Patent US2639902A successfully refreshed from Google Patents.
Patent US4153685A successfully refreshed from Google Patents.
US4153685A
Expired / Lapsed
US
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Bismuth complex preparations
Assignee: Merck Sharp & Dohme LLC
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Filing: 1973-05-21
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Granted: 1979-05-08
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Expires: 1993-05-21
Abstract
Abstract The invention relates to new pharmaceutical compositions comprising bismuth in the form of water-soluble proteinaceous complexes which are reversibly precipitable by alcohol, nondialysable and in which the bismuth is strongly bound. Preparations comprising the complexes are therapeutically useful for treating and prophylaxis against ulcers and inflammations, in particular of the gastro-intestinal tract. Altered soluble globular proteins, particularly enzymes are a preferred ligand. The preferred complexes are formed by the reaction of soluble proteinaceous material with a soluble source of bismuth in aqueous solution at up to 60 DEG C. and pH 9-10. The formation of the complexes may be tested for by alcohol precipitation and/or gel filtration. These methods may also be used to concentrate the complexes.
Inventors
- 👤 Willem J. Serfontein
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-24 20:01
CPC Classifications
A; A61; A61K; A61K38/00; A61K38/16; A61K38/43; A61K38/46; A61K38/48; A61K38/488; A61K31/00; A61K31/70; A61K33/00; A61K33/24; A61K33/245
Claims Analysis
Total Claims: 27
Claim 1
Independent Claim
101 words
A pharmaceutical preparation comprising a therapeutically effective amount of at least one essentially non-dialysable physiologically acceptable complex between: (a) bismuth in its trivalent state of oxidation and (b) a physiologically acceptable, water-soluble proteinaceous molecule having an affinity for said bismuth, (c) ammonia (d) a complex-forming organic acid, said complex being essentially water-soluble to the extent that it forms a sufficient concentration in the water-dissolved state to exhibit anti-ulcer activity in the gastro-intestinal tract, being essentially reversibly precipitable by alcohol and in which the bismuth remains essentially complexed with the proteinaceous matter under the conditions of dialysis, the complex itself being non-dialysable.
Claim 2
Dependent Claim
101 words
A pharmaceutical preparation comprising a therapeutically effective amount of at least one essentially non-dialysable physiologically acceptable complex between: (a) bismuth in its trivalent state of oxidation and (b) a physiologically acceptable, water-soluble proteinaceous molecule having an affinity for said bismuth, (c) ammonia (d) a complex-forming organic acid, said complex being essentially water-soluble to the extent that it forms a sufficient concentration in the water-dissolved state to exhibit anti-ulcer activity in the gastro-intestinal tract, being essentially reversibly precipitable by alcohol and in which the bismuth remains essentially complexed with the proteinaceous matter under the conditions of dialysis, the complex itself being non-dialysable.
Claim 3
Dependent Claim
22 words
A preparation according to claim 1 wherein said complex includes ammonia and an organic acid capable of forming watersoluble salts with bismuth.
Claim 4
Dependent Claim
36 words
A preparation according to claim 2 wherein said complex additionally includes molecules of physiologically acceptable complex forming sugars, glycols or glycerols and is maintained in aqueous solution of which the pH is adjusted to about 9-10.
Claim 5
Dependent Claim
51 words
A preparation according to claim 1 wherein the proteinaceous molecule is a globular protein which has been subjected to mild denaturation and chemical degradation, sufficiently so to open up the globular structure of the globular protein and to produce said affinity whilst essentially preserving the non-dialysable molecular size of the protein.
Claim 6
Dependent Claim
21 words
A preparation according to claim 4 which is an addition product of said protein and a watersoluble double salt of bismuth.
Claim 7
Dependent Claim
27 words
A preparation according to claim 4 which is an addition product of said protein and a watersoluble physiologically compatable bismuth ammonium salt of an organic hydroxy acid.
Claim 8
Dependent Claim
23 words
A preparation according to claim 6 wherein the globular protein is selected from the group consisting of pepsin, trypsin, papain, casein and albumins.
Claim 9
Dependent Claim
12 words
A preparation according to claim 7, wherein the globular protein is pepsin.
Claim 10
Dependent Claim
50 words
A preparation according to claim 1 in the form of an aqueous solution containing at least 27 mg bismuth per ml of said solution, derived from a water soluble bismuth ammonium salt of an organic hydroxy acid, at least 10 percent of said bismuth being stable against removal by dialysis.
Claim 11
Dependent Claim
71 words
A preparation according to claim 4 in the form of an aqueous syrup wherein at least 3 mg/ml of said bismuth is stable against removal by dialysis, the complex being an addition product of a substance selected from the group consisting of bismuth ammonium citrate, bismuth ammonium tartrate, bismuth ammonium lactate, and bismuth ammonium malate and wherein the globular protein is selected from the group consisting of pepsin, papain, and trypsin.
