Design and development of Fujicalin-based axitinib liquisolid compacts for improved dissolution and bioavailability to treat renal cell carcinoma

Introduction

Cancer, a second leading cause of mortality globally, is one of the most fatal health issues affecting today’s human population [1]. Cancer therapies at present include surgical therapy to remove cancerous tissue with surgery, radiation therapy, and chemotherapy using cytotoxic anticancer drugs [2]. In the field of chemotherapy using an anticancer agent, studies for maximizing the effect of the cancer treatment have been undertaken continuously [3] by improving the solubility of poorly aqueous soluble drugs with improved bioavailability and reduced cytotoxicity, which could contribute to minimizing side effects of the anticancer agents using pharmaceutical development techniques.
Renal cell carcinoma (RCC) accounts for 2 % to 3 % of all cancers [4]. Advanced or metastatic unresectable RCC, treated with several molecularly targeted drugs in the past decades [5]. Amongst them, axitinib (AXT) used in the treatment of advanced RCC is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 acts by blocking the action of an abnormal protein that signals cancer cells to multiply. That would slow or stop the progress of cancer cells with a daily dose of 5 mg twice a day. It has demonstrated promising single-agent antitumor activity for solid tumors, including metastatic renal cell carcinoma [6]. AXT was approved as a second-line therapy in the treatment of RCC for a better disease condition, treatment, and patient-improved survival expectations. Thus, it becomes necessary to ensure oral drug delivery of AXT formulation that provides high systemic availability. Hence in this research, an attempt was made to develop a pharmaceutical by a potential LS technique that enhances bioavailability of poorly aqueous soluble AXT.
Synthetic molecular optimization and high throughput screening approaches of drug discovery produce new chemical compounds with high lipophilicity and low solubility [7], [8].

Pharmaceutical development of such newly discovered molecules to enhance efficacy by improving solubility and lowering formulation development discrepancies results in high-cost involvement in drug discovery and pharmaceutical development. Instead, pharmaceutical development of an existing novel drug like AXT using promising LS technique for the enhancement of solubility, dissolution rate, and bioavailability would help to lower the production cost and help to provide an economic product to society. AXT is a BCS class II drug with a limited bioavailability of 58 % [4]. Such weakly water-soluble drugs present obstacles at different stages of formulation development to enhance bioavailability [9]. Therefore, there is a quest to employ suitable manufacturing techniques to develop products that would enhance the solubility as well as the dissolution rate of weakly water-soluble drugs [10], [11], [12].

AXT demonstrated superior efficacy over sorafenib as a second-line agent with a high safety profile for common adverse events [13]. Various nanocrystal drug delivery systems, nano-emulsions, nanostructured lipid carriers, nanoparticles, and liposomes, have been recently developed for targeted tumor delivery of anticancer medicines [14]. The crystalline systems have low drug loading efficiency which results in to expulsion of drug during the storage, thus need to preserve them from degrading and increase the stability [16], [17]. Higher drug loading through pharmaceutical development can improve the bioavailability of weakly water-soluble drugs, like AXT by oral drug delivery. Hence, alternative drug delivery systems or formulation strategies for RCC are needed to overcome its poor solubility with bioavailability problems [5]. Narvekar et al., developed AXT-loaded polymeric nano-particles for the treatment of age-related macular degeneration [15]. Chopade and Gorle et al., enhanced dissolution with Neusilin® US2 and PEG 400-based LS compact. However, for the confirmation of efficacy of developed product there’s a need of processability evaluation for good tablettability and investigation of in vivo drug dissolution study with pharmaceuticals potential for cytotoxicity and we observed these gaps in Chopade and Gorle et al.’s study [14]. Thus, critical formulation optimization is needed to resolve these issues. Thus, the benefit of utilizing an LS approach to modify the solubility and dissolution rate of AXT with processability parameter optimization and systemic availability estimation is of great concern. Therefore, the present research aimed to improve the solubility, dissolution properties, and bioavailability of AXT through an LS technique using promising carrier and coat. Fujicalin SG is a highly porous carrier having high specific surface area and an ability to hold large amounts of liquid. Fujicalin SG as carrier presented good liquid retention with acceptable tableting properties that making it appropriate for faster dissolution liquisolid formulation. [9] This is reported by Yadav et al. [9] and Dias et al. [38] in LS compact development.

Manufacturing processability evaluation during pharmaceutical development aids in reducing production costs involved in large-scale industrial production [9]. For the purpose of processability evaluation, LS compacts bring up to compression of admixtures of drug solutions and excipients (carrier and coat materials) into tablets. To accomplish this, ‘flowable liquid-retention potential’ (Φ) and ‘compressible liquid-retention potential’ (Ψ) values of carrier and coat materials were established. The influence of LS system that drug and excipient have on bioavailability and efficacy of formulation was established and assessed by LS flowability test (LSFT) and LS compressibility test (LSCT). These numbers specify the ability and quantity needed of carrier and coat materials to preserve their flowability and compressibility. Powder admixtures compositions and compression process parameters affect the tablet’s tensile strength. The most important powder parameters and mechanical constraints on the tablet tensile strength were acknowledged by scrutinizing data with a multivariate statistical model. Therefore, in the current research work flowability, compressibility, and compactability were determined and statistically analysed to ensure LS compact’s quality attributes [19].

The current study explored a 32 full factorial design to assess the effect of some critical formulation parameters simultaneously on experimental outcomes and to accomplish enhanced efficiency in the dissolution rate of AXT. In this study, Fujicalin-based AXT LS tablets comprising optimized carrier (Fujicalin SG) and coat excipient (Aerosil 200) with non-volatile solvent PEG 200 possessing varied drug proportions were prepared and evaluated. In vitro drug dissolution profiles of LS compacts were correlated with conventional directly compressed tablets (DCT). Furthermore, in vivo studies were performed to assess the bioavailability of AXT using New Zealand rabbits. The in vitro cytotoxicity study was carried to explore effectiveness of LS formulation over pure drug. This investigation could offer available alternatives for currently existing formulations of AXT with better bioavailability at lower production costs and provide the market with an affordable product.

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Materials

Axitinib was gifted by Cipla, Ltd. Vikroli, Mumbai. Fujicalin SG was gifted by Gangwal Chemicals Pvt. Ltd., Mumbai. Aerosil 200, Tween 20, Tween 80, PEG 200, PEG 400, propylene glycol, glycerin, lactose, and sodium starch glycolate were procured from Lobachem Pvt. Ltd. Mumbai. API and all excipients were of pharmaceutical grade. All other reagents and solvents used were of the analytical grade. Cell lines A498 for cytotoxicity assay were purchased from the National Centre for Cell Sciences Pune.

Priyanka S. Yadav, Ashok A. Hajare, Kiran S. Patil, Design and development of Fujicalin-based axitinib liquisolid compacts for improved dissolution and bioavailability to treat renal cell carcinoma, European Journal of Pharmaceutics and Biopharmaceutics, 2024, 114506, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2024.114506.

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