Development and optimization of lyophilized dry emulsion tablet for improved oral delivery of Ivermectin
Abstract
Ivermectin (IVM) is a widely used antiparasitic agent and has been repurposed for the treatment of COVID-19. However, its poor water solubility and low bioavailability present significant challenges, often requiring large doses for therapeutic effectiveness. This poses a burden on patients, as they need to take multiple tablets at once, which is both inconvenient and uncomfortable. This study aims to develop and optimize rapidly disintegrating lyophilized dry emulsion tablets (LDET) containing IVM using a quality by design (QbD) approach to enhance its solubility, dispersibility, wettability, and dissolution rate, thereby improving its absorption and bioavailability following oral administration. Oil-in-water (O/W) emulsions were prepared using sweet almond oil or Miglyol 840 as the oil phase, along with stabilizers. The optimal emulsion was subsequently lyophilized to produce IVM-LDET. Tablets’ characteristics were assessed in vitro for their properties including solubility, disintegration, and dissolution, and in vivo in rabbits for their pharmacokinetic (PK) profile. Results indicated a remarkable 600-fold increase in IVM solubility in the optimal emulsion formulation. IVM-LDET significantly enhanced the extent and rate of dissolution compared to raw IVM and the marketed tablet, Iverzine®. Furthermore, the PK profile of IVM from LDET showed a 30 % increase in maximum plasma concentration (Cmax) and area under the curve (AUC), and reduced time to reach maximum concentration (tmax) by 4 h compared to Iverzine® tablets. In conclusion, the developed IVM-LDET formulation presents a promising therapeutic alternative to conventional oral IVM products for treating parasitic or viral infections, potentially leading to improved therapeutic outcomes and patient compliance.
Introduction
Ivermectin (IVM), a semisynthetic anthelmintic agent isolated from the fermentation products of the bacterium Streptomyces avermitilis, is a mixture of avermectin A1a, 5-O-demethyl-22,23-dihydro-(component H2B1a), and avermectin A1a, 5-O-demethyl-25-de (1-methylpropyl)-22,23-dihydro-25-(1-methylethyl)-(component H2B1b) [1]. According to the Biopharmaceutics Classification System (BCS), IVM is classified as a Class II drug, characterized by poor solubility and high permeability. However, as a substrate for intestinal P-glycoprotein (P-gp), IVM may also exhibit characteristics of a BCS Class IV drug [2,3], contributing to its poor oral pharmacokinetic (PK) profile. The pKa value of IVM is approximately 12.47, indicating that it remains mostly unionized at physiologic pH [4]. Additionally, IVM has a partition coefficient (log P) value of 5.83, reflecting its high lipophilicity and poor solubility in water [5]. Metabolism of IVM primarily occurs in the liver, predominantly mediated by cytochrome P-4503A4 [6].
This drug is widely used for the treatment of multiple indications including strongyloidiasis, onchocerciasis (river blindness) [7,8], scabies [9], filariasis [7,10], lice and myiasis [11]. It must be mentioned that IVM stands as the most significant tool in the control of Neglected Tropical Diseases (NTDs), surpassing all other drugs in its effectiveness for reducing morbidity and interrupting transmission [12]. Currently, it is available in most countries around the world and has been approved by the FDA for both animal and human use. Oral (tablets), topical (creams), and injectable formulations of IVM are available; however, only the oral and topical preparations are authorized for use in humans.
IVM was also explored for potential repurposing for the prophylaxis and treatment of COVID-19 during the pandemic due to its antiviral and anti-inflammatory properties. Some studies have shown that COVID-19 patients who received this medication have experienced improved therapeutic outcomes, faster viral clearance, and enhanced symptoms resolution [[13], [14], [15]]. However, well-designed clinical trials and robust, high-quality evidence are needed to validate these findings and support therapeutic claims.
Despite the high lipophilicity of IVM, large oral doses of IVM are needed to achieve effective concentrations at its target sites due to its very poor water solubility (<0.005 mg/mL [2,16]). Additionally, administration of large doses of IVM is associated with side effects especially gastrointestinal (GI) ones. Similar rates of absorption for both solid and liquid dosage forms of IVM were reported but with varying systemic bioavailability (twice for ethanolic solution compared to capsules/tablets) [17]. This is mainly due to the poor and slow dissolution rate of IVM from traditional solid dosage forms. Suboptimal therapeutic efficacy remains an issue with conventional dosage forms of BCS class II drugs such as IVM [[18], [19], [20]].
