Highly soluble multicomponent inclusion complexes containing a b

Details Highly soluble multicomponent inclusion complexes containing a b Highly soluble multicomponent inclusion complexes containing a b

1995-11-15

1999-01-05

Webman, Edward J.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Matrices

514777, A61K 910, A61K 4740

Patent

active

058559167

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
The invention relates to highly soluble multicomponent inclusion complexes consisting of a basic-type drug, a cyclodextrin and an acid.
2. Discussion of the Background
The term basic-type drug refers to organic compounds bearing hydrophobic groups and nitrogen basic groups, such as amino, amine and guanidino groups.
A lot of drugs bear aliphatic or aromatic amine groups. These types of drugs usually have very low aqueous solubility in base form which often hampers their application.
Salt formation with inorganic or organic acids is a common method, which is very often used to increase the solubility of base-type drugs. However sometimes even the salts are poorly soluble, or by other reasons a conventional salt formation is inadequate.
It is known that the aqueous solubility of base-type drugs or their salts is much higher at low pH values whereas it is very poor at higher pH of the intestinal tract, comprised between pH 5-8. Therefore, the release site from formulations of such drugs is restricted to the stomach or to the upper part of the intestinal tract and such properties make impossible the preparation and use of such drugs in controlled release formulation, wherever it is necessary to ensure the dissolution of the drug in the intestinal juice.
The difficulties originated from the low aqueous solubility of certain drugs, such as low rate and percent of dissolution from pharmaceutical formulations, together with poor and/or variable bioavailability can be overcome by cyclodextrin complexation.
In prior art a lot of amine type drugs, such as terfenadine and cinnarizine, have been successfully complexed with cyclodextrins, with good results. However, low aqueous solubility of .beta.-cyclodextrin hinders its applications as complexing agent from a technological point of view.
Soluble complexes can be prepared from homogeneous drug-cyclodextrin solutions by removing water by freeze-drying or spray drying. This technique is widely used in the prior art in case of using well soluble .beta.-cyclodextrin derivatives such as methyl or hydroxypropyl .beta.-cyclodextrins.
The solubilizing capacity of .beta.-cyclodextrin is strongly limited by its low aqueous solubility. Therefore large volume of solutions have to be used for the preparation of soluble complexes.


SUMMARY OF THE INVENTION

Surprisingly, it has now been found that the presence of acids in the formation of complexes of amine type drugs with cyclodextrins results in easily water soluble complexes with extremely high concentrations both of the guest molecule and of cyclodextrin.
Even more surprisingly it has been found that, when the cyclodextrin is .beta.-cyclodextrin, the presence of an acid considerably enhances its water solubility.
In fact, in this kind of complexes, not only the solubility of the hydrophobic guest results enhanced by several orders of magnitude, but also the solubility of the hydrophilic .beta.-cyclodextrin may be increased up to more than 10 times.
Up to now, a mutual host-guest solubility enhancement up to a very modest extent has been reported only in the case of fendiline hydrochloride-.beta.-CD (Stadler Szoke A. et al. . . , J. Inclusion Phenomena 3, 71-84, 1985).
A first aspect of the present invention therefore relates to multicomponent inclusion complexes fundamentally consisting of a base type drug, a cyclodextrin and an acid.
A second aspect of the present invention relates to the use of an acid in the preparation of complexes with a cyclodextrin, and particularly with .beta.-cyclodextrin, with the purpose of increasing water solubility of the cyclodextrin itself.
The solubility increase of the guest molecule and/or the cyclodextrin may occur both in the presence of inorganic acids and of organic acids.
Examples of inorganic acids are halogenhydric acids, such as hydrochloric, hydrobromic acid.
Examples of organic acids are aliphatic carboxylic acids, such as acetic acid, propionic acid, butyric acid, oxalic acid, succinic acid, glutaric acid, pimelic acid, tartar

REFERENCES:
patent: 4365061 (1982-12-01), Szejtli et al.
patent: 5646131 (1997-07-01), Badwan et al.

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