Liquid delivery compositions

• US 5,780,044 A
• Filed: 12/05/1996
• Issued: 07/14/1998
• Est. Priority Date: 04/08/1994
• Status: Expired due to Term

• Current Assignee: Atrix Laboratories, Inc. (TOLMAR Holding, Inc.)
• Original Assignee: Atrix Laboratories, Inc. (TOLMAR Holding, Inc.)
• Inventors: Dunn, Richard L., Tipton, Arthur J., Yewey, Gerald L., Brouwer, Gerbrand, Radomsky, Michael L., Krinick, Nancy L.
• Primary Examiner(s): KISHORE, GOLLAMUDI S
• Application Number:
  US08/761,015
• Time in Patent Office: 586 Days
• Field of Search: 424/422-426, 424/489, 424/450, 525/937, 514/900, 514/58, 604/890.1, 604/891.1, 604/27, 604/48, 604/49, 604/54
• US Class Current: 424/426
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 38/09 Luteinising hormone-releasing hormone [LHRH] , i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61K 47/593 Polyesters, e.g. PLGA or polylactide-co-glycolide
• CPC Class Codes: A61K 47/6903 the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
• CPC Class Codes: A61K 47/6921 the form being a particulate, a powder, an adsorbate, a bead or a sphere
• CPC Class Codes: A61K 49/0017 Fluorescence in vivo
• CPC Class Codes: A61K 49/0036 Porphyrins used in photodynamic therapy A61K41/0071 or A61K41/0076; used as targeting group or modifying agent for targeting a therapeutic compound A61K47/546
• CPC Class Codes: A61K 49/0054 Macromolecular compounds, i.e. oligomers, polymers, dendrimers
• CPC Class Codes: A61K 49/0063 characterised by a special physical or galenical form, e.g. emulsions, microspheres
• CPC Class Codes: A61K 49/0091 Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/5026 : obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5047 : Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61L 2300/604 : Biodegradation
• CPC Class Codes: A61L 2300/62 : Encapsulated active agents, e.g. emulsified droplets
• CPC Class Codes: A61L 2400/06 : Flowable or injectable implant compositions
• CPC Class Codes: A61L 26/0019 : obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 26/0066 : Medicaments; Biocides
• CPC Class Codes: A61L 26/0085 : Porous materials, e.g. foams or sponges
• CPC Class Codes: A61L 27/18 : obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/56 : Porous materials, e.g. foams or sponges
• CPC Class Codes: A61L 31/06 : obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: A61L 31/146 : Porous materials, e.g. foams or sponges
• CPC Class Codes: A61L 31/16 : Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: C08L 67/04 : Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence
• CPC Class Codes: Y10S 525/937 : Utility as body contact e.g. implant, contact lens or I.U.D.
• CPC Class Codes: Y10S 977/774 : Exhibiting three-dimensional carrier confinement, e.g. quantum dots
• CPC Class Codes: Y10S 977/783 : Organic host/matrix, e.g. lipid
• CPC Class Codes: Y10S 977/906 : Drug delivery
• CPC Class Codes: Y10S 977/907 : Liposome
• CPC Class Codes: Y10S 977/915 : Therapeutic or pharmaceutical composition
• CPC Class Codes: Y10S 977/918 : Immunological

Abstract

Improved biocompatible liquid delivery compositions, which are useful for the formation of sustained release delivery systems for active agents, are provided. The compositions include liquid formulations of a biocompatible polymer or prepolymer in combination with a controlled release component. The controlled release component includes an active agent. These compositions may be introduced into the body of a subject in liquid form which then solidify or cure in situ to form a controlled release implant or a film dressing. The liquid delivery compositions may also be employed ex situ to produce a controlled release implant. Methods of forming a controlled release implant and employing the liquid formulations in the treatment of a subject are also provided.

Claims

1. A delivery composition suitable for in situ formation of a solid implant for controlled release of an active agent, the composition comprising:

(a) a biocompatible organic solvent which has a solubility range of miscible to dispersible in aqueous medium;

(b) a biocompatible, biodegradable, thermoplastic polymer dissolved in the organic solvent, the thermoplastic polymer being insoluble in aqueous medium; and

(c) an active agent incorporated into a particulate controlled release component, the particulate controlled release component being suspended in the organic solvent wherein upon contacting an aqueous medium, the organic solvent dissipates or

disperses into the aqueous medium and the thermoplastic polymer precipitates or coagulates to form the solid implant in which the particulate controlled release component is embedded.

2. The delivery composition of claim 1 wherein the particulate controlled release component includes a conjugate in which the active agent is covalently bonded to a carrier molecule.

3. The delivery composition of claim 1 wherein the particulate controlled release component is a microstructure selected from the group consisting of a microcapsule, a nanoparticle, a cyclodextrin, a liposome and a micelle.

4. The delivery composition of claim 1 wherein the particulate controlled release component is a microstructure of less than about 500 microns.

5. The delivery composition of claim 1 wherein the particulate controlled release component is a macrostructure selected from the group consisting of a fiber, film, rod, disc and cylinder.

6. The delivery composition of claim 1 wherein the particulate controlled release component is a macrostructure of at least 500 microns.

7. The delivery composition of claim 1 wherein the solid implant includes a skin and a core, the skin having pores with a substantially smaller diameter than the core.

8. The delivery composition of claim 7 wherein the skin has a porosity of about 5% to about 10% and the core has a porosity of about 40% to about 60%.

9. The delivery composition of claim 1 wherein the active agent is a bioactive agent.

10. The delivery composition of claim 9 wherein the bioactive agent is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, an antiparasitic agent, an anti-neoplastic agent, an analgesic, an anesthetic, an antipsychotic agent, a vaccine, a central nervous system agent, a growth factor, a hormone, an antihistamine, an osteoinductive agent, a cardiovascular agent, an anti-ulcer agent, a broncliodilating agent, a vasodilating agent, a birth control agent, an antihypertensive agent, an anticoagulant, an antispasmodic agent, and a fertility-enhancing agent.

11. The delivery composition of claim 1 wherein the active agent is a diagnostic agent.

12. The delivery composition of claim 1 further comprising a physiologically acceptable release rate modification agent.

13. The delivery composition of claim 11 wherein the release rate modification agent is selected from the group consisting of an ester of a moncarboxylic acid, ester of a dicarboxylic acid, ester of a tricarboxylic acid, polyhydroxy alcohol, fatty acid, triester of glycerol, sterol, alcohol, and combinations thereof.

14. The delivery composition of claim 1 further comprising a pore forming agent.

15. The delivery composition of claim 14 wherein the pore forming agent is selected from the group consisting of a sugar, a salt, and a water-soluble polymer.