Inclusion complexes of tretinoin with cyclodextrins

doi:10.1016/S0378-5173(97)00104-X

International Journal of Pharmaceutics

Volume 153, Issue 2, 30 July 1997, Pages 199-209

https://doi.org/10.1016/S0378-5173(97)00104-X Get rights and content

Abstract

Complexes of tretinoin with β-cyclodextrin, hydroxypropyl β-cyclodextrin and dimethyl β-cyclodextrin were prepared by dissolving the products in suitable organo-aqueous solvents under nitrogen and sheltered from light and then stirred for 8 days. The solvents were then evaporated, the free tretinoin eliminated and the complexes dried. Characterization of the products was carried out by electron scanning microscopy, differential scanning calorimetry, IR spectrophotometry, X-ray analysis and ¹H-NMR study, which confirmed the existence of an inclusion compound but with weak affinity between tretinoin and the different cyclodextrins. Tretinoin solubility was dramatically enhanced by inclusion, especially in dimethyl β-cyclodextrin. However, in every case, the dissolved products dissociated more or less rapidly leading to reprecipitation of free tretinoin.

Introduction

In dermopharmacy, tretinoin has been the subject of growing interest during recent years. In fact, it can be used in the treatment of acne because of its keratolytic activity (Kligman et al., 1969). It also increases collagen synthesis and epidermal growth in the cicatrization process (Elias, 1986). More recently, improvement in photo-ageing was described (Weiss et al., 1988).

However, its topical use is limited due to several drawbacks: irritation power, high instability in the presence of air, light and heat and low water solubility. Its inclusion in a cyclodextrin could possibly improve all these characteristics.

Pitha reported the improvement in solubility of various retinoids by the use of α-or β-cyclodextrin, dimethyl β-or γ-cyclodextrin, trimethyl β-cyclodextrin and hydroxypropyl β-cyclodextrin (Pitha et al., 1980Pitha and Szente, 1983Pitha, 1981Pitha, 1988). However, he did not separate the inclusion complexes. Frömming et al., 1988 prepared an inclusion complex of vitamin A acetate in β-cyclodextrin. Unfortunately, this did not result in a real increase in the stability of the product. Amdidouche et al. (1989)described the inclusion of retinoic acid in β-cyclodextrin in conditions preventing its degradation during the preparation process: stirring an isopropanol/water solution of β-cyclodextrin and retinoic acid at 6°C for 15 days.

The purpose of the present work is the preparation and isolation of inclusion complexes of retinoic acid in three different cyclodextrins: β-cyclodextrin, hydroxypropy β-cyclodextrin and dimethyl β-cyclodextrin.

Section snippets

Products

Tretinoin (retinoic acid) was provided by Produits Roche (France), β-cyclodextrin and hydroxypropyl β-cyclodextrin by Roquette Frères (France) and dimethyl β-cyclodextrin by Cyclolab (Budapest, Hungary).

All solvents used were of analytical grade. Water was obtained by bidistillation.

Complexes

Inclusion complexes were prepared using equimolecular solutions of tretinoin and cyclodextrin, in conditions leading to the best yield and to the most stable complexes.

Tretinoin/cyclodextrin molar ratio

Chromatographic dosage of the tretinoin present in the products prepared indicated that tretinoin/cyclodextrin molar ratios were 1:5 for the tretinoin/dimethyl β-cyclodextrin complex and 1:2 for tretinoin/hydroxypropyl β-cyclodextrin and tretinoin/dimethyl β-cyclodextrin. It should be pointed out that in each case the excess of cyclodextrin was not eliminated from the final product.

Scanning electron microscopy

Scanning electron microscopy (Fig. 1) showed that the preparation methods led to new compounds. In fact, tretinoin

Conclusion

Complexes of tretinoin with β-cyclodextrin, hydroxypropyl β-cyclodextrin and dimethyl β-cyclodextrin were prepared by the coprecipitation method. The products obtained have proved to be amorphous inclusion compounds in the presence of an excess of cyclodextrins. However the inclusion compounds have a low affinity constant as shown by reprecipitation of the dissolved products and as confirmed for the dimethyl β-cyclodextrin complex. Nevertheless, the increase in solubility is noticeable and can

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Inclusion complexes of tretinoin with cyclodextrins

Abstract

Introduction

Section snippets

Products

Complexes

Tretinoin/cyclodextrin molar ratio

Scanning electron microscopy

Conclusion

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Am. Acad. Dermatol.

Int. J. Pharm.

Life Sci.

Life Sci.

Inclusion of retinoı̈c acid in β-cyclodextrin

Int. J. Pharm.