Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1996-08-29
1998-07-21
Witz, Jean C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 21, 424545, 424436, A61K 3822
Patent
active
057835551
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to a suppository that contains ulinastatin as an active ingredient and which has an aqueous solution of ulinastatin emulsified in an oily base uniformly to provide a safe and stabilized formulation. More particularly, the invention relates to a ulinastatin-containing vaginal suppository and a process for its production.
BACKGROUND ART
Ulinastatin is a trypsin inhibitor derived from human urine (hereinafter abbreviated as "HUTI") and it is a glycoprotein having a molecular weight of about 67,000 as isolated and purified from human urine (Proksch et al.: Journal of Laboratory and Clinical Medicine, Vol. 79, p. 491, 1972).
The HUTI has an inhibitory activity on many enzymes such as trypsin, .alpha.-chymotrypsin, hyaluronidase, granulocyte elastase and plasmin and clinically it has been found to be effective and safe in the treatment of acute pancreatitis, acute failures in circulatory organs, etc. (Kosuzume et al.: IGAKU NO AYUMI, Vol. 125, pp. 187-190, 1983; Honjo et al.: IGAKU NO AYUMI, Vol. 129, pp. 70-83, 1984; Yamamura et al.: IGAKU NO AYUMI, Vol. 129, pp. 730-738, 1984). For its indications, HUTI was first formulated as a pharmaceutical drug by Mochida Pharmaceutical Co., Ltd. and put on the market in 1985 under the trade name "MIRACLID".
It has recently been reported that administration of ulinastatin into the vagina is effective for the treatment of threatened premature delivery and the following methods are known: ulinastatin is absorbed by a tampon, which is subsequently retained within the cervix (SHUSANKI IGAKU, Vol. 21, No. 1, pp. 57-60, 1991); the vagina is irrigated daily with physiological saline containing ulinastatin (NIHON SANFUJINKA SHINSEIJI KETSUEKI GAKKAISHI, Vol. 2, No. 1, pp. 107-110, 1992); ulinastatin is formulated as a vaginal suppository (Acta Obst. Gynaec. Jpn., Vol. 44, No. 4, pp. 477-482, 1992).
The last mentioned document discloses a ulinastatin suppository having a (Mitsuba Co., Ltd.)!; however, it has no disclosure at all about the stability of ulinastatin.
The ulinastatin-containing suppository is also disclosed in other documents, i.e., Unexamined Published Japanese Patent Application (kokai) Hei 2-145527 which teaches its use as an AIDS treating and inhibiting agent, and Unexamined Published Japanese Patent Application Sho 55-160724 which teaches its use as an anti-shock agent; however, these documents make no description of specific formulae for the suppository.
The only formula for suppository that is specifically set forth in the above-mentioned documents has several problems such as that the preliminary step of freeze-drying ulinastatin is needed and that freeze-dried powder having such a property that it will not be readily dispersed uniformly in oily bases, and even if it is dispersed, the particles tend to reaggregate and sediment. The reaggregation cannot be avoided by using gelatin as a stabilizer and substituting a base of low hydroxyl value which is known to stabilize drugs is by no means effective. Therefore, the methods mentioned above present difficulty in assuring the stability of ulinastatin in the suppository during prolonged storage and it would be difficult to realize industrial-scale production of suppositories containing ulinastatin at uniform concentration.
There are very few technologies available for incorporating proteins into oily bases with the aid of emulsifiers and no disclosure has been made of achieving stabilization within oily bases. For example, Unexamined Published Japanese Patent Application Sho 55-81812 discloses a suppository for the treatment of diabetes that has an islet-activating protein dispersed in fat-type or water-miscible bases with the aid of a nonionic and/or anionic surfactant but no mention is made of the stability of the protein. Japanese Unexamined Published Japanese Patent Application Sho 63-255216 discloses a suppository base composition exhibiting an excellent emulsifying action on water, an aqueous solution of an active ingredient and a polar active ingredient but again no
REFERENCES:
patent: 4368185 (1983-01-01), Mizuno et al.
patent: 4871777 (1989-10-01), Breitzke
patent: 5489577 (1996-02-01), Ikeda et al.
patent: 5504065 (1996-04-01), Hattori et al.
Patent Abstracts of Japan, vol. 012, No. 059 (C-478), 23 Feb. 1988 & JP 62 205033 A (Osamu Matsuo), 9 Sep. 1987, (Abstract).
Database WPI, Week 8108, Derwent Publications Ltd., London, GB; AN-12561D (08) XP002033327 (Abstract) & JP 55 160 724 A (Mochida Pharm. Co. Ltd.) 13 Dec. 1980 (Abstract).
Kanayama et al., (1992), Acta Obst Gynaec Jpn vol. 44, No. 4, pp.477-482.
Kanayama (1994), Acta Obst Gynaec Jpn vol. 46, No. 8, pp.673-685.
Suzuki Shigeharu
Takaada Katsumi
Mochida Pharmaceutical Co. Ltd.
Witz Jean C.
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