US4153689A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Stable insulin preparation for nasal administration
Assignee: Takeda Pharmaceutical Co Ltd
•
Filing: 1977-08-15
•
Granted: 1979-05-08
•
Expires: 1997-08-15
Abstract
Abstract Nasal administration of insulin is achieved by the use of an aqueous solution whose pH value is not higher than 4.7.
Inventors
- 👤 Shin-Ichiro Hirai
- 👤 Toshiaki Ikenaga
- 👤 Tai Matsuzawa
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-24 05:33
CPC Classifications
A; A61; A61K; A61K38/00; A61K38/16; A61K38/17; A61K38/22; A61K38/28; A61K47/00; A61K47/06; A61K47/08; A61K47/10; A61K47/26; A61K47/44; A61K9/00; A61K9/0012; A61K9/0043
Claims Analysis
Total Claims: 52
Claim 1
Independent Claim
87 words
A stable aqueous insulin solution having a pH value in the range of from 2.5 to 4.7, which comprises 0.1 to 10 weight percent of insulin and as a stabilizing agent 0.1 to 20 weight percent of a member selected from the group consisting of (a) at least one non-ionic surface-active agent whose hydrophile/lipophile balance value is in the range of from 9 to 22, (b) polyethylene glycol having a molecular weight in the range of from 200 to 7500 and (c) mixtures of (a) and (b).
Claim 2
Dependent Claim
87 words
A stable aqueous insulin solution having a pH value in the range of from 2.5 to 4.7, which comprises 0.1 to 10 weight percent of insulin and as a stabilizing agent 0.1 to 20 weight percent of a member selected from the group consisting of (a) at least one non-ionic surface-active agent whose hydrophile/lipophile balance value is in the range of from 9 to 22, (b) polyethylene glycol having a molecular weight in the range of from 200 to 7500 and (c) mixtures of (a) and (b).
Claim 3
Dependent Claim
87 words
A stable aqueous insulin solution having a pH value in the range of from 2.5 to 4.7, which comprises 0.2 to 5 weight percent of insulin and as a stabilizing agent 0.1 to 20 weight percent of a member selected from the group consisting of (a) at least one non-ionic surface-active agent whose hydrophile/lipophile balance value is in the range of from 9 to 22, (b) polyethylene glycol having a molecular weight in the range of from 200 to 7500 and (c) mixtures of (a) and (b).
Claim 4
Dependent Claim
87 words
A stable aqueous insulin solution having a pH value in the range of from 2.5 to 4.7, which comprises 0.2 to 5 weight percent of insulin and as a stabilizing agent 0.1 to 20 weight percent of a member selected from the group consisting of (a) at least one non-ionic surface-active agent whose hydrophile/lipophile balance value is in the range of from 9 to 22, (b) polyethylene glycol having a molecular weight in the range of from 200 to 7500 and (c) mixtures of (a) and (b).
Claim 5
Dependent Claim
87 words
A stable aqueous insulin solution having a pH value in the range of from 2.8 to 4.0, which comprises 0.1 to 10 weight percent of insulin and as a stabilizing agent 0.1 to 20 weight percent of a member selected from the group consisting of (a) at least one non-ionic surface-active agent whose hydrophile/lipophile balance value is in the range of from 9 to 22, (b) polyethylene glycol having a molecular weight in the range of from 200 to 7500 and (c) mixtures of (a) and (b).
Claim 6
Dependent Claim
87 words
A stable aqueous insulin solution having a pH value in the range of from 2.8 to 4.0, which comprises 0.1 to 10 weight percent of insulin and as a stabilizing agent 0.1 to 20 weight percent of a member selected from the group consisting of (a) at least one non-ionic surface-active agent whose hydrophile/lipophile balance value is in the range of from 9 to 22, (b) polyethylene glycol having a molecular weight in the range of from 200 to 7500 and (c) mixtures of (a) and (b).
Claim 7
Dependent Claim
87 words
A stable aqueous insulin solution having a pH value in the range of from 2.8 to 4.0, which comprises 0.2 to 5 weight percent of insulin and as a stabilizing agent 0.1 to 20 weight percent of a member selected from the group consisting of (a) at least one non-ionic surface-active agent whose hydrophile/lipophile balance value is in the range of from 9 to 22, (b) polyethylene glycol having a molecular weight in the range of from 200 to 7500 and (c) mixtures of (a) and (b).