Claim 12
Dependent Claim
51 words
A preparation according to claim 4 in the form of a syrup wherein at least 3 mg/ml of said bismuth is stable against removal by dialysis, the complex being an addition product of a water-soluble bismuth ammonium salt of a lower hydroxy carboxylic acid, and wherein the globular protein is pepsin.
Claim 13
Dependent Claim
19 words
A pharmaceutical preparation according to claim 1 consisting essentially of said at least one essentially non-dialysable physiologically acceptable complex.
Claim 14
Dependent Claim
151 words
Process for the manufacture of a pharmaceutical preparation having anti-inflammatory and anti-ulcer efficacy in the gastro-intestinal tract which comprises bringing into intimate contact with one another in an aqueous moderately alkaline medium in a pH range in which they are soluble: (a) a water-soluble double salt of bismuth in its trivalent state of oxidation, ammonia and an organic acid, and (b) a physiologically acceptable, water-soluble proteinaceous substances having sites in its molecule capable of accommodating said bismuth as a complex and maintaining said contact at a temperature not exceeding 65° C. until a water-soluble proteinaceous bismuth complex has been formed which is reversibly precipitable by alcohol, bismuth being bound so strongly as to be stable against removal by dialysis, the complex as a whole being non-dialysable, and incorporating said complex in an effective concentration in a pharmaceutical form of presentation adapted for carrying the complex into a region to be treated.
Claim 15
Dependent Claim
151 words
Process for the manufacture of a pharmaceutical preparation having anti-inflammatory and anti-ulcer efficacy in the gastro-intestinal tract which comprises bringing into intimate contact with one another in an aqueous moderately alkaline medium in a pH range in which they are soluble: (a) a water-soluble double salt of bismuth in its trivalent state of oxidation, ammonia and an organic acid, and (b) a physiologically acceptable, water-soluble proteinaceous substances having sites in its molecule capable of accommodating said bismuth as a complex and maintaining said contact at a temperature not exceeding 65° C. until a water-soluble proteinaceous bismuth complex has been formed which is reversibly precipitable by alcohol, bismuth being bound so strongly as to be stable against removal by dialysis, the complex as a whole being non-dialysable, and incorporating said complex in an effective concentration in a pharmaceutical form of presentation adapted for carrying the complex into a region to be treated.
Claim 16
Dependent Claim
13 words
Process according to claim 13 carried out in the presence of ammonium ion.
Claim 17
Dependent Claim
20 words
Process according to claim 14 wherein the aqueous medium also contains in a dissolved form a lower carboxylic hydroxy acid.
Claim 18
Dependent Claim
31 words
Process according to claim 13 wherein the complex is brought into syrup form containing at least 3 mg/ml of bismuth bound in said form which is stable against removal by dialysis.
Claim 19
Dependent Claim
37 words
Process according to claim 13 including a step of concentrating the complex to a concentration at which there is present at least 3 mg/ml of bismuth bound in said form which is stable against removal by dialysis.
Claim 20
Dependent Claim
62 words
Process according to claim 13 wherein the proteinaceous substance is a globular protein and wherein said contact is maintained for several hours with gentle heating under alkaline conditions until the globular structure of the globular protein has been opened up sufficiently to render the molecule capable of said complex formation with bismuth, whilst essentially preserving the nondialysable molecular size of the protein.
Claim 21
Dependent Claim
37 words
Process according to claim 18 wherein said contact is maintained at a pH up to about 10 and a temperature up to about 60° C. and wherein the final pH is adjusted to about 9 to 10.
Claim 22
Dependent Claim
25 words
A process as claimed in claim 13 wherein there is present during said contact in said aqueous moderately alkaline medium a sugar, glycerol or glycol.
Claim 23
Dependent Claim
36 words
A method of treating a patient suffering from ulceration of the gastro-intestinal tract which comprises introducing to the region of ulceration a pharmaceutical preparation as defined in claim 1 in amounts effective to heal said ulceration.
Claim 24
Dependent Claim
13 words
A method according to claim 21 applied to the healing of peptic ulceration.
Claim 25
Dependent Claim
32 words
A method of treating a patient suffering from peptic ulceration which comprises administering orally to such patient a pharmaceutical preparation as defined by claim 10 in amounts effective to heal said ulceration.
Claim 26
Dependent Claim
18 words
A method according to claim 23 wherein the diet of the patient is adapted to favour gastric acidity.
Claim 27
Dependent Claim
43 words
A method of prophylactic therapy for patients treated with drugs having a tendency to cause the formation of peptic ulcers, which comprises administering orally to such patient a pharmaceutical preparation as defined by claim 1 in an amount effective to combat said tendency.
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1982-05-07 | 1982-11-06 | 1983-05-08 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1986-05-07 | 1986-11-06 | 1987-05-08 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1990-05-07 | 1990-11-06 | 1991-05-08 | $7700.00 | Window Closed / Lapsed |