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The thermal behavior of water in liposome dispersions and in liposome dispersions containing mannitol at subzero temperatures was investigated with differential scanning calorimetry (DSC). The cooling curves from 20 down to -60 degrees C for a liposome dispersion (bilayer composition PL100H/DCP), monitored at cooling rates of 5 and 10 degrees C/min, showed several heat flows related to water crystallization. All lipid-containing dispersions showed water crystallization at temperatures below -40 degrees C. The magnitude of this heat flow strongly depended on the experimental variables. Cooling rate, particle size, lipid concentration, and location and nature of the cryoprotectant all influenced the water crystallization behavior as shown in the DSC cooling curve. Different fractions of water--presumably related to their location in the dispersion--could be distinguished. It is concluded that DSC provides a valuable tool for the detection of changes in the physical state of water in liposome dispersions during freezing/thawing. The insights gained from these DSC studies may make it possible to select--on the basis of rational considerations rather than by trial and error--optimum conditions for the cryopreservation of liposomes containing water-soluble drugs.

In this study 4 new, highly purified porcine insulin preparations (ORGANON) were characterized by their time action profiles and in vitro and in vivo miscibility. These insulin preparations were soluble insulin, and suspensions of amorphous zinc insulin, mixture of 30% amorphous and 70% crystalline zinc insulin and NPH insulin. The time action profiles, assessed with the euglycaemic clamp technique and measurements of plasma insulin levels, in healthy volunteers were very similar to corresponding, already available, insulins of other manufacturers. In vitro miscibility was assessed for the soluble insulin with the 3 intermediate acting insulins in mixing ratios varying from 1:1-1:5. The recovery percentages of added soluble insulin, 75 sec after mixing in a 1:1 ratio with NPH, Tardum and Sub Tardum insulin, were 97.1%, 67.8% and 42.4%, respectively. The recovery of added soluble insulin decreased significantly with time of contact and with lowering of the mixing ratio for all insulins tested. In vivo insulin miscibility was performed for soluble and NPH insulin in a mixing ratio of 2:3, administered immediately after mixing in the syringe. The insulin action profiles were not altered when soluble and NPH insulin were administered after mixing as compared with the separate injections into contralateral thighs. In conclusion, the pharmacokinetics of these highly purified porcine insulins are in agreement with corresponding already available insulins. NPH insulin can be mixed with soluble insulin without affecting the absorption kinetics of either insulin.