Lipsopheres for controlled delivery of substances

• US 5,188,837 A
• Filed: 10/03/1991
• Issued: 02/23/1993
• Est. Priority Date: 11/13/1989
• Status: Expired due to Term

• Current Assignee: Scios, Inc. (Johnson & Johnson)
• Original Assignee: Nova Pharmaceutical Corporation
• Inventors: Domb, Abraham J.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): KISHORE, GOLLAMUDI S
• Application Number:
  US07/770,706
• Time in Patent Office: 509 Days
• Field of Search: 424/450, 424/1.1, 424/9, 424/403, 424/405, 424/417, 514/937, 514/938, 514/939, 514/943, 264/4.1-4.6, 436/829, 428/402.2
• 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]

Abstract

A microsuspension system and method for its preparation is disclosed. The microsuspension contain lipospheres, which are solid, water-insoluble microparticles that have a layer of a phospholipid embedded on their surface. The core of the liposphere is a solid substance to be delivered, or a substance to be delivered that is dispersed in an inert solid vehicle, such as a wax.

Claims

1. A liposphere comprising

a core formed of a hydrophobic material existing as a solid at a temperature of at least 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 liposphere,

the combination forming a spherical structure having an average particle diameter of between 0.3 and 250 microns.

2. The liposphere of claim 1 further comprising an active compound within the liposphere.

3. The liposphere of claim 2 wherein the solid core consists of the active compound.

4. The liposphere of claim 2 wherein the solid core includes the active compound and a vehicle for the active compound which in combination with the active compound exists as a solid at 30°

C.

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, regenerated and synthetic waxes, fatty acid esters, high molecular weight fatty alcohols, solid hydrogenated vegetable oils, solid triglycerides, and biodegradable polymers.

7. The liposphere of claim 2 wherein the active compound is selected from the group consisting of nonsteroidal antiinflammatories, local anesthetics, water insoluble anticancer drugs and steroids.

8. The liposphere of claim 2 that is suitable for injection into a patent.

9. The liposphere of claim 2 wherein the active compound is selected form the group consisting of food additives, pesticides, herbicides, insecticides, pheromones, colors and inks.

10. A method of preparation of a liposphere comprising:

(a) providing a hydrophobic liquid which forms a solid at a temperature of at least 30°

C.;

(b) adding to the liquid hydrophobic material a phospholipid followed by an aqueous solution at a temperature higher than the melting temperature of the hydrophobic material to form a dispersion;

(c) mixing the dispersion at a temperature above the melting temperature of the hydrophobic material until a homogeneous fine preparation is obtained; and

(d) rapidly cooling the preparation to a temperature at which the hydrophobic material solidifies,

to form a liposphere comprising

a core formed of 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 liposphere,

the combination forming a spherical structure having an average particle diameter of between 0.3 and 250 microns.

11. The method of claim 10 further comprising selecting a hydrophobic material that has a melting point between 30°

C. and 120°

C.

12. The method of claim 10 further comprising providing an active compound to be incorporated within the liposphere.

13. The method of claim 12 wherein the active compound is the hydrophobic material.

14. The method of claim 12 wherein the active compound is dispersed or dissolved in an inert hydrophobic material which in combination with the active compound exists as a solid at a temperature of 30°

C.

15. The method of claim 12 further comprising decreasing the water solubility of the active compound before addition to the phospholipid-aqueous solution.

16. The method of claim 12 further comprising preincorporating the active compound into a hydrophobic microparticle before addition of the active compound to the hydrophobic material forming the core of the liposphere.

17. The method of claim 12 further comprising selecting an aqueous solution that the active compound has low solubility in.

18. The method of claim 12 wherein the active compound is a peptide or protein.

19. The method of claim 14 wherein the hydrophobic material is selected from the group consisting of natural, regenerated and synthetic waxes, fatty acid esters, high molecular weight fatty alcohols, solid hydrogenated vegetable oils, solid triglycerides, and biodegradable polymers.

20. The method of claim 12 further comprising selecting the active compound to be delivered from the group consisting of nonsteroidal antiinflammatories, local anesthetics, water insoluble anticancer drugs and steroids.

21. The method of claim 12 further comprising selecting the active compound to be delivered from the group consisting of food additives, pesticides, herbicides, insecticides, pheromones, colors and inks.