Porous microspheres for drug delivery and methods for making same

• US 4,818,542 A
• Filed: 03/31/1986
• Issued: 04/04/1989
• Est. Priority Date: 11/14/1983
• Status: Expired due to Term

• Current Assignee: University Of Kentucky Research Foundation (University of Kentucky)
• Original Assignee: University Of Kentucky Research Foundation (University of Kentucky)
• Inventors: Sato, Toyomi, Schroeder, Hans G., Kanke, Motoko, DeLuca, Patrick P.
• Primary Examiner(s): Lovering, Richard D.
• Application Number:
  US06/846,513
• Time in Patent Office: 1,100 Days
• Field of Search: 264/4.6, 427/213.3, 427/213.31, 427/213.35, 427/213.36, 428/402.24, 424/469, 424/486, 424/19, 424/22, 424/DIG. 7, 424/491, 424/492, 424/497, 424/499, 424/501, 34/5
• US Class Current: 424/491
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: Y10S 424/07 Microporous membranes
• CPC Class Codes: Y10T 428/2989 Microcapsule with solid core [includes liposome]

Abstract

Controlled release drug delivery systems comprised of spherical microporous polymeric network of interconnecting channels containing pore incorporated drugs or other agents wherein the drugs or agents are confined within the pore channel are described. Also disclosed are processing parameters in connection with the novel method of the invention for obtaining drug delivery systems especially suited for parenteral as well as oral administration.

Claims

1. A method for preparing a relatively homogenous essentially spherical microporous polymeric network of interconnecting channels containing a pore incorporated agent confined essentially completely inside the channels comprising preparing an agentpolymer-solvent dispersed first phase, dispersing said first phase in a continuous solvent second phase to obtain a suspension, removing solvent from said suspension by freeze drying, or dilution-extraction-precipitation and recovering said microporous polymeric network.

2. The method according to claim 1 wherein said spherical microporous polymeric network is derived from a natural or synthetic copolymer or polymer selected from the group consisting of gelatin, agar, starch, arabinogalactan, albumin, collagen, polyglycolic acid, polylactic acid, glycolide-L(-) lactide poly(ε

-caprolactone), poly(ε

-caprolactone-CO-lactic acid), poly(ε

-caprolactone-CO-glycolic acid), poly(β

-hydroxy butyric acid), polyethylene oxide, polyethylene, poly(alkyl-2-cyanoacrylate), poly(hydroxyethyl methacrylate), polyamides, poly(amino acids), poly(2-hydroxyethyl DL-aspartamide), poly(ester urea), poly(L-phenylalanine/ethylene glycol/1,6-diisocyanatohexane) and poly(methyl methacrylate).

3. The method according to claim 1 wherein said pore incorporated agent comprises a diagnostic or pharmacologically active drug.

4. The method according to claim 1 wherein the solvent in said first phase comprises an inorganic or organic solvent in which said agent-polymer are relatively soluble.

5. The method according to claim 4 wherein said solvent comprises water, hexafluoroisopropanol, methylenechloride, tetrahydrofuran, hexane, benzene, or hexafluoroacetone sesquihydrate.

6. The method according to claim 1 wherein said second solvent comprises a solvent for said continuous phase in which said first phase is emulsifiable.

7. The method according to claim 6 wherein said solvent comprises benzene, dioxane, acetone, methylenechloride, chloroform, carbon tetrachloride, toluene, ethyl alcohol, acetonitrile, p-xylene, tetrahydrofuran, or mixtures thereof.

8. The method according to claim 7 wherein said method further includes the step of employing a diluent-nonsolvent phase to dilute said continuous second solvent phase following dispersion of said agent-polymer solvent dispersed first phase.

9. The method according to claim 1 further including the step of employing a hydrophilic colloidal material to prevent phase inversion.

10. The method according to claim 1 wherein said removal of solvent from said suspension is by dilution-extraction precipitation whereby said dispersed first phase solvent is removed from said agent-polymer.

