Curcumin-loaded soluplus® based ternary solid dispersions with enhanced solubility, dissolution and antibacterial, antioxidant, anti-inflammatory activities

Abstract

Amorphous solid dispersion (ASD) has emerged to be an outstanding strategy among multiple options available for improving solubility and consequently biological activity. Interestingly several binary SD systems continue to exhibit insufficient solubility over time. Therefore, the goal of current research was to design ternary amorphous solid dispersions (ASDs) of hydrophobic model drug curcumin (CUR) to enhance the solubility and dissolution rate in turn, presenting enhanced anti-bacterial, antioxidant and anti-inflammatory activity. For this purpose several ternary solid dispersions (TSDs) consisting of Soluplus®, Syloid® XDP 3150, Syloid® 244 and Poloxamer® 188 in combination with HPMC E5 (binary carrier) were prepared using solvent evaporation method. Both solubility and dissolution testing of prepared solid dispersion were performed to determine the increase in solubility and dissolution. Solid state investigation was carried out utilizing infrared spectroscopy, also known as Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM),Differential scanning calorimetry (DSC) and X-ray diffraction (XRD). Optimized formulations were also tested for their biological effectiveness including anti-bacterial, anti-oxidant and anti-inflammatory activity. Amid all Ternary formulations F3 entailing 20 % soluplus® remarkably improved the solubility (186 μg/ml ± 3.95) and consequently dissolution (91 % ± 3.89 %) of curcumin by 3100 and 9 fold respectively. These finding were also supported by FTIR, SEM, XRD and DSC. In-vitro antibacterial investigation of F3 also demonstrated significant improvement in antibacterial activity against both gram positive (Staphylococcus aureus, Bacillus ereus) and gram negative (Pseudomonas aeruginosa, Escherichia coli) bacteria. Among all the tested strains Staphylococcus aureus was found to be most susceptible with a zone of inhibition of 24 mm ± 2.87. Antioxidant activity of F3 was also notably enhanced (93 % ± 5.30) in contrast to CUR (69 % ± 4.79). In vitro anti-inflammatory assessment also exhibited that F3 markedly protected BSA (bovine serum albumin) from denaturation with percent BSA inhibition of 80 % ± 3.16 in comparison to CUR (49 % ± 2.91). Hence, F3 could be an effective solid dispersion system for the delivery of model hydrophobic drug curcumin.

Introduction

Curcumin constitutes as one of the principal functioning components of turmeric, a spice which is obtained from the root of plant Curcuma longa. This plant belongs to ginger family that grows widely in Southeast Asia [1]. It is commonly used as a food coloring additive in different cuisines around the world however lately it has gained an excessive amount of attention for its wide range of medicinal qualities particularly anti-oxidant, anti-microbial and anti-inflammatory effects [2]. Structurally, Curcumin features two polar phenyl rings coupled with two hydroxyl and ortho-methoxy groups. These polar phenyl rings are axially joined by an aliphatic chain (C7) which makes curcumin essentially insoluble in water. This lack of solubility in water together with poor oral bioavailability has hindered its clinical applications [3]. Therefore, this calls for a pressing demand to efficiently enhance the solubility of drug. Many strategies have been devised by members of the scientific community to address this difficulty, the most prevalent of which is the production of amorphous solid dispersions (ASDs). ASD can be characterized as molecular distribution of an active ingredient in an amorphous carrier [4,5]. This process is ought to induce drug transition to amorphous structure making it more soluble in water. Both binary and ternary solid dispersions have been documented to enhance the solubility of insoluble drugs. However, an amorphous drug might revert to crystal structure with time or upon dissolution thereby reducing solubility. Therefore, an ASD system must meet rigorous standards for it to be considered successful, as it is important for the produced system to improve drug solubility while also stabilizing the amorphous molecule.

