Liposphere delivery systems for local anesthetics

• US 5,227,165 A
• Filed: 01/22/1992
• Issued: 07/13/1993
• Est. Priority Date: 11/13/1989
• Status: Expired due to Term

• Current Assignee: Scios, Inc. (Johnson & Johnson)
• Original Assignee: Nova Pharmaceutical Corporation (Johnson & Johnson)
• Inventors: Maniar, Manoj, Domb, Abraham J.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): KISHORE, GOLLAMUDI S
• Application Number:
  US07/826,218
• Time in Patent Office: 538 Days
• Field of Search: 424/450, 264/4.1-4.3, 264/4.4, 428/402.2, 428/402.24
• US Class Current: 424/450
• CPC Class Codes: A01N 25/26 in coated particulate form
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/167 with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface with further drug-free outer coating A61K9/5073
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: Y10T 428/2984 Microcapsule with fluid core [includes liposome]
• CPC Class Codes: Y10T 428/2989 Microcapsule with solid core [includes liposome]

Abstract

A local anesthetic microsuspension system is disclosed that includes lipospheres, that are solid, water-insoluble microparticles that have a layer of a phospholipid embedded on their surface. The core of the liposphere is a solid anesthetic such as lidocaine or marcaine, or an anesthetic dispersed in an inert solid vehicle, such as a wax. Anesthetic lipospheres provide a controlled delivery of local anesthetics to achieve extended, effective relief from pain by slowly releasing the anesthetic from the solid hydrophobic core. This is highly preferred over the situation in which an aqueous solution of local anesthetic must be frequently administered because it is quickly systemically absorbed.

Claims

1. A liposphere comprising:

a core formed of a hydrophobic material existing as a solid at a temperature of 30°

C. having anesthetic activity as a result of an anesthetic compound, and

a phospholipid coating surrounding the core, wherein the hydrophobic ends of the phospholipid are embedded in the solid core and the hydrophilic ends of the phospholipid are exposed on the surface of the liposphere,

the combination forming a spherical structure having an average particle diameter between 0.35 and 250 microns,

wherein the core may contain a vehicle for the anesthetic compound, and the anesthetic compound, vehicle, and phospholipid coating are in a ratio of anesthetic compound to vehicle to phospholipid between 1;

0;

0.01 and 1;

100;

100.

2. The liposphere of claim 1, wherein the anesthetic activity is produced by a local anesthetic compound.

3. The liposphere of claim 2 wherein the local anesthetic is selected from the group consisting of marcaine, procaine, chloroprocaine, cocaine, lidocaine, tetracaine, mepivacaine, etidocaine, bupivacaine, dibucaine, prilocaine, benzoxinate, proparacaine, benzocaine, butamben, and combinations thereof.

4. The liposphere of claim 1 wherein the solid core comprises an anesthetic compound in a solid inert vehicle.

5. The liposphere of claim 1 wherein the solid core has a melting point between 30°

C. and 120°

C.

6. The liposphere of claim 4 wherein the vehicle is selected from the group consisting of natural and synthetic waxes, fatty acid esters, fatty alcohols, solid hydrogenated plant oils, tristearin, and biodegradable natural and synthetic polymers.

7. The liposphere of claim 1 wherein the anesthetic activity is produced by a compound selected from the group consisting of halothane, isoflurane, enflurane, and methoxyflurane.

8. The liposphere of claim 1 in a pharmaceutically acceptable carrier for enteral administration to a patient.

9. The liposphere of claim 1 wherein the liposphere is in a pharmaceutically acceptable carrier for topical administration to a patient.

10. The liposphere of claim 1 in a pharmaceutically acceptable carrier for parenteral administration to a patient.

11. The liposphere of claim 1, further comprising a preservative.

12. The liposphere of claim 1 further comprising a pharmaceutically active agent selected from the group consisting of antibiotics, antifungals, antivirals, chemotherapeutic agents and combinations thereof.

13. A method of inducing local anesthesia comprising administering to a patient lipospheres comprising:

a core formed of a hydrophobic material existing as a solid at 30°

C. having anesthetic activity as a result of an anesthetic compound, and

a phospholipid coating surrounding the core, wherein the hydrophobic ends of the phospholipid are embedded in the solid core and the hydrophilic ends of the phospholipid are exposed on the surface of the liposphere,

the combination forming a spherical structure having an average particle diameter between 0.35 and 250 microns,

wherein the core may contain a vehicle for the anesthetic compound, and the anesthetic compound, vehicle, and phospholipid coating are in a ratio of anesthetic compound to vehicle to phospholipid between 1;

0;

0.01 and 1;

100;

100

in a pharmaceutically acceptable carrier.

14. The method of claim 13 wherein the anesthetic activity is produced by a local anesthetic compound.

15. The method of claim 14 wherein the local anesthetic is selected from the group consisting marcaine, procaine, chloroprocaine, cocaine, lidocaine, tetracaine, mepivacaine, etidocaine, bupivacaine, dibucaine, prilocaine, benzoxinate, proparacaine, benzocaine, or butamben.

16. The method of claim 13 wherein the solid core includes an anesthetic compound and a vehicle for the anesthetic compound, which in combination with the anesthetic compound exists as a solid at 30°

C.

17. The method of claim 13 wherein the solid core has a melting point between 30°

C. and 120°

C.

18. The method of claim 16 wherein the vehicle is selected from the group consisting of natural and synthetic waxes, fatty acid esters, fatty alcohols, solid hydrogenated castor and vegetable oils, tristearin, and biodegradable polymer.

19. The method of claim 13 wherein the anesthetic activity is produced by a compound selected from the group consisting of halothane, isoflurane, enflurane, and methoxyflurane.

20. The method of claim 13 wherein the liposphere is administered parenterally to the patient.

21. The method of claim 13 wherein the liposphere is administered topically in a pharmaceutically acceptable carrier for topical administration.

22. The method of claim 13 wherein the liposphere is administered enterally to the patient.

23. The method of claim 13, wherein the core further comprises a preservative.

24. The method of claim 13 further comprising a pharmaceutically active agent selected from the group consisting of antibiotics, antifungals, antivirals, chemotherapeutic agents and combinations thereof.

25. A method of making lipospheres formed of a core that is a hydrophobic material existing as a solid at a temperature of 30°

C. and a phospholipid coating surrounding the core, wherein the hydrophobic ends of the phospholipid are embedded in the solid core and the hydrophilic ends of the phospholipid are exposed on the surface of the resulting spherical liposphere structure having an average particle diameter between 0.35 and 250 microns, comprising

forming a liquid of the hydrophobic core material,

adding phospholipid to the core material,

adding an aqueous solution to the liquid core material and phospholipid mixture, and

mixing the liquid core material and phospholipid until a suspension of lipospheres is formed.

26. The method of claim 25 further comprising sonicating and cooling the liquid core material and phospholipid after mixing.

27. The method of claim 25 wherein the liquid core material and phospholipid are heated during mixing to a temperature at which the core material melts.

28. The method of claim 25 wherein the the liquid core material includes an organic solvent, further comprising evaporating the solvent while mixing the core material and phospholipid.

29. The method of claim 28 wherein aqueous buffer is added to the core material-phospholipid mixture after evaporating the solvent and before mixing until a suspension of lipospheres is formed.