Method of administering a biologically active substance

• US 5,693,608 A
• Filed: 02/28/1995
• Issued: 12/02/1997
• Est. Priority Date: 05/10/1990
• Status: Expired due to Fees

• Current Assignee: Lyfjathroun HF Biopharmaceuticals
• Original Assignee: Bechgaard International Research and Development A/S
• Inventors: Gizurarson, Sveinbjorn, Bechgaard, Erik, Hjortkj.ae butted.r, Rolf Kuhlman
• Primary Examiner(s): DAVENPORT, AVIS MICHELLE
• Application Number:
  US08/395,838
• Time in Patent Office: 1,008 Days
• Field of Search: 514/2, 514/4, 530/307, 530/311, 530/313, 530/300
• US Class Current: 514/6.5
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 9/0043 Nose

Abstract

A method for administering a therapeutically effective amount of a biologically active substance to the circulatory system of a mammal including administering a pharmaceutical composition having a total volume of 1-1000 μl to a nasal mucosal membrane of the mammal, the pharmaceutical composition including the therapeutically effective amount of the biologically active substance dissolved or suspended in a volume of 1-1000 μl of an n-ethylene glycol containing vehicle including at least one n-ethylene glycol represented by the formula:

H(OCH.sub.2 CH.sub.2).sub.p OH

wherein p is from 1 to 8, so that upon administration of the pharmaceutical composition to the nasal mucosal membrane, absorption of the biologically active substance through the mucosal membrane and into the blood stream of the mammal rapidly takes place and thereby allows the biologically active substance to exert its therapeutic effect.

Claims

1. A method for administering a therapeutically effective amount of a biologically active substance other than insulin and derivatives thereof to the circulatory system of a mammal comprising administering a pharmaceutical composition having a total volume of 1-1000 μ

l to a nasal mucosal membrane of the mammal, the pharmaceutical composition comprising the therapeutically effective amount of the biologically active substance dissolved or suspended in a volume of 1-1000 μ

l of an n-ethylene glycol-containing vehicle comprising at least one n-ethylene glycol represented by the formula II

space="preserve" listing-type="equation">H(OCH.sub.2 CH.sub.2).sub.p OH

wherein p is from 1 to 8 so that upon administration of the pharmaceutical composition to the nasal mucosal membrane, absorption of the biologically active substance through the mucosal membrane and into the blood stream of the mammal rapidly takes place and thereby allows the biologically active substance to exert its therapeutic effect.

2. The method according to claim 1 wherein the n-ethylene glycol contained in the vehicle is PEG 200.

3. The method according to claim 1 wherein the n-ethylene glycol contained in the vehicle is selected from the group consisting of tri-ethylene glycol and tetra-ethylene glycol.

4. The method according to claim 3 wherein the n-ethylene qlycol is tetra-ethylene glycol.

5. The method according to claim 1 wherein the amount of n-ethylene glycol contained in the vehicle is at least 30 v/v percent.

6. The method according to claim 5 wherein the amount of n-ethylene glycol contained in the vehicle is at least 50 v/v percent.

7. The method according to claim 6 wherein the amount of n-ethylene glycol contained in the vehicle is at least 80 v/v percent.

8. The method according to claim 7 wherein the amount of n-ethylene glycol contained in the vehicle is about 98 v/v percent.

9. The method according to claim 1 wherein the composition comprises the therapeutically effective amount of the biologically active substance dissolved or suspended in a dosage unit quantity volume of 100-300 μ

L.

10. The method according to claim 9 wherein the composition comprises the therapeutically effective amount of the biologically active substance in the form of a solution or suspension which is administered to the nasal mucosal membrane in a dosage unit quantity volume of 50-150 μ

l per nostril.

11. The method according to claim 1 wherein the absorption of the biologically active substance through the mucosal membrane and into the blood stream of the mammal results in a peak value (T_max) of the biologically active substance in the blood of the mammal within a period of 60 minutes upon administration of the substance to the nasal mucosal membrane of the mammal.

12. The method according to claim 11 wherein the absorption of the biologically active substance through the mucosal membrane and into the blood stream of the mammal results in a peak value (T_max) of the biologically active substance in the blood of the mammal within a period of 30 minutes upon administration of the substance to the nasal mucosal membrane of the mammal.

13. The method according to claim 12 wherein the absorption of the biologically active substance through the mucosal membrane and into the blood stream of the mammal results in a peak value (T_max) of the biologically active substance in the blood of the mammal within a period of 15 minutes upon administration of the substance to the nasal mucosal membrane of the mammal.

14. The method according to claim 1 wherein the absorption of the biologically active substance through the mucosal membrane and into the blood stream of the mammal results in a maximal therapeutic effect of the biologically active substance within a period of 60 minutes upon administration of the substance to the nasal mucosal membrane of the mammal.

15. The method according to claim 14 wherein the absorption of the biologically active substance through the mucosal membrane and into the blood stream of the mammal results in a maximal therapeutic effect of the biologically active substance within a period of 30 minutes upon administration of the substance to the nasal mucosal membrane of the mammal.

16. The method according to claim 5 wherein the absorption of the biologically active substance through the mucosal membrane and into the blood stream of the mammal results in a maximal therapeutic effect of the biologically active substance within a period of 15 minutes upon administration of the substance to the nasal mucosal membrane of the mammal.

17. The method according to claim 1 wherein the biologically active substance is present in the pharmaceutical composition in a concentration of from 0.0001 to 50 w/v percent.

18. The method according to claim 17 wherein the biologically active substance is present in the pharmaceutical composition in a concentration of from 0.001 to 20 w/v percent.

19. The method according to claim 1 wherein the vehicle further comprises a vegetable oil.

20. The method according to claim 1 wherein the vehicle further comprises nitric acid and/or nitrate in a concentration ranging from 0.0001 to 5 w/v percent.

21. The method according to claim 1 wherein the vehicle is anhydrous.

22. The method according to claim 1 wherein the pharmaceutical composition comprises the biologically active substance in the form of powder, microspheres or liposomes.

25. The method according to claim 1, wherein the biologically active substance is dissolved in the vehicle.

26. The method according to claim 1, wherein the pharmaceutical composition is liquid.

27. The method according to claim 1, wherein the step of administering the pharmaceutical composition comprises spraying the pharmaceutical composition to the nasal mucosal membrane of the mammal.

23. A method for administering a therapeutically effective amount of insulin or a derivative thereof to the circulatory system of a mammal comprising administering a pharmaceutical composition having a total volume of 1-1000 μ

l to a nasal mucosal membrane of the mammal, the pharmaceutical composition comprising the therapeutically effective amount of the insulin or the derivative thereof dissolved or suspended in a volume of 1-1000 μ

l of a n-ethylene glycol-containing anhydrous vehicle comprising at least one n-ethylene glycol represented by the formula II

space="preserve" listing-type="equation">H(OCH.sub.2 CH.sub.2).sub.p OH

wherein p is from 1 to 8 so that upon administration of the pharmaceutical composition to the nasal mucosal membrane, absorption of the insulin or the derivative thereof through the mucosal membrane and into the blood stream of the mammal rapidly takes place and thereby allows the biologically active substance to exert its therapeutic effect.

24. A method for administering a therapeutically effective amount of insulin or a derivative thereof to the circulatory system of a mammal according to claim 23, wherein the pharmaceutical composition comprising the therapeutically effective amount of the insulin or the derivative thereof has a pH value of about 7.4.

28. The method according to claim 23, wherein the biologically active substance is dissolved in the vehicle.

29. The method according to claim 23, wherein the pharmaceutical composition is liquid.

30. The method according to claim 23, wherein the step of administering the pharmaceutical composition comprises spraying the pharmaceutical composition to a nasal mucosal membrane of the mammal.