Experimental and Theoretical Design on the Development of Matrix Tablets with Multiple Drug Loadings Aimed at Optimizing Antidiabetic Medication

Abstract

Background: Diabetes is a growing global health crisis that requires effective therapeutic strategies to optimize treatment outcomes. This study aims to address this challenge by developing and characterizing extended-release polymeric matrix tablets containing metformin hydrochloride (M-HCl), a first-line treatment for type 2 diabetes, and honokiol (HNK), a bioactive compound with potential therapeutic benefits. The objective is to enhance glycemic control and overall therapeutic outcomes through an innovative dual-drug delivery system.

Methods: The tablets were formulated using hydrophilic polymers, such as Carbopol^® 71G NF and Noveon^® AA-1. The release kinetics of M-HCl and HNK were investigated through advanced mathematical models, including fractal and multifractal dynamics, to capture the non-linear and time-dependent release processes. Traditional kinetic models (zero-order, first-order, Higuchi equations) were also evaluated for comparison. In vitro dissolution studies were conducted to determine the release profiles of the active ingredients under varying polymer concentrations.

Results: The study revealed distinct release profiles for the two active ingredients. M-HCl exhibited a rapid release phase, with 80% of the drug released within 4–7 h depending on polymer concentration. In contrast, HNK demonstrated a slower release profile, achieving 80% release after 9–10 h, indicating a greater sensitivity to polymer concentration. At shorter intervals, drug release followed classical kinetic models, while multifractal dynamics dominated at longer intervals. Higher polymer concentrations resulted in slower drug release rates due to the formation of a gel-like structure upon hydration, which hindered drug diffusion. The mechanical properties and stability of the matrix tablets confirmed their suitability for extended-release applications. Mathematical modeling validated the experimental findings and provided insights into the structural and time-dependent factors influencing drug release.

Conclusions: This study successfully developed dual-drug extended-release matrix tablets containing metformin hydrochloride and honokiol, highlighting the potential of hydrophilic polymers to regulate drug release. The findings emphasize the utility of advanced mathematical models for predicting release kinetics and underscore the potential of these formulations to improve patient compliance and therapeutic outcomes in diabetes management.

Introduction

Diabetes is one of the fastest-growing medical conditions and represents a health emergency of the 21st century [1]. The global prevalence of diabetes in 2021 was 10.5%, with an estimated increase to 12.2% by 2045 [1]. Given the projected rise in the number of individuals affected, there is an urgent need not only to develop new therapeutic approaches but also to enhance the efficacy of existing antidiabetic drugs. Addressing this need is crucial to effectively managing the growing burden of the disease. This objective can be achieved either by synthesizing innovative molecules or by optimizing and improving the therapeutic profiles of currently available treatments through modified drug delivery systems [2,3]. The formulation and optimization of polymeric matrix antidiabetic tablets with multiple drug loadings represent an important innovation in diabetes therapy, offering significant advantages in controlling the release of active substances and improving patient compliance with treatment [4,5]. The use of polymeric matrices enables controlled and prolonged release of active substances, thereby reducing fluctuations in plasma concentrations and improving glycemic control [6]. Honokiol (HNK), or 5,3′-diallyl-2,4′-dihydroxybiphenyl (C18H18O2, Mr = 266.3 g/mol), is derived from the bark of Magnolia officinalis (dried bark from the stem and branch, containing a minimum of 2% honokiol and magnolol) and the flower of Magnolia officinalis (steamed and dried unopened flower, containing a minimum of 0.2% honokiol and magnolol) [7]. From a health perspective, HNK is a promising therapeutic agent for various conditions, including diabetes mellitus, diabetic peripheral neuropathy, cancer, neurodegenerative diseases, nonalcoholic fatty liver disease, reproductive disorders, and arthritis [8,9,10].

Metformin hydrochloride (M-HCl), also known as N,N-dimethylimidodicarbonimidic diamide or 1,1-dimethylbiguanide hydrochloride (C4H12ClN5, Mr = 165.62 g/mol), is a small molecule used as a first-line therapy in the pharmacological treatment of diabetes mellitus, particularly type 2. It improves insulin sensitivity, reduces glycemic levels, and inhibits gluconeogenesis in the liver [11]. Due to these properties, metformin (as a senotherapeutic agent) has garnered significant interest from the scientific community and pharmaceutical companies for its potential applications in human anti-aging treatments [12]. Both active molecules can be quantitatively analyzed using High-Performance Liquid Chromatography (HPLC), mass spectrometry, or UV spectroscopy [11,12,13,14,15,16,17].