Claim 8
Dependent Claim
87 words
A stable aqueous insulin solution having a pH value in the range of from 2.8 to 4.0, which comprises 0.2 to 5 weight percent of insulin and as a stabilizing agent 0.1 to 20 weight percent of a member selected from the group consisting of (a) at least one non-ionic surface-active agent whose hydrophile/lipophile balance value is in the range of from 9 to 22, (b) polyethylene glycol having a molecular weight in the range of from 200 to 7500 and (c) mixtures of (a) and (b).
Claim 9
Dependent Claim
19 words
A stable aqueous insulin solution as in claim 4, wherein the stabilizing agent is polyoxyethylene 50 hydrogenated castor oil.
Claim 10
Dependent Claim
19 words
A stable aqueous insulin solution as in claim 4, wherein the stabilizing agent is polyoxyethylene 40 stearic acid ester.
Claim 11
Dependent Claim
17 words
A stable aqueous insulin solution as in claim 4, wherein the stabilizing agent is polyethylene glycol 4000.
Claim 12
Dependent Claim
18 words
A stable aqueous insulin solution as in claim 4, wehrein the stabilizing agent is polyoxyethylene 9 lauryl ether.
Claim 13
Dependent Claim
18 words
A stable aqueous insulin solution according to claim 4 wherein the insulin is that obtained from natural sources.
Claim 14
Dependent Claim
16 words
A stable aqueous insulin solution according to claim 4 wherein the insulin is that produced synthetically.
Claim 15
Dependent Claim
15 words
A stable aqueous insulin solution according to claim 4 wherein the insulin is a monocomponent.
Claim 16
Dependent Claim
53 words
A stable aqueous insulin solution according to claim 4 wherein the non-ionic surface-active agents are selected from the group consisting of a polyoxyethylene fatty acid ester, a polyoxyethylene higher alcohol ether, a polyoxyethylene polyoxypropylene higher alcohol ether, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene alkylphenyl ether, and a polyoxyethylene hydrogenated castor oil.
Claim 17
Dependent Claim
42 words
A stable aqueous insulin solution according to claim 4 wherein a mixture of non-ionic surface active agents is employed, said agents being chosen so that the combined hydrophile/lipophile balance value of the mixture falls within the range of from 9 to 22.
Claim 18
Dependent Claim
16 words
A stable, aqueous insulin solution according to claim 4, wherein the stabilizing agent is polysorbate 80.
Claim 19
Dependent Claim
52 words
A stable aqueous insulin solution as in claim 1 wherein the stabilizing agent is a polyoxyethylene fatty acid ester of the formula RCOO--(CH.sub.2 CH.sub.2 O).sub.n H wherein R is a saturated or unsaturated alkyl group of from 7 to 17 carbon atoms, and n is an integer of from 10 to 60.
Claim 20
Dependent Claim
51 words
A stable aqueous insulin solution as in claim 1 wherein the stabilizing agent is polyoxyethylene higher alcohol ether of the formula R--O--(CH.sub.2 CH.sub.2 O).sub.n H wherein R is a saturated or unsaturated alkyl group of from 4 to 18 carbon atoms, and n is an integer of from 3 to 60.
Claim 21
Dependent Claim
65 words
A stable aqueous insulin solution as in claim 1 wherein the stabilizing agent is a polyoxyethylene polyoxypropylene higher alcohol ether of the formula R--O--(CH.sub.2 CH.sub.2 CH.sub.2 O).sub.m (CH.sub.2 CH.sub.2 O).sub.n H wherein R is a saturated or unsaturated alkyl of from 12 to 18 carbon atoms, m is an integer of from 1 to 10 and n is an integer of from 10 to 40.
Claim 22
Dependent Claim
55 words
A stable aqueous insulin solution as in claim 1 wherein the stabilizing agent is a polyoxyethylene sorbitan fatty acid ester of the formula RCOO--C.sub.6 H.sub.8 O.sub.4 --(CH.sub.2 CH.sub.2 O).sub.n H wherein R is a saturated or unsaturated alkyl of from 7 to 17 carbon atoms, and n is an integer of from 10 to 20.
Claim 23
Dependent Claim
47 words
A stable aqueous insulin solution as in claim 1 wherein the stabilizing agent is a polyoxyethylene alkylphenyl ether of the formula ##STR2## wherein R is a saturated or unsaturated alkyl of from 8 to 12 carbon atoms, and n is an integer of from 8 to 70.
