A Novel Approach to Caffeine Delivery: Formulation and Evaluation of Chicle-Based Medicated Chewing Gum

Medicated chewing gum (MCG) is a new and increasingly investigated medication delivery platform, with several benefits over traditional oral dose forms. By avoiding first-pass metabolism and facilitating systemic drug absorption through the buccal mucosa, MCG, which is intended for mastication rather than ingestion, improves bioavailability and onset of action in addition to facilitating local therapeutic effect in the oral cavity ¹. MCG has established itself as a useful dosage form in contemporary pharmaceutical research due to its user-friendly character, advantages such as simplicity of administration, quick therapeutic action, and improved patient compliance, especially among pediatric and geriatric populations. Caffeine (1,3,7-trimethylxanthine), a common central nervous system stimulant, is used to fight fatigue, improve alertness, and enhance cognitive function.There is usually a lag in the therapeutic start of traditional caffeine delivery methods, such as capsules or beverages, because of delayed gastrointestinal absorption. MCG has been suggested as a more effective distribution method to get over this restriction. Caffeine-containing chewing gum assurances quicker drug release and action by promoting buccal absorption, which is especially helpful in high-demand scenarios like emergency medicine and military operations ². Chicle, a naturally occurring gum base made from    the sap of the Manilkara zapota tree, is significant both ecologically and historically. It is a sustainable and well-liked substitute for synthetic gum bases due to its superior mechanical strength, biocompatibility, and biodegradability. Chicle's inclusion in caffeine MCG improves the chewing experience and gum matrix's structural integrity, in addition to being in line with pharmaceutical methods that are ecologically aware ³. Current studies back up MCG's viability and growing usefulness. The potential of MCG for buccal drug delivery was highlighted by Gururajbhat et al., who reported that their formulations had acceptable mechanical characteristics and drug release behavior ¹. The use of MCG for the administration of bronchodilators such as terbutaline sulfate was investigated by Mishra et al., demonstrating its suitability for systemic diseases requiring rapid onset ². The advantages of employing solid dispersion techniques to enhance solubility and release kinetics in chewing gum systems were also documented by Sharma et al. ^4. The potential of vitamin C-loaded MCG as a supplemental medication that combines nutritional and dental health benefits was also shown by Pujari et al.⁵ The current study intends to develop and assess a medicated chewing gum with caffeine based on chicles in light of these advancements. Its physical properties, drug release behavior, and therapeutic efficacy have to be evaluated, with a focus on the use of sustainable excipients. This study adds to the increasing amount of research on efficient, environmentally friendly, and patient-friendly drug delivery methods.

MATERIALS AND METHODS

Materials: All of the reagents and substances utilized in the investigation were of analytical quality. Natural rubber latex was obtained from the medicinal garden of Rani Chennamma College of Pharmacy. Glycerin and coconut oil were procured from Mehta Sons, Bangalore, while mannitol, soy lecithin, and talc were supplied by Burgoyne Burbidges, Mumbai. Caffeine was sourced from Universal Scientific Works, Bangalore. The instruments used in this study included an electronic balance and an ultrasonicator, both supplied by The Indo Sati Instruments and Chemicals. UV absorbance readings were obtained using a UV spectrophotometer (Shimadzu-1800, Japan).

METHODS

Preparation of Standard Calibration Curve of Caffeine: Using UV spectrophotometry, a standard calibration curve for caffeine was created. In chloroform, caffeine has a maximum absorbance (λmax) at 274 nm in the 200–400 nm wavelength range. Ten milligrams of pure caffeine were precisely weighed and dissolved in one hundred milliliters of chloroform to create a stock solution with a concentration of 100 µg/mL. Standard solutions including concentrations of 2, 4, 6, 8, 10, and 12 µg/mL were made from this sample by appropriately diluting it. At 272 nm, the absorbance of every solution was measured.

Extraction of Egg Lecithin from Egg Yolk

Figure 1: Extraction of Egg Lecithin from Egg Yolk

Preparation of Chicle Gum Base from Sapodilla monikara

The chicle gum base was formulated using latex extracted from Sapodilla monikara, sourced from the medicinal garden of Rani Chennamma College of Pharmacy. Latex collection was performed by making a clean incision at the tip of the plant, with the exudate immediately transferred into a sterile container. The latex was then placed in a clean, dry metal vessel and gently heated in a water bath. Upon softening of the gum base, freshly extracted egg yolk lecithin (prepared in a prior step) was introduced as an emulsifying agent. The temperature was carefully maintained at 60?°C for 45 minutes to facilitate uniform dispersion of lecithin within the latex. Glycerol was incorporated into the molten mixture to reduce the inherent stickiness of the formulation and enhance its processability. Subsequently, talcum powder was added as a structural filler to improve the physical integrity of the gum. The final gum base was stored in amber-colored glass containers to protect it from light-induced degradation and preserve its stability.⁸

