Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Patent
1996-10-22
1998-06-30
Webman, Edward J.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
514777, A61K 910, A61K 4740
Patent
active
057730296
DESCRIPTION:
BRIEF SUMMARY
The invention relates to multicomponent inclusion complexes basically consisting of a drug bearing an acidic group (hereinafter defined as acidic drug), a cyclodextrin and a base.
In Italian Patent application no MI93 A 000141, three-component inclusion complexes consisting of a basic-type drug, a cyclodextrin and an acid, characterized by a very high solubility in water, were described.
The drugs used in the formation of these complexes, in the presence of the organic or inorganic acid which acts as a counter-ion, give rise to amphyphilic structures, i.e. characterized by a strongly hydrophobic group and an hydrophilic polar head.
It is known that the molecules with such a structure have colloidal properties in aqueous solutions, i.e. they are capable of forming aggregates at suitable concentration and of lowering the surface tension of the solvent: in other words, they act as surfactants.
Among the classes of compounds which have mostly been studied from this aspect (Attwood D., Florence A. T., Surfactant Systems, their chemistry, pharmacy and biology, Chapmam and Hall, UK, 1983) are the diphenylmethane derivatives and the tricyclic derivatives, some of which (terfenadine, tamoxifen, cyclobenzaprine) turned out to be excellent agents for the formation of the multicomponent complexes.
Therefore, it has been assumed that the high, unexpected increase in the solubility of the hydrophobic guest drug and of the cyclodextrin which is observed when the multicomponent complexes are dissolved in water, is due to a reciprocal, synergistic effect of a component on the other: in other words, the cyclodextrin would increase the guest solubility by complexation, whereas the guest, once reached a concentration in solution sufficient to give aggregates and/or micells would act as a surfactant towards the cyclodextrin.
The preparation processes, which consist in removing solvent from a supersaturated solution of the components, would favour such a mutual interaction.
Measurements of the relaxation time "spin-lattice" on the proton and "spin-spin" on the carbon carried out on the multicomponent complex terfenadine-tartaric acid-.beta.-cyclodextrin confirmed that the drug guest is certainly aggregated in solution and therefore it is capable of acting as a surfactant.
Now it has surprisingly been observed that the aggregation also remains in the presence of cyclodextrins, contrary to what reported in literature.
It is known, in fact, that cyclodextrins generally increase the critical micellar concentration (c.m.c.) this creating conditions unfavourable to the Fourth International Symposium on Cyclodextrin, Eds. O. Huber and J. Szejtli., Kluwer Academic Publishers, Dordrecht, 1988, pp. 189-195; Satake I., Ikenoue T., Takeshita T., Hayakawa K. and Maeda T., Bull. Chem. Soc. Jpn., 58, 2746-2750 (1985)!.
A number of examples of formation of complexes with cyclodextrins in the Palepu, J. E. Richardson, V. C. Reinsborough: Langmuir 1989, 5, 218-221; G. Nelson, I. M. Warner: Carbohydr. Res. 1989, 192, 305-312! and the formation of complexes of cyclodextrins with amphyphilic drugs was described by Takiwasa N. et al. in Colloid. Polym. Sci. 1993, 271(5) which characterized the thermodynamic properties thereof.
Up to now, however, no examples are known using the intrinsic surfactant properties of the included molecule to obtain very soluble complexes as far as both the included molecule and the cyclodextrin itself are concerned.
This principle was verified by the Applicant also for acidic drugs having a potentially amphyphilic structure.
Thus it has been found, and it is the object of the present invention, that also with acidic molecules, the simultaneous salt formation with suitable basic counter-ions and complexation with cyclodextrins, dramatically increases the aqueous solubility.
Usually, as for basic drugs addition salts with organic or inorganic acids are prepared to enhance solubility, analogously for acidic drugs salts with organic or inorganic bases are used.
The preparation of these salts, in order to increase solubility,
Acerbi Daniela
Chiesi Paolo
Del Canale Maurizio
Fenyvesi Eva
Pasini Massimo
Chiesi Farmaceutici S.p.A.
Webman Edward J.
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