Formulation and Evaluation of Medicated Chewing Gum Containing Capsaicin-Rich Extract for Oral Pain Relief

Drug delivery science has undergone tremendous evolution over the past several decades, with increasing emphasis on patient-centric, non-invasive dosage forms that enhance therapeutic outcomes while improving patient compliance. Among the multitude of novel drug delivery systems investigated, medicated chewing gum (MCG) has emerged as a uniquely versatile platform that combines the palatability of a confectionery product with the precision of a pharmaceutical dosage form. Medicated chewing gum is defined by the European Pharmacopoeia as "solid, single-dose preparations with a base consisting mainly of gum that are intended to be chewed and not swallowed." The chewing process mechanically releases active pharmaceutical ingredients (APIs) from the gum matrix into saliva, enabling absorption through the buccal mucosa, sublingual mucosa, or gastrointestinal tract upon swallowing [1,2].

The buccal route of drug administration offers several distinct pharmacokinetic advantages. The rich vascularization of the oral mucosa, combined with the relatively high permeability of the buccal epithelium, permits rapid drug absorption and direct entry into systemic circulation, bypassing the portal circulation and hepatic first-pass metabolism that significantly reduces the bioavailability of many orally administered drugs. Furthermore, the salivary environment provides a physiologically active medium for drug dissolution and mucosal wetting, facilitating efficient absorption. The controlled and sustained nature of drug release during mastication—spanning 10 to 30 minutes depending on formulation design—makes MCG particularly suitable for medications requiring a prolonged local effect or a rapid systemic onset [3,4].

Globally, approximately 86 to 100 million pieces of medicated chewing gum are sold annually, of which approximately 55% are sugar-free formulations. Teenagers represent around 70% of gum consumers, highlighting the demographic suitability of this dosage form for pediatric and adolescent patient populations who may resist conventional tablets or capsules. Several landmark MCG products have achieved widespread clinical acceptance, including nicotine gum (NiQuitin CQ, Nicorette) for smoking cessation, aspirin gum (Aspergum) for analgesia, fluoride gum for dental caries prevention, and dimenhydrinate gum (Travell, Superpep) for motion sickness management. The regulatory recognition of MCG as a legitimate pharmaceutical dosage form by the European Commission's Council Directive on Medicinal Products further underscores its clinical and commercial significance [5].

Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is the principal pungent alkaloid of Capsicum species (red chili peppers, family Solanaceae). Its pharmacological activity is mediated through selective binding to the transient receptor potential vanilloid 1 (TRPV1) receptor, a non-selective cation channel expressed predominantly on unmyelinated C-fibers and thinly myelinated A-delta nociceptors. Upon binding, capsaicin elicits an initial depolarization of nociceptors—clinically perceived as a burning sensation—followed by a prolonged period of desensitization and functional defunctionalization of sensory terminals, resulting in analgesia. This mechanism has been exploited clinically in topical preparations (Zostrix, Qutenza) for the management of neuropathic pain, post-herpetic neuralgia, and diabetic peripheral neuropathy [1,2].

The incorporation of capsaicin into an MCG formulation presents a rational therapeutic strategy for oral pain conditions such as aphthous ulcers, oral mucositis, temporomandibular joint (TMJ) pain, and post-extraction dental pain, where the ability to deliver an analgesic agent directly to the site of nociception with minimal systemic exposure would be advantageous. However, the intrinsic pungency of capsaicin poses a significant formulation challenge that must be overcome through appropriate masking agents. The use of peppermint oil and polyol sweeteners (sorbitol, mannitol) in the present formulation addresses this challenge. Additionally, the substitution of a natural polymer-based gum base—using tragacanth and gelatin—for conventional synthetic gum bases (polyvinyl acetate, butadiene-styrene copolymer) represents an eco-friendly and cost-effective approach suitable for resource-limited pharmaceutical laboratories [6,7].

The present study was undertaken to: (i) prepare a medicated chewing gum containing capsaicin-rich Capsicum extract using a naturally derived gum base; (ii) characterize the physicochemical properties of the prepared formulation using pharmacopoeial and non-pharmacopoeial evaluation tests; and (iii) provide a comprehensive review of the composition, classification, mechanisms, marketed products, and applications of medicated chewing gum as a drug delivery platform.

AIM

To formulate and evaluate medicated chewing gum containing capsaicin-rich extract derived from Capsicum species (red chili) using a naturally derived tragacanth-based gum base, as a novel oral drug delivery system for local pain relief.

