Silicone-hardened pharmaceutical microcapsules and process of making the same

Claim 2

In a process for preparing a pharmaceutical composition in microcapsule form, said process comprising: (a) dispersing a solution containing a core material which is comprised of a pharmaceutical agent in an organic solvent containing a biocompatible encapsulating polymer, which core material has low solubility in the non-solvent of step (b) and the hardening agent of step (c); (b) adding to the dispersion a non-solvent for the encapsulating polymer and core material, which non-solvent is miscible with the organic solvent and in which the core material has a low solubility; and (c) adding the product of step (b) to a hardening solvent to extract said organic solvent and produce solid microcapsules of said pharmaceutical composition, the improvement which comprises using as the hardening solvent a volatile silicone fluid.

Claim 3

In a process for preparing a pharmaceutical composition in microcapsule form, said process comprising: (a) dispersing a core material comprising solid particles comprised of a pharmaceutical agent in a solution of a biocompatible encapsulating polymer in an organic solvent in which the core material has a low solubility; (b) stirring the dispersion produced in (a) while adding a non-solvent for said encapsulating polymer and said core material, said non-solvent being soluble in said organic solvent whereby the encapsulating polymer separates from solution as a liquid phase consisting essentially of a concentrated solution of the encapsulating polymer in said organic solvent and selectively coats the core material particles; and (c) adding the coated core particle dispersion from step (b) to a hardening agent to extract said organic solvent and produce solid microcapsules of said pharmaceutical composition, the improvement comprising utilizing as the hardening agent a volatile silicone fluid in which the core material has low solubility.

Claim 4

In a process for preparing a pharmaceutical composition in microcapsule form, said process comprising: (a) dispersing a core material comprising solid particles comprised of a pharmaceutical agent in a solution of a biocompatible encapsulating polymer in an organic solvent in which the core material has a low solubility; (b) stirring the dispersion produced in (a) while adding a non-solvent for said encapsulating polymer and said core material, said non-solvent being soluble in said organic solvent whereby the encapsulating polymer separates from solution as a liquid phase consisting essentially of a concentrated solution of the encapsulating polymer in said organic solvent and selectively coats the core material particles; and (c) adding the coated core particle dispersion from step (b) to a hardening agent to extract said organic solvent and produce solid microcapsules of said pharmaceutical composition, the improvement comprising utilizing as the hardening agent a volatile silicone fluid in which the core material has low solubility.

Claim 5

A process as defined in claim 1 wherein the non-solvent for the encapsulating polymer is a second polymer incompatible with said encapsulating polymer.

Claim 6

A process as defined in claim 2 wherein the non-solvent for the encapsulating polymer is a second polymer incompatible with said encapsulating polymer.

Claim 7

A process as defined in claim 1 wherein the biocompatible encapsulating polymer is also biodegradable.

Claim 8

A process as defined in claim 2 wherein the biocompatible encapsulating polymer is also biodegradable.

Claim 9

A process as defined in claim 1 wherein said core material comprises a vitamin or an antibiotic.

Claim 10

A process as in claim 7 wherein said vitamin is vitamin B-12.

Claim 11

A process as in claim 7 wherein the antibiotic is selected from the group consisting of tetracycline, doxycycline, minocycline, methacycline, declomycin, oxytetracycline, and chlortetracycline or the pharmaceutically acceptable salts thereof.

Claim 12

A process as in claim 7 wherein the antibiotic is a cephalosporin.

Claim 13

A process as in claim 7 wherein the antibiotic is a penicillin.

Claim 14

A process as in claim 7 wherein the antibiotic is a quinolone.

Claim 15

A process as in claim 7 wherein the antibiotic is an aminoglycoside.

Claim 16

A process as in claim 1 wherein the core material is comprised of a mixture of a penicillin antibiotic and a beta-lactamose inhibitor.

Claim 17

A process as defined in claim 1 wherein the core material comprises a peptide or pharmaceutically acceptable salt thereof.

Claim 18

A process as defined in claim 15 wherein the peptide is a luteinizing hormone releasing hormone analog or a pharmaceutically acceptable salt thereof.

Claim 19

A process as defined in claim 16 wherein the luteinizing hormone releasing hormone analog is D-Trp 6 -LH-RH or a pharmaceutically acceptable salt thereof.

Claim 20

A process as defined in claim 16 wherein the luteinizing hormone releasing hormone analog is (pyro)Glu-His-Trp-Ser-Tyr-3-Napthyl-D-Alanyl-Leu-Arg-Pro-Gly-NH 2 or a pharmaceutically acceptable salt thereof.

Claim 21

A process as defined in claim 1 wherein the core material comprises a protein or pharmaceutically acceptable salt thereof.

Claim 22

A process as defined in claim 1 wherein the core material comprises an anesthetic.

Claim 23

A process as defined in claim 20 wherein the anesthetic is selected from the group consisting of procaine, lidocaine, tetracaine and etidocaine or a pharmaceutically acceptable salt thereof.

Claim 24

A process as defined in claim 1 wherein the organic solvent comprises methylene chloride.

Claim 25

A process as defined in claim 1 wherein the encapsulating polymer comprises a polymer of lactic acid or a copolymer of lactic acid and glycolic acid.

Claim 26

A process as defined in claim 23 wherein said polymer comprises dl-lactide-co-glycolide copolymer.

Claim 27

A process as defined in claim 1 wherein said non-solvent in step (b) comprises a silicone oil, a volatile silicone fluid, a mineral oil, a vegetable oil or a mixture of any of the foregoing.

Claim 28

A process as defined in claim 11 wherein said non-solvent comprises a silicone oil.

Claim 29

A process as defined in claim 26 wherein said non-solvent comprises a polydimethylsiloxane fluid.

Claim 30

A process as defined in claim 1 wherein said volatile silicone fluid comprises octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane or a low molecular weight polydimethylsiloxane.

Claim 31

A process as defined in claim 28, wherein said volatile silicone fluid comprises octamethylcyclotetrasiloxane.

Claim 32

A process as defined in claim 1 wherein the solubility of the core material in the non-solvent is less than about 5% weight/weight.

Claim 33

A process as defined in claim 1 wherein the solubility of the core material in the non-solvent is less than about 1% weight/weight.

Claim 34

A process as defined in claim 1 wherein the solubility of the core material in the non-solvent is less than about 0.1% weight/weight.

Claim 35

A process as defined in claim 1 wherein the volatile silicone fluid is miscible with the encapsulating polymer solvent.

Claim 36

In a process of preparing a composition in microcapsule form by phase separation microencapsulation, the improvement comprising employing a hardening agent comprising a volatile silicone fluid.

Claim 37

In a process of preparing a composition in microcapsule form by phase separation microencapsulation, the improvement comprising employing a hardening agent comprising a volatile silicone fluid.

Claim 38

A process according to claim 34 in which the volatile silicone fluid comprises octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane or a low molecular weight polydimethylsiloxane.

Claim 39

A process according to claim 35 in which the volatile silicone fluid comprises octamethylcyclotetrasiloxane.