Solubilization of poorly water soluble drugs in micelles of hydrophobically modified hydroxypropylcellulose copolymers

https://doi.org/10.1016/j.jconrel.2003.08.001Get rights and content

Abstract

The main objective of this study is to exploit the solubilizing potential of hydroxypropylcellulose-g-polyoxyethylene alkyl ether (HPC-g-(POE)y-Cn) polymeric micelles towards poorly water soluble drugs in order to improve their oral bioavailability. Hydrophobically modified HPC graft copolymers of various compositions were synthesized by attaching hexadecyl or octadecyl residues to the hydrophilic HPC backbone via short POE linkers of different lengths. The onset of micellization was estimated by fluorescence spectroscopy. The hydrodynamic diameter of different HPC-g-(POE)y-Cn micelles was evaluated by dynamic light scattering (DLS). Cyclosporin A (CsA), a poorly water soluble immunosuppressant, was selected as model drug. CsA-loaded HPC-g-(POE)y-Cn micelles were prepared by a dialysis procedure and the amount of CsA incorporated in the micelles was assayed by high-performance liquid chromatography. Following 24-h incubation with human colon adenocarcinoma, Caco-2 cells, the cytotoxicity of various HPC-g-(POE)y-Cn copolymers was evaluated using the MTT colorimetric assay and compared to those of unmodified HPC and free (POE)y-Cn. In aqueous solution, different HPC-g-(POE)y-Cn copolymers formed polymeric micelles of low critical association concentrations (CAC) and micelle mean diameters ranging from 78 to 90 nm. CsA loading into HPC-g-(POE)y-Cn polymeric micelles was significantly larger than in unmodified HPC. It increased with increasing number of (POE)y-Cn units grafted per HPC chain. On the cellular level, unmodified HPC showed no cytotoxicity, while free (POE)y-Cn molecules inhibited cell growth. Most importantly, the study revealed that HPC-g-(POE)y-Cn exhibited no significant cytotoxic effect.

Introduction

Oral drug delivery continues to be the preferred gateway of a drug into the bloodstream, especially when repeated or routine administration is necessary [1]. However, for effective delivery via the oral route, a therapeutic agent must first dissolve in the gastrointestinal lumen [2], [3]. This represents a major challenge in the field of pharmaceutical drug formulation, namely the design of an oral dosage form for highly lipophilic drugs, that would enhance their notoriously poor bioavailability [4]. Among various strategies investigated for oral delivery of poorly water soluble drugs, such as nanosuspensions [5], microemulsions [6], lipids [7] and liposomes [8], the use of polymers has gained much attention because of their high diversity, biocompatibility, biodegradability and the multiple functional groups they display for the conjugation of various pilot molecules [9]. Among the different polymer-based drug delivery systems, “polymeric micelles” represent a promising delivery vehicle for poorly water soluble pharmaceutical active ingredients [10], [11]. Polymeric micelles form spontaneously when amphiphilic polymers, containing both hydrophilic and hydrophobic fragments, are dissolved in water. They consist of a hydrophobic core created upon assembly of the hydrophobic residues stabilized by a corona of highly hydrated hydrophilic polymeric chains [12].

A review of past achievements readily convinces one that, in the case of injectable drug formulations, polymeric micelles are highly effective drug delivery vehicles [13], [14]. They have been largely ignored, however, in oral drug delivery formulations. We present here a study of polymeric micelles as drug carriers capable of solubilizing high levels of lipophilic drugs, so as to improve their absorption from the gastrointestinal tract and, consequently, their bioavailability following oral administration.

Cyclosporin A (CsA), a highly lipophilic undecapeptide [15], was selected as model drug. Its water solubility, 23 μg/ml at 20 °C, is extremely low. CsA is administered as immunosuppressant to prevent allograft rejection following various organ transplantations [16]. Its oral administration has always been complicated due to the presence of the metabolizing enzyme cytochrome P-450 and the multidrug transporter P-glycoprotein (P-gp) in the small intestine [17].

We set out to investigate the suitability of polymeric micelles as carriers in the oral delivery of CsA. Hydroxypropylcellulose (HPC), a non-ionic water-soluble polymer, was selected to form the hydrophilic shell of the micelles. HPC is widely used as an excipient in oral solid dosage forms, in which it acts as a disintegrant [18], and as a binder in granulation [19]. It is essentially a non-toxic and non irritant polysaccharide [20].

Our strategy is (1) to prepare hydrophobically modified hydroxypropylcelluloses, (HPC-g-(POE)y-Cn) (see Fig. 1) by attachment of hydrophobic cetyl (C16) or octadecyl (C18) groups to hydrophilic HPC via a short polyoxyethylene (POE) linker of varying length; (2) to monitor the formation and characteristics of HPC-g-(POE)y-Cn micelles in aqueous environment; (3) to exploit the solubilizing power of HPC-g-(POE)y-Cn polymeric micelles towards CsA; and (4) to evaluate the cytotoxicity of the polymeric micelles towards epithelial intestinal cells. This approach will allow us to create nanosized entities, which entrap CsA in their hydrophobic core while forming a stable aqueous suspension via the steric stabilization promoted by hydrated HPC chains.

Section snippets

Materials

CsA, polyoxyethylene (20) cetyl ether [(POE)20-C16; C16H33(OCH2CH2)20OH; Brij 58®], polyoxyethylene (20) stearyl ether [(POE)20-C18; C18H37(OCH2CH2)20OH; Brij 78®], polyoxyethylene (10) cetyl ether [(POE)10-C16; C16H33(OCH2CH2)10OH; Brij 56®], sodium chloride (NaCl), monobasic sodium phosphate (NaH2PO4), dibasic sodium phosphate (Na2HPO4), sodium dodecyl sulphate (SDS), HPC (MW 80,000 Da, molar substitution level (MS): 3.7, where MS is defined as the average number of alkylene oxide per

Characterization of the modified HPC copolymers

Various hydrophobically modified HPC copolymers were synthesized (Fig. 1 and Table 1). They differed in three molecular aspects: (i) the level of grafting, i.e. the number of (POE)y-Cn substituents linked to the HPC backbone; (ii) the size of the (POE)y moiety; and (iii) the size of the hydrophobic alkyl group (Cn; hexadecyl group or octadecyl group). They were purified thoroughly to ensure complete removal of unreacted (POE)y-Cn and residual solvent. Analysis by GPC confirmed that the

Conclusion

In summary, we have demonstrated that aqueous solutions of HPC-g-(POE)y-Cn copolymers of various compositions increase the solubility of the lipophilic drug, cyclosporin A, through solubilization of the drug in the hydrophobic core of polymeric micelles, while the hydrophilic, non-toxic HPC outer shell stabilizes the system in the aqueous milieu. The molar contents, as well as the length of the hydrophobic substituent, have an important effect on the solubilizing power of HPC-g-(POE)y-Cn

Acknowledgements

This work was supported by the Natural Sciences and Engineering Research Council of Canada under its strategic grants program. M.F. Francis acknowledges a scholarship from the Rx&D Health Research Foundation. We would like to thank Dr. Patrice Hildgen and Dr. Albert Adam for providing some useful pieces of equipment.

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