Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-09-10
2002-08-06
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S499000, C424S485000, C424S487000
Reexamination Certificate
active
06428813
ABSTRACT:
BACKGROUND ART
Since 1983 when
Helicobacter pylori
(hereinafter sometimes abbreviated as
H. Pylori
or HP) was first isolated [Lancet, 1, 1273 (1983)], its relation to gastritis and gastrointestinal ulcer has gathered attention. This is because whereas HP is not usually found in the gastric mucus and on the gastric epithelium of healthy humans [APMIS, 96, 84 (1983)], it is detected at a high rate among patients with chronic gastritis or gastric ulcer. [Am. J. Gastroenterol., 32, 2283 (1987)].
The cure rate of gastroduodenal ulcer rose phenomenally with the development of H
2
blockers and proton pump inhibitors (briefly, PPI). However there still are refractory cases not even responding to judicious treatments with those drugs, thus posing a serious problem. According to a report reviewing such refractory gastric ulcer cases [Japanese Journal of Gastroenterology, 89, 571 (1992)], depressions were found in the amount of gastric mucus, because of apparently the ammonia produced by HP. It has also been reported that a sustained HP infection retards healing of the ulcer or is involved in relapses of the ulcer [Lancet, 335, 1233 (1990); N. Engl. J. Med., 328, 308 (1993)]. Heretofore, various drugs having anti-
Helicobacter pylori
activity have been administered to patients with gastroduodenal ulcers. For example, as antimicrobial preparations against
Helicobacter pylori,
amoxicillin, metronidazole, bismuth nitrate, and tetracycline are administered either independently or in combination, but because their effective doses are comparatively high (e.g. 750 mg amoxicillin or 500 mg metronidazole, to be administered three times daily), those preparations frequently entail side effects such as diarrhea, abdominal pain, and nausea.
Meanwhile, in order to maintain its life,
Helicobacter pylori
is obliged to decompose urea into ammonia with the urease which it elaborates for itself. Therefore, urease inhibitors such as hydroxamic acid derivatives (the 15th Medical Chemistry Symposium, Synopsis of Lectures at the 4th Annual Meeting of Medical Chemistry Group, page 167, P-41), a cassia bark extract [Synopsis of Lectures at the 117th Congress of Pharmaceutical Society of Japan 27 [H1] 9-5, p81 (1997)], and flurofamide [Micro. Ecol. Health Dis., 4 (Suppl.) S145 (1991)] are expected to have anti-
Helicobacter pylori
activity.
For an improved expression of the efficacy of a active ingredient and a reduced risk for side effects, an attempt was made to formulate amoxicillin, for instance, into a gastric mucosa-adherent composition to prolong its intragastric residence time and let amoxicillin be released at a controlled rate and with consequent improved availability of active ingredient (WO 94/00112). It has been demonstrated that the rate of clearance of
Helicobacter pylori
can be improved by causing an anti-HP substance to stay in the stomach longer to ensure prolonged exposure of the bacteria to the active substance [Scand. J. Gastroenterol., 29, 16-42 (1994)].
A combination drug delivery system has also been constructed, in which an antimicrobial substance and/or an antiulcer substance is supplied in a gastric mucosa-adherent solid composition. It has been shown that with this drug delivery system,,the efficacy of the antimicrobial substance and that of the antiulcerative substance can be synergistically exploited (Japanese Patent Unexamined Publication No. 126189/1995).
The present invention has for its object to provide a pharmaceutical composition which has enhanced mucosa-adherent activity compared with other gastric mucosa-adherent preparations, and consequently, an extremely improved efficacy of the active ingredient, in particular, an anti-
Helicobacter pylori
composition and a pharmaceutical preparation, for the prophylaxis, treatment or prevention of relapse of gastroduodenal ulcers, which is very satisfactory and favorable in having anti-HP effect, low risk for side effects, sustained effect, and safety.
