Optimization of solid self-dispersing micelle for enhancing dissolution and oral bioavailability of valsartan using Box-Behnken design

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Abstract

A novel solid self-dispersing micelle (S-SDM) was developed to enhance the oral bioavailability of valsartan (VST) and to reduce the total mass of solidified supersaturable self-microemulsifying drug delivery system (S-SuSMEDDS), composed of Capmul MCM, Tween 80 (T80), Gelucire 44/14 (G44), Poloxamer 407, Florite PS-10 (FLO), and low-substituted hydroxypropyl cellulose B1 (HPC). Excluding oil component from S-SuSMEDDS, S-SDM was optimized using a Box-Behnken design with three independent variables: X1 (T80/G44, 0.63), X2 (FLO/HPC, 0.41), and X3 (solid carrier, 177.6 mg); and three response factors: Y1 (droplet size, 191.9 nm), Y2 (dissolution efficiency at 15 min, 55.0%), and Y3 (angle of repose, 32.4°). The desirability function was 0.636, showing an excellent agreement between the predicted and experimental values. With approximately 75% weight of S-SuSMEDDS, no distinct crystallinity of VST was observed in S-SDM, resulting in critical micelle concentration value of 32 μg/mL. Optimized S-SDM showed an approximate 4-fold improved dissolution (pH 1.2, 500 mL) compared with raw VST. Following oral administration in rats, optimized S-SDM improved relative bioavailability by approximately 235%, 216%, and 127% versus raw VST, Diovan® (commercial reference), and S-SuSMEDDS, respectively. Thus, optimized S-SDM could be a selectable candidate for developing water-insoluble drugs in reduced quantity.

Introduction

Valsartan (VST), an angiotensin Ⅱ receptor antagonist, has been widely used to treat cardiovascular diseases such as high blood pressure and congestive heart failure (Beg et al., 2012). Because of limited water solubility, VST belongs to class Ⅱ of the biopharmaceutical classification system (BCS) and has a relatively low bioavailability (BA; ~23%) after oral administration in healthy subjects (Beg et al., 2012, Dixit et al., 2010). VST exhibits pH-dependent solubility; it is poorly soluble under acidic conditions but highly soluble at pH levels of 5.0 or above (Siddiqui et al., 2011). Moreover, considering a main absorption site of VST that is limited to the upper gastrointestinal (GI) tract (Cao et al., 2012), the solubilization of VST in an acidic condition remains a major challenge. To overcome this obstacle, numerous approaches – such as solid dispersion, self-microemulsifying drug delivery system (SMEDDS), and nanoparticle – have been widely studied (Kim, and Baek, 2014, Li et al., 2017b, Park et al., 2010).

Previously, to enhance the dissolution and oral absorption of VST, we have formulated a supersaturable SMEDDS (SuSMEDDS) composed of Capmul MCM as an oil, Tween 80 (T80) as a surfactant, Gelucire 44/14 (G44) as a cosurfactant, and poloxamer 407 (P407) as a supersaturating agent, a technique which was further developed as a solidified SuSMEDDS (S-SuSMEDDS) by employing the solid carriers (Shin et al., 2019). However, because of the liquid components (such as oil and surfactant), it is still difficult to obtain a solidified formulation in a limited quantity. The required amounts of solid carriers were proportionally increased to the liquid contents, resulting in greater mass of solid dosage forms. Alternatively, oil-free nanodispersion systems, including micelles, might be suggested. Excluding an oil component from conventional SMEDDS could be a strategy for reducing the total mass of the solidified formulation. No significant difference in intestinal permeability was found between sulpiride-loaded SMEDDS and oil-free micelle (Chitneni et al., 2011). Similar to SMEDDS, following an oral administration of this oil-free system, in situ micelle formation can spontaneously occur in the GI tract, as derived by the mixing-propulsive force of the gut movement (Arien et al., 2006).

Micelles have been recognized as one of the most promising systems to deliver poorly water-soluble drugs (Ozeki and Tagami, 2013). Above the critical micelle concentration (CMC), amphipathic surfactant molecules spontaneously assemble each other and generate a hydrophobic core in an aqueous solution. This hydrophobic core has sufficient capacity to accommodate poorly soluble drugs, resulting in increased dissolution and oral absorption (Rangel-Yagui et al., 2005). So far, diverse micellar formulations have been introduced by incorporating drugs such as genistin and paclitaxel (Kwon et al., 2007, Yang et al., 2015). Aboud et al. (2019) developed a VST-loaded mixed micelle using P407 and T80, exhibiting in rats (after oral administration) an approximate 3-fold increased BA as compared with that by VST suspension. Curcumin-loaded self-dispersing micelles using disodium glycyrrhizin increased oral BA approximately 19-fold compared with that by curcumin suspension (Zhang et al., 2018).

