Systems for sustained intraocular delivery of low solubility compounds from a port delivery system implant

• US 9,968,603 B2
• Filed: 03/14/2014
• Issued: 05/15/2018
• Est. Priority Date: 03/14/2013
• Status: Active Grant

• Current Assignee: Forsight Vision4, Inc. (Roche Holding AG)
• Original Assignee: Forsight Vision4, Inc. (Roche Holding AG)
• Inventors: Astafieva, Irina, Horvath, Judit, Farinas, Kathleen Cogan, Bueche, Blaine, Erickson, Signe
• Primary Examiner(s): Su, Susan
• Application Number:
  US14/212,817
• Publication Number:
  US 20140276482A1
• Time in Patent Office: 1,523 Days
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/416 condensed with carbocyclic ring systems, e.g. indazole
• 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 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/40 Cyclodextrins; Derivatives thereof
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00

Abstract

Therapeutic agent delivery formulations for the sustained release of therapeutic agents from a Port Delivery System (PDS) implant is described in this application.

Claims

1. A formulation for controlled release of a therapeutic agent in vitreous of an eye from a therapeutic delivery device having a reservoir chamber coupled to a porous structure, the formulation comprising a solution which comprises:

(i) from about 20 mg/mL to about 100 mg/mL of a low water soluble therapeutic agent, (ii) a cyclodextrin, and (iii) a polysorbate, a block copolymer of ethylene oxide and propylene oxide, a di-block copolymer of polyethylene oxide and polypropylene oxide, a tri-block copolymer of polyethylene oxide and polypropylene oxide, an ethoxylated emulsifier, a polyethylene glycol ester, sucrose laurate, tocopherol-polyethyleneglycol-succinate, a phospholipid, or a combination of two or more thereof;

wherein a ratio of the cyclodextrin to the therapeutic agent is from 1;

1 to 15;

1; and

wherein the therapeutic agent remains in solution in the reservoir chamber upon contact with the vitreous fluid of the eye.

2. A formulation for controlled release of a therapeutic agent in vitreous of an eye from a therapeutic delivery device having a reservoir chamber coupled to a porous structure, the formulation comprising:

(i) from about 20 mg/mL to about 100 mg/mL of a low water soluble therapeutic agent, (ii) and a cyclodextrin, and (iii) a polysorbate, a block copolymer of ethylene oxide and propylene oxide, a di-block copolymer of polyethylene oxide and polypropylene oxide, a tri-block copolymer of polyethylene oxide and polypropylene oxide, an ethoxylated emulsifier, a polyethylene glycol ester, sucrose laurate, tocopherol-polyethyleneglycol-succinate, a phospholipid, or a combination of two or more thereof;

wherein a ratio of the cyclodextrin to the therapeutic agent is from 1;

1 to 15;

1.

3. The formulation of claim 2, wherein the therapeutic agent remains in solution in the reservoir chamber upon contact with the vitreous fluid of the eye.

4. The formulation of claim 2, wherein the therapeutic agent has a solubility in water of less than 1 mg/mL.

5. The formulation of claim 2, comprising from about 20 mg/mL to about 80 mg/mL of the therapeutic agent.

6. The formulation of claim 2, wherein the formulation has a pH from about 7 to about 8.

7. The formulation of claim 2, wherein the cyclodextrin is 2-hydroxypropyl-β

-cyclodextrin, methyl-β

-cyclodextrin, randomly methylated-β

-cyclodextrin, ethylated-β

-cyclodextrin, triacetyl-β

-cyclodextrin, peracetylated-β

-cyclodextrin, carboxymethyl-β

-cyclodextrin, hydroxyethyl-β

-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β

-cyclodextrin, glucosyl-β

-cyclodextrin, maltosyl-β

-cyclodextrin, sulfobutyl ether-β

-cyclodextrin, branched-β

-cyclodextrin, hydroxypropyl-γ

-cyclodextrin, randomly methylated-γ

-cyclodextrin, trimethyl-γ

-cyclodextrin, or a combination of two or more thereof.

