SBIR-STTR Award

Opportunistic infections are widespread in HIV infected and other immunosuppressed individuals. Cochleate cylinders are an innovative and relatively new lipid based delivery system. The long term goals of this research program are to determine the feasibility and technical merit of drug-cochleate formulations to enhance the efficacy of some currently available antimicrobials by increasing therapeutic index and patient compliance. The present application will focus on investigating the properties of Amphotericin B cochleate formulations on the growth of the microorganisms in vitro and in vivo. Achieving efficacious oral delivery for systemic infections is a major emphasis of the present application. The following specific aims will be investigated: I. Formulation development to maximize oral delivery of Amphotericin B. II. Determine the toxicity, pharmacokinetics and biodistribution of AmB- cochleate formulations in vivo. III. Extend the in vivo protection of AmB-cochleates delivered systemically into an Aspergillus/rat model. IV. Investigate the in vivo efficacy of orally delivered AmB cochleates in the Candida/mouse and Aspergillus/rat models. The strategy is to continue and expand on ongoing collaboration among three established investigators with different but overlapping and complementary areas of scientific expertise. In addition, this collaboration combines the technology and resources of a recently established biotechnology company and an internationally recognized research institute. PROPOSED COMMERCIAL APPLICATIONS: The long term commercial goals are to develop drug-cochleate formulations which will enhance the efficacy of some currently available antimicrobials by increasing the therapeutic index, (decreasing toxicity and decreasing the minimal inhibitory dose), and increasing patient compliance, (by decreasing the dosing regime and improving routes of delivery). The present application will focus on investigating the properties of Amphotricin B cochleate formulations on the growth of the microorganisms in vitro and in vivo. Positive results in these studies will provide the rationale for future Phase II studies.

Thesaurus Terms:
antifungal agent, cation, drug delivery system, drug design /synthesis /production, phospholipid amphotericin B, aspergillosis, candidiasis, opportunistic infection, oral administration, pharmacokinetics high performance liquid chromatography, laboratory mouse, laboratory rat

The long term goals of our research are to develop new formulations of therapeutically important drugs using cochleates as the delivery vehicle. Such formulations would have an improved route of delivery (oral rather than injectable to improve ease of administration and to reduce adverse effects of parenteral therapy), and lower toxicity, thereby improving the safety profile of drugs. The SBIR Phase I advanced the development of a new formulation of amphotericin B (AmB) that has low toxicity and allows the oral delivery of AmB. Oral amphotericin B cochleates showed excellent activity in murine models of clinically relevant invasive fungal infections: Disseminated candidiasis, disseminated aspergillosis, and central nervous system cryptococcosis. The overall objective of this SBIR Phase II is to further develop this new AmB cochleate formulation for the following target indications: 1) Treatment of azole-susceptible and azole-resistant oropharyngeal and esophageal candidiasis in immunosuppressed patients, 2) empiric therapy for presumed fungal infection in febrile, neutropenic patients, 3) treatment of selected patients with proven or probable invasive infections due to Aspergillus species, Candida species, and other life-threatening invasive fungal infections. To this end the following specific aims will be investigated: 1. To optimize cochleate AMB formulations (CAMB) as a commercially viable human therapeutic by testing CAMB prepared with less expensive raw materials (mainly phosphatidylserine) and simplified protocols. 2. To perform preclinical studies in a higher animal model. 3. To determine the mechanism of drug delivery mediated by cochleate 4. To initiate Phase I trials with CAMB in humans

Thesaurus Terms:
antifungal agent, cation, drug delivery system, drug design /synthesis /production, drug screening /evaluation, phospholipid amphotericin B, aspergillosis, azole, candidiasis, clinical trial phase I, opportunistic infection, oral administration, pharmacokinetics clinical research, human subject, laboratory mouse, laboratory rabbit