Liposome composition as gas transport agents

• US 4,675,310 A
• Filed: 11/21/1985
• Issued: 06/23/1987
• Est. Priority Date: 03/23/1984
• Status: Expired due to Fees

• Current Assignee: Biocompatibles Incorporated (Boston Scientific Corporation)
• Original Assignee: Biocompatibles Incorporated (Boston Scientific Corporation)
• Inventors: Hayward, James A., Chapman, Dennis
• Primary Examiner(s): Rosen, Sam
• Application Number:
  US06/803,404
• Time in Patent Office: 579 Days
• Field of Search: 514/6, 514/786, 514/759, 514/75, 514/76, 514/78, 424/101
• US Class Current: 424/450
• CPC Class Codes: A61K 38/42 Haemoglobins; Myoglobins
• CPC Class Codes: A61K 9/1273 Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances polymers grafted or coated on phosphatidyl liposomes A61K9/1271, on non-phosphatidyl liposomes A61K9/1272

Abstract

The invention herein involves the use of ligands and phospholipid liposomes as a carrier for the transport of various gases.

Claims

1. An aqueous dispersion of liposomal phospholipid polymers wherein the liposome contains a ligand that will reversibly bind with molecular oxygen or with nitrogen or carbon monoxide or carbon dioxide and wherein the liposome is formed from an intermolecularly and/or intramolecularly cross-linked polymer of a conjugated di-yne of the general formula:

##STR9## wherein at least one of B₁ and B₂ is a group of the formula;

space="preserve" listing-type="equation">--(CO).sub.p --X.sub.1 --C.tbd.C--C.tbd.C--Y.sub.1

wherein p is 0 or 1, X₁ is a direct bond or a divalent aliphatic or cycloaliphatic group, Y₁ is H or a monovalent aliphatic or cycloaliphatic group, the total number of carbon atoms in X₁ and Y₁ in each B₁ and/or B₂ being 8 to 26, and the other of B₁ and B₂ is either (a) the same or a different group of the formula;

space="preserve" listing-type="equation">--(CO).sub.p --X.sub.1 --C.tbd.C--C.tbd.C--Y.sub.1

or (b) is an aliphatic or cycloalkphatic group containing at least 8 carbon atoms;

n is 0 or 1, m is 2, 3 or 4 and each R independently represents an alkyl group containing 1 to 4 carbon atoms.

2. An aqueous dispersion according to claim 1 wherein n=1, m=2 and each R is CH₃.

3. An aqueous dispersion according to claim 1 wherein B₁ and B₂ each is an identical --(CO)_p --X₁ --C.tbd.C--C.tbd.C--Y₁ group.

4. An aqueous dispersion according to claim 3 wherein in B₁ and B₂ each p is 1 and there are 16-26 carbon atoms in B₁ and 16-26 carbon atoms in B₂.

5. An aqueous dispersion according to claim 1 wherein both of B₁ and B₂ are straight chain aliphatic groups.

6. An aqueous dispersion according to claim 1 wherein B₁ and B₂ each is a group of formula:

space="preserve" listing-type="equation">--CO--(CH.sub.2).sub.8 --C.tbd.C--C.tbd.C--(CH.sub.2).sub.n CH.sub.3

where n is 9 or 13.

7. An aqueous dispersion according to claim 1 wherein one of B₁ and B₂ is a group of formula:

space="preserve" listing-type="equation">--CO--(CH.sub.2).sub.8 --C.tbd.C--C.tbd.C--(CH.sub.2).sub.9 CH.sub.3

and the other of B₁ and B₂ is a mixture of --(CH₂)₁₅ --CH₃ and --(CH₂)₁₇ CH₃ groups.

8. An aqueous dispersion according to claim 1 wherein the ligand is deoxyhaemoglobin or haemoglobin and the dispersed liposomes are capable of reversibly binding with molecular oxygen.

9. An aqueous dispersion according to claim 1 wherein the liposome is formed from a mixture of the conjugated di-yne I together with cholesterol or a negatively charged phospholipid.

