Preparation of colloidal aqueous solutions of active substances of low solubility and a lipid therefor

#The administration of a medicinal substance by, for example, injection or infusion into the blood stream is often prevented by its low solubility in aqueous systems. This is why in recent years various processes have been developed for formulating, with the aid of suitable solubilizers, the medicinal substance in an aqueous phase.

#Most of these processes make use of the solubilizing effect of detergents or emulsifiers (cf. Voigt: Lehrbuch der pharmazeutischen Technologie 5th Edition, Verlag Chemie. p. 334). Although the preparation of such solutions is very straightforward, and a large number of medicinal substances can be solubilized thereby, the toxicity deriving from the detergents often causes considerable problems.

#Another possibility is to mix the medicinal substances with the aid of cyclic carbohydrates (cyclodextrins) which complex the medicinal substance (Pharm. Techn. Intern., February 1991, p. 15) and thus often crucially improve the solubility. However, since the internal cavity of the cyclodextrins is limited, many molecules cannot be complexed for steric reasons although the cyclodextrins are to be regarded as more toxicologically favorable than the detergents.

#U.S. Pat. No. 4,874,683 describes active substances which have a bisnaphthalimide structure. Because the solubility in water is very low, it is very difficult to prepare aqueous solutions of active substance with sufficient concentration. Although it is possible with the aid of solubilizers such as dimethyl sulfoxide to prepare solutions for injection, the active substance rapidly flocculates out of these again in the blood after the injection.

#The solubility in aqueous formulations was investigated using a derivative of these bisnaphthalimides ##STR4## as follows:

#40 mg of Z were dissolved in 10 ml of methylene chloride/methanol (9+1). The solvent was completely removed again from the solution under reduced pressure in a rotary evaporator. 8 ml of a 0.14 molar phosphoric acid solution (pH.about.1.5) were added to the residue, and the flask was rotated on the rotary evaporator (without reducing the pressure) at a waterbath temperature of 50.degree. C. for 1 h. It was possible in this way for a considerable part of the active substance to be dissolved. Cooling to room temperature was followed by titration with 2 molar sodium hydroxide solution to a pH of 6.8, and the volume was made up to 10 ml with phosphate buffer pH 6.8. Most of the active substance then precipitated. The clear supernatant was filtered through a 0.2 .mu.m syringe sterile filter, and the active substance concentration in this solution was determined by photometry. The active substance content in this solution was 0.04 mg/ml.