Characterization of a pseudo ternary phase diagram of poloxamer 407 systems for potential application of 5-aminolevulinic acid in photodynamic therapy

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Abstract

A poloxamer 407 (POX) gel containing dimethyl isosorbide (DMIS), isopropyl alcohol (IPA), propylene glycol dicaprylocaprate (MIG) and water has been suggested in a previous study for permeation enhancement of 5-aminolevulinic acid (ALA) across isolated human stratum corneum. The purpose of this study was to characterize other formulations coming from the same pseudo ternary phase diagram as the “Thermogel” in order to find out which of them show appropriate characteristics to be used as a vehicle for ALA since it could be shown that variation of the ingredients’ content had an influence on the permeation rate. A pseudo ternary phase diagram was developed with water, a fixed combination of 1:1 of IPA and DMIS and a fixed ratio of 4:1 POX to MIG. The systems were categorized according to their consistencies and ringing gel characteristics with special emphasis on appropriate formulations for dermal application. Polarizing microscopy enabled a clear differentiation between isotropic and anisotropic systems. Wide angle X-ray diffraction analyzes confirmed that anisotropy was due to crystalline POX. Furthermore both methods showed that IPA/DMIS was an inferior solvent mixture for POX related to water.

Introduction

Poloxamer 407 (POX), a polyoxyethylene–polyoxypropylene block copolymer, forming gels of thermoreversible characteristics (Kim et al., 2000, Gilbert et al., 1986) and featuring the best toxicological data among this kind of block copolymers (Schmolka, 1972) has widely been studied in the last years. Due to these favorable properties a variety of pharmaceutical applications as drug carriers for different purposes has been studied. For example a buccal application for triamcinolone acetonide (Shin and Kim, 2000), a rectal formulation for quinine (Fawaz et al., 2004), an ophthalmic gel for pilocarpine (Desai and Blanchard, 2000) and a liposomal intramuscular gel for the administration of ibuprofen (Paavola et al., 2000) have been considered. The major interest has though been focused on the topical and dermal application of POX systems. Many different active pharmaceutical ingredients (APIs) as well as vehicles and techniques have been examined for this purpose. Several authors incorporated analgesic drugs in POX gels and reported advantages on application and release characteristics (Fang et al., 2002, El-Kattan et al., 2000, Escobar-Chavez et al., 2005). Furthermore classical APIs for dermal application such as antibiotics (Zhang et al., 2002) and antiseptic drugs (Gilbert et al., 1986) were investigated, even a transdermal application by means of iontophoresis for drugs like insulin (Pillai and Panchagnula, 2003) and vasopressin (Nair and Panchagnula, 2003) was considered.

In a previous study from our group a POX hydrogel (thermogel) of a complex composition has been proposed for the topical application of 5-aminolevulinic acid (ALA) for the treatment of skin diseases like actinic keratosis and superficial skin cancer (Grüning and Müller-Goymann, 2008). Although esterification of ALA improves its penetration (Winkler and Müller-Goymann, 2005, Uehlinger et al., 2000, De Rosa et al., 2003), prodrugs need to be metabolized into the active form prior to the patient's exposure to the appropriate irradiation in the photodynamic therapy (PDT). The interval between topical application and irradiation takes up to several hours. That is why the topical application of ALA in novel vehicles is still of major interest in terms of providing permeation enhancement and reducing the time between administration and irradiation in PDT. Since a commercial formulation of the NSAID ibuprofen, Dolgit® Mikrogel, enhanced the permeation of ALA (Winkler and Müller-Goymann, 2005), an ibuprofen-free system containing the same excipients, named thermogel, was developed and compared to the commercial formulation as well as to water containing hydrophilic ointment (Wasserhaltige Hydrophile Salbe, WHS) from the German Pharmacopeia and Basiscreme DAC from the German Drug Code. The latter are bases commonly used in retail pharmacies for the application of ALA (Grüning and Müller-Goymann, 2008). The thermogel showed a 19.5-fold increase of ALA's permeation coefficient across isolated human stratum corneum compared to that from WHS. This novel thermogelling formulation contained 20% POX, 12.5% isopropyl alcohol (IPA), 12.5% dimethyl isosorbide (DMIS), 5% propylene glycol dicaprylocaprate (MIG) and 50% water (all w/w) and showed thermoreversible characteristics: in the refrigerator e.g. at 4 °C it was in the liquid state and above 13 °C (determined by means of oscillation rheometry upon increasing the temperature) it turned semisolid (Grüning, 2007). This gelation was completely reversible and occurred repeatedly upon adjusting the temperature accordingly.

Furthermore it could be demonstrated that POX hydrogels containing either none, one or two additives were inferior in terms of permeation enhancement and that a system containing all ingredients in a different ratio from that mentioned above was even able to enhance permeation compared to thermogel (Grüning, 2007). Thus a synergistic effect of the ingredients regarding the permeation was suggested.

The aim of this study was to establish a pseudo ternary phase diagram of water and fixed combinations of POX/MIG (4:1) and IPA/DMIS (1:1) in order to identify systems of appropriate consistencies for dermal application of APIs including ALA and to characterize them macroscopically as well as by polarizing microscopy (PLM) and wide angle X-ray diffraction (WAXD).

Section snippets

Materials

Poloxamer 407 Ph. Eur. (POX) is a surface active polyoxyethylene–polyoxypropylene block copolymer (PEO100–PPO56–PEO100) being responsible for the stabilization and consistency of the formulations. Dimethyl isosorbide (DMIS) is a solvent and solubilising agent and was also included in the formulations. Both were kindly provided by Dolorgiet (St. Augustin, Bonn, Germany). Miglyol® 840 (MIG) is the trade name of propylene glycol dicaprylocaprate Ph. Eur. and was purchased from Sasol Germany GmbH

Macroscopical examination

For the characterization of the systems a macroscopical examination was performed which included the determination of ringing gel characteristics. The appearance of the gels varied during the first 24 h. Since it took a few hours after manufacture until the structure of the gel was completely built up, all the determinations were made after at least 24 h of storage at 20 °C. The pseudo ternary phase diagram in Fig. 1 presenting the consistency of the formulations was established 24 h after

Conclusions

This study investigated a pseudo ternary phase diagram of water and fixed combinations of POX/MIG (4:1) and IPA/DMIS (1:1) macroscopically as well as by means of PLM and WAXD. An area could be identified containing formulations (gel- and cream-like) for appropriate dermal application, whereas other systems were either too hard or liquid and thus inappropriate for this purpose. Some of the liquid inhomogeneous systems could also gel around body temperature and could thus be used as vehicles for

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