Self-emulsifying micelles as a drug nanocarrier system for itraconazole oral bioavailability enhancement; in vitro and in vivo assessment

Abstract

Itraconazole (ITZ) is a renowned antifungal medication, however its therapeutic efficacy is limited by low solubility and oral bioavailability. The current research work attempted to augment the oral bioavailability of ITZ by incorporating into self-emulsifying micelles (SEMCs). To fabricate the SEMCs, various preparation techniques including physical mixture, melt-emulsification, solvent evaporation and kneading, were opted by using different weight ratio of drug and solubilizers i.e. Gelucire-50/13 or Gelucire-44/14 and characterized both in vitro and in vivo. The prepared SEMCs were found to be in the size range from 63.4 ± 5.2 to 284.2 ± 19.5 nm with surface charges ranging from −16 ± 1.2 to −27 ± 2.0 mV. The drug solubility was improved to a reasonable extent with all investigated formulations, however, SEMCs in group 6 prepared by kneading method (KMG6) using Gelucire-44/14: drug (10:1 presented 87.6 folds’ increase (964.93 ± 2 μg/mL) compared to solubility of crystalline ITZ (11 ± 2 μg/mL) through kneading method. In addition, KMG6 SEMCs shows the fast drug release compared to other SEMCs. Further, KMG6 SEMCs also exhibited 5.12-fold higher relative intestinal serosal fluid absorption compared to crystalline ITZ. The pharmacokinetic parameters such C_max, AUC and T_max of KMG6 SEMCs significantly improved compared to crystalline ITZ. In conclusion, the manipulation of ITZ solubility, dissolution rate and absorption using SEMCs is a promising strategy for bioavailability enhancement.

Introduction

The bioavailability of poorly soluble drugs may be hampered by many factors i.e. absorption solubility, or dissolution rate. It is noteworthy that solubility is the rate limiting factor for the oral bioavailability, so, the oral bioavailability can be improved with the help of solubility enhancing strategies (Khan et al., 2022). In addition, the bioavailability of drugs depends on drug absorption from oral solid dosage forms. Many strategies were previously opted to enhance the oral bioavailability by addressing the dissolution and absorption of an active pharmaceutical ingredients (APIs) (Shekhawat and Pokharkar, 2017).

ITZ as an API has been extensively used for fungal infections treatment. ITZ has good tissue distribution properties and strong affinity for fungal cytochrome P-450 that makes it broad spectrum candidate for systemic fungal infections (Lestner and Hope, 2013). Besides, ITZ evades serious invasive fungal infections through prophylaxis (Allegra et al., 2017). It is categorized in Biopharmaceutical Classification System in class-II drugs owing to its poor solubility (Matsui et al., 2016). The prevailing ITZ formulations have shown large variability in results from dosage form to interpersonal pharmacokinetics (Abuhelwa et al., 2016). In fact, ITZ has showed 50 % oral bioavailability (Heykants et al., 1989, De Beule, 1996). Along with the poor aqueous solubility, P-glycoprotein (P-gp) and high metabolism rate might be the other possible reasons of low bioavailability of ITZ. Therefore, dissolution and absorption enhancement is necessary to improve the bioavailability of ITZ and good therapeutic results (Deshpande et al., 2018).

Previously, various approaches have been tried to address oral bioavailability issue of ITZ. Among them, solid dispersion (Thiry et al., 2017), spray dried dispersion (Adhikari and Polli, 2020), liquisolid compacts (Thakkar et al., 2020), liposomes (Li et al., 2017), polymeric film (Karagianni and Peltonen, 2020), porous spheres (Pawar et al., 2017), nanoparticles (Bilgili et al., 2018), nanoemulsion (Botros et al., 2020), self-micro-emulsifying drug delivery system (Quan et al., 2017), and nanocomposities (Bhakay et al., 2018), are few approaches that were applied to improve the oral bioavailability. Moreover, the main reason of SEMCs selection for oral bioavailability enhancement of ITZ is that SEMCs as a binate system have shown promising results in improving bioavailability of different poorly soluble drugs (Zhang et al., 2017). SEMCs can increase the solubility by decreasing the molecular size of drug particles (Italiya et al., 2019). Further SEMCs can convert the crystalline drug to amorphous form (Indulkar et al., 2019). SEMCs preparation is very simple, easy and economical method to increase solubilization and bioavailability of poorly soluble drug molecules at industrial scale (Hwang et al., 2020). Generally, the solubilization of lipophilic drugs with lipid excipients increases dissolution rate, absorption and bioavailability. Thus biopharmaceutical properties along with physiochemical features of drug might be improved with lipophilic polymers (Patel et al., 2018).

Mixture of glycerides and polyethylene glycol (Gelucire-44/14 and Gelucire-50/13) with HLB values of 13 and 14 is promising for micelles preparation, high drug loading, and stability of SEMCs (Panigrahi et al., 2018, Teixeira et al., 2018, Etezadi et al., 2020). In addition, these amphiphilic polymers have self-emulsifying properties that can help in the solubilization and absorption of ITZ (Ali and Staufenbiel, 2020, Nardin and Köllner, 2019). Besides, these polymers can promote water solubility of hydrophobic drugs (Tran et al., 2019, Alshehri et al., 2020). Thus they are well recognized for solubilizing poorly soluble drugs and act as polymer in SEMCs (Eedara and Bandari, 2017).

The current research work was planned to improve therapeutic efficiency of ITZ by increasing its oral bioavailability by preparing SEMCs using Gelucire-44/14 and Gelucire-50/13. In SEMCs preparation, solubilizers were used in various weight ratios following different preparation methods to evaluate relevant parameters that could be involved in improving the solubility and bioavailability. The performance of solubilizers was assessed on the basis of their solubility and bioavailability enhancing efficiency of ITZ. The novelty of this work is that self-emulsifying polymers were used first time for the bioavailability enhancement of ITZ through micellar system and can be an excellent clinical slant.

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Materials

Itraconazole was generously donated by Vision Pharmaceuticals Islamabad, Pakistan. Gelucire-50/13, Gelucire-44/14 and Transcutol-P® were provided by Gattefossé, France. All analytical grade chemicals were used for analysis.

Nayyer Islam, Naveed Ullah Khan, Anam Razzaq, Zaheer Ullah Khan, Farid Menaa, Mohammad Y. Alfaifi, Serag Eldin I. Elbehairi, Haroon Iqbal, Jiang Ni, Self-emulsifying micelles as a drug nanocarrier system for itraconazole oral bioavailability enhancement; in vitro and in vivo assessment, Saudi Pharmaceutical Journal, Volume 31, Issue 12, 2023, 101839, ISSN 1319-0164, https://doi.org/10.1016/j.jsps.2023.101839.

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