Process for the preparation of an inclusion complex of N-(1--phe

Details Process for the preparation of an inclusion complex of N-(1--phe Process for the preparation of an inclusion complex of N-(1--phe

1982-12-22

1985-05-21

Brown, Johnnie R.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

536 46, 536103, A61K 3173, C08B 3716

Patent

active

045185883

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The invention relates to the preparation of an inclusion complex of N-(1-phenylethyl)-3,3-diphenyl-propylamine or the hydrochloride thereof with cyclodextrin.
The inclusion complex can be prepared by reacting N-(1-phenylethyl)-3,3-diphenylpropylamine base or the hydrochloride thereof with cyclodextrin under stirring at 4.degree.-60.degree. C. in an aqueous and/or ethanolic medium and optionally treating the obtained complex of the base with hydrochloric acid.


BACKGROUND OF THE INVENTION

N-(1-phenylethyl)-3,3-diphenylpropylamine (referred to hereinafter as phendiline), is a coronary dilator calcium antagonist (see Hungarian Pat. No. 150 534). The substance is an oily liquid and its hydrochloride salt is used as an active ingredient of a pharmaceutical composition known under the trade name Sensit. A solid pharmaceutical composition can be prepared only from the hydrochloride. However, phendiline hydrochloride is an extremely hydrophobic substance. Thus the rate and extent of the resorption of phendiline are not satisfactory.


OBJECT OF THE INVENTION

The object of the invention is to provide a process by which phendiline or its hydrochloride can be prepared in a form which is more soluble and thus its in vivo resorption can be accelarated and increased.


DESCRIPTION OF THE INVENTION

We have now found that if phendiline or its hydrochloride is converted to a cyclodextrin inclusion complex the obtained complex is much more soluble at a pH and temperature corresponding to these of gastric acid than is the original molecule. The rate and extent of the dissolution are increased.
Cyclodextrin molecules are known to have a cylindric structure, the inner surface of which is apolar and thus they are capable of binding hydrophobic molecules in the form of an inclusion complex. Such hydrophobic molecules may in the present case be phendiline or its hydrochloride, the solubility of which in water is very poor. Our experiments have shown that when reacting phendiline with cyclodextrins, two molecules of cyclodextrin form an inclusion complex with each molecule of phendiline, which surprisingly loses one of its cyclodextrin molecules in an aqueous hydrochloric acid solution corresponding to the pH of gastric acid and the complex is readily converted to a molecularly dispersed state. The solubility is thus increased and a better biological activity can be observed. When stirring cyclodextrins vigorously with phendiline in an aqueous and/or ethanolic medium, the phendiline molecule displaces the water molecules in the hollow of the cyclodextrin and due to the formed apolar-apolar interaction an inclusion complex is formed.
This intensive dissolution process for the product of molecular encapsulation by cyclodextrins, combined with salt formation and partial release of cyclodextrin is new. The essence of the process is that the host molecule is ionized in the cyclodextrin inclusion complex of the non-ionic molecule, and due to the formation of the ionic bond the appearing intensive charge and the accompanying intensive hydrated state casts off part of the cyclodextrin casing of the host molecule. If an inclusion complex of a non-ionic host molecule which is not well soluble in water and which has a crystalline grid structure is thus converted to the ionic state, then the crystal granule disintegrates explosively and the entire amount of substance is transformed to molecularly dispersed state, i.e. to a solution.
The resulting, molecular structure is relatively highly soluble as its one end is hydrated due to the ionized state and its other end--which is apolar to a great extent and causes thus a poor solubility of the molecule--is covered from the outside by a hydrophilic cyclodextrin ring.
Phendiline is not soluble in water, but even the solubility of its hydrochloride is extremely poor. If the free base is treated with hydrochloric acid, then the hydrophobic hydrochloride on the surface of the oil drops of the base not only inhibits the dissolution but further salt formation as well. If one m

REFERENCES:
patent: 3553191 (1971-01-01), Parmerter et al.
patent: 4407795 (1983-10-01), Nicolau et al.

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