Formulation of semi-solid dosage forms indented for transdermal delivery of ivermectin

The story of ivermectin originated in 1974, when scientist Satoshi Omura discovered Streptomyces avermitilis, which later led to the isolation of an active compound, avermectin and finally, ivermectin [1]. Ivermectin, which consists of two homologs (namely dihydro-avermectin B1b and dihydro-avermectin B1a) [2], is a broad-spectrum anti-parasitic drug. It was initially employed in the veterinary field of medicine; however, in 1987 it was brought on by Merck as a treatment regime for onchocerciasis, a disease that effected a great percentage of the population in Africa [3]. Since then, ivermectin has been widely used in the treatment of both topical and systemic diseases, which includes, scabies, rosacea, and other filarial infections [4],[5]. Ivermectin stimulates the gamma-aminobutyric acid (GABA)-gated chloride ion channels, commonly found in nematodes, insects, and ticks, which leads to paralysis [6],[1].

However, its safety in humans has been established due to its inability to cross the blood brain barrier [1]. Despite ivermectin’s use over the past few decades, the coronavirus disease 2019 (COVID-19) pandemic has shed a light on the drug; hence, its reported anti-viral activity against the virus has become an intriguing, yet controversial research topic. The speculated mechanism of action in the treatment of the virus, is due to the inhibition of the viral importin (IMB) / -mediated nuclear import, resulting in the reduction of viral replication [7], [8]. Although this active pharmaceutical ingredient (API) is generally well tolerated, some adverse effects, including gastrointestinal upset and abdominal pain, have been reported with oral dosages [5]. Additionally, there are reports documenting the low bioavailability of the drug [9].

The transdermal drug delivery route offers many advantages over conventional routes; some of which includes, avoidance of hepatic first-pass metabolism to increase bioavailability and avoidance of gastrointestinal upset [10], [11]. During this study, the focus was on the transdermal and/or topical delivery of ivermectin. Although transdermal drug delivery has many benefits, there are some drawbacks that should be taken into consideration, i.e., the number of APIs that can be delivered via this route is limited [11], [12]. Ivermectin is a highly lipophilic drug that presents with physicochemical properties far from the ideal physicochemical properties required for transdermal drug delivery, which is why it is anticipated that it will have difficulties permeating the skin. Therefore, three semi-solid formulations, i.e., emulgel, cream, and ointment were formulated during this study to investigate whether any of the formulations could potentially assist in delivering ivermectin transdermally and/or topically.

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Materials

Ivermectin was obtained from DB Fine chemicals (Sandton, South Africa). The surfactants, Span® 60 and Tween® 80 as well as polyethylene glycol 400 (PEG 400) was obtained from Sigma-Aldrich® (Johannesburg, South Africa). Cetyl alcohol, used as a thickening agent and polyethylene glycol 4000 (PEG 4000) was obtained from Merck chemicals. Sodium hydroxide (NaOH) and orthophosphoric acid used for the preparation of phosphate buffered solution (PBS, pH 7.4) were purchased at Sigma-Aldrich®

Zia Aucamp, Wilna Liebenberg, Hendrik JR. Lemmer, Minja Gerber, Formulation of semi-solid dosage forms indented for transdermal delivery of ivermectin, Journal of Drug Delivery Science and Technology, 2024, 106174, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2024.106174.

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