Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1998-03-12
1999-11-02
Weddington, Kevin E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
A61K 31215
Patent
active
059771720
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a lyophilized composition containing prostaglandin E.sub.1 (hereinafter referred to as PGE.sub.1).
BACKGROUND ART
PGE.sub.1, a substance having potent vasodilative and platelet aggregation inhibitory activities, is known to be a drug useful for the treatment of certain diseases such as chronic obstructive arterial diseases [thromboarteritis obliterans (TAO), arteriosclerosis obliterans (ASO)]. Nonetheless, because PGE.sub.1 is inactivated rapidly in the pulmonary circulation, continuous arterial therapy which calls for an extraordinary skill, intravenous drip injection, or massive administration has been attempted clinically but these therapeutic modalities unavoidably entail adverse reactions such as vascular pain, venotitis, and systemic hypotension.
Recently, for overcoming the above disadvantage of PGE.sub.1 and exploiting the outstanding efficacy of the drug, many explorations have been made for formulating PGE.sub.1 into fat emulsions (Japanese Kokai Tokkyo Koho S58-222014, Kokai Tokkyo Koho H4-69340, Kokai Tokkyo Koho H4-338333, Kokai Tokkyo Koho H4-338334, Kokai Tokkyo Koho H4-338335, etc.). Actually, the PGE.sub.1 fat emulsion-described in Japanese Kokai Tokkyo Koho S58-222014 is commercially available today.
The above commercial PGE.sub.1 fat emulsion is a useful PGE.sub.1 preparation, for PGE.sub.1 entrapped in emulsion vehicles is inactivated in the lungs only to a limited extent and this advantage coupled with the vascular lesion-targeting effect of the emulsion due to the characteristic distribution of its fine vesicles in the body produces a potent and lasting vasodilative effect at a low dose, not to speak of a reduced risk for local ADRs, for example mitigated irritancy. It is reported that this fat emulsion contains approximately 20% of decomposition products of PGE.sub.1 even immediately following its manufacture and that the PGE.sub.1 content declines at a rate of about 2.5% per month even when stored at 5.degree. C. [Kazuo Mizuguchi et al., The Clinical Report, 26, 1647-1653 (1992)], thus being not impeccable in quality and stability.
As a means for insuring a sufficient stability of PGE.sub.1 in a fat emulsion, lyophilization of such a PGE.sub.1 -containing fat emulsion was contemplated and actually much study has been undertaken for implementing a lyophilized fat emulsion (PCT WO92/07552, Japanese Kokai Tokkyo Koho H5-43450, Japanese Kokai Tokkyo Koho H6-157294, etc.). However, none of the efforts have borne fruit.
Meanwhile, each drug has a definite pH range in which it is stable and barring an extraordinary circumstance, pharmaceutical products are conventionally formulated within the pH range in which the active substance is stable for insuring a reasonable shelf-life. In the case of PGE.sub.1, it is known to be stable in the weakly acidic region (Pharmaceutical Research, Vol. 5, No. 8, 482-487 (1988); Pharmaceutical Research, Vol. 6, No. 3, 210-215 (1989)), and the above-mentioned fat emulsion available on the market has also been adjusted to a weakly acidic region (pH 4.5-6.0).
DISCLOSURE OF THE INVENTION
The present invention has for its object to provide a pharmaceutical product in the field of PGE.sub.1 -containing fat emulsions, which is of higher quality and more stable bacteriologically, thermally, and against aging.
After an intensive research endeavor, the inventors of the present invention made a departure from the convention by adjusting the pH of a PGE.sub.1 -containing fat emulsion to the neutral region of pH, not to the pH range in which PGE.sub.1 is known to be stable, and lyophilizing the fat emulsion and found fortunately that a pharmaceutical product meeting the above object could result from the new approach. The present invention has been developed on the basis of the above finding.
The present invention, therefore, is directed to a PGE.sub.1 -containing lyophilized composition derived from a fat emulsion comprising PGE.sub.1, an oil component, an emulsifier, and water and having a pH controlled within th
REFERENCES:
patent: 4493847 (1985-01-01), Mizushima et al.
patent: 5091417 (1992-02-01), Watanabe et al.
patent: 5650172 (1997-07-01), Matsuda et al.
Sasaki Hideki
Seki Junzo
Yoshikawa Hirofumi
Nippon Shinyaku Co. Ltd.
Weddington Kevin E.
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