Oil-in-oil microencapsulation technique with an external perfluorohexane phase

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Abstract

Commonly, the microencapsulation of a lipophilic drug in a polymeric matrix via an ordinary oil/oil emulsification allows entrapping limited drug amounts due to its loss into the external phase. In this present paper, a new microencapsultion method describes the use of perfluorohexane as an external oil phase in order to produce microparticles of polyvinylpyrrolidon/vinylacetate (copovidone) and Eudragit® RS. Due to its highly non-solvent properties to most compounds, very limited miscibility with organic solvents, and very low toxicity, perfluorohexane (PFH) represents an excellent liquid for an external phase of the emulsion. Copovidone and Eudragit® RS microparticles were prepared by an oil/PFH method trapping ibuprofen as a lipophilic model drug and compared to results from conventional methods (oil/water and oil/oil). Morphological analyses of the obtained particles underlined the general matrix structure. The particle size varied between 75 μm (oil/oil) and 400 μm (oil/PFH) largely influenced by the stirring speed. Although drug release kinetics were principally similar for all preparation methods, it was generally found that encapsulation rates of oil/water and oil/PFH systems (oil/water: 74 ± 9%; oil/PFH: 86 ± 10%) were superior to ordinary oil/oil emulsification (3 ± 1%). The use of PFH was found to be a new promising tool for the preparation of microparticles. This modified emulsification method allowed the entrapment of lipophilic drugs into hydrophilic or lipophilic polymers in the absence of an aqueous phase.

Introduction

Microparticles can be designed for a large variety of therapeutic applications and for a nearly unlimited number of drugs. This has led to the creation of many different microencapsulation methods specifically adapted to the requirements of each drug's properties and of each production setup (Benita, 1996). The most widely applied methods for pharmaceuticals are based on the use of preformed polymers, employed to entrap the drug, for instance by an emulsification step followed by solvent evaporation solidifying the polymer with the drug entrapped. In such cases, microparticle preparation is achieved by an emulsification with mechanical stirring with the prerequisite that the inner phase solvent is highly volatile to ensure fast microparticle formation (Bodmeier and McGinity, 1988, Lamprecht et al., 2000). In most cases, strategies based on oil/water or oil/oil emulsifications are mainly related to two major decisive parameters: the solubility properties of the polymer and of the drug to be encapsulated. In particular, a low solubility of the drug in the external phase is required, otherwise low encapsulation rates may result due to drug leakage into the external phase (Nixon and Jalil, 1990). In consequence, for hydrophilic drugs to be entrapped in a water-insoluble polymer, the well-known double emulsion method has been developed (Alex and Bodmeier, 1989, Nihant et al., 1994, Hombreiro-Perez et al., 2003). In contrast, when oil/oil emulsification is applied for hydrophilic polymer matrices, the entrapment of lipophilic drugs still remains a problem due to leakage into the external oily phase providing sufficient solubility for the drug (Lamprecht et al., 2004).

An omnipotent and ideal external phase liquid to encapsulate hydrophilic as well as lipophilic drugs into various polymers independent of their hydrophilicity would have the following properties: high non-solvent properties to most compounds, and very limited miscibility with organic solvents, and a lower volatility then the internal phase solvent. Perfluorated hydrocarbons are potentially of interest in this context since some of them possess such limited solubility and miscibility properties. Perfluorohexane (PFH) represents an excellent example of such a compound. Moreover, PFH is considered to be ‘practically non-toxic’ which is the lowest rating of toxicity an equivalent to more than 1 kg for a 70 kg human (Knovel Library, 2006). Thus, it is used for a variety of pharmaceutical purposes (Krafft and Riess, 1998) such as in aerosol technologies (von der Hardt et al., 2002) or in medical diagnostics, especially in ultra-sonic imaging and magnetic resonance imaging. Intravenously injected PFH micrometer sized bubbles provide an efficient tool for magnetic resonance imaging (Riess, 2001, Pisani et al., 2006). PFH is also able to dissolve gases, such as oxygen and consequently such formulations can be used to deliver oxygen to several tissues (Riess, 2001). All these applications prove that perfluorohexane is an adequate excipient in terms to pharmaceutical requirements to formulate microspheres (MS).

The objectives of this study were firstly to evaluate the use of PFH for the microencapsulation of drugs by an emulsification method and secondly to characterize the MS with respect to particle size and morphology, drug loading, and release kinetics. Ibuprofen was encapsulated as a lipophilic model drug. The characteristics of the developed MS were compared with particles obtained from oil/oil or oil/water emulsification methods, which were used as a standard.

Section snippets

Materials

Perfluorohexane and perfluoropolyester were generous gifts from H. Moebius & fils (Allschwil, Switzerland), Copovidone (vinylpyrrolidone–vinylacetate copolymer 60/40) was obtained from BASF (Ludwigshafen, Germany), and Eudragit® RS PO was a kind gift from Degussa/Röhm Pharma Polymers (Darmstadt, Germany). Polyvinyl alcohol, Polycaprolactone, ibuprofen, dichloromethane (DCM), heptadecyl-fluoro-1-decanol were purchased from Sigma–Aldrich (Deisenhofen, Germany). 1-Hexadecanol, 2-octyl-1-dodecanol,

Results and discussion

The perfluorohexane is a very dense liquid (d  1.68 g/cm3), which exhibited a very low, non-determinable solubility of Eudragit® RS, Copovidone or ibuprofen (data not shown). Although other studies mentioned a miscibility of PFH in DCM, where mass fraction of PFH was around 1% (Pisani et al., 2006), PFH exhibited a large non-miscibility range in the DCM/PFH ratios applied in this study. This was advantageous for the emulsification step, but rather delicate in terms of finding an appropriate

Conclusion

The use of PFH was found to be a new promising tool for the preparation of MS. A modified emulsification method allowed the entrapment of lipophilic drugs into hydrophilic or lipophilic polymers in the absence of an external aqueous phase. This method turns the parameter of drug's solubility in the external phase to a factor of negligible importance and could tremendously facilitate the design of drug loaded MS. The obtained MS differ only slightly from properties found with particles obtained

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