Biodegradable compositions for the controlled release of encapsulated substances

• US 6,793,938 B2
• Filed: 05/17/2001
• Issued: 09/21/2004
• Est. Priority Date: 07/17/1998
• Status: Expired due to Fees

• Current Assignee: Pacira Pharmaceuticals, Inc. (Pacira Biosciences, Inc.)
• Original Assignee: SKYE Pharma Incorporated
• Inventors: Sankaram, Mantripragada
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Nolan-Baron, Liliana Di
• Application Number:
  US09/859,847
• Publication Number:
  US 20010048945A1
• Time in Patent Office: 1,223 Days
• Field of Search: 424/483, 424/499, 424/500, 424/501, 424/502, 424/484, 424/422, 424/423, 424/424, 424/425, 424/426, 424/450, 264/4.6
• US Class Current: 424/489
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: Y10T 428/2985 Solid-walled microcapsule from synthetic polymer

Abstract

Pharmaceutical compositions that enable the release of a physiologically active substance over a prolonged period of time following administration to a patient are described. The pharmaceutical compositions are provided by encapsulation of a physiologically active substance into a matrix comprising biodegradable polymers and lipids. The rate of release of the physiologically active substance from the pharmaceutical composition is controlled by varying the ratio of the polymer to the lipid. The compositions can be stored in an aqueous suspension or as a solid dosage form. The physiologically active substances include small molecules, peptides, proteins, nucleic acids and vaccines. The biodegradable polymers include homopolymers, or random or block copolymers. The lipids include phospholipids, cholesterol and glycerides.

Claims

1. A process for producing biodegradable lipid/polymer-containing compositions, the process comprising:

a) forming a “

water-in-oil”

emulsion from a first aqueous phase and a volatile organic solvent phase comprising at least, one volatile organic solvent, at least one biodegradable polymer or copolymer which is soluble in organic solvent, and at least one lipid;

b) dispersing the “

water-in-oil”

emulsion into a surfactant-free second aqueous phase to form solvent spherules, and

c) removing the volatile organic solvent from the solvent spherules to form a microsphere composition suspended in the second aqueous phase, wherein the boundary of the microsphere compartment comprises the biodegradable lipid/polymer.

9. A composition produced according to the process of claim 1.

2. A process for producing biodegradable lipid/polymer-containing pharmaceutical compositions, the process comprising:

a) forming a “

water-in-oil”

emulsion from a first aqueous phase comprising at least one hydrophilic physiologically active substance, and a volatile organic solvent phase comprising at least one volatile organic solvent, at least one biodegradable polymer or copolymer which is soluble in organic solvent, and at least one lipid;

b) dispersing the “

water-in-oil”

emulsion into a surfactant-free second aqueous phase to form solvent spherules; and

c) removing the volatile organic solvent from the solvent spherules to form a pharmaceutical microsphere composition suspended in the second aqueous phase, wherein the boundary of the microsphere compartment comprises the biodegradable lipid/polymer, and wherein the lipid;

polymer ratio is chosen to modulate the in vivo release rate of the physiologically active substance.

3. The process of claim 2, further comprising removing substantially all of the organic solvent from the solvent spherules.

4. A pharmaceutical composition produced by the process of claim 2.

8. The process of claim 2, wherein the volatile organic solvent phase further comprises at least one tryglyceride.

5. A process for producing biodegradable lipid/polymer-containing pharmaceutical compositions, the process comprising:

a) forming a “

water-in-oil”

emulsion from a first aqueous phase, and a volatile organic solvent phase comprising at least one hydrophobic physiologically active substance, at least one volatile organic solvent, at least one biodegradable polymer or copolymer which is soluble in organic solvent, and at least one lipid;

b) dispersing the “

water-in-oil”

emulsion into a surfactant-free second aqueous phase to form solvent spherules; and

c) removing the volatile organic solvent from the solvent spherules to form a pharmaceutical microsphere composition suspended in the second aqueous phase, wherein the boundary of the microsphere compartment comprises the biodegradable lipid/polymer, and wherein the lipid;

polymer ratio is chosen to modulate the in vivo release rate of the physiologically active substance.

6. The process of claim 5, further comprising removing substantially all of the organic solvent from the solvent spherules.

7. A lipid/polymer-containing pharmaceutical composition produced according to the process of claim 5.