Drug delivery from rapid gelling polymer composition

• US 9,326,934 B2
• Filed: 05/01/2012
• Issued: 05/03/2016
• Est. Priority Date: 12/30/2002
• Status: Expired due to Fees

• Current Assignee: Angiotech Pharmaceuticals Incorporated
• Original Assignee: Angiotech Pharmaceuticals Incorporated
• Inventors: Gravett, David M., Takacs-Cox, Aniko, Toleikis, Philip M., Maiti, Arpita, Embree, Leanne
• Primary Examiner(s): ROGERS, JAMES WILLIAM
• Application Number:
  US13/461,424
• Publication Number:
  US 20120252905A1
• Time in Patent Office: 1,463 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/54 having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
• 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 47/6903 the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
• CPC Class Codes: A61K 51/1213 Semi-solid forms, gels, hydrogels, ointments, fats and waxes that are solid at room temperature
• 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 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61L 2300/434 of enzymes
• CPC Class Codes: A61L 31/041 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C08L 71/02 Polyalkylene oxides
• CPC Class Codes: C08L 89/06 derived from leather or skin , e.g. gelatin

Abstract

Compositions are disclosed that afford drug delivery from two-part polymer compositions that rapidly form covalent linkages when mixed together. Such compositions are particularly well suited for use in a variety of tissue related applications when rapid adhesion to the tissue and gel formation is desired along with drug delivery. For example, the compositions are useful as tissue sealants, in promoting hemostasis, in effecting tissue adhesion, in providing tissue augmentation, and in the prevention of surgical adhesions.

Claims

1. A drug-delivery system comprising:

a first container comprising a first component consisting of a sulfhydryl group-containing compound of formula;

Compound₁-(SH)_m wherein m≧

3, the first container further comprising a hydrophobic drug in a micelle, where the micelle is formed from a sulfhydryl group-containing thiol compound and an A-B block copolymer where A is a poly(alkylene oxide) and B is a degradable polyester; and

a second container comprising a second component consisting of a sulfhydryl reactive group-containing compound of formula;

Compound₂-Y_n, wherein Y is a sulfhydryl reactive acrylate group and wherein n≧

3;

wherein each of Compound₁ and Compound₂ is a multi-arm polymer comprising polyalkylene oxide;

wherein a biocompatible gel forms in less than one minute after contact between the contents of the first container and the contents of the second container, the gel comprising covalent bonds formed between the sulfhydryl reactive groups of the second component and the sulfhydryl groups of each of the first component and the thiol compound; and

wherein the hydrophobic drug is admixed in the biocompatible gel.

2. The drug-delivery system of claim 1, wherein m and n are each 4 or 12.

3. The drug-delivery system of claim 1, wherein the polyalkylene oxide is polyethylene glycol.

4. The drug-delivery system of claim 1 wherein the first component is in a liquid medium having an alkaline pH and the second component is in powder form or a liquid medium having a neutral or acidic pH.

5. The drug-delivery system of claim 1 wherein the hydrophobic drug is a cell cycle inhibitor.

6. A method for forming a drug-loaded biocompatible gel in situ, comprising:

providing a first container comprising a first component consisting of a sulfhydryl group-containing compound of formula;

Compound₁-(SH)_m in a liquid medium having an alkaline pH, wherein m≧

3, where the first container further comprises a hydrophobic drug in a micelle, where the micelle is formed from a sulfhydryl group-containing thiol compound and an A-B block copolymer where A is a poly(alkylene oxide) and B is a degradable polyester;

providing a second container comprising a second component consisting of a sulfhydryl reactive acrylate group-containing compound of formula;

Compound₂-Y_n in powder form or a liquid medium having a neutral or acidic pH, wherein Y is a sulfhydryl reactive acrylate group and wherein n≧

3;

wherein each of Compound1 and Compound2 is a multi-arm polymer comprising polyalkylene oxide; and

combining the contents of the first container and the second container to form a gel incorporating the hydrophobic drug, wherein the sulfhydryl groups of each of the first component and the thiol compound react with the sulfhydryl reactive acrylate groups of the second component to form covalent bonds there between.

7. The method of claim 6, wherein m and n are each 4 or 12.

8. The method of claim 6 wherein the hydrophobic drug is a cell cycle inhibitor.

9. A method for forming a drug-loaded biocompatible gel in situ, comprising:

providing a powdered mixture of a sulfhydryl group-containing compound of formula;

Compound₁-(SH)_m, wherein m≧

3, a sulfhydryl reactive group-containing compound of formula;

Compound₂-Y_n, wherein Y is a sulfhydryl reactive acrylate group and wherein n≧

3, and wherein each of Compound1 and Compound2 is a multi-arm polymer comprising polyalkylene oxide;

and a hydrophobic drug in a micelle;

providing a first buffer having an acidic pH;

providing a second buffer having an alkaline pH;

combining the powdered mixture with the first buffer to obtain a solution;

combining the solution of the powdered mixture with the second buffer to form a gel incorporating the hydrophobic drug in a micelle, where the micelle is formed from a sulfhydryl group-containing thiol compound and an A-B block copolymer where A is a poly(alkylene oxide) and B is a degradable polyester, and wherein the sulfhydryl groups react with the sulfhydryl reactive groups to form covalent bonds there between.

10. The method of claim 9, wherein m and n are each 4 or 12.

11. The method of claim 9, wherein the hydrophobic drug is a cell cycle inhibitor.