Methods and compositions for enhanced delivery of bioactive molecules

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

RELATED APPLICATIONS[0001]This application is a Continuation application of U.S. patent application Ser. No. 10 / 766,106, filed Jan. 27, 2004, which is a Continuation application of U.S. patent application Ser. No. 09 / 999,820 filed on Oct. 31, 2001 and claims priority to U.S. Provisional Application No. 60 / 244,499 entitled “Methods and Compositions for Enhanced Delivery of Bioactive Molecules” filed on Oct. 31, 2000, the contents of which are incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]Encapsulation of pharmaceuticals in biodegradable polymer microspheres and nanospheres can prolong the maintenance of therapeutic drug levels relative to administration of the drug itself. Sustained release may be extended up to several months depending on the formulation and the active molecule encapsulated. However many bioactive molecules, and especially proteins, are damaged or made unstable by the procedures required to encapsulate them in the polymeric carriers. Furthermore,...

AI Technical Summary

Benefits of technology

"The present invention provides novel formulations for controlled, prolonged release of bioactive molecules such as therapeutic proteins, peptides, and oligonucleotides. The formulations are based on microparticles or nanoparticles made of biodegradable polymers such as poly(lactic acid) and poly(glycolic acid). The bioactive molecules are attached to hydrophilic polymers such as poly(ethylene glycol) or polypropylene glycol and then formulated with the solid microparticles or nanoparticles. The controlled release formulations can be administered by injection, inhalation, nasally, or orally. The invention also provides the advantage of reduced immunogenicity, increased bioavailability, increased duration, increased stability, decreased burst, and controlled, sustained release of bioactive molecules in vivo."

Problems solved by technology

However many bioactive molecules, and especially proteins, are damaged or made unstable by the procedures required to encapsulate them in the polymeric carriers.

Furthermore, the charged, polar nature of many proteins may limit the extent of encapsulation in polymer drug carriers and may lead to rapid loss of a fraction of the encapsulated bioactive molecule when first administered (“burst”).

While this is a desired result in certain cases, it is undesirable when the purpose is delivery of the bioactive molecule for therapeutic purposes.

While it is known in the art that such attachment may lead to an apparent increase in molecular mass and decreased blood clearance rate for the modified therapeutic protein (see e.g., U.S. Pat. No. 5,320,840 to Camble et al.

), the prior art does not teach that diminished immunogenicity can be achieved or that the duration of release from biodegradable polymer drug delivery systems can be extended using pegylated proteins.