It is suggested that incorporating an additional polymer to an already existing binary system might alleviate these shortcomings. A number of studies have also demonstrated that ternary ASD are far more efficient than binary ASD in terms of enhancing solubility, stability and bioavailability [6] however polymers with different physicochemical attributes could affect the performance of the ternary ASD, thereby determining the best polymer remains critical [7]. Multiple studies had been carried out in the past years to demonstrate the efficacy of the binary SD approach in enhancing the solubility of curcumin. Our earlier work to improve aqueous solubility of curcumin also employed a binary ASD approach, wherein various binary dispersions of curcumin were prepared using bovine serum albumin (BSA), Hydroxy propyl methyl cellulose (HPMC E5), Poly ethylene glycol (PEG 6000) and Poly vinyl pyrolidine (PVP K30). Two different techniques namely kneading (KN) and solvent evaporation (S.E) were used to formulate dispersions and it was found that CUR: HPMC E5 (1:4 SE) and CUR: PVP K30 (1:4 kN) exhibited notable improvement in solubility and dissolution. In comparison, CUR: HPMC E5 (1:4 SE) presented highest solubility and thus was selected for the current investigation [8].

The current study is intended to formulate Ternary ASD of curcumin to further examine the possibilities of increasing curcumin’s solubility and dissolving performance. Polymers chosen for this study are Soluplus®, Syloid® XDP 3150, Syloid® 244 and Poloxamer® 188. Soluplus® is a biocompatible polymer with exceptional solubilizing characteristics. In contrast to traditional solubilizers, it has dual functional properties such as an active solubilizer as well as matrix-forming polymer [9,10]. Based on a theoretical standpoint, it is an intriguing material to be employed as a vehicle as it is polar, non-ionic and its solubility remains constant throughout the alimentary system. Furthermore, it has somewhat surface activity too which may be beneficial to sustain overall super saturation [11,12]. Incorporating drugs molecules within mesoporous silica has recently been deemed an interesting choice in solid dispersion development as nanosized mesopores can not only encapsulate API effectively but also prevent recrystallization [13,14]. Poloxamer 188® is poly (oxy) (ethylene) poly (propylene) co-block polymer. Multiple studies have reported their ability to superiorly enhance solubility in comparison to other polymers including cyclodextrins and poly ethylene glycols. They also present oral safety, surface activity and low melting temperature [15,16]. Even though some of these polymers have already been employed independently as binary carriers in enhancing the solubility of curcumin [17,18] however, the novelty of our work lies in evaluating the effect of these polymers as ternary carriers in enhancing the solubility of curcumin. To the best of our knowing, no prior work has been carried out regarding physicochemical evaluation and biological effectiveness of these polymers as ternary carriers in combination with HPMC-E5.

Therefore, the purpose of the current work was to demonstrate the impact of various ternary carriers (Soluplus®, Syloid® XDP 3150, Syloid® 244 and Poloxamer® 188) on the solubility, dissolution and biological activity of curcumin. In order to find a suitable polymer, twelve different ternary solid dispersions were formulated using solvent evaporation method. Different characterization studies were performed to determine the physicochemical properties of prepared ternary solid dispersions. Optimized formulations were also investigated for various biological activities including anti-bacterial, anti-oxidant and anti-inflammatory activity.

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Materials

Curcumin was obtained from Natural remedies private limited, Bangalore, India. Soluplus® was kindly gifted by BASF, Ludwigshafen, Germany. Syloid® XDP 3150 and Syloid® 244 were procured from Grace Davison discovery sciences, New Jersey, USA. Poloxamer® 188 was purchased from Sigma Aldrich, St. Louis, USA. Chemicals were employed as received.

Memoona Ishtiaq, Hina Manzoor, Ikram Ullah Khan, Sajid Asghar, Muhammad Irfan, Norah A. Albekairi, Abdulrahman Alshammari, Abdulrahman F. Alqahtani, Saad Alotaibi, Rabia Munir, Pervaiz A. Shah, Liaqat Hussain, Muhammad Abubakar Saleem a,h, Fizza Abdul Razzaq, Syed Haroon Khalid, Curcumin-loaded soluplus® based ternary solid dispersions with enhanced solubility, dissolution and antibacterial, antioxidant, anti-inflammatory activities, Heliyon, RESEARCH ARTICLE| VOLUME 10, ISSUE 14, E34636, JULY 30, 2024, Published:July 13, 2024, DOI:https://doi.org/10.1016/j.heliyon.2024.e34636

Read also our introduction article on Mesoporous Silica here:

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