10. An aqueous dispersion according to claim 1 wherein the liposome is formed from a mixture of the conjugated di-yne I together with alpha-tocopherol and/or butyl hydroxy toluene.

11. An aqueous dispersion according to claim 1 wherein the liposome is formed from a mixture of the conjugated di-yne I together with a phosphate and/or carbohydrate.

12. An aqueous dispersion according to claim 1 additionally containing a carbohydrate.

13. A solid polymer, forming on rehydration an aqueous dispersion capable of reversible binding molecular oxygen or nitrogen or carbon monoxide or carbon dioxide, which is obtained by removing water from an aqueous dispersion according to claim 12.

14. A solid polymer according to claim 13 wherein the carbohydrate is trehalose, galactose or glucose.

22. A method of transporting a gas which is molecular oxygen, nitrogen, carbon monoxide or carbon dioxide which comprises bringing the gas into contact with an aqueous dispersion according to claim 1 at a first station to form a gas rich aqueous dispersion, transporting the gas rich aqueous dispersion to a second station and releasing the gas from the gas rich dispersion at the second station.

15. A method of producing an aqueous dispersion of liposomal phospholipid polymers by forming an aqueous dispersion comprising liposomes of a conjugated di-yne I ##STR10## wherein at least one of B₁ and B₂ is a group of the formula:

space="preserve" listing-type="equation">--(CO).sub.p --X.sub.1 --C.tbd.C--C.tbd.C--Y.sub.1

wherein p is 0 or 1, X₁ is a direct bond or a divalent aliphatic or cycloaliphatic group, Y₁ is H or a monovalent aliphatic or cycloaliphatic group, the total number of carbon atoms in X₁ and Y₁ in each B₁ and/or B₂ being 8 to 26, and the other of B₁ and B₂ is either (a) the same or a different group of the formula;

space="preserve" listing-type="equation">--(CO).sub.p --X.sub.1 --C.tbd.C--C.tbd.C--Y.sub.1

or (b) is an aliphatic or cycloaliphatic group containing at least 8 carbon atoms;

n is 0 or 1, m is 2, 3 or 4 and each R independently represents an alkyl group containing 1 to 4 carbon atoms;

introducing a ligand that will reversibly bind with molecular oxygen or with nitrogen or with carbon monoxide or carbon dioxide, the ligand being introduced before, during or after the conjugated di-yne is formed into liposomes, and finally polymerising the conjugated di-yne.

16. A method according to claim 15 wherein the conjugated di-yne is formed into liposomes by sonication.

17. A method according to claim 16 wherein multi-lamellar or small diameter unilamellar liposomes are formed.

18. A method according to claim 15 wherein the ligand is introduced into the dispersion after liposome formation and the dispersion containing the ligand and liposomes is subjected to at least two cycles of freezing and thawing to incorporate the ligand in the liposomes.

19. A method according to any claim 15 wherein the conjugated di-yne is polymerised by exposure to actinic radiation.

20. A method according to claim 15 wherein the dispersion additionally contains a carbohydrate and wherein the water is removed from the dispersion to leave a solid polymer which, on rehydration, gives an aqueous dispersion capable of reversibly binding molecular oxygen or nitrogen or carbon monoxide or carbon dioxide.

21. A method according to claim 20 wherein the carbohydrate is trehalose, galactose or glucose.

23. A method according to claim 15 wherein n=1, m=2 and each R is CH₃.

24. A method according to claim 15 wherein one of B₁ and B₂ is a group of formula:

space="preserve" listing-type="equation">--CO--(CH.sub.2).sub.8 --C═

C--C═

C--(CH.sub.2).sub.9 CH.sub.3

and the other of B₁ and B₂ is a mixture of --(CH₂)₁₅ CH₃ and --(CH₂)₁₇ CH₃ groups.

25. A method according to claim 15 wherein the ligand is deoxyhaemoglobin or haemoglobin.