Original Article FIXED DOSE COMBINATION THERAPY OF IBRUTINIB AND QUERCETIN BY SNEDDS- DEVELOPMENT AND EVALUATION BY DESIGN OF EXPERIMENT RASHMI BAGRI 1,2* , RAVOURU NAGARAJU 2 1 Malla Reddy Pharmacy College, Maisammaguda, Secunderabad-500100, Telangana, India. 2 Institute of Pharmaceutical Technology, Sri Padmavati Mahila Visvavidyalayam (Women’s University), Tirupati-517502, Andhra Pradesh, India * Corresponding author: Rashmi Bagri; * Email: rashmi.hsg1@gmail.com Received: 13 Mar 2023, Revised and Accepted: 05 Aug 2023 ABSTRACT Objective: Self-nano emulsifying drug delivery system (SNEDDS) comprising quercetin and ibrutinib as a fixed dosage combination therapy is being investigated to increase drug solubility and dissolution rate. Methods: On the basis of preliminary solubility tests, castor oil, Kolliphor® RH 40, and PEG600 were utilised to construct ternary phase diagrams. The effect of the amount of Castor oil (A), Kolliphor® RH 40 (B), and PEG600 (C) on the particle size and encapsulation efficiency of ibrutinib and quercetin was evaluated and statistically analysed using multiple regression in 17 trials planned using a 33 Box-Behnken design. FTIR, XRD, DSC, SEM, and stability experiments were employed to characterise the optimised formulation. The particle size, zeta potential, polydispersity index, encapsulation efficiency, and in vitro drug release of ibrutinib and quercetin were also investigated. Results: Ibrutinib and quercetin had encapsulation efficiencies of 61.56-87.22% (Y3) and 60.12-87.12%, respectively, according to the size range of SNEDDS formulations (1-17) of 70.18-200.56 nm. The optimised SNEDDS formulations (S1–S3) showed a particle size range of 71.12–76.38 nm, PDI of 0.126–0.312, zetapotential of-24.6–28.4, and encapsulation efficiencies of 88.98–90.22% and 84.96–86.78% for ibrutinib and quercetin, respectively. According to in vitro testing, the medication released from SNEDDS was released more quickly (>90% 600 min). The formulation was further evaluated using FTIR, XRD, DSC, SEM, and stability investigations, which validated the complexation of ibrutinib and quercetin in the drug's amorphous state and stability for six months. Conclusion: This study revealed that SNEDDS could be used as a drug carrier for ibrutinib and quercetin due to their improved solubility and dissolution rate. Keywords: Ibrutinib, Quercetin, Box behnken design, Solubility, SNEDD © 2023 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/) DOI: https://dx.doi.org/10.22159/ijap.2023v15i5.47820. Journal homepage: https://innovareacademics.in/journals/index.php/ijap INTRODUCTION The simultaneous modulation of various cell-signaling mechanisms through multimodal chemotherapy is considered a vital protocol for enhancing therapeutic efficacy and reducing systemic toxicity. In recent years, the utilization of nanocarriers for delivering a combination of chemotherapeutic medications has emerged as a promising approach in cancer treatment [1]. Co-delivery systems offer a solution to the challenges associated with poor solubility and stability of certain drugs. These systems enable simultaneous transportation of multiple medications to the intended site, controlled release of the payloads in precise doses, synchronization of drug exposure, maximization of therapeutic efficacy, and minimization of toxicity [2]. The concurrent administration of antioxidants with anti- proliferative properties, along with their inherent antioxidant capabilities, holds significant potential for enhancing the overall effectiveness of antitumor treatments while reducing the toxicity associated with anticancer medications. In our study, we specifically aim to investigate the combination of two medications, namely Ibrutinib and quercetin. By studying the therapeutic effects of this medication combination, we hope to gain insights into how the synergistic interaction between these compounds can lead to improved antitumor outcomes and reduced side effects [3]. Ibrutinib is used to treat B-cell malignancies because it is a specific and covalent inhibitor of the Bruton's tyrosine kinase (BTK) enzyme [4]. Ibrutinib has a pKa of 3.74, making it a weak base. It is essentially insoluble in water (mole fraction solubility: 1.43 x 10-7 at room temperature), easily soluble in dimethyl sulfoxide, soluble in methanol, and has a very limited oral bioavailability (2.9%). Quercetin is a polyphenolic flavonoid molecule that has been shown to have a number of potential biological actions. Some of these activities include the activation of apoptosis, the prevention of angiogenesis, and an anti-proliferative effect on a number of human cancer cells. There are a few different approaches that may be taken in order to improve the bioavailability of anticancer drugs and ensure that they are effectively delivered. Some of these technologies include lipid- based delivery systems, polymeric nanoparticulate systems, crystal engineering (nanocrystals technology, co-crystal technology), liquisolid technology, self-emulsifying solid dispersions, and P-efflux inhibition strategies [5]. When a synthetic or natural oil, a surfactant, and a co-surfactant are introduced to an aqueous phase while being gently stirred, they produce a fine oil-in-water nanoemulsion that is known as a SNEDDS. SNEDDS are multi-component drug delivery systems that are isotropic. In addition to enhancing solubility and dissolving, researchers have been looking at the effects that SNEDDS have on increasing permeability, the hepatic first-pass effect, and bypassing the P-glycoproteins efflux [6]. In the area of formulation development, the Design of Experiment method has seen significant growth in popularity during the past several years [7]. In the present study, we have chosen the self-nano- emulsifying drug delivery system (SNEDDS) as the preferred method for delivering the proposed combination therapy of ibrutinib and quercetin. SNEDDS is a promising drug delivery system known for its ability to enhance the solubility, bioavailability, and therapeutic efficacy of poorly soluble drugs. By using SNEDDS, we aim to overcome the challenges associated with the limited solubility of ibrutinib and quercetin, ensuring their efficient delivery to the target site. The utilization of SNEDDS as a drug delivery method in our combination therapy approach holds the potential for achieving enhanced treatment outcomes and promoting the clinical translation of ibrutinib and quercetin as an effective therapeutic option. All of the ingredients used to make SNEDDS are nontoxic and fall into the category of excipients that are widely recognised as safe. Utilizing a 3-factor, 2-level Box Behnken design, the SNEDDS were optimised (BBD). International Journal of Applied Pharmaceutics ISSN- 0975-7058 Vol 15, Issue 5, 2023