Microcapsules, method of making and their use

• US 6,333,021 B1
• Filed: 11/08/1995
• Issued: 12/25/2001
• Est. Priority Date: 11/22/1994
• Status: Expired due to Fees

• Current Assignee: Bracco Research SA
• Original Assignee: Bracco Research SA
• Inventors: Bussat, Philippe, Schneider, Michel
• Primary Examiner(s): Hartley, Michael G.
• Application Number:
  US08/555,147
• Time in Patent Office: 2,239 Days
• Field of Search: 424/9.5, 424/9.51, 424/9.52, 424/489, 424/502, 424/498, 600/458, 600/441
• US Class Current: 424/9.52
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 9/0065 Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars

Abstract

The invention relates to microcapsules to a microcapsule with a mean size from a fraction of micrometer to 1000 micrometers having a biodegradable membrane encapsulating a gas core. The membrane comprising one or more biodegradable water insoluble lipids or mixtures thereof and optionally mixtures of the lipids with up to 75% by weight of biodegradable polymers encapsulates the core which is filled with air or a gas. Microcapsules disclosed, may be non-coalescent, dry and instantly dispersible, when in suspension in a physiologically acceptable carrier are useful as delivery vehicles for therapeutically active agents and/or as contrast agents for echographic imaging of organs of human or animal body. The microcapsules of the invention are made by a method in which a water-in-oil emulsion is made from an organic solution comprising dissolved a mono-, di-, triglyceride preferably tripalmitin or tristearin and optionally therapeutically active substance and an aqueous solution containing a surfactant, optionally evaporating part of the solvent, adding a redispersing agent and freeze drying the mixture. The freeze dried mixture is then redispersed in an aqueous carrier to separate microcapsules from debris and the semi-spherical or spherical microcapsules are dried.

Claims

1. A solid microcapsule for use in ultrasound echography with a mean size from a fraction of micrometer to 1000 micrometers, the microcapsule having a biodegradable, 50 to 500 nm thick solid membrane encapsulating an air or a gaseous core, wherein the solid membrane consists essentially of the membrane-forming constituents:

(a) one or more biodegradable, water insoluble and at room temperature solid triglycerides, and, optionally

(b) up to 75% by weight of a biodegradable polymer.

5. The microcapsule of claim 1 wherein the tri-glyceride is tri-myristin, palmitin or stearin, or mixtures thereof.

6. The microcapsule of claim 1, where in the membrane is at least partly crystalline or semi-crystalline.

7. The microcapsule of claim 1 wherein the membrane comprises up to 10% by wt of biodegradable polymers.

8. The microcapsule of claim 1 wherein the microcapsule has an average size distribution between 0.1 μ

m and 100 82 m.

9. The microcapsule of claim 1, wherein the microcapsule is porous and has a porosity of 20 to 2,000 nm.

10. The microcapsule of claim 1, wherein the microcapsule is non-coalescent, dry and instantly dispersible in a liquid carrier.

11. The microcapsule of claim 10, wherein the microcapsule further comprises a redispersing agent.

12. The microcapsule of claim 11, wherein the redispersing agent is selected from albumin, polyvinyl alcohol, and polyethylene glycol.

13. The microcapsule of claim 7, wherein the biodegradable polymer is present in an amount of between 0.5-10% by wt.

14. The microcapsule of claim 1, wherein the biodegradable polymer is selected from polyamino acids, polylactides and polyglycolides and their copolymers, copolymers of lactides and lactones, polypeptides, poly-(ortho)esters, polydioxanone, poly-β

-aminoketones, polyphosphazenes, polyanhydrides, polyhydroxy-butyrate and polyalkyl-(cyano)-acrylates.

15. The microcapsule of claim 1, wherein the microcapsule further comprises a surfactant selected from polyoxyethylene-polyoxypropylene block copolymers and phospholipids.

16. The microcapsule of claim 1, wherein the membrane further comprises a lipophilic active substance.

17. The microcapsule of claim 16, wherein the lipophilic active substance is selected from vitamin E, prednisolone, chloramphenicol palmitate and salbutamol.

18. A method of making an ultrasound contrast agent by suspending the microcapsules of claim 1 in a physiologically acceptable carrier phase.

19. Injectable composition comprising a suspension of an effective amount of microcapsules of claim 1 in a pharmaceutically acceptable liquid carrier with additives and stabilizers.

20. The microcapsule of claim 5, wherein the tri-glyceride is tripalmitin or tristearin.

21. The microcapsule of claim 1, wherein the biodegradable polymer is present in an amount of up to 20% by wt.

2. A solid microcapsule for use in ultrasound echography with a mean size from a fraction of micrometer to 1000 micrometers, the microcapsule having a biodegradable, 50 to 500 nm thick solid membrane encapsulating an air or a gaseous core, wherein the solid membrane comprises, as the membrane-forming constituents:

(a) one or more biodegradable, water insoluble and at room temperature solid triglycerides, and, optionally

(b) up to 75% by weight of a biodegradable polymer,

wherein the solid membrane is biodegradable and after being administered for ultrasound echography is cleared from a body in 24 hours or less.

3. A solid microcapsule for use in ultrasound echography with a mean size from a fraction of micrometer to 1000 micrometers, the microcapsule having a biodegradable, 50 to 500 nm thick solid, at least partially non amorphous, dense membrane encapsulating an air or a gaseous core, wherein the solid membrane is a tangible, material envelope consisting essentially of as the membrane-forming constituents:

(a) one or more biodegradable, water insoluble and at room temperature solid triglycerides, and,

(b) 0.1 to 75% by weight of a biodegradable polymer.

4. A solid microcapsule for use in ultrasound echography with a mean size from a fraction of micrometer to 1000 micrometers, the microcapsule having a biodegradable, 50 to 500 nm thick solid, at least partially non-amorphous, dense membrane encapsulating an air or a gaseous core, wherein the solid membrane is a tangible, material envelope consisting essentially of the membrane-forming constituents:

(a) one or more biodegradable, water insoluble and at room temperature solid triglycerides, and, optionally

(b) up to 75% by weight of a biodegradable polymer.