Ivermectin-Loaded Oral Microemulsion for Oral Use

Abstract

The oral bioavailability of marketed ivermectin (IVR) tablets is 50% compared to an oral hydroalcoholic solution. In this study, we developed an oral liquid microemulsion of IVR to improve compliance in pediatric patients. Oils, surfactants, and co-surfactants were screened and selected using solubility and emulsification tests. Using the selected oil, surfactant, and co-surfactant, a pseudo-ternary phase diagram was developed at surfactant-to-co-surfactant ratios of 1:1, 2:1, and 3:1 for the purpose of identifying the microemulsion region. The final formulation was evaluated for its physical properties, stability, and in vitro release. Based on the solubility studies and emulsification ability, the oil, surfactant, and co-surfactant were selected. Different regions in the pseudo-ternary diagrams were identified: phase separation region, microemulsion area, emulsion gel region, microemulsion gel, w/o macroemulsion, and o/w macroemulsion. The globule size and zeta potential of the microemulsion were 25.01 ± 1.13 nm and -5.45 ± 0.130 mV, respectively. In vitro release studies indicated 100% release after 4 h. Stability studies showed that the formulation was stable for 1 month at 30 ± 2°C/65% RH and 40 ± 2°C/75% RH. An optimized, stable IVR-loaded oil-in-water microemulsion was successfully prepared to improve the drug’s solubility.

Introduction

Onchocerciasis, also known as ‘river blindness’, is a disease caused by the nematode Onchocerca volvulus, which spreads to humans through blackflies that act as vectors for the parasite [1-3]. When the mature worms start producing microfilariae (MF) one to three years after infection, onchocerciasis starts to show clinical symptoms. Acute papular onchodermatitis (APOD) and chronic papular onchodermatitis (CPOD) lesions are caused by host inflammatory responses to dead microfilariae in the tissue [4]. Active MF can enter the cornea, and if it persists there, the cornea eventually becomes opaque, turning white and hard (sclerosing keratitis), which can result in blindness [5,6]. The treatment regimen for onchocerciasis includes oral IVR tablets. IVR is a semi-synthetic anti-parasitic agent discovered in 1980 that is obtained from the bacteria Streptomyces avermitilis [6,7]. IVR has a high affinity for binding to glutamate-gated chloride ion channels in the nerve and muscle cells of invertebrates, which is thought to be the primary cause of its anti-parasitic effectiveness. The pharyngeal pump, in particular, is paralyzed as a result of the opening of these chloride ion channels, which causes a gradual and irreversible increase in membrane conductance, leading to paralysis and the death of the parasite [8-10]. IVR is practically insoluble in water, has a molecular weight of 875 g/mol, and is a lipophilic molecule with a log P value of 4.4 [10-12].

The bioavailability of the marketed tablets is 50% compared with an oral hydroalcoholic solution [6,13]. The oral bioavailability of the drug can be increased by increasing its solubility. The pediatric population has a particularly difficult time swallowing tablets and capsules [14,15]. Also, due to the discomfort and pain accompanied by intravenous administration, they naturally reject injections, affecting patient compliance. Most children’s medications are available in solution, emulsion, or suspension form, as these are easier for kids to swallow. Solutions are the most popular and convenient dosage form, especially for children, as opposed to tablets and capsules [16]. The oral route is the only approved route of administration for IVR in humans for the treatment of onchocerciasis [17].

The solubility of IVR can be enhanced by administering the drug in a microemulsion. Microemulsions are isotropic, thermodynamically stable, transparent emulsions consisting of oil, surfactant, and co-surfactant, with particle sizes ranging from 20 to 200 nm. These systems can be used to deliver poorly aqueous-soluble drugs by incorporating them into the oily phase. Certain components of microemulsions have been shown to inhibit P-glycoprotein (P-gp)mediated efflux, which helps improve the concentration of the drug in plasma [18,19, 20]. Thus, microemulsions are excellent candidates for delivering poorly water-soluble drugs. The objective of this study was to incorporate IVR into a stable microemulsion system and evaluate it for its appearance, globule size, dilution potential, drug content, and other characteristics. The composition of the microemulsion was determined by systematically conducting solubility and transmission studies using various oils, surfactants, and cosurfactants. Release and stability studies of the optimized microemulsion were performed to investigate its performance and stability.

Materials and Methods

IVR IP (Assay 98.60 %; specific rotation -18.8) was generously supplied by Karunesh Remedies, Ankleshwar, Gujarat, as a gift sample. Stelliesters MCT 55/45 (Medium-chain triglycerides), Stelliesters OLGA (Polyoxylglycerides/ and macrogol glycerides), Dubcare GPE M, and Dubcare GPE 810 (PEG-8 caprylic and capric glycerides) were supplied by Arihant Innochem, Mumbai, India. Miglyol 812 N (Medium-chain triglycerides) was obtained from IOI Chemical. Labrafac™ Lipophile WL 1349 (Medium-chain triglycerides), Lauroglycol™ 90 (Propylene glycol monolaurate (type II)), Transcutol® HP (Diethylene glycol monoethyl ether), and Capryol® 90 (Propylene glycol monocaprylate) were supplied by Gattefosse, India. Kolliphor® PS 80 (Polysorbate 80/Tween 80), Kolliphor® RH 40 (Polyoxyl 40 Hydrogenated Castor Oil), and Kolliphor® ELP (PEG-35 Castor Oil) were procured from BASF, India, as gift samples. All additional chemicals and reagents required for the study were of analytical grade. Millipore water was used to prepare the microemulsion.

See the full research paper as PDF: Ivermectin-Loaded Oral Microemulsion for Oral Use

Rajashree Hirlekar  , Mangal Nagarsenker , Komal Chandra
Letters in Applied NanoBioScience, Volume 14, Issue 4, 2025, 272, Open-Access Journal (ISSN: 2284-6808)