Development of mucoadhesive films with high polaprezinc content for oral mucositis: A study on formulation and near-infrared spectroscopy-based quality control
Abstract
Polaprezinc (PLZ) has drawn attention to its potential to prevent oral mucositis caused by chemotherapy and radiotherapy. PLZ-containing lozenges have been developed in previous reports; however, for patients with mucositis, taking them may be challenging because of pain. Therefore, this study aimed to develop a mucoadhesive film containing the same amount (18.75 mg) of PLZ as a lozenge as a new dosage form to replace lozenges and evaluate its characteristics. First, various films were created using solvent casting to screen polymers with high PLZ content. Thus, hydroxypropyl cellulose (HPC) was selected; however, film curvature and reduced flexibility necessitated formulation optimization. The optimized films exhibited excellent content uniformity, stability, and mucoadhesive properties, with no significant changes in the drug content after storage. Furthermore, the possibility of using portable near-infrared spectroscopy (Micro NIR™) for the quality control of PLZ films was investigated. Multivariate analysis revealed that the Micro NIR calibration model predicted drug concentrations comparable to those measured by high-performance liquid chromatography. These results suggest that a mucoadhesive film with high PLZ content has been developed and that efficient quality control is possible using Micro NIR™.
Introduction
Oral mucositis is a common and severe complication of radiotherapy and chemotherapy. It typically develops within a few days of treatment and persists for approximately 3 weeks [1], [2]. This condition is caused by tissue damage due to free radicals and the release of inflammatory cytokines, such as interleukin-1 and tumor necrosis factor-alpha, resulting in painful ulcers that interfere with eating, speaking, and sleeping, thereby significantly affecting the patient’s quality of life [2], [3]. Furthermore, chemotherapy-induced neutropenia and compromised immune function increase the risk of bacterial infection in mucosal ulcers, increasing the risk of systemic infections [4]. Therefore, preventing oral mucositis is important in managing the side effects of radiotherapy and chemotherapy.
Palifermin is the only Food and Drug Administration-approved treatment for oral mucositis, approved in 2004 [5]; however, it is not yet available in Japan, where management remains largely dependent on the patient’s symptoms. Common treatments include cryotherapy, laser therapy, lidocaine gargles, and analgesics [6], [7]. Among alternative approaches, polaprezinc (PLZ), a chelate compound of zinc (Zn) and L-carnosine known for its antiulcer effects, is a promising candidate for the prevention of oral mucositis induced by chemotherapy and radiotherapy [8], [9], [10], [11], [12], [13], [14]. PLZ has been used for many years in Japan for the treatment of gastric ulcers. Although its bioavailability is relatively low, it is believed that it exerts therapeutic effects by maintaining high zinc concentrations for a long time in the ulcerated areas of the gastric mucosa [15]. Furthermore, PLZ has also been reported to be a promising candidate for the management of oral mucositis because it not only scavenges free radicals but also exhibits mucosal protective effects, promotes tissue repair, and modulates immune responses [11].
Initially, PLZ was developed as a suspension with sodium alginate; however, due to issues with taste and texture, research has shifted toward lozenge development [9]. However, lozenges must be dissolved in the oral cavity several times a day for an extended period, which can be challenging for pediatric patients or those already experiencing pain due to mucositis. To address this issue, the development of a PLZ formulation that is easy to administer regardless of age and does not require prolonged dissolution in the oral cavity was started.
Film formulations have been shown to be well-accepted by individuals of various age groups, ranging from children to the elderly [16], [17], [18]. Oral mucosal films, in particular, are associated with low stress for both the person administering the medication and the patient receiving it because they are less likely to be accidentally spat out, being adhered to the inside of the mouth. Furthermore, local delivery of the drug to the oral mucosa is also possible. Thus, compared with lozenges, a PLZ oral film formulation could improve patient acceptance and ease of use. However, to incorporate the same amount of the active pharmaceutical ingredient (API) as a lozenge (18.75 mg, approximately 20 % by weight) into a 20 × 30-mm film while maintaining its handling properties, a polymer capable of accommodating a high drug load should be selected [9]. This is because increasing the API concentration may compromise the mechanical and physicochemical properties of the films [19]. Hence, polymers that could contain the same amount of PLZ as a lozenge tablet were first screened.
Furthermore, to facilitate the production of these film formulations by pharmacists in pharmacy settings in the future, simple manufacturing and quality control methods were explored. Rigorous quality control is essential for preventing potential manufacturing errors that could harm patients. Although high-performance liquid chromatography (HPLC) is commonly used for this purpose, it is often costly and time-consuming [20]. In contrast, near-infrared spectroscopy provides rapid, nondestructive analysis, and several studies have reported its effectiveness for pharmaceutical quality control [21], [22], [23], [24]. This study investigated the feasibility of using a portable NIR device, Micro NIRTM, for the quality control of PLZ films.
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Materials
Hydroxypropyl cellulose (HPC-SL; Nippon Soda, Tokyo, Japan), hydroxypropyl methylcellulose (HPMC) (60SH-50,TC-5R; Shin-Etsu Chemicals, Tokyo, Japan), carbomer (Carbopol; Carbopol 974P NF Polymer®; Lubrizol Advanced Materials, Inc., Ohio, USA), polyvinyl alcohol (PVA) (GOHSENOL™ EG-05P; Mitsubishi Chemical Corporation, Tokyo, Japan), carboxymethyl cellulose sodium salt (CMC) (FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan), and polyvinylpyrrolidone (PVP) (K90; BASF SE, Ludwigshafen.
Takuya Ito, Eriko Yamazoe, Miyui Funato, Takaaki Ito, Akio Suzuki, Kohei Tahara, Development of mucoadhesive films with high polaprezinc content for oral mucositis: A study on formulation and near-infrared spectroscopy-based quality control, European Journal of Pharmaceutics and Biopharmaceutics, 2025, 114707, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2025.114707.
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