Doxorubicin skin penetration from monoolein-containing propylene glycol formulations

https://doi.org/10.1016/j.ijpharm.2006.08.021Get rights and content

Abstract

Topical chemotherapy with the antineoplastic doxorubicin (DXR) could be an alternative to treat skin cancer, however its poor skin penetration often limits the efficacy of topical formulations. The aim of this work was to study the effect of monoolein (MO), a penetration enhancer, on the in vitro skin permeation and retention of DXR. DXR was incorporated in a propylene glycol preparation containing 0–20% of MO. DXR release rate and topical delivery were evaluated in vitro using acetate cellulose membrane and porcine skin, respectively, mounted in a Franz diffusion cell. At 5%, MO did not significantly change DXR release rate, but MO concentrations larger than 10% decreased almost twice its release. In vitro skin penetration studies showed that the presence of MO in the propylene glycol formulations markedly increased DXR presence in the stratum corneum (SC). At 5%, MO significantly increased the amount of DXR in the SC already in the first hours, attained a maximum in 6 h. Comparing propylene glycol formulations containing more than 10% MO with that containing 5%, the former took the double of the time (12 h) to reach the same amount of DXR in the skin, result that is in agreement with in vitro release studies. Interesting, despite the fact that MO significantly increased the amount of DXR in the SC, drug transdermal delivery did not change. These findings suggest a cutaneous delivery of DXR that is an important condition for topical treatment of skin tumors. Further in vivo experiments can show DXR delivery to deeper skin layers.

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.

References (42)

Cited by (61)

  • Potential of supercritical fluid myrtle extracts as an active ingredient and co-preservative for cosmetic and topical pharmaceutical applications

    2022, Sustainable Chemistry and Pharmacy
    Citation Excerpt :

    Chlorhexidine was tested at 0.2%, through dilution of the 20% commercial solution, since this is the normal concentration found in oral elixirs. Propylene glycol has been widely used in the preparation of plant extracts and in topical products as a permeation promoter, emollient, humectant and emulsion stabilizer (Herai et al., 2007; Hosmer et al., 2009). According to the European Committee for the Safety Assessment of Cosmetic Ingredients, propylene glycol is considered a safe ingredient for the skin and is present in numerous cosmetic and pharmaceutical products on the market (Fiume et al., 2012).

  • Poly (vinyl alcohol) microneedles: Fabrication, characterization, and application for transdermal drug delivery of doxorubicin

    2018, European Journal of Pharmaceutics and Biopharmaceutics
    Citation Excerpt :

    The hydrophilicity, charge, and high molecular weight of DOX limited its diffusion through the lipophilic layer of stratum corneum [20,21]. Furthermore, the anthracycline structure of DOX interacted with anionic lipids in the stratum corneum to prevent the drug penetration into the underlying skin layers [21]. These characteristics of DOX contributed to almost no delivery of DOX by passive diffusion in the untreated group.

  • Noscapinoids bearing silver nanocrystals augmented drug delivery, cytotoxicity, apoptosis and cellular uptake in B16F1, mouse melanoma skin cancer cells

    2017, Biomedicine and Pharmacotherapy
    Citation Excerpt :

    In this way, both Nos and Red-Br-Nos demonstrated their vital anticancer profile at higher and multiple doses. Topical administration of chemotherapeutic drugs has been investigated to increase their permeation across thicker stratum corneum layer and thereby to favour drug accumulation in deep skin layers, where tumour is usually located [16–19]. In this framework, several organic and inorganic nanovectors have been implicated for the topical delivery of chemotherapeutic drugs to implanted skin cancer cells [19–22].

View all citing articles on Scopus
View full text