Steroidal liposomes

• US 6,352,716 B1
• Filed: 08/18/1993
• Issued: 03/05/2002
• Est. Priority Date: 04/12/1984
• Status: Expired due to Fees

• Current Assignee: Transave Inc. (Insmed Incorporated)
• Original Assignee: The Liposome Co., Inc. (Perrigo Company PLC)
• Inventors: Janoff, Andrew S., Bolcsak, Lois E., Swenson, Christine E., Tremblay, Paul A., Weiner, Alan L., Popescu, Mircea C.
• Primary Examiner(s): Lovering, Richard D.
• Application Number:
  US08/108,822
• Time in Patent Office: 3,121 Days
• Field of Search: 264/4.1, 264/4.6, 424/1.21, 424/7.1, 424/450, 424/9.1, 436/829, 514/78, 514/167, 514/887, 514/967, 514/182, 604/891.1
• US Class Current: 424/450
• CPC Class Codes: A61K 2039/55555 Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/28 Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61K 9/02 Suppositories; Bougies; Bases therefor; Ovulesapparatus for making A61J3/08; devices for introducing into the body A61M31/00
• CPC Class Codes: A61K 9/12 Aerosols; Foams A61K9/0043, A61K9/0056, A61K9/006, A61K9/0073 take precedence; spray-films A61K9/7015
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: C12N 15/88 using microencapsulation, e.g. using amphiphile liposome vesicle
• CPC Class Codes: Y10S 424/15 Suppositories
• CPC Class Codes: Y10S 436/829 Liposomes, e.g. encapsulation
• CPC Class Codes: Y10T 428/2984 Microcapsule with fluid core [includes liposome]

Abstract

Methods and compositions are described for the preparation of bioactive agents entrapped in lipid vesicles the bilayers of which comprise a salt form of an organic acid derivative of a sterol, such as the tris-salt form of a sterol hemisuccinate, and to bompositions comprising a mixtue of tris(hydroxymethyl)aminomethane salt of cholesteryl hemisuccinate with either an antifungal compound or a peptide. These compositions have various applications in vivo.

Claims

1. A method for preparing a pharmaceutical composition which comprises liposomes having bilayers comprising a lipid which consists essentially of a salt form of an organic acid sterol derivative capable of forming closed bilayers, the method comprising:

(i) mixing an amount of the salt form of the organic acid sterol derivative sufficient to form closed vesicles with an aqueous phase so as to form a mixture comprising the aqueous phase and the sterol derivative, wherein the mixture is essentially free of organic solvent; and

(ii) agitating the mixture until vesicles are formed, wherein when the sterol derivative is negatively charged at neutral pH the mixture is substantially free of multivalent cations or when the derivative is positively charged at neutral pH the mixture is substantially free of multivalent anions.

2. The method of claim 1, wherein the aqueous phase comprises a bioactive agent.

3. The method of claim 1, wherein the salt form comprises an antifungal compound.

4. The method of claim 1, wherein the organic acid is an aliphatic dicarboxylic acid.

5. The method of claim 4, wherein the acid comprises up to seven carbon atoms.

6. The method of claim 5, wherein the acid is succinic acid.

7. The method of claim 1, wherein the sterol derivative is a cholesterol, phytosterol, vitamin D or hormonal derivative.

8. The method of claim 7, wherein the sterol derivative is a cholesterol derivative.

9. The method of claim 8, wherein the cholesterol derivative is a cholesterol hemisuccinate derivative.

10. The method of claim 9, wherein the derivative is a tris(hydroxymethyl)aminomethane cholesterol hemisuccinate salt.

11. The method of claim 1, wherein the concentration of the derivative in the aqueous phase is from about 4.5 mg per ml to about 200 mg per ml.

12. The method of claim 1, wherein the salt is a tris(hydroxymethylamino)methane salt.

13. The method of claim 1, wherein the salt is a 2-amino-2-methyl-1,3-propanediol salt.

14. The method of claim 1, wherein the salt is a 2-aminoethanol salt.

15. The method of claim 1, wherein the salt is a bis-tris-propane salt.

16. The method of claim 1, wherein the salt is a triethanolamine salt.

17. The method of claim 1, wherein the aqueous phase contains the salt form of the counterion of the salt form of the organic acid sterol derivative.

18. The method of claim 17, wherein the counterion is a sodium or potassium ion.