OBJECTIVES

• To prepare a natural polymer-based gum base using tragacanth, gelatin, mannitol, and glycerin as a biocompatible substitute for synthetic gum bases.
• To prepare capsaicin-rich extract from dried red chilies by ethanol solvent extraction and estimate its capsaicin content.
• To formulate medicated chewing gum by incorporating capsaicin-rich extract into the prepared gum base with appropriate excipients.
• To mask the characteristic pungency of capsaicin using peppermint oil and polyol sweeteners for improved palatability.
• To evaluate the physicochemical properties of the prepared MCG including appearance, color, texture, stickiness, chewability, weight variation, and visual drug content uniformity.
• To compare the advantages of MCG with conventional dosage forms and review its broader pharmaceutical applications.

REVIEW OF LITERATURE

Classification of Medicated Chewing Gum

Medicated chewing gums are classified based on several criteria including sugar content, physical form, coating, and therapeutic function. Based on sugar content, MCGs are categorized as sugar-based gums (containing 80% sugar and glucose syrup with gum base) and sugar-free gums (employing polyols such as sorbitol, mannitol, and xylitol as bulk sweeteners with high-intensity sweeteners). Sugar-free formulations are preferred in contemporary pharmaceutical use due to their reduced cariogenicity and suitability for diabetic patients. Based on physical structure, MCGs are classified as coated gums (with outer sugar or polyol coating for improved appearance and stability), center-filled gums (containing a liquid or semi-solid center), and uncoated gums. Functionally, MCGs are categorized as medicated, nutraceutical, and functional gums (delivering minerals, vitamins, or botanical actives). Based on shape, gum products are available as sticks, tablets, balls, dragees, ribbons, and wrap gums [3,4,8].

Composition of Medicated Chewing Gum

Water-Insoluble Gum Phase

The water-insoluble phase comprises the gum base, elastomers, plasticizers, and fillers. The gum base constitutes 20-30% of sugar-containing MCG and up to 50% of sugar-free MCG. Historically, natural chicle derived from the sapodilla tree (Manilkara zapota, Sapotaceae) was the primary gum base material, but its high cost and limited availability led to replacement with synthetic elastomers. Common synthetic elastomers include polyvinyl acetate (PVAc), butadiene-styrene copolymer, isobutylene-isoprene copolymer, and polyisobutylene. Natural elastomers include jelutong, latex, lechi caspi, and crown gum. Elastomers provide the characteristic cohesion and elasticity of chewing gum. Elastomer solvents such as terpinene resins, glycerol esters of resins, and pentaerythritol esters are used at concentrations of 5-75% w/w of the gum base to control elastomer dissolution and flavour retention [3,9].

Plasticizers enhance the softness and mouthfeel of the gum during mastication. Natural plasticizers include glycerol, partially hydrogenated resins, glycerol esters of fatty acids (oleic, palmitic, stearic acid), and lecithin. Synthetic plasticizers include glyceryl triacetate, glyceryl monoacetate, and acetylated monoglyceride. Fillers such as calcium carbonate, magnesium carbonate, talc, di-calcium phosphate, and titanium dioxide are incorporated to modify texture, provide bulk, and reduce cost [3,4].

Water-Soluble Gum Phase

The water-soluble phase contains bulk sweeteners, high-intensity sweeteners, softeners, emulsifiers, flavoring agents, colorants, and antioxidants. Bulk sweeteners (30-75% of total gum weight) include nutritive sweeteners (sucrose, glucose syrup, corn syrup, dextrose) and non-nutritive polyols (sorbitol, mannitol, xylitol, maltitol, hydrogenated starch hydrolysates). Corn syrup maintains gum freshness and flexibility by regulating moisture. High-intensity sweeteners such as aspartame, acesulfame-K, saccharin, and steviol glycosides provide sweetness at very low concentrations. Emulsifiers including glycerin, lecithin, stearic acid, mono-/di-/tri-glycerides improve chewability and mouthfeel at 0.5-15% concentration. Flavoring agents such as peppermint oil, spearmint oil, cinnamon oil, citrus oils, fruit essences, and clove oil mask unpleasant drug tastes and enhance palatability—a critical factor for patient compliance. Antioxidants such as BHA and BHT protect lipid-soluble excipients from oxidative degradation during shelf life [3,5,8].

