Doxorubicin skin penetration from monoolein-containing propylene glycol formulations
Introduction
Doxorubicin hydrochloride (DXR) is an anthracyclin antibiotic widely used in antitumor chemotherapy especially for the treatment of solid tumors (Heywang et al., 1998, Gewirtz, 1999). However, DXR, in common with many other chemotherapeutic agents, has toxic side effects such as myelosupression, mucositis and cardiac toxicity (Chabner and Longo, 2001). Topical chemotherapy for the treatment of cutaneous malignancies, as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), could be an alternative to reduce drug systemic toxicity. Also, smaller residual tumors could be completely removed by less extensive surgery (Guthrie and Porubsky, 1982, Wieman et al., 1983, Guthrie et al., 1985, Luxenberg and Guthrei, 1986, Chang et al., 1993). Partially effective DXR local application in selected cases of advanced and recurrent breast cancer (Shimizu et al., 1986) and carcinosarcoma (Moore et al., 1985) has been reported. However, formulations used in these cases of DXR topical administration were simple ointments. Theoretically, to improve tumor DXR bioavailability in topical treatments, drug skin penetration should be increased either by varying vehicle composition in order to increase drug solubility in the skin, or by altering skin permeability to the drug using, for example, chemical penetration enhancers (Pereira et al., 2002, Guy and Hadgraft, 2003). Glyceryl monooleate (Monoolein, MO), a fusogenic and polar lipid, has been proposed as a enhancer as it causes temporary and reversible disruption of the ordered lamellar structure of the bilayers in the stratum corneum, leading to increased fluidization of the intercellular lipid medium (Maggio and Lucy, 1976, Giannakou et al., 1995, Ogiso et al., 1995, Lopes et al., 2005).
In the present study, the influence of MO on the percutaneous absorption of DXR and its retention in the skin was investigated in vitro. Drug release from different formulations was also studied to better understand skin permeation experiments.
Section snippets
Chemicals
Myverol 18–99 K, as a source of monoolein, was kindly offered by Quest International (Campinas, Brazil) and was used as received. Doxorubicin hydrochloride (DXR) was purchased from Eurofarma (São Paulo, Brazil), methanol and tetrahidrofuran from Ominsolve (Merck, Darmstadt, Germany), propylene glycol and ZnSO4 from Synth (Diadema, Brazil). All other chemicals were analytical grade. Deionized water (Milli-Q Millipore Simplicity 185, Bedford, MA) was used to prepare all solutions.
Skin
Experiments were
Results and discussion
Monoolein assumes a variety of structures in aqueous media, forming different mesophases, by self-association depending on water content, temperature and monoolein concentration (Engström, 1990, Esposito et al., 2003). Monoolein-containing propylene glycol formulations in the concentrations used in this report were characterized by polarized light microscopy as isotropic liquids over a temperature range of 25–40 °C (Lopes et al., 2005). Fig. 1 shows the DXR release profile from the formulations
Acknowledgment
This work was supported by Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP), Brazil.
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