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Method and compositions for enhanced delivery of bioactive molecules

A bioactive molecule and composition technology, applied in the direction of drug combination, non-active ingredient medical preparations, medical preparations containing active ingredients, etc., can solve the problem of reducing drug burst release, increasing drug loading, prolonging duration, etc. problem, to achieve the effect of reducing burst release and controlling, increasing bioavailability, and increasing duration

Inactive Publication Date: 2004-06-23
PR药品有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While it is well known in the art that such linkages can result in a significant increase in molecular weight and can reduce blood clearance of the modified therapeutic protein (see, for example, Camble et al., U.S. Pat. No. 5,320,840), the prior art does not teach the use of pegylated Proteins that reduce immunogenicity or extend the duration of release from biodegradable polymeric drug delivery systems
The prior art does not demonstrate that PEGylated drugs increase the achievable loading of drugs in biodegradable drug delivery systems relative to non-PEGylated drugs, nor does it demonstrate For drugs, the pegylated moiety reduces burst release of the drug

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Preparation of leu-enkephalin (PEG-leu-enkephalin) conjugated to embodiment 1-polyethylene glycol

[0040] Ieu-enkephalin covalently modified with polyethylene glycol was prepared as follows: 25 mg leu-enkephalin was dissolved in 500 μL of anhydrous DMSO containing 50 μL TEA. 250 mg of mPEG(5000)-SPA was dissolved in 1.5 mL of anhydrous DMSO and added to the peptide solution by direct injection. The reaction was allowed to proceed at room temperature for 2 hours or until >90% of the peptide was converted to its PEG-modified form. The product, mPEG(5000)-leu-enkephalin, was isolated from the reaction by recrystallization (2x) in EtOH. The reaction product was >95% PEGylated white solid (analyzed by RP-HPLC).

Embodiment 2

[0041] Embodiment 2-conventional (w) containing leu-enkephalin 1 / o / w 2 ) Preparation and Characterization of Microparticles

[0042] Conventional w containing leu-enkephalin was prepared as follows 1 / o / w 2 Microparticles: leu-enkephalin was dissolved in a 1:9 DMSO:PBS mixture to a final concentration of 35 mg / mL (its maximum solubility in PBS). PLGA (50:50 lactide:glycolide; acid end groups; intrinsic viscosity 0.16 L / g) was dissolved in dichloromethane to a final concentration of 200 mg / mL. A primary emulsion (w / o) was prepared by homogenizing 200 μL of the peptide solution with 3 mL of the polymer solution at 10,000 rpm for 3 minutes. The primary emulsion was poured into 100 mL of 0.5% PVA solution, and stirred at 750 rpm for 3-6 hours. After the solvent had evaporated and the microparticles had hardened, they were collected by filtration and dried in vacuo before analysis. The particles were characterized by their core loading (CL), encapsulation efficiency (EE), pa...

Embodiment 3

[0044] Example 3 - Conventional (w 1 / o / w 2 ) Preparation and Characterization of Microparticles

[0045] Conventional w containing PEG-leu-enkephalin was prepared as follows 1 / o / w 2 Microparticles: PEG-leu-enkephalin was dissolved in a 1:9 DMSO:PBS mixture to a final concentration of 50 mg / mL. PLGA (50:50 lactide:glycolide; acid end groups; intrinsic viscosity 0.16 L / g) was dissolved in dichloromethane to a final concentration of 200 mg / ml. A primary emulsion (w / o) was prepared by homogenizing 200 [mu]L of peptide solution with 3 ml of polymer solution at 10,000 rpm for 3 minutes. The primary emulsion was poured into 100ml of 0.5% PVA solution, and stirred at 750rpm for 3-6 hours. After the solvent had evaporated and the microparticles had hardened, they were collected by filtration and dried in vacuo before analysis. As described in Example 2, the particles were characterized by core loading (CL), encapsulation efficiency (EE), particle size (PS) and initial release (...

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Abstract

Formulations for controlled, prolonged release of bioactive molecules such as therapeutic proteins, peptides and oligonucleotides have been developed. These formulations are based on solid microparticles or nanoparticles formed of the combination of biodegradable, synthetic polymers such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and copolymers thereof. Bioactive molecules are coupled to hydrophilic polymers such as polyethylene glycol or polypropylene glycol and formulated to provide controlled release. The bioactive molecules are more stable, less immunogenic and have improved release rate profiles with lower burst levels and increased drug loading relative to the same bioactive molecules lacking coupled hydrophilic polymers. The controlled release formulations can be administered by injection, by inhalation, nasally, or orally.

Description

[0001] related application [0002] This application claims priority to US Provisional Application Serial No. 60 / 244,499, filed October 31, 2000, and entitled "Methods and Compositions for Enhanced Delivery of Biologically Active Molecules," the contents of which are incorporated herein by reference. Background of the invention [0003] Encapsulation of drugs with biodegradable polymeric microspheres and nanospheres allows prolonged maintenance of therapeutic drug levels relative to administration of the drug itself. Depending on the dosage form and the active molecule encapsulated, sustained release can be extended up to several months. However, many biologically active molecules, especially proteins, are disrupted or destabilized by the manipulations required to encapsulate them with polymeric carriers. Additionally, the charged, polar nature of many proteins can limit the extent of encapsulation with polymeric drug carriers and can lead to rapid loss of the encapsulated bi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/50A61K9/51A61K38/00A61K47/34A61K47/48A61P25/04
CPCA61K47/4823A61K47/48215A61K47/482A61K47/48876A61K47/60A61K47/593A61K47/61A61K47/6927A61P25/04A61P43/00
Inventor D·路易斯P·施密德特K·欣德斯
Owner PR药品有限公司
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