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Sunitinib formulations and methods for use thereof in treatment of ocular disorders

a technology of sunitinib and ocular disorders, which is applied in the direction of capsule delivery, drug composition, nervous disorder, etc., can solve the problems of tumor shrinkage, tumor vascularization and cancer cell death reduction, etc., and achieve the effect of preventing optic nerve damag

Inactive Publication Date: 2017-09-28
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes methods for increasing the ability of a drug called sunitinib to be released from polymer matrices over time. This can be useful in treating cancer, inhibiting the growth of new blood vessels in the eye, and other diseases. The methods involve dissolving the drug in an organic solvent and mixing it with a polymer solution, which is then mixed with an aqueous solution to form microparticles. These microparticles can be used to treat diseases like corneal neovascularization and optic nerve damage. The patent also discusses the use of specific polymers and additives to improve drug loading and sustained release.

Problems solved by technology

The simultaneous inhibition of these targets leads to both reduced tumor vascularization and cancer cell death, and, ultimately, tumor shrinkage.
This has proven difficult, however, due to poor solubility of the drug in pharmaceutical excipients, limiting drug loading, and leading to instability.

Method used

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  • Sunitinib formulations and methods for use thereof in treatment of ocular disorders
  • Sunitinib formulations and methods for use thereof in treatment of ocular disorders
  • Sunitinib formulations and methods for use thereof in treatment of ocular disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

Effects of Surfactants, the Form of Sunitinib, and the Overall Alkalinity on the Drug Loading And In Vitro Release Profiles of Microparticles (Mps)

[0205]Materials and Methods

[0206]Materials—Two Forms of Sunitinib

[0207]Two forms of sunitinib were used, i.e., sunitinib malmate and sunitinib free base, both acquired from LC Lab (Woburn, Mass., USA).

[0208]Poly (D, L-lactic-co-glycolic acid (PLGA, 50:50), 2A was acquired from Alkermes, Waltham, Mass., US; poly (D, L-lactic-co-glycolic acid (PLGA, 50:50), 2A from Lakeshore Biomaterials, Birmingham, Ala., US; poly (D, L-lactic-co-glycolic acid (PLGA, 50:50), 4A from Lakeshore, Biomaterials, Birmingham, Ala., US; poly (D, L-lactic-co-glycolic acid (PLGA, 75:25), PURASORB PDLG 7502A from PURAC, Netherlands; polyethylene glycol-Poly (D, L-lactic-co-glycolic acid), PEG-PLGA (5K, 45K), PEG 10%, PLGA 50:50, from Jinan Daigang Biomaterials Co, Ltd., Jinan, Shandong, China and purified by dissolved in chloroform and precipitated in ether. PLA, pol...

example 2

Preparation and in Vitro Release Profiles of Nanoparticles (NPs) Encapsulating Sunitinib

[0250]Materials and Methods

[0251]Formulation IDs

[0252]For ease of identification, nanoparticles prepared in an aqueous phase containing 1% of PVA in PBS (pH 7.4) according to different formulations were each given an ID, e.g. NP-n (n is a number from 21 to 27).[0253]NP-21: 100 mg PLGA (2A, Lakeshore biomaterials) was dissolved in 1 mL methylene chloride. 20mg sunitinib malmate was added in 250 μl DMSO and then poured into 1% PVA. 5 mL was sonicated 3 mins and poured into 80 mL 0.1% PVA, stirred for 2 hours, particles collected, washed with double distilled water, and freeze dried.[0254]NP-22: 100 mg PLGA (2A, Lakeshore biomaterials) was dissolved in 1 mL methylene chloride. 20 mg sunitinib malmate was added in 250 μl DMSO and then poured into 1% PVA in PBS(7.4). 5 mL was sonicated for 3 mins and poured into 80 mL 0.1% PVA, stirred for 2 hours, particles collected, washed with double distilled wat...

example 3

Effect of Aqueous Ph on Encapsulation Efficiency of Sunitinib

[0261]Materials and Methods

[0262]Polymer microparticles of PLGA and / or a diblock copolymer of PLGA and PEG covalently conjugated to PLGA (Mw 45 kDa) (PLGA45k-PEG5k) with or without sunitinib malate were prepared using a single emulsion solvent evaporation method. Briefly, PLGA and / or PLGA-PEG were first dissolved in dichloromethane (DCM) and sunitinib malate was dissolved in dimethyl sulfoxide (DMSO) at predetermined concentrations. The polymer solution and the drug solution were mixed to form a homogeneous solution (organic phase). The organic phase was added to an aqueous solution of 1% polyvinyl alcohol (PVA) (Polysciences, Mw 25 kDa, 88% hydroplyzed) and homogenized at 5,000 rpm for 1 min using an L5M-A laboratory mixer (Silverson Machines Inc., East Longmeadow, MA) to obtain an emulsion.

[0263]The solvent-laden microparticles in the emulsion were then hardened by stirring at room temperature for >2 hr to allow the DCM ...

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Abstract

Methods for increasing the encapsulation or incorporation of Sunitinib into polymeric matrices have been developed. The resulting formulations provide for more sustained controlled release of sunitinib or its analog or a pharmaceutically acceptable salt thereof. Increased loading is achieved using an alkaline solvent system. The pharmaceutical compositions can be administered to treat or prevent a disease or disorder in or on the eye of a patient associated with vascularization, such as corneal neovascularization and acute macular degeneration. Upon administration, the sunitinib or its analog or salt is released over an extended period of time at concentrations which are high enough to produce therapeutic benefit, but low enough to avoid unacceptable levels of cytotoxicity.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to and benefit of U.S. Provisional Application No. 62 / 092,118 “Controlled Release Sunitinib Formulations” filed on Dec. 15, 2014, and U.S. Provisional Application No. 62 / 139,306 “Method Of Prevention Of Corneal Neovascularization” filed Mar. 27, 2015, the disclosures of which are hereby incorporated herein by reference in their entirety.FIELD OF THE INVENTION[0002]The present invention relates to formulations of sunitinib and its analogs and pharmaceutically acceptable salts and methods of use thereof, especially for use in the treatment of ocular diseases and disorders.BACKGROUND OF THE INVENTION[0003]Sunitinib (marketed in the form of the (−)-malic acid salt as SUTENT® by Pfizer, and previously known as SU11248) is an oral, small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointes...

Claims

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Application Information

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IPC IPC(8): A61K9/00A61K9/16A61K31/404
CPCA61K9/0051A61K9/1647A61K31/404A61K9/1694A61K9/19A61K9/0002A61K9/1635A61K9/1641A61K9/1652A61K45/00A61K31/506A61P25/00A61P25/02A61P27/02A61P27/06A61P43/00A61K9/00A61K9/16A61K9/5153A61K9/5192
Inventor FU, JIEHANES, JUSTINKAYS, JOSHUAYU, YUNYANG, MINGCLELAND, JEFFREYSTARK, WALTERXU, QINGGUOYANG, JIN
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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