IVM’s safety, efficacy, affordability, and availability make it highly attractive both as an established treatment for parasitic infections and as a repurposed drug for COVID-19. Therefore, a novel oral dosage form of IVM that allows for uniform, rapid, and maximal absorption in humans is highly needed to improve its oral bioavailability.
Research has demonstrated multiple approaches for the enhancement of solubility of poorly water-soluble drugs including nanoparticles, nanocrystals, micelles, solid dispersions, and complexation with cyclodextrin and others [[21], [22], [23], [24], [25]]. These formulations have been reported to improve the solubility of lipophilic drugs, result in sustained drug release, and improve drug’s PK profile as well as stability. However, some of them still suffer from low drug loading capacity, challenges in biocompatibility and safety, or toxicities resulting from high tissue accumulation of non-biodegradable material [[26], [27], [28]]. Specific factors need to be considered when attempting to improve a drug’s solubility including the drug’s characteristics, dosage form type, choice of excipients, cost, and ease of manufacture [23].
One of the most promising approaches to improve the solubility of poorly water-soluble drugs, thus enhancing their dissolution and absorption from the gastrointestinal tract (GIT), is using liquid emulsified lipid formulations that can be dried to form a solid dosage form such as tablets. Liquid emulsions can also control drug release, minimize inter- and intra-subject variability in bioavailability after oral delivery, and conceal the bitter taste of the drug [[29], [30], [31]]. However, they have several disadvantages attributable to their liquid state such as poor stability (prone to phase separation), high production costs, and poor acceptability by patients. Dry emulsions on the contrary show higher physical stability and are easy to use. It gets reconstituted in vivo to form the original emulsion and achieve improved bioavailability of poorly water-soluble drugs by increasing the lymphatic absorption and transport of the drug as well as achieving adequate solubility of the drug in the oil/water phases of the emulsion. Concomitant administration of lipids raises chylomicron synthesis in enterocytes, which allows the lipophilic drug to better disperse and taken up by intestinal lymph vessels thus improving its oral bioavailability [[32], [33], [34]].
Rapidly disintegrating lyophilized dry emulsion (LDE) tablets (LDET) offer a practical solution for delivering poorly soluble drugs for which fat co-administration or drug incorporation into oil-in-water (O/W) emulsion results in improving its oral bioavailability. Freeze-dried emulsion tablets offer the same favorable traits of freeze-dried dosage forms such as fast reconstitution and good preservation. Additionally, these tablets disintegrate rapidly in the mouth upon contact with saliva, facilitating easy swallowing and enhancing patient compliance and acceptability [35].
The use of LDE-technology in developing effective and stable LDET of IVM can enhance its solubility, dispersibility, wettability, and permeability. These improvements collectively might enhance its oral bioavailability, potentially leading to dose reduction and reduced side effects associated with the administration of large doses of IVM, subsequently improving treatment outcomes and patient compliance.
In this work rapidly disintegrating lyophilized dry O/W emulsion tablets containing IVM (IVM-LDET) were developed. To the best of our knowledge, this is the first study to investigate the use of LDE approach for reformulating IVM into tablets to enhance its oral delivery and therapeutic efficacy. The preparation, optimization, and characterization of IVM-LDET are reported. In addition, the in vivo performance and PK profile of IVM from the optimal IVM-LDET was investigated in rabbits and compared to that of the commercially available tablets (Iverzine, Ivermectin 6 mg/tablet, UniPharma).
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Materials
Ivermectin (IVM) was generously supplied by Hovione PharmaScience Limited (Taipa, Macau). High Performance Liquid Chromatography (HPLC) grades of methanol (Sigma-Aldrich, France) and acetonitrile (Honeywell, Germany) were used. In addition, the following chemicals were used: sodium hydroxide (Sigma-Aldrich, Sweden), sodium phosphate monobasic dihydrate (Sigma-Aldrich, Germany), gelatin (250 bloom) (Spectrum, USA), Miglyol® 840 (MedLab International), sweet almond oil (Spectrum, USA).
Eiman Abdalla Madawi, Hanan M. El-Laithy, Nihal Mohamed Elmahdy Elsayyad, Mutasem Rawas-Qalaji, Amjad Alhalaweh, Iman Saad Ahmed, Development and optimization of lyophilized dry emulsion tablet for improved oral delivery of Ivermectin, Journal of Drug Delivery Science and Technology, Volume 108, 2025, 106941, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2025.106941.
Read also our introduction article on Gelatin here:
