Decreased stability in liposomal suspensions: accelerated loss of p-nitrophenyl acetate.

The goal of this investigation was to determine the reason for the previously reported increase in the rate of hydrolysis of p-nitrophenyl acetate to p-nitrophenol in the presence of positively charged liposomes. When this charge was due to incorporation of stearylamine, the rate of loss increased 5- to 10-fold relative to the control buffers. This rate enhancement was accompanied by formation of N-stearylacetamide, an event which was not previously considered. Similar results were obtained with either L-alpha- or dimyristoyl phosphatidylcholine. When the positive charge on the liposomes was conferred by the cetrimonium ion, however, the acceleration was replaced by a reduction in rate together with the absence of amide formation. Separation of the continuous phases from the liposomes provided media which were kinetically equivalent to the control buffers, indicating that rate enhancement and reduction were both due to the liposomal phases. Increasing the pH produced an increase in ester clearance values due to the stearylamine-containing liposomal phase, which is consistent with the formation of free amine, providing increased aminolysis. Although amide formation was also observed in stearylamine suspensions, the rate of p-nitrophenyl acetate loss was much greater in liposomal suspensions. Accelerated loss in the presence of positively charged liposomes is due to the formation of N-stearylacetamide by reaction with stearylamine and not to the positive charge, a hypothesis disproved by use of cetrimonium ion containing liposomes.

Liposomal formulation of mirfentanil hydrochloride.

Mirfentanil hydrochloride, a novel CNS analgesic with a short duration of action, was successfully encapsulated in liposomes having a variety of compositions. The lipid composition of the formulation was varied to optimize the stabilization of liposomes and the encapsulation of solutes. Retention of mirfentanil hydrochloride was evaluated by storing loaded liposomes at several temperatures, and also after the physical stressing of formulations. High efficiency of drug encapsulation was observed in liposomes prepared using dipalmitoyl-L-alpha-phosphatidylcholine (DPPC) and the ternary mixture of dimyristoyl-L-alpha-phosphatidylcholine, cholesterol, and dicetyl phosphate (DMPC/CHOL/DCP), both with and without the further incorporation of monosialoganglioside (GM1). Only 35% of encapsulated drug was lost when the formulations containing GM1 were incubated with human plasma over a 24 hour period, suggesting that liposomal formulations containing GM1 could be used to control drug release in vivo.

Stability of Revex, nalmefene hydrochloride injection.

The stability of Revex, nalmefene hydrochloride injection, has been studied at several temperatures for periods up to 36 months. The data were obtained using a HPLC method for the potency determination, and for the level of the sole degradation product (2,2'-bisnalmefene). These methods were found to be characterized by excellent precision, linearity, and accuracy over the analyte concentration ranges established. The stability data were found to be interpretable using first-order kinetics, and essentially comparable rate constants were calculated for both the potency loss and the formation of 2,2'-bisnalmefene. Applying the Arrhenius equation to these data, a rate constant of 0.00441 month-1 was deduced for the reactions taking place at 25 degrees C. This low value is consistent with the excellent stability exhibited by the product, and amply justifies its shelf life.