Controlled Release of Injectable Drugs
Medusa® (PDF file) hydrogel (pGluVE, or PGA A1) is based on a hydrophilic biodegradable polyglutamate chain grafted with hydrophobic Vitamin E. The polymer self assembles in aqueous medium to form a stable solution of nano-sized hydrogels comprising multiple polymer chains and 95% water. The hydrogel is formed by hydrophobic interactions only, no chemical cross linking agent is required.
After subcutaneous injection, a depot is formed at the injection site and the fully active biologic is slowly released in vivo over one to fourteen days in humans.
Medusa hydrogel has been proven to be safe and biodegradable: Flamel Technologies submitted a DMF for Medusa to the FDA on February 12, 2011 (assigned number 024634).
Medusa’s Key Attributes
- Subcutaneous administration and potential for other routes of administration (intra-muscular, intravenous, ocular, intra-joint, intra-thecal, etc.);
- Maintains the full activity of biologics (no protein engineering and/or chemical modifications required, with consequent lack of additional impaired immunogenicity);
- Preserves the structural integrity of peptide/protein antigens for vaccine applications (DeliVax®).
- Non-denaturing formulation and delivery of fully structured and active biologics;
- Fully biocompatible and biodegradable hydrogels: glutamic acid and Vitamin E are Generally Recognized As Safe (GRAS);
- Versatile “Bio friendly” injectable formulation compatible with a wide range of variables:
- size,
- structure,
- physico-chemical properties (hydrophobicity, hydrophilicity, charges contents) and stability (e.g. cytokines, blood factors, hormones, metabolic peptides or proteins , antibodies and fragments thereof, and vaccines)
- Cost effective, easy to implement and scale-up process using mostly water (solvent- and surfactant-free); and
- Strong intellectual property position and Freedom to Operate (no third party licensing obligations).
Medusa-based Products Pipeline
Clinical Trials Results
Medusa-based products have been successfully tested in a number of clinical trials:
- IFN-α XL (PDF file), Flamel Technologies’ long acting human interferon alpha-2b (α-2b) for the treatment of hepatitis C virus infection (HCV), has successfully completed two phase 1 trials and is currently in phase 2 study (in comparison with Pegintron®).
- Intermediate analysis of that study was presented in November 2011 at the AASLD’s “Liver Meeting” in San Francisco: improved safety profile of IFN-α XL versus PegIntron during a 3-month course of combined therapy with weight-based ribavirin was confirmed.
- Abstracts “Interim report on safety and efficacy of a new sustained release IFN as compared to standard of care” and “Aggregate report on safety and efficacy of a new sustained release IFN as compared to standard of care” (Christian Trepo et al.) were presented at the 14th International Symposium on Viral Hepatitis and Liver Disease (ISVHLD) held on June 22 – 25, 2012 in Shanghai;
- FT-105 (PDF file), Flamel Technologies’ long acting basal human insulin for the treatment of type I and II diabetes, has successfully completed a phase 1 study (in comparison with Lantus®);and,
- IL-2 XL (PDF file), Flamel Technologies’ long-acting human interleukin-2 for the treatment of renal cell carcinoma, for which proof-of-concept has been obtained in a phase 1/2 study (in comparison with Proleukin®).
Other Medusa-based products are at preclinical stage, including:
-
hGH XL (PDF file), a long-acting human growth hormone (hGH) for the treatment of growth disorders (proof-of-concept obtained in animal model); and,
-
GLP-1 XL, long-acting human Glucagon-like peptide-1 analog for the treatment of type II diabetes (proof-of-concept obtained in animal model).
Publications
Chan Y.-P., Meyrueix R., Rivail C. and Chatellier J. (2011) ONdrugDELIVERY “Injectable Drug Delivery 2011: Formulation Focus”
Issue August 2011: 4-6.
Review on Medusa®: a polymer-based sustained release technology for protein and peptide drugs
Chan Y-P., Meyrueix R., Kravtzoff R., Nicolas F. and Lundstrom K. (2007) Expert Opinion on Drug Delivery 4: 441-451.
The polymer-based Medusa system (Flamel Technologies) has been designed for slow release of therapeutic proteins and peptides. The Medusa II consists of a poly L-glutamate backbone grafted with hydrophobic a-tocopherol molecules, creating a colloidal suspension of nanoparticles (10 – 50 nm) in water. The sustained drug release is based on reversible drug interactions with hydrophobic nanodomains within the nanoparticles. In vivo, it is suggested that the therapeutic protein is displaced by endogenous proteins present in physiological fluids, leading to a slow drug release. The peak concentration is dramatically decreased and the protein release substantially extended. The Medusa technology has been applied to subcutaneous injection for several therapeutic proteins, such as IL-2 and IFN α-2b, in animal models (rats, dogs, monkeys) and clinical trials in renal cancer (IL-2) and hepatitis C (IFN α-2b) patients.