Hot Melt Extrusion for Improving the Physicochemical Properties of Polydatin Derived from Polygoni cuspidati Extract; A Solution Recommended for Buccal Applications

Abstract

Three different types of solid dispersions based on polyvinyl polymers and related copolymers (Kollidon^® VA64, Soluplus^® and Kollicoat IR^®) comprising polydatin-rich Polygoni cuspidati extract were prepared by hot melt extrusion. The systems were characterized using X-ray powder diffraction, infrared spectroscopy as well as by polydatin release and in vitro permeability. Mucoadhesive tablets were prepared from the extrudates based on Kollidon^® VA64 and Soluplus^® to obtain a suitable pharmaceutical form, where (hydroxypropyl)methyl cellulose was added as a mucoadhesive agent. The tablets were evaluated in terms of the kinetics of polydatin release as well as their mucoadhesive properties. The best tabletability properties, polydatin release profile and adequate mucoadhesive properties were obtained by the formulation containing the Kollidon^® VA64-based extrudate, which makes it an excellent prototype for enhancing the release of poorly water-soluble compounds.

Introduction

Polygoni cuspidati rhizoma et radix is one of the most resveratrol- and polydatin-rich plant materials [1]. A variety of disorders is treated with Polygonum cuspidatum, also known as Hu Zhang in China, because of its antiviral, antibacterial, anti-inflammatory, neuroprotective, and cardioprotective properties. Importantly, the traditional use of P. cuspidatum as an oral hygiene agent is justified by its influence on bacterial viability and the virulence factors of Streptococcus mutans [2,3]. Such activity indicates the possibility of using extracts from this plant in dentistry. However, of relevance to topical use, the solubility of the active compounds and the achievement of a therapeutic concentration at the site of application are extremely important. Despite many advantages, the key active compounds in P. cuspidatum (polydatin and resveratrol) have low solubility [4], a barrier to ensuring the effectiveness of topical therapy.

Enhancement of solubility of poorly water-soluble active compounds has been one of the greatest challenges for researchers in the pharmaceutical industry. Amorphization has been shown as a successful and industry-relevant approach due to the increased apparent solubility of the compounds. A technique that can be effective in amorphizing drugs is hot melt extrusion (HME). HME is a solvent-free process requiring fewer unit steps than other disorder-inducing techniques. The formation of amorphous dispersions due to extrusion with selected polymers leads to crystallization inhibition, significantly improving the systems’ physical stability [5]. In addition, the dissolution rate of the active compounds from amorphous solid dispersions is often increased. This is the effect of limiting the energy needed to overcome the energy of the crystal lattice during the dissolution process. In addition, the presence of a hydrophilic carrier may improve the surface’s wettability to assist dissolution [6]. It should be remembered that the use of a high temperature may cause the decomposition of active ingredients, so it is also important to monitor the content of both active ingredients and decomposition products [7].

Amorphization of active compounds has also been used for substances of natural origin, including resveratrol. The resveratrol–Eudragit® EPO system prepared by HME exhibited good miscibility and significant dissolution enhancement [8]. Eudragit EPO has also been used to make a solid dispersion with Polygoni cuspidati extract to improve the dissolution rate of resveratrol and emodin [9], while a hydrophobic–hydrophilic polymeric mix (based on a Eudragit RS and PEG 6000 combination) was employed to control the release of resveratrol. With the dispersive mixing and high shear forces of HME, resveratrol’s thermodynamic properties and dispersion were changed to improve its solubility and, thus, bioavailability to 140%, compared to resveratrol alone [10]. Moreover, HME was used to increase the chemical stability of resveratrol through the formation of eutectic systems with small molecules [11]. However, there are no further literature reports on the use of HME to simultaneously improve the properties of polydatin and resveratrol and obtain amorphous dispersions containing plant extracts rich in these two compounds. Bearing in mind the biological effects of both compounds and their synergism, it is justified to obtain amorphous dispersions comprising these two important polyphenols [12,13].

The success of HME is the application of appropriate carriers. Some of the most commonly used are polyvinyl-based copolymers. Due to the presence of various groups in the polymer’s backbone, polyvinyl polymers and related copolymers have a strong solubilizing capacity, which is their significant advantage. Polyvinyl alcohol–polyethylene glycol copolymer (Kollicoat IR®) is utilized for the production of immediate-release formulations, while polyvinyl pyrrolidone polymers (Kollidon®) and polymers containing polyvinyl chains are generally known to act as crystallization inhibitors, facilitating the formation and long-term stabilization of solid solutions (e.g., Soluplus®) or amorphous solid dispersions [14].

The work presented herein aims at investigating the impact of various polyvinyl-based copolymers on the molecular characteristics and pharmaceutical effects, such as the dissolution rate, of polydatin-rich P. cuspidati extract in amorphous solid dispersions. In addition, the mechanical properties and tableting behavior of the dispersions were tested. Finally, the usefulness of the developed buccal formulations was assessed, including polydatin release, ensuring product effectiveness and mucoadhesive properties keeping the product in the application place.

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Materials

Resveratrol (≥99%, HPLC) and polydatin (≥95%, HPLC) were obtained from Sigma-Aldrich (Poznan, Poland). Excipients, such as Kollidon® VA64, Soluplus®, and Kollicoat IR®, were supplied by BASF (Warsaw, Poland), and (hydroxypropyl)methyl cellulose (HPMC) with average Mn ~ 90.000 (~15.000 cP) and magnesium stearate were supplied by Sigma-Aldrich (Poznan, Poland). Mucin from a porcine stomach was obtained from Sigma-Aldrich (Poznan, Poland). HPLC grade acetonitrile and water were obtained from Merck. High-quality pure water and ultra-high-quality pure water were prepared using a Direct-Q 3 UV Merck Millipore purification system (Darmstadt, Germany).

Paczkowska-Walendowska, M.; Tajber, L.; Miklaszewski, A.; Cielecka-Piontek, J. Hot Melt Extrusion for Improving the Physicochemical Properties of Polydatin Derived from Polygoni cuspidati Extract; A Solution Recommended for Buccal Applications. Pharmaceuticals 2023, 16, 1226. https://doi.org/10.3390/ph16091226

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