Preparation of colloidal aqueous solutions of active substances

Details Preparation of colloidal aqueous solutions of active substances Preparation of colloidal aqueous solutions of active substances

1995-07-19

1998-02-24

Kishore, Gollamudi S.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

264 41, A61K 9127

Patent

active

057209731

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP94/00333 filed Feb. 7, 1993.
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.
Another suitable class of solubilizers comprises the phospholipids which, as endogenous molecules (they are a constituent of every cell membrane), show very good tolerability even in injection solutions. However, the use of phospholipids often fails because in aqueous systems they form not molecular solutions but only colloidal aggregates. However, on simple dispersion of phospholipids in aqueous solutions these colloid particles are so large that such phospholipid-containing solutions generally cannot be used for formulations for injection and infusion (risk of embolism). The coarsely colloidal cloudy solutions obtainable by suspending phospholipids in aqueous systems must therefore first be homogenized by suitable methods before use thereof so that the size of the particles in the solutions is reduced to values permitting use of the phospholipids in solutions for injection or infusion (cf. U.S. Pat. No. 5,008,050). Only in very few cases is it possible with selected medicinal substances to obtain injectable medicinal substance formulations direct from active substance and phospholipid in aqueous systems without it first being necessary to reduce the size of the colloidal particles by relatively elaborate homogenization methods.
Most of all known pharmaceutical active substances are weakly basic, ie. have an amino group which can be protonated. Such weakly basic substances often have sufficient solubility in water by forming salts with suitable organic or inorganic acids. However, the salts generally have adequate solubility only in the acidic medium. pH values of this type are unacceptable for pharmaceutical formulations for injection. On attempting to adjust to neutral pH values, the active substances precipitate to a considerable extent so that usually only relatively low concentrations can be obtained at physiological pH values, or recourse must be had to cosolvents from which, however, the active substances likewise often precipitate again after injection (J. Pharm. Sci. 72 (1983) 1014).
The present invention relates to a process for producing solutions of active substances of low solubility, which comprises lipid in an organic solvent, elevated temperature until a colloidal solution is produced, sterilizing.
Particularly suitable active substances for the novel process are those which normally have a low solubility in water but dissolve in the presence of acids. Examples of substances of this type are, in particular, active substances with amino groups which can be protonated in the molecule, ie. all basic medicinal substances whose solubility in demineralized water, even in the form of the salts, is on .average below 1 mg/ml.
If the intention is to produce solutions of active substances which have low solubility and do not even dissolve in acids, it is necessary to

REFERENCES:
patent: 3960935 (1976-06-01), Samour
patent: 4619794 (1986-10-01), Hauser
Voigt: Lehrbuch der Pharm. Tech, Tech. 5th Ed. Verlag Chemie p. 334, 1984.
Pharm. Techn. Intern., Feb. 1991, p. 15J.
J. Pharm. Sci. 72 (1983) 1014.

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