.
Tiagabine is disclosed in U.S. Pat. No. 5,010,090 incorporated herein by reference. (2E)-5-amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide is disclosed in WO 97/23508 incorporated herein by reference. Raloxifene is disclosed in U.S. Pat. No. 4,418,068 and U.S. Pat. No. 4,133,814 incorporated herein by reference. Idoxifene is disclosed in EP 260066 B1 and U.S. Pat. No. 4,839,155 incorporated herein by reference. Tamoxifene is disclosed in U.S. Pat. No. 4,536,516 incorporated herein by reference. 4-hydroxy Tamoxifene is disclosed in U.S. Pat. No. 4,623,660 incorporated herein by reference. Toremifene is disclosed in U.S. Pat. No. 4,996,225 incorporated herein by reference. Droloxifene is disclosed in EP 792640 incorporated herein by reference.
An object of the present invention is to provide a novel granulate or oral solid dosage form with improved stability properties.
A further object of the present invention is to provide a novel tablet or capsule with possibility of extension of long term shelf-life.
Further objects of the present invention will become apparent from the specification.
Accordingly, the present invention relates to a wet granulation method for preparing a granulate comprising an active ingredient and one or more carriers, the method comprising
a) formation of a mixture of the active ingredient and one or more carriers,
b) granulation of the mixture and
c) drying the mixture,
wherein the granulation is performed in a high shear mixing means with a temperature regulating means for keeping the temperature below about 40° C. in the mixture during granulation.
In another aspect of the present invention the wet granulation method for preparing a granulate comprising an active ingredient and one or more carriers, further comprises processing the granulate into an oral solid dosage formulation. In other words the present invention relates to a wet granulation method for preparing an oral solid dosage formulation comprising an active ingredient and one or more carriers, the method comprising
a) formation of a mixture of the active ingredient and one or more carriers,
b) granulation of the mixture,
c) drying the mixture, and
d) processing the granulate into an oral solid dosage formulation,
wherein the granulation is performed in a high shear mixing means with a temperature regulating means for keeping the temperature below about 40° C. in the mixture during granulation. In one embodiment the oral solid dosage formulation is a tablet.. In another embodiment the oral solid dosage formulation is a capsule. In a further embodiment the oral solid dosage formulation, such as tablet or capsule, is coated with a film.
In a further embodiment of the present method the temperature in the granulation mixture is lower than about 35° C. In a particular embodiment the temperature is from about 0° C. to about 35° C., more preferred from about 0° C. to about 30° C., even more preferred from about 0° C. to about 25° C., still even more preferred from about 15° C. to about 30° C., and most preferred from about 20° C. to about 25° C. In still further embodiments of the present method, which embodiments should be considered independently of each other, the temperature in the granulation mixture is from about −20° C. to about 40° C., from about −10° C. to about 40° C., from about −10° C. to about 0° C., from about 0° C. to about 10° C., from about 10° C. to about 20° C., from about 20° C. to about 30° C.,

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