DISCLOSURE OF INVENTION
In view of the above state of the art, the inventors of the present invention have discovered that the effectiveness of active ingredients (e.g. anti HP effect) can be potentiated by incorporating an agent (e.g. a curdlan and/or a low-substituted hydroxypropylcellulose) which swells a viscogenic agent, in the objective gastrointestinal mucosa-adherent composition containing an active ingredient (e.g. anti HP substance), and that the composition has favorable safety characteristics and an enhanced adhesion the mucosa.
The present invention, therefore, is directed to:
(1) A gastrointestinal mucosa-adherent pharmaceutical composition comprising a material which swells a viscogenic agent capable of being viscous with water(viscogenic agent),
(2) A pharmaceutical composition according to (1), wherein the material is a curdlan and/or a low-substituted hydroxypropylcellulose,
(3) A pharmaceutical composition according to (2), which is matrix comprising a polyglycerol fatty acid ester and/or a lipid,
(4) A pharmaceutical composition according to (3), wherein the curdlan and/or the low-substituted hydroxypropylcellulose is dispersed,
(5) A pharmaceutical composition according to (4), which is in a granule form,
(6) A pharmaceutical composition according to (1), which is an anti-
Helicobacter pylori
preparation,
(7) A pharmaceutical composition according to (1), which is an antimicrobial preparation,
(8) A pharmaceutical composition according to (2), wherein the hydroxypropoxy content of the low-substituted hydroxypropylcellulose is about 7.0 to about 13.0%,
(9) A pharmaceutical composition according to (3), wherein the lipid is a hydrogenated castor oil,
(10) A pharmaceutical composition according to (3), wherein the polyglycerol fatty acid ester is an ester of a polyglycerol having a degree of polymerization from about 2 to about 20 with a fatty acid containing about 8 to about 40 carbon atoms.
(11) A pharmaceutical composition according to (3), wherein the amount of the polyglycerol fatty acid ester and/or the lipid used is about 20 to about 95 weight % to the total weight of the composition,
(12) A pharmaceutical composition according to (3), wherein the amount of the polyglycerol fatty acid ester and/or the lipid used is about 0.1 to about 100 times by weight to the active ingredient in the composition,
(13) A pharmaceutical composition according to (3), comprising a viscogenic agent in the matrix,
(14) A pharmaceutical composition according to (12), wherein the amount of the viscogenic agent used is about 0.5 to about 45 weight % to the total weight of the composition,
(15) A pharmaceutical composition according to (3), wherein the HLB number of the polyglycerol fatty acid ester is about 1 to about 9,
(16) A pharmaceutical composition according to (6), wherein the amount of the anti-
Helicobacter pylori
substance used is about 10 to about 50 weight % to the 5 total weight of the composition,
(17) A pharmaceutical composition according to (3), wherein the matrix is coated with a coating material comprising a viscogenic agent,
(18) A pharmaceutical composition according to (13) or (17), wherein the viscogenic agent is an acrylic polymer or salt thereof,
(19) A pharmaceutical composition according to (6), wherein the anti-
Helicobacter pylori
substance is amoxicillin,
(20) A pharmaceutical composition according to (6), wherein the anti-
Helicobacter pylori
substance is N-(diaminophosphinyl)-5-methyl-2-thiophenecarboxamide,
(21) A pharmaceutical composition according to (6), wherein the anti-
Helicobacter pylori
substance is a tryptophanyl-t-RNA synthesis inhibitor,
(22) A pharmaceutical composition according to (6), wherein the anti-
Helicobacter pylori
substance is a oxazolone derivative,
(23) A pharmaceutical composition according to (6), wherein the anti-
Helicobacter pylori
substance is indolmycin,
(24) An accelerant of gastrointestinal mucosa-adherent activity of a gastrointestinal mucosa-adherent composition, comprising a curdlan and/or a low-substituted
Akiyama Yohko
Kitano Megumi
Nagahara Naoki
Nakao Masafumi
Chao Mark
Ramesh Elaine M.
Takeda Chemical Industries Ltd.
Webman Edward J.
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