11. The method according to claim 1 wherein said agent-polymer solvent dispersed first phase is maintained at a temperature ranging between about 10°

to 20°

C. during said dispersing step.

12. A spherical microporous polymeric network containing a pore incorporated agent therein obtained according to the method of claim 1.

13. A method for preparing a relatively homogenous essentially spherical microporous polymeric network of interconnecting channels containing a pore incorporated agent confined essentially completely inside the channels comprising preparing an agentpolymer-solvent dispersed first phase in which the concentration of said polymer ranges between about 2.5 percent to 18 percent w/w, and said agent-polymer ratio ranges between about 1:

1 to 1;

10, dispersing said first phase in a continuous solvent second first phase by pressure forcing said first phase through a droplet forming orifice nozzle to obtain a suspension, removing solvent from suspension by freeze drying or dilution-extraction-precipitation, and recovering said microporous polymeric network.

14. The method for preparing a relatively homogenous essentially spherical microporous polymeric network of interconnecting channels containing a pore incorporated agent therein comprising preparing an agent-polymer-solvent dispersed first phase, dispersing said first phase in a continuous solvent second phase to obtain a suspension, removing dispersed first phase solvent from said suspension, and recovering said microporous polymeric network, wherein said removal of solvent from said suspension is by freeze drying of said suspension by a two step freezing procedure to effect separate freezing of first dispersed phase solvent and second continuous phase solvent followed by a two step drying procedure whereby the solvent in both said first and second phases are removed separately allowing recovery of said spherical microporous polymeric network of interconnecting channels.

15. A drug delivery system comprising a spherical microporous polymeric network of interconnecting channels containing a drug wherein said drug is distributed essentially within the channels of said microporous polymeric network.

16. The drug delivery system according to claim 15 wherein said spherical microporous polymeric network is selected from the group consisting of gelatin, agar, starch, arabinogalactan, albumin, collagen, polyglycolic acid, polylactic acid, glycolide-L(-)lactide copolymer poly(ε

-caprolactone), poly(ε

-caprolactone-CO-lactic acid), poly(ε

-caprolactone-CO-glycolic acid), poly(ε

-hydroxy butyric acid), polyethylene oxide, polyethylene, poly(alkyl-2-cyanoacrylate), poly(hydroxyethyl methacrylate), polyamides, poly(amino acids), poly(2-hydroxyethyl DL-aspartamide), poly(ester urea), poly(L-phenylalanine/ethylene glycol/1,6-diisoyanatohexane) and poly(methyl methacrylate).

17. The drug delivery system according to claim 15 or 16 wherein said polymer comprises a polyester polymer of polyglycolic acid or polylactic acid or a co-polymer of glycolide and L(-)lactide.

18. The drug delivery system according to claim 17 wherein said polymer is biodegradable.

19. The drug delivery system according to claim 17 wherein said system is suitable for parenteral administration to a human host in need thereof.

20. The drug delivery system according to claim 15 wherein said spherical microporous polymeric network comprises microspheres between about 0.5 to 150 microns in diameter.

21. The microspheres according to claim 20 wherein said diameter ranges between 0.5 to 50 microns.

22. The drug delivery system according to claim 15 wherein said system comprises a sustained release system for the rate controlled release of drug to a specific target site.

23. The drug delivery system according to claim 15 wherein said spherical microporous polymeric network has a degree of porosity of between about 80 to 98 percent as determined by relative void space in relation to the starting concentration of polymer.

24. The drug delivery system according to claim 15 further comprising a coating on said spherical microporous polymeric network capable of promoting targeting of said drug containing microporous polymeric structure to targeted cells or organ systems whereby said drug upon release from said drug delivery system acts predominantly upon the targeted cells or organ systems.

25. The drug delivery system according to claim 24 wherein said coating is comprised of agents selected from the group consisting of proteins, surfactants, antibodies and host receptor site specific drugs.