Liquid spray formulations of xibornol by using self-microemulsifying drug delivery systems
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.
References (27)
Modelling the semisolid processing of metallic alloys
Prog. Mater. Sci.
(2005)- et al.
An investigation into mechanism of self emulsification using particle size analysis and low frequency dielectric spectroscopy
Int. J. Pharm.
(1995) - et al.
Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability, 2003
J. Pharm. Sci.
(2003) - et al.
Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs
Eur. J. Pharm. Biopharm.
(2000) - et al.
Bioavailability of seocalcitol II: development and characterisation of self-microemulsifying drug delivery systems (SMEDDS) for oral administration containing medium and long chain triglycerides
Eur. J. Pharm. Sci.
(2006) - et al.
Preparation of microemulsions using polyglycerol fatty acid esters as surfactant for the delivery of protein drugs
J. Pharm. Sci.
(1996) - et al.
Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs
Int. J. Pharm.
(2004) - et al.
Formulation design and bioavailability assessment of lipidic self-emulsifying formulations and halofantrine
Int. J. Pharm.
(1998) - et al.
Systemic bioavailability of penclomedine (NSC-338720) from oil-in-water emulsions administered intraduodenally to rats
Int. J. Pharm.
(1992) Self-emulsifying drug delivery systems: assessment of the efficiency emulsification
Int. J. Pharm.
(1985)