Claim 24
Dependent Claim
41 words
A stable aqueous insulin solution as in claim 1 wherein the stabilizing agent is a polyoxyethylene hydrogenated castor oil of the formula C.sub.3 H.sub.5 (COOC.sub.17 H.sub.34 O).sub.3 --(CH.sub.2 CH.sub.2 O).sub.n H wherein n is an integer of from 20 to 120.
Claim 25
Dependent Claim
28 words
A stable aqueous insulin solution as in claim 1 wherein the stabilizing agent is polyethylene glycol having a molecular weight in the range of from 200 to 7500.
Claim 26
Dependent Claim
26 words
A stable aqueous insulin solution as in claim 21 wherein the molecular weight of the polyethylene glycol is in the range of from 600 to 7500.
Claim 27
Independent Claim
46 words
A method for the treatment of diabetes mellitus which comprises administering in the form of a spray through the nasal mucous membrane of a patient suffering from diabetes mellitus a pharmaceutically effective amount of an aqueous, insulin solution whose pH value is not higher than 4.7.
Claim 28
Independent Claim
46 words
A method for the treatment of diabetes mellitus which comprises administering in the form of a spray through the nasal mucous membrane of a patient suffering from diabetes mellitus a pharmaceutically effective amount of an aqueous, insulin solution whose pH value is not higher than 4.7.
Claim 29
Dependent Claim
18 words
A method according to claim 23 wherein the pH range of the solution is from 2.5 to 4.0.
Claim 30
Dependent Claim
18 words
A method according to claim 23 wherein the pH range of the solution is from 2.8 to 4.0.
Claim 31
Independent Claim
114 words
A method for the treatment of diabetes mellitus which comprises administering through the nasal mucous membrane of a patient suffering from diabetes mellitus a pharmaceutically effective amount of a stable, aqueous insulin solution having a pH value in the range of from 2.5 to 4.7 which comprises 0.1 to 10 weight percent of insulin and as a stabilizing agent 0.1 to 20 weight percent of a member selected from the group consisting of (a) at least one nonionic surface-active agent whose hydrophile/lipophile balance is in the range of from 9 to 22, (b) polyethylene glycol having a molecular weight in the range of from 200 to 7500 and (c) mixtures of (a) and (b).
Claim 32
Independent Claim
114 words
A method for the treatment of diabetes mellitus which comprises administering through the nasal mucous membrane of a patient suffering from diabetes mellitus a pharmaceutically effective amount of a stable, aqueous insulin solution having a pH value in the range of from 2.5 to 4.7 which comprises 0.1 to 10 weight percent of insulin and as a stabilizing agent 0.1 to 20 weight percent of a member selected from the group consisting of (a) at least one nonionic surface-active agent whose hydrophile/lipophile balance is in the range of from 9 to 22, (b) polyethylene glycol having a molecular weight in the range of from 200 to 7500 and (c) mixtures of (a) and (b).
Claim 33
Dependent Claim
19 words
A method according to claim 26 wherein the aqueous insulin solution is administered in the form of a spray.
Claim 34
Independent Claim
121 words
A method for the treatment of diabetes mellitus which comprises administering in the form of a spray through the nasal mucous membrane of the patient suffering from diabetes mellitus a pharmaceutically acceptable amount of a stable aqueous insulin solution having a pH value in the range of from 2.8 to 4.0 which comprises 0.2 to 5 weight percent of insulin and as a stabilizing agent 0.1 to 20 weight percent of a member selected from the group consisting of (a) at least one nonionic surface-active agent whose hydrophile/lipophile balance value is in the range of from 9 to 22, (b) polyethylene glycol having a molecular weight in the range of from 200 to 7500 and (c) mixtures of (a) and (b).
Claim 35
Independent Claim
121 words
A method for the treatment of diabetes mellitus which comprises administering in the form of a spray through the nasal mucous membrane of the patient suffering from diabetes mellitus a pharmaceutically acceptable amount of a stable aqueous insulin solution having a pH value in the range of from 2.8 to 4.0 which comprises 0.2 to 5 weight percent of insulin and as a stabilizing agent 0.1 to 20 weight percent of a member selected from the group consisting of (a) at least one nonionic surface-active agent whose hydrophile/lipophile balance value is in the range of from 9 to 22, (b) polyethylene glycol having a molecular weight in the range of from 200 to 7500 and (c) mixtures of (a) and (b).
