Hydrophobic core carrier compositions for delivery of therapeutic agents, methods of making and using the same

a carrier composition and hydrophobic technology, applied in the direction of antimycotics, depsipeptides, peptide/protein ingredients, etc., can solve the problems of inability to meet the needs of outpatients requiring high levels of mobility, short biological half-lives of peptides and proteins with low molecular mass, and associated disadvantages of quality of life and potential intravenous administration, so as to achieve the effect of being easily adjusted

Inactive Publication Date: 2007-06-21
PHARMAIN CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009] It is an object of the present invention to provide a sustained release therapeutic agent delivery system that is safe, biocompatible, readily prepared from known chemistries and compounds, amenable to a wide variety of therapeutic agents, and where the release rate can be readily adjusted by simple mechanisms of altering physical characteristics of the delivery system.
[0010] It is a further object of the present invention that the sustained release delivery system includes a targeting moiety for efficient delivery of the therapeutic agent to a site in need thereof.
[0011] It is another object of the present invention to provide a method of treating a disorder by delivering a therapeutic agent to a patient in need thereof in a controlled manner and at a release rate that is safe and effective and readily adjusted to be so.

Problems solved by technology

In addition, peptides and proteins that have low molecular masses tend to have short biological half-lives due to their efficient removal from systemic circulation via kidneys.
This strategy is proven efficient in clinical practice but may be impractical for outpatients requiring high levels of mobility, associated disadvantages of quality of life and potential intravenous (I.V.) line infections.
Due to limited volume of these capsules, peptides and proteins are often used in a concentrated formulation which leads to a loss of solubility due to aggregation and potential loss of specific activity.
However, Bogdanov et al. does not disclose a therapeutic agent delivery composition that works for a wide variety of therapeutic agents and has a means of adjusting the release rates.

Method used

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  • Hydrophobic core carrier compositions for delivery of therapeutic agents, methods of making and using the same
  • Hydrophobic core carrier compositions for delivery of therapeutic agents, methods of making and using the same
  • Hydrophobic core carrier compositions for delivery of therapeutic agents, methods of making and using the same

Examples

Experimental program
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Effect test

example 1

Preparation of N-Hydoxysuccinamide Esters of Fatty Acids and Aromatic-Alkyl Carboxylic Acids

[0404] The N-hydoxysuccinamide esters of fatty and aromatic-alkyl carboxylic acids will facilitate the synthesis of hydrophobic-core carriers of the present invention since these esters react readily with amino groups along the carrier. The following method was taken from Lapidot et al. [Lapidot, Y., Rappoport, S. and Wolman, Y. (1967) J. Lipid Res., 8, 142]: (i) prepare a 230 mM solution of N-hydroxysuccinimide by dissolving 3.45 g (30 nmol) in 30 ml of ethyl acetate dried over molecular sieve pellets in a stoppered 250-ml glass conical flask; (ii) to the above solution add 30 nmol of desired fatty acid; (iii) prepare a solution containing 30 mmol (6.18 g of dicyclohexyl carbodiimide in 10 ml ethyl acetate, and add it to the solution of fatty acid; (iv) allow the reaction to proceed overnight at room temperature; (v) remove the precipitated dicyclohexyl urea by filtration using a suction t...

example 2

[0406] Synthesis of MPEG-poly-L-lysine (5000; 40.000; 73%) (PLPEG-I) The reagents, MPEG-succinimdyl-succinate and polylysine, are commercially available and their syntheses are well known in the art. Poly-L-lysine (200 mg; Polylysine Hydrobromide; Sigma chemical Co.; DPvis: 264; MWvis: 55,200; DPmalls: 190; MWmalls: 39,800; 0.7 mmoles aminogroup by TNBS assay Sparado et al. Anal Biochem 96:317, 1979) was dissolved in 10 ml of 0.1 M carbonate buffer pH 8.35 and 1150 mg of MPEG-succinimdyl-succinate was added, vortexed, and incubated overnight at room temperature. The next day, aliquots were taken and the amount of amino groups remaining was quantified using trinitrobenzenesulfonic acid (Sparado et al. Anal Biochem 96:317, 1979). The result indicated that 73% of amino group had been conjugated to MPEG. To cap the carboxyl terminal of polylysine that can potentially interfere with the next reaction (addition of hydrophobic group), 600 ul of ethylenediamine and 100 mg EDC was added mixe...

example 3

[0407] Synthesis of MPEG-poly-L-lysine (5000;40,000;55%)(PLPEG-II) The reagents, MPEG-succinimdyl-succinate and polylysine, are commercially available and their syntheses are well known in the art. Poly-L-lysine (200 mg; Polylysine Hydrobromide; Sigma chemical Co.; DPvis: 264; MWvis: 55,200; DPmalls: 190; MWmalls: 39,800; 0.7 mmoles aminogroup by TNBS assay Sparado et al. Anal Biochem 96:317, 1979) was dissolved in 10 ml of 0.1 M carbonate buffer pH 8.35 and 900 mg of MPEG-succinimdyl-succinate was added, vortexed, and incubated overnight at room temperature. The next day, aliquots were taken and the amount of amino groups remaining was quantified using trinitrobenzenesulfonic acid (Sparado et al. Anal Biochem 96:317, 1979). The result indicated that 55% of the amino groups had been conjugated to MPEG. To cap the carboxyl terminal of polylysine that can potentially interfere with the next reaction (addition of hydrophobic group), 600 ul of ethylenediamine and 100 mg EDC was added mi...

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Abstract

The present invention relates, in part, to a biocompatible hydrophobic-core carrier comprising a carrier, and a plurality of hydrophobic groups covalently linked to the polymeric carrier. The hydrophobic groups are capable of dissociably linking load molecules such as therapeutic agents. The hydrophobic-core carrier may also comprise protective side chains, orienting molecules, and targeting molecules.

Description

RELATED APPLICATION INFORMATION [0001] This application claims the benefit of priority under 35 U.S.C. section 119(e) to U.S. Provisional Application 60 / 813,629 that resulted from the conversion of U.S. patent application Ser. No. 11 / 311,895 filed Dec. 19, 2005.GOVERNMENTAL LICENSE RIGHTS [0002] Work described herein was made with government support under 5 R43 DK069727-01 awarded by the National Institute on Aging. The U.S. Government may have certain rights in subject matter provided herein.BACKGROUND OF THE INVENTION [0003] The development of new drugs, formulations and other systems for administration of physiologically active peptides, proteins, organic drugs, other therapeutics and materials is driven by the need to achieve the desirable physiological effects. With respect to peptides and proteins, many of them have been observed to be unstable in the gastro-intestinal tract and therefore may need to be stabilized or protected or delivered via systemic circulation. In addition...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/48A61K39/395A61K38/22A61K38/23A61K38/24A61K38/25A61K38/26A61K38/27A61K31/4439A61K31/355A61K31/375A61K9/20
CPCA61K38/1808A61K38/1841A61K38/2207A61K31/4439A61K47/48215A61K47/48315A61K47/488A61K38/26A61K47/60A61K47/645A61K47/6907A61P1/00A61P3/10A61P5/00A61P5/06A61P5/18A61P5/24A61P5/30A61P5/50A61P7/04A61P31/04A61P31/12A61P35/00A61P37/04A61P43/00A61K9/20A61K38/22A61K47/32
Inventor CASTILLO, GERARDO M.BOLOTIN, ELIJAH M.
Owner PHARMAIN CORP
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