Acoustically active drug delivery systems

• US 6,416,740 B1
• Filed: 05/11/1998
• Issued: 07/09/2002
• Est. Priority Date: 05/13/1997
• Status: Expired due to Fees

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Unger, Evan C.
• Primary Examiner(s): Dudash, Diana
• Assistant Examiner(s): SHARAREH, SHAHNAM J
• Application Number:
  US09/075,343
• Time in Patent Office: 1,520 Days
• Field of Search: 424/9.52, 424/9.5, 424/9.51, 424/450
• US Class Current: 424/9.52
• CPC Class Codes: A61K 41/0028 Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/6925 the form being a microcapsule, nanocapsule, microbubble or nanobubble
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 9/0009 involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis microelectromechanical systems A61K9/0097
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/127 Liposomes
• 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: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/5123 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

The present invention is directed to targeted therapeutic delivery systems comprising a gas or gaseous precursor filled microsphere wherein said gas or gaseous precursor filled microsphere comprises an oil, a surfactant, and a therapeutic compound. Methods of preparing the targeted therapeutic delivery systems are also embodied by the present invention which comprise processing a solution comprising an oil and a surfactant in the presence of a gaseous precursor, at a temperature below the gel to liquid crystalline phase transition temperature of the surfactant to form gas or gaseous precursor filled microsphere, and adding to said microspheres a therapeutic compound resulting in a targeted therapeutic delivery system, wherein said processing is selected from the group consisting of controlled agitation, controlled drying, and a combination thereof.

Claims

1. A method for the controlled delivery of a therapeutic compound to a region of a patient comprising:

(i) administering to a patient a targeted therapeutic delivery system comprising, in combination with a therapeutic compound, stabilized lipid microspheres encapsulating a gas or gaseous precursor and an oil, wherein said microspheres comprises at least one phosphatidylcholine, at least one phosphatidylethanolamine, and at least one phosphatidic acid, wherein said phosphatidylcholine is selected from the group consisting of dioleoylphosphatidylcholine dimyistoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoyl-phosphatidylcholine;

said phosphatidylethanolamine is selected from the group consisting of dipalmitoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine-PEG 5,000, dioleoyl-phosphatidylethanolamine, and N-succinyl-dioleoyl-phosphatidylethanolamine; and

said phosphatidic acid is dipalmatoylphosphatidic acid;

(ii) monitoring the targeted therapeutic delivery system using diagnostic ultrasound to determine the presence of the microspheres in said region; and

(iii) applying therapeutic ultrasound to said region to induce rupturing of said microspheres, thereby releasing the therapeutic compound in said region, wherein said therapeutic compound is encapsulated or embedded in said microspheres, and said therapeutic ultrasound is applied at a level below the threshold level for lethal cytotoxicity.

2. A method of claim 1 for use in treating macular degeneration wherein said therapeutic compound comprises a-tocopherol and retinoic acid, said oil is soybean oil, said microspheres comprise 82 mol percent dipalmitoylphosphatidyl choline, 10 mol percent dipalmitoylphosphatidic acid, and 8 mol percent dipalmitoylphosphatidyl ethanolamine-polyethylene glycol 5000, and said gaseous precursor is perfluorobutane.

3. A method of claim 1 for use in treating retinoblastoma wherein said therapeutic compound comprises taxol and retinoic acid, said oil is soybean oil, said microspheres comprise 82 mol percent dipalmitoylphosphatidyl choline, 10 mol percent dipalmitoylphosphatidic acid, and 8 mol percent dipalmitoylphosphatidyl ethanolamine-polyethylene glycol 5000, and said gaseous precursor is perfluorobutane.

4. A method of claim 1 wherein said therapeutic compound is amphotericin-B, said oil is soybean oil, said microspheres comprise 82 mol percent dipalmitoylphosphatidyl choline, 10 mol percent dipalmitoylphosphatidic acid, 8 mol percent dipalmitoylphosphatidylethanolamine-polyethylene glycol 5000 and apoloxamer, and said gaseous precursor is perfluorobutane.

5. A method of claim 4 used to treat fungal ophthalmitis.

6. A method of claim 1 for treating retinitis pigmentosa wherein said therapeutic compound is bendazac, said oil is soybean oil, said microspheres comprise 82 mol percent dipalmitoylphosphatidyl choline, 10 mol percent dipalmitoylphosphatidic acid, 8 mol percent dipalmitoylphosphatidylethanolamine-polyethylene glycol 5000 and a poloxamer, and said gaseous precursor is perfluorobutane.

7. A method of claim 1 for eating benign prostatic hyperplasia wherein said therapeutic compound is doxazosin, said oil is soybean oil, said micropheres comprises 82 mol percent dipalmitoylphosphatidyl choline, 10 mol percent dipalmitoylphosphatidic acid, 8 mol percent dipalmitoylphosphatidyl ethanolamine-polyethylene glycol 5000 and a poloxamner, and said gaseous precursor is perfluorobutane.

8. A method of claim 1 wherein said therapeutic compound is α

-tocopherol, said microspheres comprises CF₃(CF₂)₈(CH₂)₆COOH, said oil is canola oil, and said gaseous precursor is perfluorobutane.

9. A method of claim 1 wherein said therapeutic compound is a dye, said oil is soybean oil, said micropheres comprises 82 mol percent dipalmitoylphosphatidylcholine, 8 mol percent dipalmitoylphosphatidylethanolamine-polyethylene glycol 5000, and 10 mol percent dipalmitoylphosphatidic acid, and said gaseous precursor is perfluoropropane.

10. A method of claim 1 wherein said therapeutic compound is dexamethasone, said micropheres comprises 82 mol percent dipalmitoylphosphatidylcholine, 8 mol percent dipalmitoylphosphatidylethanolamine-polyethylene glycol 5000, and 10 mol percent dipalmitoylphosphatidic acid, and said gas is perfluorobutane and nitrogen.

11. A method of claim 1 wherein said therapeutic compound is amphotericin, said micropheres comprises 82 mol percent dipalmitoylphosphatidylcholine, 8 mol percent dipalmitoylphosphatidylethanolamine-polyethylene glycol 5000, and 10 mol percent dipalmitoylphosphatidic acid, and said gas is selected from the group consisting of perfluorobutane and nitrogen.

12. A method of claim 1 for treating prostate cancer or benign prostate hypertrophy wherein said therapeutic compound is selected from the group consisting of testosterone, methyltestosterone, fluoxymesterone, finasteride, and Sa reductase enzyme inhibitors.

13. A method according to any preceding claim wherein said diagnostic ultrasound has a frequency equal to 1×

, and wherein said therapeutic ultrasound has a frequency equal to 2×

, 3×

, or 5×

.

14. A method according to claim 13 wherein said therapeutic ultrasound is superimposed upon said diagnostic ultrasound.

15. A method according to claim 14 wherein said therapeutic ultrasound is administered as a train of continuous wave pulses.