Marketed Medicated Chewing Gum Products

Table 1: Selected Marketed Medicated Chewing Gum Products Worldwide

*Sources: Rassing MR [6]; Allen LV [5]; European Pharmacopoeia [EP]

Advantages of Medicated Chewing Gum

• Convenient route of administration; no water required for intake, making it suitable for use anywhere.
• Highly suitable for patients with dysphagia (difficulty swallowing), elderly patients, and pediatric populations who resist conventional tablets and capsules.
• Bypasses hepatic first-pass metabolism through buccal mucosal absorption, enhancing bioavailability of drugs susceptible to extensive first-pass effect.
• Provides rapid onset of action due to direct buccal and sublingual absorption.
• Stimulates salivary secretion, counteracting xerostomia (dry mouth) and protecting against dental caries and oral candidiasis.
• Highly acceptable to children due to its confectionery-like appearance and taste, improving medication adherence.
• Reduces gastric mucosal irritation by avoiding direct contact of high drug concentrations with gastric epithelium.
• Enables controlled and sustained drug release during mastication (10-30 min), allowing for prolonged local or systemic effect.
• Suitable for acute medication where rapid symptom relief is required.

Disadvantages and Limitations

• Excipient-related side effects: sorbitol may cause flatulence and osmotic diarrhea at high doses; certain flavoring agents may cause oral mucosal ulceration; liquorice extract may cause hypertension with prolonged use.
• The strong taste and tooth-staining property of chlorhexidine limits its acceptability in buccal gum formulations.
• MCG may adhere to dental enamel, dentures, and dental fillings, potentially causing mechanical difficulties.
• The drug content per unit dose is limited by the physical dimensions of the gum unit, restricting use to low-dose APIs.
• Stability of moisture-sensitive or thermolabile APIs may be compromised during manufacturing (elevated temperature, mechanical kneading) and storage.
• Requires patient cooperation and coordination for effective drug release; not suitable for unconscious or uncooperative patients.

Applications of Medicated Chewing Gum

The therapeutic versatility of MCG has been demonstrated across multiple clinical domains. In pain management, NSAID-containing formulations (aspirin in Aspergum, ibuprofen gum) provide rapid analgesia for headache, dental pain, and musculoskeletal discomfort through the buccal route. In smoking cessation, nicotine gum formulations (Nicorette, NiQuitin CQ) facilitate controlled nicotine replacement therapy by releasing nicotine gradually during mastication, reducing withdrawal symptoms. In dental health, fluoride-containing gums prevent dental caries by delivering fluoride ions directly to tooth enamel; chlorhexidine gums suppress periodontal pathogens and oral bacteria responsible for plaque formation, gingivitis, and pharyngeal infections. In motion sickness, dimenhydrinate gums offer an advantage over tablets by providing faster absorption in nausea-prone patients who may have difficulty swallowing. Nutraceutical gums deliver vitamins (C, D), minerals (calcium), omega-3 fatty acids, and botanical extracts for general health maintenance. Caffeine gums enhance cognitive alertness and athletic performance. Xylitol-based gums prevent cariogenic bacterial adhesion by inhibiting Streptococcus mutans activity [3,5,6,8].

Table 2: Comparison of Medicated Chewing Gum with Conventional Dosage Forms

MATERIALS AND METHODS

Materials

Dried red chilies (Capsicum annuum, locally sourced), tragacanth gum (Hi-Media Laboratories Pvt. Ltd., Mumbai), gelatin (food grade, SRL Chemicals), powdered sugar, mannitol (Hi-Media), glycerin (analytical grade), magnesium stearate (Hi-Media), propyl paraben (Hi-Media), sorbitol (Hi-Media), Tween 80 (polysorbate 80, Merck India), peppermint oil (food grade), and absolute ethanol (99.9%, Changshu Yangyuan Chemical, China) were used. All chemicals were of analytical or pharmaceutical grade. Reagents were used without further purification unless otherwise specified.

Preparation of Capsaicin-Rich Extract

Dried red chilies (Capsicum annuum) were procured from a local market, authenticated by a qualified botanist, and dried in a hot air oven at 50°C for 2 hours to reduce residual moisture. The dried material was ground to a fine powder using a laboratory grinder (mesh size 40). Twenty grams of chili powder was subjected to maceration with 100 mL of absolute ethanol in a tightly sealed glass container for 24-48 hours at room temperature (25 ± 2°C) with occasional stirring every 6 hours to ensure thorough extraction. The mixture was filtered through Whatman No. 1 filter paper. The filtrate was collected and the solvent was evaporated on a water bath at 60°C until a semi-solid, reddish-brown extract was obtained. The extract was stored in an amber glass vial at 4°C until use. The capsaicin content of Capsicum extract is reported in the range of 0.1-1.0%; for this study, an average content of 0.5% was assumed for calculation purposes, yielding 0.05 mg of capsaicin per gum unit [1,2].

