Dehydrated hydrogel inclusion complex

Patent metadata

Field	Value
Publication number	US-10149912-B2
Application number	US-201615295630-A
Country	US
Kind code	B2
Filing date	Oct 17, 2016
Priority date	Jun 3, 2008
Publication date	Dec 11, 2018
Grant date	Dec 11, 2018

Abstract

The invention provides a controlled release biodegradable polymer formulation adapted for administering bioactive agents, such as therapeutic proteins, to a patient through implantation of a bolus that forms a depot within the patient's body tissues. The formulation includes a dehydrated inclusion complex of the bioactive agent within a hydrogel. A method of forming the inventive formulation is also provided, as well as a method for using the formulation in the treatment of a malcondition in a patient in need thereof.

First claim

What is claimed is:

1. A method of treating a malcondition in a patient in need thereof, the method comprising administering by injection a therapeutically effective amount of a formulation to the patient to treat the malcondition; wherein the formulation comprises a dehydrated inclusion complex dispersed in a solution, wherein the dehydrated inclusion complex comprises a bioactive agent stabilized within a hydrogel, wherein the hydrogel comprises a polyalkyleneglycol diacrylate, and wherein the solution comprises (i) a poly(lactide-glycolide) copolymer, and (ii) N-methylpyrrolidone, dimethylacetamide, dimethylformamide, dimethylsulfoxide, a polyethyleneglycol, or a combination of two or more thereof.

2. The method of claim 1 , wherein the bioactive agent is a protein or a compound having a molecular weight of about 1,000 Daltons or less.

3. A kit comprising:
(i) a first container comprising (i) a poly(lactide-glycolide) copolymer, and (ii) N-methylpyrrolidone, dimethylacetamide, dimethylformamide, dimethylsulfoxide, a polyethyleneglycol, or a combination of two or more thereof;
(ii) a second container comprising a dehydrated inclusion complex which comprises a bioactive agent within a hydrogel, wherein the hydrogel comprises a polyalkyleneglycol diacrylate; and
(iii) instructions for use.

4. The kit of claim 3 , wherein the first container is a syringe; and wherein the second container is syringe.

5. The kit of claim 3 , wherein the bioactive agent is a protein or a compound having a molecular weight of about 1,000 Daltons or less.

6. The kit of claim 3 , wherein the polyalkyleneglycol diacrylate is a polyalkyleneglycolyl dimethacrylate.

7. The kit of claim 3 , wherein the first container comprises the poly(lactide-glycolide) copolymer and N-methylpyrrolidone.

8. A process for preparing an injectable formulation, the process comprising the steps of:
(i) contacting a bioactive agent and a hydrogel comprising a polyalkyleneglycol diacrylate in an aqueous medium to form a hydrated inclusion complex;
(ii) dehydrating the hydrated inclusion complex to form a dehydrated inclusion complex;
(iii) dispersing the dehydrated inclusion complex in a solution comprising (i) a poly(lactide-glycolide) copolymer, and (ii) N-methylpyrrolidone, dimethylacetamide, dimethylformamide, dimethylsulfoxide, a polyethyleneglycol, or a combination of two or more thereof; thereby forming the formulation.

9. The process of claim 8 , wherein step (i) comprises the steps of:
(a) providing a dehydrated hydrogel;
(b) hydrating the dehydrated hydrogel in the aqueous medium;
(c) adding the bioactive agent to the aqueous medium, thereby contacting the bioactive agent and the hydrogel in the aqueous medium to form the hydrated inclusion complex.

10. The process of claim 8 , wherein the polyalkyleneglycol diacrylate is polyethyleneglycolyl dimethacrylate.

11. The process of claim 8 , wherein the hydrogel further comprises hyaluronic acid, chitosan, agarose, polyvinylacetate, polyvinylpyrrolide, or polyvinyl alcohol nanoparticles.

12. The process of claim 8 , wherein the solution comprises the poly(lactide-glycolide) copolymer and N-methylpyrrolidone.

13. The process of claim 8 , wherein step (i) comprises the step of:
(a) polymerizing the polyalkylenglycolyl diacrylate or copolymerizing the polyalkylenglycolyl diacrylate and a polyalkylenglycolyl monoacrylate in a first aqueous medium, thereby forming a hydrogel
(b) optionally dehydrating the hydrogel; and
(c) contacting the hydrogel with the bioactive agent in a second aqueous medium to form the hydrated inclusion complex.

14. The process of claim 13 , wherein the step of polymerizing is initiated by ultraviolet light.

15. The process of claim 13 , wherein the first aqueous medium comprises an initiator.

16. The process of claim 13 , wherein step (b) comprises dehydrating the hydrogel by lyophilization.

17. The method of claim 1 , wherein the polyalkyleneglycol diacrylate has a molecular weight of about 500 Daltons to about 10,000 Daltons.

18. The method of claim 1 , wherein the polyalkyleneglycol diacrylate is polyethyleneglycolyl dimethacrylate.

19. The method of claim 1 , wherein the solution comprises a poly(lactide-glycolide) copolymer and N-methylpyrrolidone.

20. The method of claim 1 , wherein the dehydrated inclusion complex is present in a concentration of about 5 wt % to about 50 wt %.

Assignees

• Indivior Uk Ltd

Inventors

• Dadey Eric
• Watkins Andrew

Classifications

• A61K47/34

  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 title

• A61K47/58 Primary

  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 title

• A61K9/0024 Primary

  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 title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61J1/2096

  Combination of a vial and a syringe for transferring or mixing their contents · CPC title