Molecular Inclusion Complexes of β-Cyclodextrin Derivatives Enhance Aqueous Solubility and Cellular Internalization of Paclitaxel: Preformulation and In vitro Assessments - PubMed (original) (raw)

Molecular Inclusion Complexes of β-Cyclodextrin Derivatives Enhance Aqueous Solubility and Cellular Internalization of Paclitaxel: Preformulation and In vitro Assessments

Milin Shah et al. J Pharm Pharmacol (Los Angel). 2015.

Abstract

Drugs with low aqueous solubility and permeability possess substantial challenges in designing effective and safe formulations. Synergistic solubility and permeability enhancement in a simple formulation can increase bioavailability and efficacy of such drugs. To overcome limitations of the clinical formulation of Taxol®, Paclitaxel (PTX) was reformulated with various β-cyclodextrin (CD) derivatives suitable for parenteral administration. Results indicated that β-CDs can efficiently form complexes with PTX at lower molar ratios, enhance aqueous solubility up to 500 times and improved cellular internalization of PTX. All β-CD derivatives were found to be safe as excipient since none showed detectable signs of cyto-genotoxicity. As a result, the CD-PTX complexes significantly increased the cytotoxicity of the drug. The study concluded that CD-PTX formulations could substitute the current intravenous infusion of PTX obviating the use of non-inert excipient Cremophor EL.

Keywords: Compounds; Cyclodextrins; Enhancement; Inclusion; Permeability enhancement; Preformulation; Solubility.

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Figures

Figure 1

Figure 1

Representative differential scanning calorimetry (DSC) thermograms of free paclitaxel (PTX), _β_-cyclodextrins (CDs) and their mixtures and inclusion complexes with PTX; (a) – Chemical structure of PTX. (b) – Free PTX; (c) – Hydroxy propyl _β_-cyclodextrin (HPCD); (d) Physical mixture of HPCD and PTX (e) – Hydroxy propyl _β_-cyclodextrin-paclitaxel (HPCD-PTX); (f) – Methyl _β_-cyclodextrin (MeCD); (g) Physical mixture of MeCD and PTX; (h) – Methyl _β_-cyclodextrin-paclitaxel (MeCD-PTX); (i) – Sulfobutyl ether _β_-cyclodextrin (SBCD); (j) – Physical mixture of SBCD and PTX; (k) – Sulfobutyl ether _β_-cyclodextrin-paclitaxel (SBCD-PTX). A vertical bar on ordinate corresponds to 1 W/g of heat flow.

Figure 2

Figure 2

Representative nuclear magnetic resonance (NMR) spectra of _β_-cyclodextrins (CDs) and their inclusion complexes with paclitaxel (PTX). (a) – Hydroxy propyl _β_-cyclodextrin (HPCD); (b) – Hydroxy propyl _β_-cyclodextrin-paclitaxel (HPCD-PTX); (c) – Methyl _β_-cyclodextrin (MeCD); (d) – Methyl _β_-cyclodextrin-paclitaxel (MeCD-PTX); (e) – Sulfobutyl ether _β_-cyclodextrin (SBCD); (f) – Sulfobutyl ether _β_-cyclodextrin-paclitaxel (SBCD-PTX).

Figure 3

Figure 3

Representative X-ray diffraction spectra of free paclitaxel (PTX) and _β_-cyclodextrin (CD) inclusion complexes with PTX. (a) – Free PTX; (b) – Methyl _β_-cyclodextrin-paclitaxel (MeCD-PTX); (c) – Sulfobutyl ether _β_-cyclodextrin-paclitaxel (SBCD-PTX); (d) – Hydroxy propyl _β_-cyclodextrin-paclitaxel (HPCD-PTX).

Figure 4

Figure 4

Genotoxicity of _β_-cyclodextrins (CDs). (a) – (j) – representative images of cells stained with nuclear dye incubated with the following substances: (a) – Media (untreated cells, negative control); (b) – DMSO (negative control for the solvent); (c) – Cyclophosphamide (Cyc) with metabolic activator – S9 mix (positive control 1); (d) – Ethyl methanesulfone – EMS (positive control 2); (e) – Hydroxy propyl _β_-cyclodextrin (HPCD); (f) – HPCD + S9; (g) – Methyl _β_-cyclodextrin (MeCD); (h) – MeCD + S9; (i) – Sulfobutyl ether _β_-cyclodextrin (SBCD); (j) – SBCD + S9. (k) – Quantitative analysis of micronuclei formation. Means ± SD are shown. *P < 0.05 when compared with control (untreated cells). Arrows indicate micronuclei.

Figure 5

Figure 5

Cytotoxicity of _β_-cyclodextrin (CD) – Paclitaxel (PTX) inclusion complexes in different cell lines. Specified cell types were incubated within 24 h with free PTX and CD-PTX complexes indicated. Means ± SD are shown. *P < 0.05 when compared with free PTX.

Figure 6

Figure 6

Cellular internalization of free and _β_-cyclodextrin – bound fluorescently labelled paclitaxel. (a) Representative light and fluorescence images of cells incubated within 3 h with substances indicated. (b) Representative flow cytometry fluorescence intensity charts. PTX – free non-bound paclitaxel; HPCD-PTX – Hydroxy propyl _β_-cyclodextrin-paclitaxel; MeCD-PTX – Methyl _β_-cyclodextrin-paclitaxel; SBCD-PTX – Sulfobutyl ether _β_-cyclodextrin-paclitaxel.

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