Currently, about 30% of drugs that appear on the World Health Organization (WHO) Essential Drug List were reported to be poorly water-soluble, based on the Biopharmaceutics Classification System (BCS) [1, 2]. Over 40% of newly developed pharmaceutically active substances have solubility issues [3]. The poor dissolution and/or permeability of these drugs often result in low and highly variable bioavailability. The major obstacle of successfully commercializing these compounds is the difficulty of enhancing their dissolution rate and extent of dissolution.

The Enavail’s particle engineering technologies allow for generation of nano-structured drug particles with increased surface area and thermodynamic potential, which allow for enhanced dissolution of poorly water-soluble drugs and improved bioavailability.

Administration of these compositions can produce high supersaturation levels rapidly in biological fluid.  Pulmonary delivery of these compositions can also provide improved lung local drug exposure and potentially reduce dose and systemic side effects.  The flexibility and versatility of these processes allow for the use of a wide variety of FDA approved and generally regarded as safe (GRAS) biodegradable and biocompatible excipients which can also enhance the stability, patient compliance, safety, and therapeutic efficacy of these drugs.

The Enavail processes have been successfully demonstrated on more than 20 compounds reviewed in over 50 peer reviewed publications. The case studies presented here demonstrate the potential of the Enavail process for enhancing poorly soluble compounds.

Case Study 1: Rapid Freezing Engineering of Itraconazole (ITZ)

Itraconazole, a broad-spectrum antifungal drug for both prophylaxis and treatment of invasive fungal infections, has extremely low aqueous solubility (estimated at approximately 1 ng/mL at neutral pH, with a calculated log P of 6.2). Currently marketed products show low oral absorption and considerably varied pharmacokinetics in patients. Itraconazole levels of greater than 0.5 mcg/g in lung tissue or 0.5 mcg /mL in blood are generally required for adequate treatment of invasive fungal infections.

GOAL: TO ACHIEVE HIGH SUPERSATURATION ENABLING IMPROVED BIOAVAILABILITY IN AN ORAL FORMULATION

Study Details

• ITZ and Cellulose Acetate Phthalate (1:2) formulation
• Amorphous formulation of ITZ generated for oral delivery

DiNunzio, J.C., et al., Molec. Pharma ., 5:968-980 (2008).

Enavail process resulted in ~15 times higher surface area than micronized ITZ (45m2/g) period

DiNunzio, J.C., et al., Molec. Pharma ., 5:968-980 (2008).

Case Study 2: Rapid Freezing Engineering of Tacrolimus (TAC)

TAC is a hydrophobic macrolide antibiotic used as a potent immunosuppressant for treatment of transplanted organ rejection as well as different immunological diseases such as pulmonary fibrosis and bronchiolar asthma. It has 10 to 100 times more potent immunosuppressive properties compared to similar drugs and is currently available in both an intravenous and oral dosage forms. However, these dosage forms are either poorly tolerated or provide erratic absorption with mean oral bioavailability reported to be 25%, ranging from 4 to 93%.

GOAL: TO ACHIEVE HIGH SUPERSATURATION ENABLING IMPROVED BIOAVAILABILITY IN AN ORAL FORMULATION

Overhoff, K.A., et al., Pharma. Res., 25:167-175 (2008)

Study Details

• Formulation of TAC and Sodium Dodecyl Sulfate (SDS), Poly (vinyl alcohol) (PVA), or Poloxamer 407 (P407)
• Amorphous oral formulation generated of TAC
• Enavail process resulted in up to ~ 110 times higher surface area than bulk TAC (55m2/g)

Overhoff, K.A., et al., Pharma Res.175 (2008)

Case Study 3: Controlled Precipitation of Cyclosporine A

CsA is a cyclic undecapeptide used for immunosuppression in organ transplantation patients, autoimmune diseases, and chronic and inflammatory conditions (e.g. asthma). It is highly lipophilic and very poorly water soluble (log P of 4.3; solubility of 7.3 mcg/mL in water). The delivery of therapeutic effective amounts of CsA to lung tissue with oral or parenteral formulations can cause severe renal and liver toxicity. Additionally, the bioavailability of oral CsA formulations has been highly variable in clinical trials.

GOAL: TO ACHIEVE HIGH SUPERSATURATION WITH ENHANCED LUNG DELIVERY AND SYSTEMIC LEVELS BELOW TOXIC LIMITS

Study Details

• Formulation of CsA and Polysorbate 80 (10:1)
• Amorphous nanoparticle aqueous dispersion of CsA generated for pulmonary delivery
• Achievement of aerosols delivered to mice via nebulization (8.4 mg/ml CsA)