Recently, to avoid liquid-type micellar formulations, solidified micelles have been introduced (Hou et al., 2019, Sultan et al., 2017). In the development of a solid self-dispersing micelle (S-SDM), various factors –such as the selection of surfactant or solid carriers, and the ratio of surfactants to solid carriers – can affect the flowability and/or pharmaceutical responses thereof. To establish a desirable formulation, these factors should be optimized appropriately. In the past, developing an optimized formulation was based on one-factor-at-a-time approaches; however, these traditional trials are rather time consuming and sometimes entail inadequate data (Cho et al., 2013). In contrast to conventional empirical methods, constructing a design of experiment (DoE) enables one to implement effective statistical approaches and establish mathematical correlations between independent variables and response variables (Peres et al., 2017). Among the experimental models, response surface methodology is widely used to optimize the formulation system due to its capability to combine mathematical and statistical approaches, consequently suggesting optimized responses (Bezerra et al., 2008, Liu et al., 2009). The Box-Behnken design method, one of the response surface methodologies, has been widely used for pharmaceutical development because it provides an accurate response requiring fewer treatment combinations when compared with central composite design (Villar et al., 2012).

This study aimed to develop and optimize a VST-containing S-SDM by employing a two-step process: VST-containing micelles were developed by excluding the oil component from the earlier SuSMEDDS formulation, then further solidified by adsorbing into solid carriers using Florite PS-10 (FLO) and low-substituted hydroxypropyl cellulose B1 (HPC). The solidification process was optimized using a Box-Behnken design method with input variables including (but not exclusively) the ratio of surfactants, the ratio of solid carriers, and the total mass of solid carriers. The optimized S-SDM showed several advantages: it significantly reduced total mass compared with previously developed S-SuSMEDDS, displayed excellent powder flowability, increased dissolution in a pH-independent manner, and enhanced oral BA in rats. This nanodispersion system could offer practical development of a solid dosage form with reduced unit quantity.

Section snippets

Materials

VST was supplied by Daewon Pharm. Co., Ltd. (Seoul, Korea). Diovan® tablets containing 80 mg of VST was purchased from a commercial source. Capmul MCM (glyceryl caprylate/caprate) was purchased from Abitec Co. (Janesville, WI, USA). FLO (calcium silicate) was purchased from Tomita Pharmaceutical Co., Ltd. (Tokushima, Japan). G44 (lauroyl polyoxyl-32 glycerides) was supplied by Gattefossé (Saint Priest, France). High-performance liquid chromatography (HPLC)-grade acetonitrile were purchased from

Statistical analysis using the Box-Behnken design

S-SDM was designed based on the previously reported S-SuSMEDDS, with the exception of the oil component (Table 1) (Shin et al., 2019). To optimize S-SDM, a Box-Behnken design was employed using Minitab software (ver. 18.0; Minitab Inc, State College, PA, USA). In this design, responses are predicted by mathematically calculating the effect of each independent variable and their interactions in a defined experimental region. The ratio of T80 to G44, the ratio of FLO to HPC, and the total mass of

Conclusions

VST-loaded S-SDM formulation was successfully developed using a Box-Behnken design. Three independent variables of X1 (T80/G44, 0.63), X2 (FLO/HPC, 0.41), and X3 (solid carrier, 177.6 mg) were selected, resulting in droplet size (191.9 nm), DE15 (55.0%), and AR (32.4°) with sufficiently low percentage prediction error (<5%). Whilst VST existed in amorphous state, optimized S-SDM exhibited approximately 75% weight of S-SuSMEDDS and showed a pH-independent dissolution profile. Compared with raw

CRediT authorship contribution statement

Yoon Tae Goo: Conceptualization, Methodology, Data curation, Writing - original draft. Sun Young Park: Data curation. Bo Ram Chae: Methodology. Ho Yub Yoon: Validation, Investigation. Chang Hyun Kim: Validation, Investigation. Ji Yeh Choi: Data curation, Formal analysis. Seh Hyon Song: Funding acquisition, Resources. Young Wook Choi: Conceptualization, Resources, Supervision, Project administration.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korea government (MSIP) (No. 2019R1G1A1100173) and also partially supported by the Ministry of Health and Welfare, Republic of Korea through the Korea Health Industry Development Institute (KHIDI), grant number HI17C0710. We also thank to Editage (www.editage.co.kr) for English language editing (CAUNE_5718).

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