Process for producing controlled porosity microcapsules

• US 4,322,311 A
• Filed: 04/25/1980
• Issued: 03/30/1982
• Est. Priority Date: 08/04/1978
• Status: Expired due to Term

• Current Assignee: Repligen Corporation
• Original Assignee: Damon Corporation (Thor Industries Incorporated)
• Inventors: Moss, Richard D., Lim, Franklin
• Primary Examiner(s): Lovering, Richard D.
• Application Number:
  US06/143,932
• Time in Patent Office: 704 Days
• Field of Search: 252/316, 424/32
• US Class Current: 264/4.7
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: B01J 13/16 Interfacial polymerisation
• CPC Class Codes: G01N 33/5375 by changing the physical or chemical properties of the medium or immunochemicals, e.g. temperature, density, pH, partitioning
• CPC Class Codes: G01N 33/549 with antigen or antibody entrapped within the carrier
• CPC Class Codes: G01N 33/74 involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
• CPC Class Codes: Y10S 424/07 Microporous membranes

Abstract

A process for producing microcapsules of controlled porosity containing a chemically active core material. A core material such as a biologically active material and a first monomer in aqueous solution are emulsified in a hydrophobic solvent. A monomer complementary to the first and soluble in the continuous, hydrophobic phase of the emulsion is added to initiate interfacial polymerization about the aqueous droplets. During the course of the reaction, the affinity of the continuous phase for the first monomer is varied by adding a solvent to the continuous phase to vary its polarity. The continuous phase may be relatively nonpolar at the outset and a polar solvent may be added to increase its affinity for the first monomer, or it may be relatively polar at the outset and a nonpolar (or less polar) solvent may be added. This technique allows production of microcapsules having a selected pore size so that, for example, encapsulated material cannot escape, yet lower molecular weight materials can diffuse through the capsule wall.

Claims

1. A process for encapsulating a chemically active material within a membrane of a selected porosity, said process comprising the steps of:

A. solubilizing said material in water together with a water soluble first monomer selected from the group consisting of multifunctional amines, polyols, and diols to produce an aqueous phase;

B. emulsifying the aqueous phase in a continuous phase comprising a hydrophobic solvent;

C. adding a substantially water insoluble second monomer selected from the group consisting of multifunctional acid halides, diacids, diisocyanates, and multifunctional sulfonyl halides to said emulsion to produce porous membranes comprising a polymer formed by interfacial polymerization about the members of the aqueous, discontinuous phase, said first and second monomers having differing solubility characteristics and being capable of reacting by polycondensation or polyaddition;

D. adding hydrophobic solvent-miscible material to said hydrophobic solvent to vary the polarity of said continuous phase, thereby to alter the affinity of said first monomer for the continuous phase during the polymerization of said first and second monomers;

E. allowing said first and second monomers to further polymerize at the interface of the altered continuous phase; and

F. quenching the interfacial polymerization when microcapsules of the selected porosity have been produced.

2. The process as set forth in claim 1 wherein the hydrophobic solvent is relatively nonpolar and the hydrophobic solvent-miscible material is a polar solvent which increases the affinity of the first monomer for the continuous phase.

3. The process as set forth in claim 1 wherein the hydrophobic solvent is a relatively polar solvent and the hydrophobic solvent-miscible material is a nonpolar solvent which decreases the affinity of the first monomer for the continuous phase.

4. The process as set forth in claim 1 wherein the first monomer is a polyfunctional amine and the second monomer is a polyfunctional acid halide.

5. The process as set forth in claim 4 wherein the amine is selected from the group consisting of 1,6 hexane diamine, lysine, 4,4'"'"' diamino 2,2'"'"' biphenyl disulfonic acid, 4,4'"'"' diamino stilbene, 2,2'"'"' disulfonic acid, and 2,5 diaminobenzenesulfonic acid.

6. The process as set forth in claim 4 wherein the acid halide is selected from the group consisting of sebacyl chloride and terephthaloyl chloride.

7. The process as set forth in claim 4 wherein the first monomer includes a portion of tetraethylene pentamine.

8. The process as set forth in claim 4 wherein the hydrophobic solvent is cyclohexane and the hydrophobic solvent-miscible material is chloroform.

9. The process as set forth in claim 1 wherein a carrier material for the chemically active material is included in the aqueous phase.

10. The process as set forth in claim 9 wherein the carrier material is selected from the group consisting of polyvinylpyrrolidone, dextran, polyethylene glycol, ficol, hemoglobin, and albumin.

11. The process as set forth in claim 1 wherein the second monomer is added to the emulsion incrementally as the interfacial polymerization proceeds.

12. The process as set forth in claim 1 wherein the chemically active material is a labile biological material.

13. The process as set forth in claim 1 wherein the hydrophobic solvent-miscible material is added incrementally as the interfacial polymerization proceeds.

14. A process for encapsulating a chemically active material within a membrane of a selected porosity, said process comprising the steps of:

A. solubilizing said material in water together with a polyfunctional amine to produce an aqueous phase;

B. emulsifying the aqueous phase in a continuous phase comprising a nonpolar hydrophobic solvent;

C. adding a substantially water insoluble diacid halide to said emulsion to produce a membrane framework comprising a polymer about the surface of the members of the discontinuous aqueous phase by interfacial polymerization;

D. adding a hydrophobic solvent-soluble polar solvent to the emulsion to increase the affinity of the poly-functional amine for the continuous phase thereby to promote diffusion of said poly-functional amine into the framework;

E. allowing an additional quantity of said poly-functional amine to react with additional quantities of said diacid halide within said framework; and

F. quenching the interfacial polymerization when microcapsules of the selected porosity have been produced.

15. The process as set forth in claim 14 wherein the diacid halide is a diacid chloride selected from the group consisting of sebacyl chloride and terephthaloyl chloride, and the polyfunctional amine is selected from the group consisting of 1, 6 hexane diamine, tetraethylene pentamine, lysine, 4, 4'"'"' diamino 2, 2'"'"' biphenyl disulfonic acid, 4, 4'"'"' diamino stilbene 2, 2'"'"' disulfonic acid, 2, and 5 diaminobenzenesulfonic acid.

16. The process as set forth in claim 14 wherein the hydrophobic solvent is cyclohexane and the polar solvent is chloroform.

17. The process as set forth in claim 14 wherein the polar solvent is added to the emulsion incrementally as the interfacial polymerization proceeds.

18. The process as set forth in claim 14 wherein additional quantities of the diacid halide are incrementally added to the emulsion as the interfacial polymerization proceeds.

19. The process as set forth in claim 14 wherein the chemically active material is a labile biological material.

20. The process as set forth in claim 14 wherein a carrier material for the chemically active material is included in the aqueous phase.

21. The process as set forth in claim 20 wherein the carrier material is selected from the group consisting of polyvinylpyrrolidone, dextran, polyethylene glycol, ficol, hemoglobin, and albumin.

22. The process as set forth in claim 14 wherein both a pentamine and a diamine are solubilized in the aqueous phase.

23. The process as set forth in claim 22 wherein the mole ratio of pentamine to diamine is on the order of 0.05.