Lignin as a Bioactive Additive in Chlorzoxazone-Loaded Pharmaceutical Tablets

Abstract

In the present work, the application of lignin (LIG) as a bioactive additive for the preparation of drug-loaded tablets by direct compression has been studied, and its influence on the release of chlorzoxazone (CLZ) from the hydrophilic matrices has been followed. In hydrophilic matrices, the excipients Kollidon^® SR (KOL) and chitosan (CHT) have been used in various amounts and tested in the preparation of 500 mg tablets. They were used as matrix-forming agents, and their influence on the flow and the compressibility properties as well as their effect on the pharmaco-chemical characteristics of the matrix tablets have been studied. Based on the initial evaluation of the pharmaco-technical analysis, pharmaco-chemical characteristics, and in vitro release profile, three matrix tablet formulations (FLa, FLb, and FLc) were selected and further tested. They were evaluated through Fourier-transform infrared spectrometry (FTIR), X-ray diffraction (XRD), thermogravimetry (TG), differential scanning calorimetry (DSC), and in vitro dissolution tests.

The three formulations were comparatively studied regarding the release kinetics of active substances using in vitro release testing. The in vitro kinetic study reveals a complex release mechanism occurring in two steps of drug release. The first one is a burst effect that occurs within the first 0–2 h, involving a rapid release of the majority of the drug in a short time, followed by the second step as a prolonged release of the drug, which is relatively constant with a fixed rate over the next 2–36 h. Two factors have been calculated to assess the release profile of chlorzoxazone: f1—the similarity factor and f2—the difference factor together with the correlation coefficient R². Comparing their values, the three optimal formulations have been selected, containing 55 mg LIG (FLa), 60 mg LIG (FLb), or 65 mg LIG (FLc), confirming that LIG next to KOL and CHT influenced the release characteristics of the matrix tablets. Due to the presence of lignin in the matrix of the three formulations, FLa, FLb, and FLc tablets with CLZ, the antioxidant activity has improved.

The antioxidant activity of FLc was found to be 21.36% ± 1.06 greater than that of FLa and FLb. The tablets FLa, FLb, and FLc also presented higher antimicrobial activity against Staphylococcus aureus, Escherichia coli, Candida albicans, and colistin-resistant Klebsiella spp. The higher the concentration of LIG in the matrix (FLc), the higher the antimicrobial activity. By using LIG, the drug dose could be decreased. It can be concluded that lignin can be used as a multifunctional pharmaceutical bioactive additive/excipient for tablets. Its interesting properties have been proven, and its use as a pharmaceutical active additive should be exploited for different applications.

Introduction

Tablets are the most commonly used pharmaceutical oral dosage form [1]. They are relatively simple to manufacture, show good physical stability, and are extensively accepted by patients [1,2]. They are typically composed of several small amounts of active pharmaceutical ingredients and, to the greatest extent, of excipients that contribute to the preservation of the tablet’s structure and stability, as well as, ideally, provide drug delivery and/or protection function after ingestion. The clinical and formulation performances of pharmaceutical forms (tablets, capsules, suspensions, etc.) depend on the physicochemical properties of the excipients [3]. Biopolymers are being used for this purpose since they not only meet the need of the industry to develop efficient oral dosage forms with good solubility, release, and biocompatibility but also have low toxicity, biodegradability, and low price [4].

Biomolecules like inulin, chitin, starch chitosan, pectin, cellulose, etc. are being used as excipients for the delivery and controlled delivery of active ingredients, although they are typically high in price [5]. Drug loading into a matrix system is the most popular way to prevent its release [6]. Different pharmaceutical excipients can be used for direct compression, including a wide range of polymers [7]. These polymers include synthetic macromolecules, such as poly (vinyl pyrrolidone) or poly (acrylic acid), and natural polymers, such as cellulose [8].

Chlorzoxazone (5-chloro-2,3-dihydro-1,3-benzoxazol-2-one) (CLZ) is considered a Class II drug (according to the Biopharmaceutical Classification System (BCS)) because it has low solubility and high membrane permeability. CLZ has been licensed for treating musculoskeletal disorders [9] and is used to relieve muscle spasms and subsequent pain and discomfort [10]. The recommended starting oral dosage is 500 mg three or four times per day; however, this can frequently be lowered to 250 mg three or four times per day in the future. CLZ is typically administered alongside analgesics. The three most typical side effects of CLZ are headache, lightheadedness, and drowsiness [11]. Rarely, there have been reports of severe—even fatal—hepatocellular toxicity with CLZ treatment. Early hepatotoxicity signs and/or symptoms, such as fever, rash, anorexia, nausea, vomiting, lethargy, right upper quadrant pain, dark urine, or jaundice, should be reported by patients [12]. Chlorzoxazone is rapidly absorbed from the gastrointestinal tract. Therapeutically active plasma concentrations are maintained for 3–4 h.

Water-insoluble medicines have limited therapeutic effects due to their low solubility and dissolving rates [13]. The gastrointestinal absorption of any active substance, such as amiodarone, is significantly reduced due to its low water solubility.

In earlier research, we examined various methods to improve the active ingredient’s solubility (amiodarone) and the impact of formulation parameters on CLZ’s stability [14,15,16].

The study is based on novel oral matrix tablets designed to maximize the low oral bioavailability using lignin, chitosan, and Kollidon® SR.

Lignin is one of the most abundant polymers on Earth, second after cellulose [17]. Lignin is a complex organic polymer found in the cell walls of plants, particularly in wood and bark. The potential applicability of lignin is aimed at biomedical applications, including tissue engineering, wound dressings, and pharmaceutical uses, i.e., excipients and drug delivery systems [18].

