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| Glucaric acid monoamides and their use to prepare poly(glucaramides) |
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"Burst-free" sustained release poly-(lactide/glycolide) microspheres
| Details |
Inventors: Jevanthi, Ramasubbu; Van Hamont, John E.; Friden, Phil; Reid, Robert H.; Roberts, F. Donald; McQueen, Charles E.; Setterstrom, Jean A.;
Assignee: The United States of America as represented by the Secretary of the Army (Washington, DC)
Primary Examiner: Page; Thurman K.
Assistant Examiner: Tran; S.
Attorney, Agent or Firm: Arwine; Elizabeth
Novel burst-free, sustained release biocompatible and biodegrable microcapsules which can be programmed to release their active core for variable durations ranging from 1-100 days in an aqueous physiological environment. The microcapsules are comprised of a core of polypeptide or other biologically active agent encapsulated in a matrix of poly(lactide/glycolide) copolymer as a blend of uncapped (free carboxyl end group) and end-capped forms ranging in ratios from 100/0 to 1/99. |
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DETAILED DESCRIPTION OF THE INVENTION This invention relates to the design of biocompatible and biodegradable microspheres for novel, programmable sustained release of biologically active agents, including polypeptides over a period of up to 100 days in an aqueous physiological environment with little or no burst release.
Unlike currently available release systems which rely on the use of fillers/additives such as gelatin, albumin, dextran, pectin, polyvinyl pyrrolidone, polyethylene glycol, sugars, etc.
, and are still prone to low encapsulation efficiencies and "burst effects", this invention achieves high encapsulation efficiency and 'burst-free' release without the use of any additive.
In this invention, burst-free, programmable sustained release is achieved through the use of a unique blend of the 'uncapped' and end-capped forms of poly (lactide/glycolide) polymer.
The 'uncapped' form refers to "poly(lactide/glycolide) with free carboxyl end groups" which renders the polymer more hydrophilic compared to the routinely used end-capped form.
Currently used 'end-capped' polymer hydrates between 4-12 weeks depending on the molecular weight, resulting in an intermediate 'no release' or a 'lag phase'.
The uncapped polymer hydrates typically between 5 to 60 days depending on the molecular weight, thus releasing its core continuously without a lag phase.
A careful blend of the two forms and appropriate molecular weights and L/G ratios, results in a continuous release between 1 to 100 days.
In addition, release within this time is programmable by a judicious selection of process parameters such as polymer concentration, peptide concentration and the aqueous/oil phase ratio.
The copolymer in this invention includes molecular weight ranging from 2,000 to 60,000 daltons, a lactide/glycolide ratio of 90/10 to 40/60 and a blend of the uncapped/capped forms in the ratio of 100/0 to 1/99.
The molecular weight of the polypeptide may be in the range of 1000 to 250,000 daltons while that of other biologically active agents may range from 100 to 100,000 daltons
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Gene Therapy 