8. The formulation of claim 2, wherein the cyclodextrin is a sulfobutyl ether-β

-cyclodextrin.

9. The formulation of claim 8, wherein the sulfobutyl ether-β

-cyclodextrin has six or seven sulfobutyl ether groups per cyclodextrin molecule.

10. The formulation of claim 2, wherein the cyclodextrin is a sodium salt of sulfobutyl ether-β

-cyclodextrin.

11. The formulation of claim 2, wherein the ratio of the cyclodextrin to the therapeutic agent is in the range of 1.7:

1 to 9;

1.

12. The formulation of claim 2, wherein the ratio of the cyclodextrin to therapeutic agent achieves a release rate of about 0.1 μ

g/day to about 25 μ

g/day.

13. The formulation of claim 2, wherein (iii) is the polysorbate.

14. The formulation of claim 2, further comprising a solubilizing agent, a stabilizing agent, a pH adjusting agent, a buffering agent, or a combination of two or more thereof.

15. The formulation of claim 14, wherein the solubilizing agent is trehalose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium hyaluronate, sodium alginate, chitosan and its derivatives, polyethylene glycol, glycerin, propylene glycol, triacetin, N,N-dimethylacetamide, poly(vinyl pyrrolidone), pyrrolidone, dimethyl sulfoxide, ethanol, N-(-beta-hydroxyethyl)-lactamide, 1-methyl-2-pyrrolidinone, a triglyceride, monothioglycerol, sorbitol, lecithin, methylparaben, propylparaben, or a combination of two or more thereof.

16. The formulation of claim 14, wherein the pH adjusting agent is sodium hydroxide, hydrochloric acid, citric acid, malic acid, tartaric acid, acetic acid, phosphoric acid, maleic acid, glycine, sodium lactate, lactic acid, sodium citrate, ascorbic acid, sodium acetate, acetic acid, sodium bicarbonate, sodium carbonate, carbonic acid, sodium succinate, succinic acid, sodium benzoate, benzoic acid, sodium phosphates, tris(hydroxymethyl)aminomethane, histidine, histidine hydrochloride, or a combination of two or more thereof.

17. The formulation of claim 2, further comprising sodium chloride, sodium phosphate, or a combination thereof.

18. The formulation of claim 2, wherein the therapeutic agent is solubilized in the formulation comprising the cyclodextrin before or after placing into the reservoir.

19. The formulation of claim 2, wherein the therapeutic agent is stable from at least 30 days to 6 months when (i) in the reservoir;

(ii) delivered from the therapeutic delivery device at the vitreous;

or (iii) both (i) and (ii).

20. The formulation of claim 2, wherein the therapeutic agent is a tyrosine kinase inhibitor.

21. The formulation of claim 2, wherein the therapeutic agent is sunitinib, pazopanib, linifanib, motesanib, axitinib, sorafenib, or a pharmaceutically acceptable salt of any of the foregoing.

22. A formulation for controlled release of a therapeutic agent in vitreous of an eye from a therapeutic delivery device having a reservoir chamber coupled to a porous structure, the formulation comprising:

(i) from about 1 mg/mL to about 100 mg/mL of a low water soluble therapeutic agent, (ii) a cyclodextrin, and (iii) a polysorbate, a block copolymer of ethylene oxide and propylene oxide, a di-block copolymer of polyethylene oxide and polypropylene oxide, a tri-block copolymer of polyethylene oxide and polypropylene oxide, an ethoxylated emulsifier, a polyethylene glycol ester, sucrose laurate, tocopherol-polyethyleneglycol-succinate, a phospholipid, or a combination of two or more thereof;

wherein a ratio of the cyclodextrin to the therapeutic agent is from 1;

1 to 15;

1; and

wherein the formulation has a pH from about 7 to about 8.