Effect of chitosan on progesterone release from hydroxypropyl-β-cyclodextrin complexes

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Abstract

An inclusion complex composed of progesterone (Prog) and hydroxypropyl-β-cyclodextrin (HPβCD) was prepared by the spray-drying and freeze-drying methods. Prog alone and its inclusion complex with HPβCD were incorporated into chitosan by spray-drying and freeze-drying. The inclusion complex was characterized by IR and DSC. The inclusion complex was investigated in solution by phase solubility diagrams and stability constant was determined at pH 7.4 and at different temperatures (10, 25 and 37 °C) to obtain the thermodynamic parameters of inclusion. The results indicate that the Prog–HPβCD inclusion complex is more water soluble than Prog alone. Release data from all samples showed significant improvement of the dissolution rate of Prog and a controlled release is obtained in the presence of chitosan.

Introduction

Progesterone (Prog) is a lipophilic drug used to control reproductive function and as postmenopausal therapy (Buntner et al., 1998, Latha et al., 2000). The oral delivery of Prog is limited since it is not tolerated in higher doses, but its biological half-life is short. One of the possibilities of a controlled delivery of Prog involves the application of a biodegradable drug containing microspheres incorporated into the body by injection (Buntner et al., 1998). Sidman et al. (1977) prepared injectable biodegradable drug reservoirs from glutamic acid/leucine copolymers in the form of tubes and solid rods to provide controlled release of Prog. Lee et al. (1981) incorporated Prog into glutaraldehyde cross-linked serum albumin microspheres and showed that an extended release of 1–2 ng/h/ml of serum was possible for about 20 days. Recently, albumin microcapsules and microspheres cross-linked with formaldehyde, 2,3-butanedione and glutaraldehyde were investigated for Prog delivery by Orienti and Zecchi (1993). In a recent study, Jameela et al. (1998) showed that cross-linked chitosan microspheres loaded with Prog, injected intramuscularly in rabbits, could sustain a plasma concentration of 1–2 ng/ml of the steroid for about 5 months.

The main aim of this study was to investigate the effect of chitosan on the complexation of 2-hydroxypropyl-β-cyclodextrin (HPβCD) with Prog. Cyclodextrins are used as complexing agents to improve the aqueous solubility of non-polar drugs, and consequently their bioavailability, or to modify some physico-chemical characteristics of drugs by means of inclusion into the hydrophobic cavity of the cyclodextrin (Duchene, 1987). 2-HPβCD has a higher water solubility than β-cyclodextrin which decreases its renal toxicity allowing parenteral administration (Irie et al., 1992, Irie and Uekama, 1997).

Chitosan is a cationic polysaccharide derived by deacetylation of chitin, and has been widely used for drug carrying devices in controlled drug delivery systems (Paul and Sharma, 2000, Ravi Kumar, 2000, Filipovic-Grcic et al., 2000). It is a hydrophilic, biocompatible and biodegradable polymer of low toxicity (Sawayanagi et al., 1983, Hirano et al., 1990, Vila et al., 2002).

Section snippets

Materials

Prog, 2-HPβCD (with an average MS value of 0.6), high-molecular weight chitosan (MW: 600,000, viscosity: 400 mPa s (1% solution in 1% acetic acid), degree of deacetylation: 80%) was purchased from Fluka (Milan, Italy).

Preparation of Prog–HPβCD inclusion complex

Prog–HPβCD inclusion complex (Prog–HPβCD) was prepared by the spray-drying (Prog–HPβCDs) and the freeze-drying (Prog–HPβCDf) techniques.

For Prog–HPβCDs, a suspension of Prog and HPβCD was prepared in the molar ratio 1:1. Briefly, Prog (0.31 g) was dispersed in 50 ml of water

Prog–HPβCD complexation

The phase solubility diagram for complex formation between Prog and HPβCD is presented in Fig. 1. The plot shows a typical AL-type solubility curve classified by Higuchi and Connors (1965), showing that soluble complex was formed. The solubility of Prog increased in a linear fashion as a function of HPβCD concentration. Table 1 lists the 1:1 apparent stability constants of the inclusion complex (Ks). The stability constant decreased with increasing temperature, probably due to the decrease in

Conclusions

The solubility of Prog can be increased by inclusion complexation with HPβCD. The Prog–HPβCDs and Prog–HPβCDf complexes were characterized by enhanced dissolution rates with respect to the drug. The presence of chitosan significantly decreased the dissolution rate of Prog–HPβCDs and Prog–HPβCDf complexes.

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