Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-07-07
2001-11-20
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S192000, C514S196000, C514S200000, C514S204000, C514S338000
Reexamination Certificate
active
06319904
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a formulation which comprises an antibacterial substance and an antiulcer substance, wherein at least either of them is formulated into a gastrointestinal mucosa-adherent solid preparation. The formulation of the present invention is used as an antiulcer agent and for other purposes.
BACKGROUND OF THE INVENTION
Since the isolation of
Helicobacter pylori
(hereinafter also referred to as HP) in 1983 [Lancet, 1, 1273 (1983)], its association with gastritis and digestive ulcer has drawn attention. This is because HP is found at high positivity rates in chronic gastritis or gastric ulcer [American Journal of Gastroenterology, 82, 2283 (1987)], despite the fact that it is normally not found in the mucosa of healthy humans [APMIS, 96, 84 (1988)].
On the other hand, the development of H
2
blockers and proton pump inhibitors (hereinafter also referred to as PPI) has resulted in markedly improved healing rates for gastric/duodenal ulcer. However, there are some contractile cases in which no improvement occurs despite the appropriate treatment using these drugs, posing major problems. According to a report of such cases of contractile gastric ulcer [Japanese Journal of Gastroenterology, 89, 571 (1992)], the HP positivity rate is extremely high, with a reduction in the amount of gastromucosal mucus attributable to the ammonia produced by HP. Also, there are some reports of sustained infection with HP which delays ulcer healing or which is involved in ulcer recurrence [Lancet, 335, 1233 (1990); New England Journal of Medicine, 328, 308 (1993)]. Judging from these many clinical findings, HP elimination is believed to be useful in early healing of ulcer or prevention of its recurrence.
For the reasons described above, various anti-HP drugs have been administered to patients with gastric/duodenal ulcer. Although some PPIs possessing anti-HP activity have been developed, they remain unsatisfactory as to healing effect when used alone because their antibacterial action against HP is not always sufficient. Also, concomitant therapy has been performed with fair therapeutic results in which antiulcer agents such as H
2
blockers and PPI are used in combination with antibacterial substances [Medical Journal of Australia, 151, 431 (1988); George LL et al., Medical Journal of Australia, 153, 145 (1990); Peterson WL et al., New England Journal of Medicine, 324, 1043 (1991); New England Journal of Medicine, 328, 308(1993)].
Antibacterial substances such as amoxicillin (hereinafter also referred to as AMOX), metronidazole (hereinafter also referred to as MZ), bismuth subacetate and tetracycline, have been used against HP singly or in combination; however, their administration often causes side effects such as diarrhea, nausea and retching because of the considerable doses (e.g., 750 mg of AMOX or 500 mg of MZ administered three times a day). Also, a pharmaceutical composition containing an anti-HP antibiotic (e.g., AMOX) and pantoprazol (WO 92/03135), and an administration comprising AMOX and omeprazole in combination (Scandinavian Journal of Gastroetherology, 24, 49 (1989) are reported, but their antiulcer action is unsatisfactory and their administration causes side effects as mentioned above.
Meantime, there have been developed gastrointestinal mucosa-adherent matrices to allow the preparation to adhere to the gastrointestinal mucosa to extend its retention in the gastrointestinal tract and hence improve the bioavailability of active ingredients. Although antiulcer agents, antigastritis agents etc. have been mentioned as active ingredients appropriate for use in the above-described preparation (EP-A-514008), none have been applied to formulation for concomitant therapy wherein at least one of them is prepared as a gastrointestinal mucosa-adherent solid preparation.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide a formulation for treating a gastrointestinal ulcer which exhibits antiulcer effect with more potent anti-HP activity.
This object as well as other objects and advantages of the present invention will become apparent to those skilled in the art from the following description.
SUMMARY OF THE INVENTION
The present inventors investigated to obtain a safer therapeutic formulation for gastric/duodenal ulcer that exhibits antiulcer effect with more potent anti-HP activity. As a result, the present inventors found that a formulation comprising an anti-HP antibiotic and an antiulcer substance, wherein at least one is formulated into a gastrointestinal mucosa-adherent solid preparation, synergistically enhances the antibiotic's anti-HP activity, as well as the action of antiulcer substance due to the combined effect of both agents, thus providing a formulation of lower prevalence of side effects. The inventors made further investigations based on these findings, and developed the present invention.
According to the present invention, there is provided:
1) A formulation which comprises an antibacterial substance and an antiulcer substance, wherein at least one of them is formulated into a gastrointestinal muscosa-adherent solid preparation,
2) The formulation according to 1) above, wherein the antibacterial substance is an antibacterial substance against
Helicobacter pylori,
3) The formulation according to 1) above, wherein the gastrointestinal mucosa-adherent solid preparation comprises a matrix containing a polyglycerin fatty acid ester,
4) The formulation according to 1) above, wherein the gastrointestinal mucosa-adherent solid preparation contains the antibacterial substance,
5) The formulation according to 1) above, wherein the antibacterial substance is a penicillin,
6) The formulation according to 1) above, wherein the antibacterial substance is a macrolide antibiotic,
7) The formulation according to 5) above, wherein the penicillin is amoxicillin,
8) The formulation according to 1) above, wherein the antiulcer substance is a proton pump inhibitor,
9) The formulation according to 8) above, wherein the proton pump inhibitor is a compound represented by the formula:
wherein ring A may optionally be substituted, R
1
, R
3
and R
4
are, the same or different, hydrogen, or an alkyl or alkoxy group, R
2
is a hydrocarbon group which may optionally be substituted, and n is 0 or 1, or a salt thereof,
10) The formulation according to 3) above, wherein the gastrointestinal mucosa-adherent solid preparation comprises a viscogenic agent capable of developing viscosity on contact with water,
11) The formulation according to 10) above, wherein the viscogenic agent is dispersed in the gastrointestinal mucosa-adherent solid preparation,
12) The formulation according to 10) above, wherein the viscogenic agent coats the gastrointestinal mucosa-adherent solid preparation,
13) The formulation according to 10) above, wherein the viscogenic agent is an acrylic acid polymer or its salt, and
14) A set for the use in treating a gastrointestinal ulcer in mammals which comprises (1) an antibacterial substance and a pharmaceutically acceptable carrier thereof, and (2) an antiulcer substance and a pharmaceutically acceptable carrier thereof, wherein at least one of the substances is formulated into a gastrointestinal mucosa-adherent solid preparation.
Useful antibacterial substance for the invention include antibacterial substances against
Helicobacter pylori
, bismuth salt, imidazole compounds, quinolone compounds, and the like. Among others, antibacterial substances against Helicobacter pylori are preferred.
Useful antibacterial substance against
Helicobacter pylori
(HP) for the present invention include penicillin (e.g., amoxicillin, benzylpenicillin, piperacillin, mecillinam), cephem antibiotics (e.g., cefixime, cefaclor), macrolide antibiotics (e.g., erythromycin), tetracycline antibiotics (e.g., tetracycline, minocycline, streptomycin), aminoglycoside antibiotics (e.g, gentamycin, amikacin), imipenem, and the like. Among others, penicillin, macrolide antibi
Akiyama Yohko
Iwasa Susumu
Nagahara Naoki
Nakao Masafumi
Foley & Lardner
Goldberg Jerome D.
Takeda Chemical Industries Ltd.
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