Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Patent
1995-08-02
1997-05-06
Bleutge, John C.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
514937, A61K 4724, A61K 4726
Patent
active
056268645
DESCRIPTION:
BRIEF SUMMARY
The administration of a medicinal substance by, for example, injection or infusion into the bloodstream is often prevented by its low solubility in aqueous systems. This is why in recent years there has been development of various processes in order to formulate the medicinal substance in an aqueous phase with the aid of suitable solubilizers.
Most of the processes use for this purpose the solution-promoting effect of detergents or emulsifiers (cf. Voigt: Lehrbuch der pharmazeutischen Technologie, 5th edition, Verlag Chemie page 334). Although the preparation of such solutions is very straightforward, and a large number of medicinal substances can be solubilized in this way, the toxicity deriving from the detergents often entails considerable problems.
Another possibility is to mix the medicinal substances with cyclic carbohydrates (cyclodextrins) which complex the medicinal substance (Pharm. Techn. Intern., February 1991, page 15) and thus often crucially improve the solubility. However, since the internal cavity of 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), are very well tolerated even in injection solutions. The excellent tolerability of phospholipids has therefore led to them also being used in formulations of active substances which, although readily soluble in water, entail problems because of unacceptable local intolerance, eg. in the veins on intravenous administration. Improving the local tolerability by the choice of phospholipid formulations is known (Europ. J. Cancer; 16 (1980) 945-950). However, the use of phospholipids is often prevented by the fact that, in aqueous systems, they form not molecular solutions but only colloidal aggregates. However, these colloidal particles are so large when phospholipids are simply dispersed in aqueous solutions that such phospholipid-containing solutions cannot in general be used for preparations for injection and infusion (danger of embolism). The turbid solutions containing large colloidal particles which can be obtained by suspending phospholipids in aqueous systems must therefore be homogenized by suitable processes before they are used, so that the size of the particles in the solutions is reduced to values which permit the phospholipids to be used in injection or infusion solutions (U.S. Pat. No. 5,008,050).
Another disadvantage of phospholipid-containing solutions is that sterilization of the finished solutions in the final container by autoclaving almost always results in the phospholipids flocculating out.
Various processes are known for bringing the large size of the colloidal particles in phospholipid solutions into the submicrometer range. These include established laboratory methods such as sonication, but also processes on the production scale such as high-pressure homogenization. However, these methods are relatively expensive.
The present invention relates to a process with whose aid active substances of low solubility can be processed together with phospholipids to give a homogeneous solution, which comprises residue at elevated temperature, and stirring this mixture at elevated temperature until a homogeneous colloidal solution is produced, and
The novel process is suitable for basic active substances which have nitrogen atoms which can be protonated in acids and which are in ionic form in the acidic pH range, such as active substances containing basic amino groups which can be protonated. These compounds are often relatively readily soluble in water at strongly acidic pH values but crystallize out again, substantially in the form of the bases, on titration to weakly acidic to neutral pH values.
The process is particularly suitable for cationic active substances (which can be protonated) which have a solubility of less than 1 mg/ml in water even in the form of
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patent: 4309421 (1982-01-01), Ghyczy et al.
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patent: 5008050 (1991-04-01), Cullis et al.
patent: 5085864 (1992-02-01), Cannon et al.
patent: 5432196 (1995-07-01), Rosenberg et al.
Layton et al., Europ. J. Cancer, vol. 16, pp. 945-950.
J. Szejtli, Pharm. Tech. Int., Feb. 1991, pp. 15-22.
Heberger Juergen
Romerdahl Cynthia
Rosenberg Joerg
Bleutge John C.
Harrison Robert H.
Knoll Aktiengesellscahft
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