Pharmaceutical Development and Characteristics of Orally Disintegrating Tablets with Dihydroquercetin Formulation Modifications

Abstract

Oral diseases cause a wide range of difficulties for patients. The natural bioactive compound dihydroquercetin (DHQ), which demonstrates regenerative, anti-inflammatory, antioxidative, and antibacterial effects, is of interest for their treatment. The combination of DHQ and l-lysine DHQ is “very easily soluble”. The aim of this study is to compare orally disintegrating tablets based on raw DHQ and on the DHQ-l-lysine composition. Following the guidelines outlined in the ICH Q8 (R2) standard, a fundamental quality target product profile and critical quality attributes were established. The Sediment Delivery Model (SeDeM) method was used to evaluate the substance suitability for direct compression. Quantitative analysis of the DHQ release was carried out by high-performance liquid chromatography, and infrared (IR) spectroscopy was performed using the attenuated total reflection technique without any prior sample preparation. The DHQ-l-lysine composition shows improved dimensions (4.12) and flowability (4.96). The release rate constants (K_release) were 8.14 and 3.61%/min, while the half-release periods (t_50%) were 6.14 and 13.85 min for tablets with DHQ (TF1) and DHQ-l-lysine compositions (TF2), respectively. The difference factor (f₁) and similarity factor (f₂) were 23.43% and 43.37%, respectively. The tablet manufacture had a critical impact on the characteristics of the IR spectra (the r values −0.8785 and 0.5474 for TF1 and TF2). The conducted study demonstrates the promise of using DHQ-l-lysine composition for developing effective dosage forms with improved technological characteristics and controlled release of the active substance.

Introduction

Inflammatory oral diseases are a significant challenge for modern medical science. Oral diseases are among the most common pathological states, especially in older adults, affecting about 90% of the global population at some point in their lives, with about 14% of cases (periodontitis, gingivitis, etc.) being directly related to inflammatory oral diseases. In addition, other pathological states can also lead to inflammation in the oral cavity. Furthermore, clinical evidence of some inflammatory oral diseases can be found in almost all adults, even if they have not been diagnosed with them [1,2,3].

There are several factors leading to inflammatory oral diseases: common risk factors (tobacco use, poor diet, etc.), poor oral hygiene, infections [4], uncontrolled diabetes mellitus [5,6], a dysregulated hyper-inflammatory response, plaque biofilm accumulation at the gingiva–tooth interface, neglected dental caries, rare syndromes, and disorders of collagen metabolism and neutrophil function [7].

Oral diseases, and inflammatory oral diseases in particular, cause a wide range of difficulties for patients, such as a negative impact on psychological state, painful sensations [1], systemic inflammation [8], bleeding, tooth loss (up to complete edentulism), and destruction of nearby tissues [3].

Inflammatory oral diseases are commonly treated with antibiotics and antiseptics (chlorhexidine, doxycycline, metronidazole, etc.) [9,10]. Antibiotic administration disturbs the oral microflora and can lead to physiological disorders and bacterial or fungal infections [11,12]. Moreover, antibiotics are frequently associated with side effects such as gastrointestinal symptoms, abdominal pain, and diarrhea [13].

Another way to treat inflammatory oral diseases is laser therapy, which provides an anti-infective effect. However, some types of laser therapy, such as low-energy and Nd:YAG lasers and photodynamic therapy, have shown no significant results and, consequently, can be used only as adjunctive therapy. Other types (diode and CO2 lasers), meanwhile, can cause excessive heat and root damage [9].

Other methods, such as dietary changes or improved oral hygiene, are also used in clinical practice but require a higher level of patient involvement and discipline [14].

Due to the complicated etiology and accompanying negative effects, it is reasonable to combine etiological treatment of inflammatory oral diseases with symptom-managing therapy [15]. Against the background of growing interest in phytotherapy, natural bioactive compounds such as flavonoids, which have a high safety profile, are of interest in wound healing [16,17]. Particularly promising is dihydroquercetin (DHQ), the major flavonoid component of larch wood, which demonstrates skin-regenerative [18,19], anti-inflammatory [20,21,22], antioxidative [23,24], and antibacterial [25,26] effects—all of which are crucial in the treatment of inflammatory oral diseases.

According to opinion of some researchers [27], poor solubility in water at room temperature [28] (“very slightly soluble” according to the European Pharmacopoeia) is one of the reasons for the low bioavailability of DHQ, which makes it challenging to develop medications based on this compound and integrate them into clinical practice. There are several approaches that were previously applied to improve the solubility of flavonoids, including solid dispersion preparation [29,30], amorphization [31,32], glycosylation [33,34], and crystallization [35,36].

The proteinogenic amino acid l-lysine may also be beneficial for reducing inflammation [37]. In combination with l-lysine (DHQ-l-lysine), DHQ becomes “very easily soluble” according to the European Pharmacopoeia due to the formation of hydrogen bonds [38,39]. Previous studies have shown that the topical application of a DHQ-l-lysine composition solution was beneficial for wound healing in rats compared to the initial substances [39].

However, the influence of the DHQ-l-lysine composition on the pharmaceutical–technological properties of orally disintegrating tablets has not yet been studied. Therefore, the aim of this study is to conduct a comparative analysis of tablets based on raw DHQ and on the DHQ-l-lysine composition.

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2.1. Materials

DHQ was provided by JSC “Ametis” (Blagoveshchensk, Russia), l-lysine was acquired from NeoFroxx GmbH (Darmstadt, Germany), high-functionality excipient PROSOLV^® ODT G2 was purchased from JRS PHARMA GmbH & Co. KG (Rosenberg, Germany), ascorbic acid was supplied by Tereos S.A. (Moussy-le-Vieux, France), and sucrose was from the Northeast Pharmaceutical Group Co., Ltd. (Shenyang, China).

Distilled water was produced before use, acetonitrile—99.9% (HPLC Gradient Grade) was acquired from Fisher Scientific (Loughborough, UK), and trifluoroacetic acid—98% was provided by Pallav Chemicals & Solvents Pvt. Ltd. (Mumbai, India). For HPLC analysis the water was deionized by Vodoley-M (Himelectronica SPE, Moscow, Russia).

Terekhov, R.P.; Korochkina, M.D.; Krivozubova, E.V.; Evzikov, G.Y.; Svotin, A.A.; Anurova, M.N.; Selivanova, I.A. Pharmaceutical Development and Characteristics of Orally Disintegrating Tablets with Dihydroquercetin Formulation Modifications. Sci. Pharm. 2026, 94, 56. https://doi.org/10.3390/scipharm94030056