Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Patent
1993-08-10
1996-11-19
Webman, Edward J.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
5147726, 424400, A61K 4732
Patent
active
055760120
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to pharmaceutical formulation forms, specifically those which are intended for intravenous use.
DESCRIPTION OF RELATED ART
Pharmaceutical active compounds which are intended for intravasal use must be administered in the form of aqueous solutions. Problems occur here in the case of active compounds which do not have an adequate water-solubility. Thus, for example, the water-solubility of diazepam, nifedipine, propofol and the like is too low to dissolve the therapeutic dose in an acceptable volume. The use of solubilizing auxiliaries is necessary for development of suitable formulations for these active compounds. These auxiliaries must be soluble in water or miscible therewith. They should not have their own pharmacological action and should be distinguished by the lowest possible toxicity. In general, a distinction is made between three groups of solubilizing agents which are used pharmaceutically:
The water-miscible cosolvents are distinguished by a high dissolving power for lipophilic active compounds. Therapeutically suitable concentrations of the active compounds can be achieved in aqueous solution by addition of a non-stoichiometric amount of these hydrophilic solvents. This form of solubilization is sometimes called hydrotropy. However, the use of these hydrophilic solvents is not acceptable from the toxicological aspect. Thus, in more than 50% of cases, superficial thrombophlebitis has been found. Intravasal hemolytic reactions are detectable for propylene glycol and ethanol. Moreover, injection of these substances is found to be very painful, since tissue lesions occur at the puncture point.
The solubilizing effect of the molecular complexes is as a general rule insufficient for dissolving a therapeutic dose. Since the ligands are employed in equimolar portions, they are present in a high concentration. Possible sensorial (color, smell) and/or pharmacological effects of the ligand therefore cannot be excluded. However, the physical stability of the systems may be mentioned as being advantageous.
Cyclodextrins (CDs), which are obtained by enzymatic degradation of starch, are cyclic molecules which are built up from 6, 7 and 8 glucose units. They are called .alpha., .beta. and .gamma.-cyclodextrin. They have the ability to form inclusion compounds with numerous active compound molecules. The driving force for inclusion of the substances is, in addition to van der Waals interactions and the formation of H bridges between the guest molecule and OH groups of the glucose units, the gain in entropy of the water molecules displaced from the hollow space. On inclusion in the hollow space, the guest molecule must eject the water molecules present therein and cast off its own hydrate shell. The water molecules are absorbed by the surrounding water, gain degrees of freedom and contribute towards the stability of the complexes by an increase in entropy. The solubilizing action of cyclodextrins is relatively high; in many cases, it is superior to that of nonionic surfactants. The limiting effect is the poor water-solubility of .beta.-CD itself, which is 1.8%. .alpha.-CD dissolves in water to the extent of 17.4%, and .gamma.-CD to the extent of 25.8%. The toxic effects of cyclodextrins are not insignificant. When administered parenterally, .beta.-CD exhibits a nephrotoxic action. The hemolytic activity of cyclodextrins is in the sequence .beta.>.alpha.>.gamma.-CD (Bloois et al, Acta Pharm. Techn. 33, 1987, page 136). Owing to the not insignificant toxicity, oral administration is preferably indicated for cyclodextrin.
A distinction is made between two classes of amphiphilic auxiliaries: on the one hand micellar solubilization by surfactant-containing systems, and on the other hand liposomal solubilization by double layers of lecithin molecules and phospholipid molecules. The solubilization capacity of the surfactant-containing systems is of the same order of magnitude as liposomal solubilization (Y. Okada et al, Chem. Pharm. Bull, 36, 1988, page 217
REFERENCES:
patent: 3868447 (1975-02-01), Kliment
patent: 4740546 (1988-04-01), Masuda et al.
Chemical Pharm. Bull, vol. 36, 1988, Okada, et al, pp. 2176-2185.
Acta Pharmaceutica Technologica, vol. 33, No. 1-4, (1987), pp. 136-139.
Hagers Handbuch, 1971, pp. 404-407.
Technologie, Bauer, et al.-1989, pp. 284 and 285.
Bauer Kurt H.
Kiefer Markus
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