Microcapsules, method of making and their use

• US 6,403,057 B1
• Filed: 06/23/2000
• Issued: 06/11/2002
• 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:
  US09/599,576
• Time in Patent Office: 718 Days
• Field of Search: 424/9.52, 424/9.51, 516/11, 516/77
• 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 process of making 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 membrane encapsulating air or a gaseous core, wherein the membrane is obtained from:

(1) one or more biodegradable, water insoluble and at room temperature solid lipids selected from di-glycerides, tri-glycerides, fatty acids having at least 12 carbon atoms, sterols, waxes and mixtures thereof, and

(2) up to 75% by weight of biodegradable polymers, said process comprising the steps of;

(a) dissolving the biodegradable lipid and optionally a biodegradable polymer in an organic solvent or a solvent mixture,

(b) admixing the solution of step (a) with an aqueous phase,

(c) emulsifying the mixture of step (b) to form oil-in-water emulsion,

(d) adding a redispersing agent,

(e) freezing the emulsion,

(f) lyophilizing the frozen product of step (e) to form a powder containing semi-spherical or spherical air or gas filled microcapsules,

(g) dispersing the lyophilized powder in an aqueous carrier,

(h) separating the air or gas containing microcapsules from any debris by decantation, and

(i) drying the recovered microcapsules.

2. The method of claim 1, wherein after formation of the oil-in-water emulsion part of the organic solvent is evaporated.

3. The method of claim 1, wherein the solvent mixture is a mixture of a water soluble and water insoluble organic solvents.

4. The method of claim 3, wherein the water insoluble organic solvent is selected from alkanes, cycloalkanes, aromatic hydrocarbons, ethers and halogenated hydrocarbons.

5. The method of claim 4, wherein the solvent is selected from toluene, xylene, cyclooctane, cyclohexane, chloroform, tetrachloro methane, difluorotetrachloroethane, dibutylether, diisopropyl ether, isobutylmethyl ketone and mixtures thereof.

6. The method of claim 1, wherein the redispersing agent is selected from polyoxyethylene-polyoxypropylene block copolymers and phospholipids.

7. The method of claim 1, wherein a lipophilic active substance is added to the solution of lipids prior to admixing with the aqueous phase.

8. The method of claim 7, wherein the lipophilic active substance is selected from vitamin E, prednisolone, chloramphenicol palmitate, salbutamol, gentamycin, rifampacin, amphotericin B, antimony, mitomycin C, doxorubicin, cisplatinum, norgestrel, spironolactone, estradiol, glucocorticoids, carboxy fluorescein, salicylic acid, ibuprofen, bupivacaine, lidocaine.