Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-14
2002-10-01
Chang, Ceila (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S506000
Reexamination Certificate
active
06458824
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a crystal of [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic acid (hereinafter, occasionally referred to as Compound A), and a pharmaceutical preparation containing as a drug substance the crystal of Compound A, especially the present invention relates to a solid preparation wherein the size (volume) of the preparation, the content uniformity of the drug substance, and the stability of the drug substance, are secured, and further the dissolution of the drug substance from the preparation is rapid.
BACKGROUND ART
Compound A exhibits a potent &bgr;
3
-adrenergic receptor-stimulating activity with excellent adrenoceptor selectivity, and it is useful in the prophylaxis or treatment of diabetes mellitus and obesity (WO 96/16938).
Compound A exhibits extremely potent pharmaceutical activities, and when it is formulated into a pharmaceutical composition, such composition should be a low-content preparation wherein the content of the active compound per dosage unit is low. However, in compliance with the decrease of the content of Compound A in a preparation, there has been discovered a phenomenon that the chemical stability of Compound A per se is extremely lowered. In addition, when the amount of excipients other than Compound A is increased so that the size being suitable to be used as a pharmaceutical preparation is secured, the content of Compound A per each dosage unit becomes uneven and it is difficult to give a preparation having uniform content of Compound A. Under the circumstances, it has been desired to develop a preparation of Compound A without the above-mentioned defects from which Compound A can rapidly dissolve.
An object of the present invention is to provide a preparation of Compound A wherein the size (cubic capacity) of the preparation, the content uniformity of Compound A, and the stability of Compound A are secured, as well as from which Compound A can rapidly dissolve out.
DISCLOSURE OF INVENTION
The present invention includes the inventions of the following various embodiments.
(1) A crystal of [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1H-indol-7-yloxy]acetic acid (hereinafter, occasionally referred to as “crystal of Compound A”);
(2) A crystal of [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1H-indol-7-yloxy]acetic acid, which have characteristic diffraction peaks at the diffraction angles (2&thgr;) of about 5.9°, about 17.9°, about 20.5° and about 24.0° in the powder X-ray diffraction pattern (hereinafter, occasionally referred to as “Compound A type-I crystal”);
(3) A crystal of Compound A having a particle size of not larger than 100 &mgr;m at the cumulative weight distribution value of 50%, and a particle size of not larger than 200 &mgr;m at the cumulative weight distribution value of 95% (hereinafter, occasionally referred to as “drug substance”);
(4) A granule consisting of the crystal of the above (3) (drug substance);
(5) A granule consisting of (a) a drug substance, (b) a filler, (c) a disintegrant, and (d) a binder;
(6) A solid preparation containing the granule of the above (4);
(7) A tablet which is formulated by compressing the granule of the above (4);
(8) A tablet which is formulated by compressing the granule of the above (4) and external excipients;
(9) A &bgr;
3
-adrenergic receptor agonist, which comprises the crystal of the above (3) (drug substance);
(10) An agent for treatment of diabetes mellitus, which contains the crystal of the above (3) (drug substance); and
(11) An agent for treatment of obesity, which contains the crystal of the above (3) (drug substance)
Throughout the present description and claims, the “crystal of Compound A” means a pure crystal of 3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy acetic acid, and as described below, the crystal of Compound A can be grouped into type-1 crystal (“Compound A type-I crystal”) and type-II crystal (“Compound A type-II crystal”), based on the diffraction peaks of the powder X-ray diffraction pattern thereof. The type-I crystal, the type-II crystal, or a mixture of these crystals are obtained according to the process for production thereof. The “crystal of compound A” includes all of these crystals.
The “drug substance” means the above crystal of Compound A, having a particle size of not larger than 100 &mgr;m at the cumulative weight distribution value of 50%, and a particle size of not larger than 200 &mgr;m at the cumulative weight distribution value of 95%. Preferable particle size of the drug substance is not larger than 50 &mgr;m at the cumulative weight distribution value of 50%, and not larger than 150 &mgr;m at the cumulative weight distribution value of 95%. More preferable particle size is not larger than 30 &mgr;m at the cumulative weight distribution value of 50% and not larger than 100 &mgr;m at the cumulative weight distribution value of 95%. The “drug substance” of the present invention includes all of these.
The “cumulative weight distribution value” means a value which is obtained by classifying the powders based on the particle size thereof, and by adding up the weights of each particle size from the end of the distribution, and is expressed by percentages to the total weight of the powders. As a method for expressing the mean particle size of the powders (aggregate of particles) having a distribution in the size of particles, the “particle size at the cumulative weight distribution value of 50%” is commonly used. In addition, throughout the present description and claims, the “particle size of the cumulative weight distribution value of 95%” is used as an index for regulating the content of coarse particles which affect the dissolution pattern of the compound from the preparation (see Alfonso R. Gennard (Ed.): Particle Size Measurement and Classification, Remington's Pharmaceutical Sciences 17th edition, Part 8 Chapter 89, pp 1588-1589, 1985; Swithenbank, J., Beer, J. M., Taylot, D. S., Abbot, D. and McCreath, G. C.: A laser diagnostics technique for the measurement of droplet and particle size distribution. AIAA Paper no. 76-79 (1976); and H.ayashi, S.: A laser small angle scattering instrument for the determination of size and concentration distribution in sprays, (Hirleman, E. D. and others Eds.), Liquid particle Size Measurement Techniques: 2nd Volume, Philadelphia, ASTM, 1990).
REFERENCES:
patent: 5817689 (1998-10-01), Kato et al.
Fujii Akihito
Fujita Megumi
Fujiwara Keiichi
Harada Hiroshi
Iwata Motokazu
Birch & Stewart Kolasch & Birch, LLP
Chang Ceila
Dainippon Pharmaceutical Co., Ltd.
Small Andrea D.
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