Oil-in-oil microencapsulation technique with an external perfluorohexane 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
References (21)
- et al.
Solvent selection in the preparation of poly(dl-lactide) microspheres prepared by the solvent evaporation method
Int. J. Pharm.
(1988) - et al.
Non-degradable microparticles containing a hydrophilic and/or a lipophilic drug: preparation, characterization and drug release modelling
J. Controlled Release
(2003) - et al.
Highly fluorinated amphiphiles and colloidal systems, and their applications in the biomedical field
Biochimie
(1998) - et al.
Biodegradable microparticles as a two-drug controlled release formulation: a potential treatment of inflammatory bowel disease
J. Controlled Release
(2000) - et al.
Design of pH-sensitive microspheres for the colonic delivery of the immunosuppressive drug tacrolimus
Eur. J. Pharm. Biopharm.
(2004) - et al.
Design of microencapsulated chitosan microspheres for colonic drug delivery
J. Controlled Release
(1998) - et al.
Controlled release indomethacin microspheres prepared by using an emulsion solvent-diffusion technique
Int. J. Pharm.
(1990) - et al.
Design of a new multiparticulate system for potential site-specific and controlled drug delivery to the colonic region
J. Controlled Release
(1998) - et al.
Encapsulation of water-soluble drugs by a modified solvent evaporation method. I. Effect of process and formulation variables on drug entrapment
J. Microencaps.
(1989) - (1996)
Cited by (28)
Microencapsulation of oxalic acid via oil-in-oil (O/O) emulsion solvent evaporation
2017, Powder TechnologyCitation Excerpt :Especially, the non-aqueous emulsions can provide important advantages for the microencapsulation of hydrolytically unstable actives and some poorly water-soluble actives [2,6]. However, non-aqueous emulsions are much less commonly reported because of the rare immisible oils [7–9]. Microcapsules with characteristic sustained release properties have been commonly used in pharmaceutical field [10–13], agricultural agent industry [14–16], food [17–19] and cosmetics industry [20], biomedical engineering [21], textiles [22,23] and even electronics [24].
Amphiphilic block-random copolymer surfactants with tunable hydrophilic/hydrophobic balance for preparation of non-aqueous dispersions by an emulsion solvent evaporation method
2017, Reactive and Functional PolymersCitation Excerpt :Emulsion solvent evaporation can be adapted to not only aqueous system [6–10] but also non-aqueous system. Examples of the non-aqueous system are the formations of poly(d,l-lactide-co-glycolide) nanoparticles from acetonitrile in a liquid paraffin emulsion [11], biodegradable microspheres containing cisplatin from dimethylformamide in a liquid paraffin emulsion [12], nanocapsules incorporating nitric oxide from hexafluoroisopropanol in a cyclohexane emulsion [13], and microcapsules containing lipophilic drugs from a mixture of acetone and ethanol in a triglyceride emulsion [14]. The non-aqueous emulsion solvent evaporation requires a suitable surfactant to stabilize the non-aqueous emulsion and resulting dispersion, depending on the dispersed and continuous phases.
Plasma deposited stability enhancement coating for amorphous ketoprofen
2011, European Journal of Pharmaceutics and BiopharmaceuticsCitation Excerpt :Films were plasma polymerized from perfluorohexane (C6F14), a monomer known to form highly hydrophobic films therefore allowing very limited water vapor penetration [28]. In addition, C6F14 is practically non-toxic when taken orally suggesting that it is an adequate excipient for the formulation of oral dosage forms [29]. Properties of uncoated and plasma-coated RF-KET were investigated employing a wide variety of techniques.
Development of ethylcellulose-polyethylene glycol and ethylcellulose- polyvinyl pyrrolidone blend oral microspheres of Ibuprofen
2010, Journal of Drug Delivery Science and TechnologyInfluence of the solvent on the microencapsulation of an hydrated salt
2010, Carbohydrate PolymersPhysico-chemical analysis of metronidazole encapsulation processes in Eudragit copolymers and their blending with amphiphilic block copolymers
2009, International Journal of PharmaceuticsCitation Excerpt :The organic solvent in the inner phase is completely eliminated from the evaporation, characterizing this as a completely anhydrous process. The convenient choice of the outer oil phase allows that the diffusion of hydrophilic drug from the inner phase can be minimized, improving the entrapment efficiency of drug (Kobaslija and McQuade, 2006; Mana et al., 2007; Yang et al., 2005). Using this procedure (as indicated in Scheme 3) a solution containing 10 mg of metronidazole and 90 mg of the Eudragit in 5–10 mL of chloroform (inner oil phase) was added dropwise to 80 mL of liquid paraffin.