Noveon and Carbopol have been used successfully in commercial formulations for decades and are highly efficient gel-forming and matrix table binders, allowing for controlled drug release tablets, taste masking, and mucoadhesion. The choice of Carbopol 71G NF is based on the fact that it is suitable for direct compression; it is a prolonged release excipient, an effective diluent, and suitable for solid oral dosage forms. The unique feature of the Carbopol 71G NF polymer is its free-flowing granular form, allowing for tablet manufacturing by direct compression. However, in order to achieve a robust final dosage form, a direct compression formulation requires an excipient like Carbopol 71G NF that exhibits good flowability and compressibility. Other advantages of Carbopol and Noveon include the following: optimal performance as extended release polymers or controlled release polymers; ability to produce smaller, easier to swallow tablets compared to other polymers like cellulosics; highly efficient gel matrix formation, used either alone or with other co-excipients, which are effective at low polymer usage levels; ability to produce multimedia compliant, controlled release oral solid dose formulations in combination with a broad spectrum of active pharmaceutical ingredients (APIs) and co-excipients; excellent mucoadhesion properties and taste masking of bitter drugs and versatile processing options, such as direct compression [18].

The aim of this study is to develop matrix tablets with modified release based on the acrylic derivatives Carbopol 71G NF and Noveon AA-1, using metformin hydrochloride and honokiol as active pharmaceutical ingredients. These molecules are formulated into polymeric matrix tablets with modified release properties, representing innovative formulations designed for antidiabetic therapy with multiple drug loadings. The matrix tablets were prepared through direct compression, utilizing the two matrix-forming agents in different concentrations: Carbopol 71G NF at 15% and 25%, and Noveon AA-1 at 3% and 7%. Based on the analysis of the dissolution test results, the study aims to develop mathematical models that predict the release kinetics of the two active molecules, metformin hydrochloride and honokiol, in relation to physicochemical phenomena.

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Materials

Metformin hydrochloride or 1,1-Dimethylbiguanide hydrochloride (M-HCl, 97% purity, C4H11N5·HCl; Mr = 165.6) was obtained from Sigma Aldrich Chemie GmbH (Steinheim, Germany), honokiol (HNK, 98% purity, C18H18O2; Mr = 266.3) was obtained from New Natural Biotechnology (Shanghai, China), sodium acetate or sodium ethanoate (CH3COONa, ≥99%; Mr = 82.03) was purchased from Chimreactiv SRL (Bucharest, Romania), potassium dihydrogen phosphate (KH2PO4, ≥99.5%; Mr = 136.01) was purchased from Utchim SRL (Ramnicu Valcea, Romania), potassium chloride (KCl, ≥99%; Mr = 74.5) was purchased from Silal Trading SRL (Bucharest, Romania), acetic acid, glacial (CH3COOH, 99.9%; Mr = 60.1) was obtained from Chemical Company S.A. (Iasi, Romania), hydrochloric acid, concentrated (HCl, ≥37%; Mr = 36.46) was purchased from Chimreactiv SRL (Bucharest, Romania), sodium hydroxide (NaOH, 98.5%; Mr = 40.00) was obtained from Chemical Company S.A. (Iasi, Romania), and methanol (CH3OH, Mr = 32.04) for HPLC, ≥99.9% (Chromasolv™) was purchased from Honeywell Riedel-de Haën (Seelze, Germany). Ultrapure water (resistivity of 18.2 MΩ·cm, TOC < 10 ppb and bacterial count < 10 CFU/mL) was obtained from a local pharmaceutical company. Distilled water was obtained with the equipment of distillation GFL type 2004, no. 11918315J (Burgweld, Germany). All reagents used meet the quality requirements in accordance with national and European standards and are used as such, without any additional purification operations. Carbopol® 71G NF Polymer (carbomer homopolymer type A or carbomer homopolymer) and Noveon® AA-1 (Noveon® Polycarbophil) were obtained from The Lubrizol Corporation (Wickliffe, OH, USA). Magnesium stearate (C36H70MgO4, 4.0–5.0% of magnesium content; Mr = 591.24) was obtained from Union Derivan S.A (Barcelona, Spain). MicroceLac® 100 is a co-processed excipient obtained from Meggle Group (Wasserburg, Germany). The multicomponent matrix tablets (M-HCl/HNK) are based on extended-release polymers, using the granular Carbopol® 71G and Noveon® AA-1.

Sha’at, M.; Ochiuz, L.; Rusu, C.M.; Agop, M.; Barsan, A.; Cretan, M.S.; Hartan, M.; Spac, A.F. Experimental and Theoretical Design on the Development of Matrix Tablets with Multiple Drug Loadings Aimed at Optimizing Antidiabetic Medication. Pharmaceutics 2024, 16, 1595. https://doi.org/10.3390/pharmaceutics16121595

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