Preparation of Natural Gum Base

A novel natural polymer-based gum base was prepared as described in Table 3 (Gum Base Formulation, 10 g batch) as an alternative to conventional synthetic gum bases, using biocompatible and readily available natural polymers. Tragacanth was hydrated in a minimal volume of warm water (45°C) to form a gel. Separately, gelatin was soaked in cold water for 10 minutes and then dissolved on a water bath at 50-55°C. The tragacanth gel and gelatin solution were combined with mixing. Powdered sugar, mannitol, and glycerin were then added sequentially with continuous mixing. Magnesium stearate and propyl paraben were incorporated last. The resulting mass was kneaded to homogeneity and cooled to room temperature before use.

Table 3: Gum Base Formulation (10 g Batch)

*Note: This gum base employs natural polymers as a biocompatible substitute for conventional synthetic gum bases

Preparation of Medicated Chewing Gum

The medicated chewing gum was prepared by the kneading / direct incorporation method. The following steps were followed:

1. The prepared natural gum base (10 g) was softened by heating on a water bath at 50-60°C until pliable and homogeneous.
2. The capsaicin-rich extract (100 mg) was mixed with glycerin (1 mL) in a glass mortar to ensure uniform distribution of the extract within the plasticizer matrix, minimizing aggregation.
3. Sorbitol (5 g) and mannitol (3 g) were added to the softened gum base in small portions, mixing thoroughly after each addition to achieve uniform incorporation.
4. Tween 80 (200 mg) was added as an emulsifying agent to improve extract-gum base miscibility, followed by the capsaicin-glycerin mixture.
5. Peppermint oil (2-3 drops) and magnesium stearate (100 mg) were incorporated into the mass in the final step. Thorough kneading was performed for 10 minutes to achieve a uniform, homogeneous mass.
6. The total mass was divided into 10 equal portions using a spatula and manual rolling. Each portion was molded into an oval gum shape and pressed to a uniform thickness.
7. The prepared gums were allowed to cool at room temperature for 30 minutes and subsequently stored in airtight containers at room temperature (25 ± 2°C) until evaluation.

Table 4: Complete Formulation Table for Medicated Chewing Gum (Batch of 10 Gums)

*Average weight per gum = Total batch weight (19.4 g) ÷ 10 units = 1.94 g per gum

Evaluation Parameters

Organoleptic / Physical Evaluation

All 10 gum units from the batch were visually and manually examined for appearance (shape, surface finish, cracks), color, odour, texture (softness, elasticity, cohesiveness), and stickiness. These were compared against reference descriptors for acceptable MCG characteristics as per European Pharmacopoeia (EP) guidelines for medicated chewing gums.

Weight Variation

The weight of each of the 10 prepared gum units was recorded individually using a digital analytical balance (Sartorius, d = 0.001 g). The average weight was calculated and the percentage weight variation was computed relative to the average weight. A variation of ≤ ±5% was considered acceptable as per Indian Pharmacopoeia (IP) and United States Pharmacopeia (USP) criteria for uncoated dosage forms.

Chewability and Adhesion

Chewability was assessed by manual chewing of individual gum units by trained evaluators for 5 minutes. The gum was assessed for ease of chewing, absence of disintegration, cohesiveness during chewing, and absence of tooth adhesion. A Monsanto-type hardness tester was used to assess resistance to deformation under compressive load as a surrogate measure of hardness.

Drug Content Uniformity (Visual)

Due to the absence of HPLC instrumentation, drug content uniformity was assessed visually by cross-sectioning each gum unit and examining the distribution of the brown capsaicin extract throughout the gum matrix. Uniform coloration across cross-sections was taken as indicative of uniform distribution. Formal UV-Vis spectrophotometric analysis at 280 nm would be recommended for future quantitative drug content estimation.

Stability Assessment

The prepared chewing gum units were subjected to accelerated stability testing by storage at 30 ± 2°C / 65 ± 5% relative humidity (RH) in sealed containers for a period of 4 weeks (short-term assessment), as per WHO Guidelines for Stability Testing of Pharmaceutical Products (Technical Report Series No. 953). Units were examined at intervals of 1, 2, and 4 weeks for signs of physical deformation, color change, texture alteration, or odour change.

RESULTS

The prepared medicated chewing gum units were systematically evaluated for a range of physicochemical parameters. All results are presented in Table 5.

Table 5: Physicochemical Evaluation Results of Capsaicin-Rich Medicated Chewing Gum