Claim 36
Dependent Claim
49 words
A method according to claim 26 wherein the stabilizing agent is a polyoxyethylene fatty acid ester of the formula RCOO--(CH.sub.2 CH.sub.2 O).sub.n H wherein R is a saturated or unsaturated alkyl group of from 7 to 17 carbon atoms, and n is an integer of from 10 to 60.
Claim 37
Dependent Claim
48 words
A method according to claim 26 wherein the stabilizing agent is polyoxyethylene higher alcohol ether of the formula R--O--(CH.sub.2 CH.sub.2 O).sub.n H wherein R is a saturated or unsaturated alkyl group of from 4 to 18 carbon atoms, and n is an integer of from 3 to 60.
Claim 38
Dependent Claim
62 words
A method according to claim 26 wherein the stabilizing agent is a polyoxyethylene polyoxypropylene higher alcohol ether of the formula R--O--(CH.sub.2 CH.sub.2 CH.sub.2 O).sub.m (CH.sub.2 CH.sub.2 O).sub.n H wherein R is a saturated or unsaturated alkyl of from 12 to 18 carbon atoms, m is an integer of from 1 to 10 and n is an integer of from 10 to 40.
Claim 39
Dependent Claim
52 words
A method according to claim 26 wherein the stabilizing agent is a polyoxyethylene sorbitan fatty acid ester of the formula RCOO--C.sub.6 H.sub.8 O.sub.4 -(CH.sub.2 CH.sub.2 O).sub.n H wherein R is a saturated or unsaturated alkyl of from 7 to 17 carbon atoms, and n is an integer of from 10 to 20.
Claim 40
Dependent Claim
44 words
A method according to claim 26 wherein the stabilizing agent is a polyoxyethylene alkylphenyl ether of the formula ##STR3## wherein R is a saturated or unsaturated alkyl of from 8 to 12 carbon atoms, and n is an integer of from 8 to 70.
Claim 41
Dependent Claim
38 words
A method according to claim 26 wherein the stabilizing agent is a polyoxyethylene hydrogenated castor oil of the formula C.sub.3 H.sub.5 (COOC.sub.17 H.sub.34 O).sub.3 --(CH.sub.2 CH.sub.2 O).sub.n H wherein n is an integer of from 20 to 120.
Claim 42
Dependent Claim
25 words
A method according to claim 26 wherein the stabilizing agent is polyethylene glycol having a molecular weight in the range of from 200 to 7500.
Claim 43
Dependent Claim
23 words
A method according to claim 35 wherein the molecular weight of the polyethylene glycol is in the range of from 600 to 7500.
Claim 44
Dependent Claim
16 words
A method according to claim 28 wherein the stabilizing agent is polyoxyethylene 50 hydrogenated castor oil.
Claim 45
Dependent Claim
16 words
A method according to claim 28 wherein the stabilizing agent is polyoxyethylene 40 stearic acid ester.
Claim 46
Dependent Claim
14 words
A method according to claim 28 wherein the stabilizing agent is polyethylene glycol 4000.
Claim 47
Dependent Claim
15 words
A method according to claim 28 wherein the stabilizing agent is polyoxyethylene 9 lauryl ether.
Claim 48
Dependent Claim
15 words
A method according to claim 28 wherein the insulin is that obtained from natural sources.
Claim 49
Dependent Claim
13 words
A method according to claim 28 wherein the insulin is that produced synthetically.
Claim 50
Dependent Claim
12 words
A method according to claim 28 wherein the insulin is a mono-component.
Claim 51
Dependent Claim
50 words
A method according to claim 28 wherein the nonionic surface-active agents are selected from the group consisting of a polyoxyethylene fatty acid ester, a polyoxyethylene higher alcohol ether, a polyoxyethylene polyoxypropylene higher alcohol ether, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene alkylphenyl ether, and a polyoxyethylene hydrogenated castor oil.
Claim 52
Dependent Claim
37 words
A method according to claim 28 wherein a mixture of nonionic surface-active agents is employed, said agents being chosen so that the combined hydrophile/lipophile balance value of the mixture falls within the range of 9 to 22.
References Cited (Backward Citations)
US2055083A
Cited
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 |