Microemulsion systems to enhance the transdermal permeation of ivermectin in dogs: A preliminary in vitro study
Introduction
Ivermectin (IVM) is a macrocyclic lactone, widely used in veterinary medicine against both endoparasites and ectoparasites (Ashour, 2019). This drug can be used orally or via subcutaneous injection in dogs and is indicated for the prevention of heartworm disease, as well as in the treatment of sarcoptic mange (Sarcoptes scabiei var. Canis), demodectic mange (Demodex canis), otoachariasis (Otodectes cynotis), infestations by Cheyletiella spp. and verminoses (Ancylostoma caninum, A. braziliense - adult forms and larvae, Uncinaria stenocephala - adults and larvae, Capillaria spp., Trichuris vulpis, Toxocara canis, Toxascaris leonina and Strongyloides spp.). The product is even effective against microfilariae of Dirofilaria immitis and its larval tissue stages during the first 6 weeks of infection (L3, L4 and juvenile adult) (Laing et al., 2017).
The drug presents few side effects when compared to the other molecules from the same class. However, IVM is practically insoluble in water (0.0004% m/v) and in aqueous preparations as conventional formulations (Canga et al., 2009; Sharun et al., 2019). The high frequency of administration and the consequent low compliance of the owners are also relevant disadvantages related to the use of this drug (Mueller et al., 2012). Neurological side effects have also been observed in dogs when high doses are used (Mueller, 2004; Mueller et al., 2012). In order to avoid these drawbacks, strategies such as the use of new delivery systems, via alternative routes such as the transdermal, can be used in veterinary medicine.
The administration of drugs through the skin is a non-invasive, convenient and comfortable way to administer drugs without trauma or risk of infection (Prausnitz and Langer, 2008; Riviere and Papich, 2001). This procedure avoids gastric metabolism and the first-pass effect through the liver found in the oral treatment. It also reduces side effects and increases the interval between administrations, thereby facilitating treatment compliance from pet owners (Prausnitz and Langer, 2008; Riviere and Papich, 2001; Ansari et al., 2011; Magnusson et al., 2001; Mills and Cross, 2006; Roberts et al., 2002).
Historically, topical formulations for the control of ectoparasites are powders, shampoos, sprays or aqueous solutions. Therefore, over time, some methods have been developed to prolong the release of therapeutic agents, especially in pets. The system known as “spot-on”, in which a small volume of product is applied directly to the animal's back, can promote sustained release for up to one month with only a single application, as observed in treatments for sarcoptic mange in dogs using moxidectin in combination with imidacloprid (Ahmed and Kasraian, 2002; Bernigaud et al., 2019).
It is known that the pharmacokinetic behavior of IVM is significantly affected by the selected administration route, animal species, physiological state and body condition (Canga et al., 2009). The vehicle employed may also influence the absorption process and drug concentration in the bloodstream (Lifschitz et al., 2007). In this context, microemulsions (MEs) stand as systems capable of increasing the permeation of drugs into the skin (Kogan and Garti, 2006; Kreilgaard, 2002) and promoting its sustained release through the transdermal route. IVM is a lipophilic drug that tends to be accumulated in the adipose tissue, where it can act as a drug reservoir (Canga et al., 2009). These systems also present adequate viscosity for administration as “spot-on” formulations (solvent-free) and represent versatile therapeutic formulations for various applications, including the release of the drug into (topical action) or through (systemic action) the skin for the treatment of ectoparasites and endoparasites, respectively (Lawrence and Rees, 2000; Santos et al., 2008; Sintov and Shapiro, 2004).
Some studies have observed that microemulsions phase behavior can change their permeation profile of drugs using pig and human skin (Araújo et al., 2010; Zhang and Michniak-Kohn, 2011; Zhang and Michniak-kohn, 2018). In these grounds, supposedly the phase behavior of the microemulsions can influence the permeation of IVM in canine skin. Therefore, this study aims to investigate the use of MEs with different phase behaviors in the transdermal administration of IVM for future use in the therapy of ectoparasites and endoparasites in dogs.
Section snippets
Material
IVM (≥ 97%) purchased from Sigma-Aldrich (St. Louis, USA) was used in method validation for HPLC. IVM used in the preparation of MEs and Isopropyl myristate (IPM) were obtained from local suppliers (Brazil). PEG-8 capric/caprylic glyceride (Labrasol) was acquired from Selecthimie/Gattefossé (Saint-Priest, France). All solvents used in HPLC quantification were HPLC grade. Other solvents and reagents were of analytical grade and obtained from national suppliers.
Construction of pseudoternary phase diagrams
Three phase diagrams using
Pseudoternary phase diagram and formulation selection
The pseudoternary phase diagrams in this study were composed of isopropyl myristate as oily phase, tween 80 and labrasol as surfactant and cosurfactant, respectively, and ultrapure water as the aqueous phase. Three phase diagrams containing different surfactant/cosurfactant ratios (1:1, 1:2 and 1:3) were obtained. As shown in Fig. 1, the diagrams presented only 2 distinct regions: region of MEs and phase separation. It was also possible to observe that the diagram III (1:3) presented a larger
Discussion
The MEs F2 (w/o), F5 (bicontinuous) and F8 (o/w) were selected and characterized by electrical conductivity, SAXS and rheology measurements. Characterization data demonstrated that MEs containing IVM were successfully obtained and that there was little influence on the structural characteristics of the MEs after incorporation of IVM.
It is widely accepted that the microemulsions phase behavior can influence their permeation performance of some drugs (Araújo et al., 2010;Zhang and Michniak-Kohn,
Conclusion
Three microemulsions, F2 (w/o), F5 (bicontinuous) and F8 (o/w) have been successfully obtained. Ivermectin was incorporated in these formulations promoting few modifications in the microemulsions. In coclusion, the phase behavior has influenced the drug permeation in the canine skin differently from other animal models and microemulsions can be used as transdermal delivery systems (w/o) or topical delivery systems (o/w) for ivermectin administration. The microemulsions studies may be promising
Acknowledgements
The authors thank the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil) for the scholarship. We also acknowledge the Laboratório Nacional de Luz Síncroton (LNLS, Campinas SP, Brazil) for the provision of the synchrotron radiation facilities. We would like to thank the SAXS staff for the assistance in using the SAXS1 beamline through the approved project number 20160301.
Declaration of interest
The authors report no declarations of interest.
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