RESUMEN
A-71623 (BOC-Trp-Lys(epsilon-N-2-methylphenylaminocarbonyl)- Asp-(N-methyl)-Phe-NH2) is a tetrapeptide which has high affinity and selectivity for cholecystokinin receptors; it is a potent appetite suppresser in animal studies. Because of its low (< 1%) oral bioavailability, studies were performed to assess the feasibility of delivery of A-71623 by pulmonary, sublingual, and transdermal routes of administration. The pKa was determined to be 4.2 by spectrophotometric titration; aqueous solubility is increased by increasing pH and by increasing ethanol content. The solubility of A-71623 in ethanol/propellant mixtures was investigated; solubility ranged from 1.0 to 2.5 mg/mL in mixtures of ethanol, propellant 11 (trichlorofluoromethane), and propellant 12 (dichlorodifluoromethane). The log apparent octanol/water partition coefficient was 2.8 at pH 5 and 1.0 at pH 8. Maximum stability at 70 degrees C was seen in the range of pH values of 5.5-7.5; hydrolysis of the N-terminal BOC group appears to be the primary route of degradation. Increasing ethanol content increases the stability; Arrhenius analysis indicated a t90 of 150 days under ambient conditions in 25% ethanol. Intratracheal delivery of 3 mumol/kg A-71623 in 50% ethanol to rats showed rapid and efficient absorption of drug from the lungs, with a Cmax of 2.7 microM and an AUC of 85 microM*min. Similar studies in dogs showed bioavailabilities of 59% and 46% for 2 and 3 mumol/kg intratracheal doses, respectively, relative to intravenous administration. Sublingual administration of 1 mumol/kg A-71623 in a vehicle of 80% ethanol/2% Klucel/2.5% peppermint oil gave high prolonged plasma levels of A-71623, with a Cmax of 0.37 microM, indicating high bioavailability and favorable partitioning and distribution effects from the sublingual cavity for this formulation. Transdermal delivery was examined by in vitro diffusion through human skin; the permeability coefficient of A-71623 in 40% ethanol was 2.6 x 10(-5) cm/hr, suggesting that transdermal delivery of up to 2 mg/day may be feasible. In conclusion, the results provide preliminary indications that delivery of efficacious doses of A-71623, and perhaps other CCK analogs, by alternate routes of delivery is probably feasible.