Liquid spray formulations of xibornol by using self-microemulsifying drug delivery systems

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Abstract

Xibornol is a lipophilic drug mainly used in Italy and Spain in spray dosage forms for the local treatment of infection and inflammation of the throat. Its poor water solubility makes difficult the development of aqueous formulations of the drug, thus giving rise to a limited number of stable and pharmaceutically accepted preparations. In fact, xibornol is actually marketed only as spray aqueous suspension. The aim of this work was to evaluate the possibility of developing a stable liquid formulation of the drug intended for oral spray administration using a self-microemulsifying drug delivery system (SMEDDS). These systems are able to adequately improve the drug solubility, allowing the introduction of relatively high concentration of drugs in the form of solution. Labrafil M1944, Labrafil M2125 and Labrafac CC were screened as oil phases, Labrasol and Labrafac PG as surfactants and Transcutol as co-surfactant. Pseudo-ternary phase diagrams were constructed, by titration with the aqueous phase of different oil phases and surfactant/co-surfactant mixtures in order to identify the self-microemulsification region and the optimal micro-emulsion composition. Then, complete pharmaceutical formulations were prepared and evaluated for stability and viscosity properties. The final selected formulations, containing Labrafil M1944, Transcutol, Labrafac PG and a hydrophilic co-solvent (propylene glycol or PEG 200) allowed complete solubilization of the required xibornol concentration (3%, w/v) and showed physical good stability up to 2 months at 25 and 4 °C, suitable viscosity and organoleptic properties.

Introduction

Xibornol [6-(isoborn-2-yl)-3,4 xylenol] is a highly lipophilic and poorly soluble drug used as spray mouthwash for the local treatment of infection and inflammation of the throat and in the dental care, due to both its bacteriostatic activity, mainly against Gram positive micro-organisms and its antiviral properties (Fabbri et al., 1988, Scaglione et al., 1988).

The drug concentration required for the therapeutic activity is 3% (w/v). Its poor water solubility makes difficult to set up drug formulations based on aqueous solvents, so xibornol is at present commercially available only as spray aqueous suspension (http://www.biam2.org).

Among the most common approaches aimed to improve the oral bioavailability of poorly water soluble compounds, lipid-based formulations such as drug incorporation into oils (Burcham et al., 1997), emulsions (Myers and Stella, 1992) and in particular self-microemulsifying formulations (Gursoy and Benita, 2004, Ghosh and Murthy, 2006) are known to be successful.

However, in the present case, the use of oil solvents to obtain solutions of the drug is not recommended because of the topical oral use of such formulations, that could give rise to problems of unpleasantness or irritancy.

Thus, the formulation approach of self-microemulsifying drug delivery systems (SMEDDS) was considered. Self-emulsifying and self-microemulsifying drug delivery systems have recently received increasing attention in the development of oral dosage forms with improved solubility and bioavailability of lipophilic drugs, particularly in virtue of the successful results obtained by using such a strategy with compounds such as cyclosporin A, lipid-soluble vitamins and the HIV protease inhibitors (Pouton, 2000, Ho et al., 1996, Gursoy et al., 2003, Gao et al., 2003, El-Laithy, 2003, Kang et al., 2004, Grove et al., 2006).

SMEDDS are isotropic and thermodynamically stable solutions consisting of an oil, surfactant, co-surfactant and drug mixtures which spontaneously form oil-in-water micro-emulsions when mixed with water under gentle stirring. The advantages of these systems include not only improved drug solubilization, but also enhanced release and absorption properties, due to the already dissolved form of the drug in the formulation and the resulting small droplets size, providing a large interfacial surface area (Farah et al., 1994, Craig et al., 1995, Gershanik and Benita, 2000).

However, SMEDDS have to be carefully formulated on a case-by-case basis according to the characteristics of the drug compound. In fact, both the amount and hydrophobicity of the solubilized drug, the nature, combination, mixing ratio and amount of each of the oil, surfactant and co-surfactant used greatly affect the self-emulsification process (Pouton, 1985, Wakerly et al., 1986, Wakerly et al., 1987, Warisnoicharoen et al., 2000, Rhee et al., 2001). Several authors have demonstrated that only specific excipient combinations can give rise to efficient self-emulsification formulations (Charman et al., 1992, Chanana and Sheth, 1995, Kimura et al., 1994). Therefore, when designing a SMEDDS, a very thoughtful selection of both type and amount of excipients is necessary in order to define the optimal combination of the components that will create stable, fluid and reproducible micro-emulsion systems.

In the present work we evaluate the possibility of developing and optimizing a new oral liquid spray formulation of xibornol as a valid alternative to the current aqueous suspension formulations by using the self-emulsifying micro-emulsion approach in order to adequately improve the drug solubility. Both long and medium chain triglyceride oils with different degrees of saturation were mainly used as oily-phase of SMEDDS, whereas non-ionic compounds with a relatively high hydrophilic-lipophilic balance (HLB) are the most widely recommended as surfactants (Gursoy and Benita, 2004). On this basis, Labrafil M1944, Labrafil M2125 and Labrafac CC were screened as possible oil phases, and Labrasol (HLB 14) and Labrafac PG (HLB 10) as surfactants, whereas Transcutol was used as co-surfactant.

Section snippets

Materials

The following materials were kindly donated by Gattefossé (Milan, Italy): Labrafil M1944 (Oleoyl macrogol-6 glycerides), Labrafil M2125 (Linoleoyl macrogol-6 glycerides) and Labrafac CC (Medium chain triglycerides), used as oily-phases, Labrasol (Caprylocaproyl macrogol-8 glycerides) and Labrafac PG (Propylene Glycol caprylate/caprate) used as surfactants and Transcutol (Diethylene glycol monoethyl ether) as co-surfactant. Propylene glycol and PEG 200, used as hydrophilic solvents were from

Results and discussion

Pseudo-ternary phase diagrams were constructed, as described in Section 2, by titration with water of mixtures of each of the selected oils with different surfactant/co-surfactant ratios, in order to find the optimal component concentration range to obtain transparent and stable O/W micro-emulsions. The shaded areas in the pseudo-ternary phase-diagrams shown in Fig. 1A represent the existence field of stable, clear and transparent O/W micro-emulsions containing Labrafil M1944 as oil and with

Conclusions

The self-microemulsifying approach was found to be effective to formulate stable and pharmaceutically acceptable liquid spray formulations of xibornol. In fact, it was possible to introduce in these systems an adequate concentration of the drug for therapeutic effects in the form of solution, thus making it possible to develop a valid alternative to the current aqueous suspension formulations.

Moreover, this study also highlighted the importance of carefully selecting specific pharmaceutical

Acknowledgements

The authors would like to thank Dr. Peter Mario Worsch (Anton Paar GmbH, Graz, Austria) for kindly performing SAXS analysis.

Vincenzo Di Marzio (PANalytical S.r.l., Milan, Italy) is also gratefully acknowledged for his availability and helpful technical assistance.

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