However, the use of LIG as an excipient for pharmaceutical formulations is scarce, and only a few studies describe its use [18]. This biopolymer has been used in a wide variety of applications, such as antimicrobial agents, antioxidant additives, and UV protective agents. Lignin has significant antioxidant properties due to its phenolic structure, which allows it to scavenge free radicals. This activity is beneficial in reducing oxidative stress in biological systems and can be harnessed in the development of health supplements and pharmaceuticals [19].

Some studies suggest that lignin and its derivatives can reduce inflammation by modulating the activity of inflammatory mediators. Certain lignin derivatives have been found to exhibit cytotoxic effects on cancer cells, inhibiting their growth and proliferation. This anticancer potential is an ongoing area of research, with the goal of developing lignin-based therapeutic agents [20]. Due to its biocompatibility and biodegradability, lignin is being explored as a carrier material for drug delivery systems [21].

Lignin nanoparticles can encapsulate drugs, enhancing their stability and controlled release. Lignin can act as a prebiotic, promoting the growth of beneficial gut bacteria. This property is essential for maintaining a healthy digestive system and could be utilized in the development of functional foods and dietary supplements. Lignin can inhibit key enzymes involved in microbial metabolism.

The phenolic compounds in lignin can bind to the active sites of these enzymes, preventing them from catalyzing essential biochemical reactions [22]. Lignin and its derivatives can interact with microbial DNA, causing structural changes or damage. This interaction can inhibit DNA replication and transcription, thereby preventing microbial proliferation. Lignin can chelate essential metal ions such as iron and magnesium, which are necessary for microbial growth and enzyme function. By sequestering these ions, lignin deprives microorganisms of critical nutrients, inhibiting their growth [23]. Lignin can act synergistically with other antimicrobial agents, enhancing their efficacy. This synergy can occur through various mechanisms, such as disrupting microbial defenses or facilitating the entry of other antimicrobials [24].

Kollidon® SR (Crospovidone) (KOL) is a physical mixture of polymers. KOL is one of the utilized hydrophilic excipients in the formulation and production of modified-release matrix tablets [25]. Kollidon® SR forms chemical reversible complexes or associates with a large number of drugs. The formation of the complexes with a drug depends very much on its chemical structure. The ability to form complexes has many uses in pharmaceuticals, including the following:

Improving the dissolution and bioavailability of drugs;
Adsorbing and removing polyphenols and tannins from tinctures and herbal extracts and improving the taste of azithromycin, paracetamol, and vitamins [26]

Chitosan (CHT) is a heteropolysaccharide formed by deacetylation of chitin, an abundant biopolymer extracted from insects/crustacean shells/mushroom cell walls. It possesses bioadhesive, wound-healing, and film-forming characteristics [27].

CHT is a biodegradable and biocompatible polymer that acts as an absorption promoter for hydrophobic active substances with high molecular weight in the gastrointestinal tract [28].

Other materials used in the present study were microcrystalline cellulose as Avicel® PH (AV) and magnesium stearate (ST). All used compounds accomplish the quality requirements according to the laws of force. These excipients facilitate the application of the direct compression method to obtain optimal dispersibility of the hydrophobic substances (CLZ).

In the present work, we proposed the use of LIG as an excipient for direct compression in the preparation of drug-containing tablets and selected Chlorzoxazone. Additionally, LIG was combined with KOL, CHT, AV, and ST to prepare different types of tablets. In previous studies, the optimal amount of KOL was 30% (w/w %) and CHT was 5% (w/w %) for the hydrophilic matrix of tablets with CLZ [29]. In the new tablet formulations containing CLZ, the hydrophilic matrix maintained identical amounts of KOL and CHT excipients, while the quantity of LIG was varied and pressure was applied to obtain the tablets. In the studies that were conducted, the influence of LIG on the release of CLZ from the hydrophilic matrices and the antioxidant and antimicrobial actions of the tablets due to LIG presence and quantity were monitored. The new tablets were characterized by evaluating their pharmaco-technical parameter of the matrix, drug-excipients compatibility, in vitro dissolution tests, and drug release kinetics, as well as their antioxidant and antimicrobial properties.

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Materials

The following materials have been utilized: Chlorzoxazone (5-chloro-2,3-dihydro-1,3-benzoxazol-2-one) (Orchid Chemicals Ltd., Chennai, India), alkali lignin (Sigma Aldrich), Kollidon® SR (BASF, Ludwigshafen, Germany), chitosan (practical grade, BASF, Germania), (Chemtrec, Falls Church, VA, USA), magnesium stearate (Union Derivan S.A., Barcelona, Spain) and 2,2′ diphenyl-1-picrylhydrazyl (DPPH) Sigma Aldrich; Dorset, UK.

Chlorzoxazone is a centrally acting muscle relaxant with sedative properties, and it is used for the symptomatic treatment of painful muscle spasms.

Kollidon® SR is a physical mixture of 80% polyvinyl acetate (average molecular weight of 450,000 Daltons) and 20% polyvinyl pyrrolidone (povidone) (average molecular weight of 40,000 Daltons). Avicel ®PH-113 is a microcrystalline cellulose used for direct compression, and in wet, dry, and granulated states, it is a binder and compression aid.

Creteanu, A.; Lisa, G.; Vasile, C.; Popescu, M.-C.; Pamfil, D.; Panainte, A.-D.; Tantaru, G.; Vlad, M.-A.; Lungu, C.N. Lignin as a Bioactive Additive in Chlorzoxazone-Loaded Pharmaceutical Tablets. Molecules 2025, 30, 1426. https://doi.org/10.3390/molecules30071426