Characterization of Isolated gum base:

1. Color: A visual examination was used to assess the gum base's color.
2. Swelling Index: A 10 mL graduated cylinder was filled with 1 g of the gum base extract, which had been precisely weighed to calculate the swelling index. After recording the starting volume, distilled water was added. The cylinder was gently shaken and then allowed to sit at room temperature in the natural environment for a full day. Next, the final volume that the enlarged sediment occupied was measured.
3. Solubility: The following solvents were used to evaluate the gum base's solubility:
   • Water: Ten milliliters of distilled water were combined with one gram of gum base.
   • Ethanol: 10 mL of ethanol was combined with 1 g of gum base.
   • Methanol: Ten milliliters of methanol were combined with one gram of gum base.
   • Dilute Hydrochloric Acid (Dil. HCl): 10 mL of diluted hydrochloric acid was combined with 1 g of gum base. ⁹

Figure 2: Flow chart for preparation of Caffeine-Medicated Chewing Gum

The process involved precisely weighing the gum base and then placing it in a china dish over a water bath at 60°C until it became soft. Once softened, caffeine powder (active ingredient) was incorporated, followed by coconut oil as a lubricant. The mixture was thoroughly blended to ensure uniform distribution. Subsequently, mannitol was added and mixed until a homogeneous composition was achieved. After achieving a uniform mixture, the temperature was reduced to below 40°C. Coloring and flavoring agents were gradually added while continuous mixing was maintained. The final gum mass was molded into the desired shape and set at room temperature before packaging, as in Figure 2.¹⁰

1. Organoleptic properties: The physical characteristics of each batch of the chewing gum formulation, such as color, taste, and odor, were evaluated visually.
2. Texture Analysis: Using the thumb and forefinger to compress the chewing gum, the texture was physically assessed. The tactile response was classified as solid bulk, nice mass, or sticky mass.
3. Stickiness Test: The chewing gum formulation was put on a level surface and weighed 250 g for ten minutes. Following the allotted time, the gum's adhesion to the weight's surface was assessed.^11-12
4. Weight Variation: Twenty chewing gum pieces were chosen at random and weighed separately. To evaluate weight uniformity, the average weight was computed, and the percentage departure of each unit from the mean was ascertained ^{1, 13}
5. Hardness: A Monsanto hardness tester was used to gauge the medicated chewing gum's hardness. The findings were presented as standard deviation and mean hardness values.¹⁴
6. Content Uniformity: For the investigation of content uniformity, three gum samples were chosen at random. A UV-visible spectrophotometer (UV-1800, Shimadzu) was used to measure absorbance at 272 nm after each sample was dissolved in 100 mL of phosphate buffer (pH 6.8) to determine the amount of caffeine present.¹²
7. Drug Release Study: Mechanical motion is necessary for the release of medication from medicated chewing gum, in contrast to traditional dose forms. Using a basket and bead device, an in vitro dissolution study was carried out to simulate the chewing process. Every gum sample was submerged in 70 milliliters of phosphate buffer (pH 6.8) while attached to a magnetic bead in a basket. To replicate mastication, the device was set up on a magnetic stirrer running at 310–320 rpm. Sink conditions were maintained by taking out 0.5 mL aliquots of buffer at predefined intervals and replacing them right away with new buffer. To ascertain the caffeine content of the samples, UV-visible spectrophotometry was used. The release profile was assessed by plotting a cumulative drug release (%) vs. time graph.¹¹
8. Stability Studies: Stability studies were carried out in accordance with the International Conference on Harmonization's (ICH) guidelines. A short-term accelerated stability investigation was carried out for three months. Room temperature (25 ± 2°C), refrigerator temperature (4–8°C), and oven temperature (45°C ± 2°C) were the three temperatures at which the samples were stored. Each month, the sample was removed and analyzed for weight change, drug content uniformity (%), hardness (kg/cm2), physical appearance, and percentage CDR.

RESULTS:

Figure 3:   Standard Calibration Curve of Caffeine:

A standard calibration curve was created using the resultant data, which plotted absorbance against concentration. According to the obtained linear regression equation, y = 0.0478x + 0.008, where y stands for absorbance and x for concentration in µg/ml, the calibration curve showed a good linear connection. The calibration curve's high linearity and reliability for the quantitative detection of caffeine in the specified solvent system were indicated by the coefficient of determination (R²), which came out to be 0.999.

The fundamental physicochemical characteristics of the separated gum base were assessed. Table 2 illustrates how the gum looked yellow. When exposed to water, it did not swell, suggesting that hydrophilic expansion was absent. Furthermore, the gum base's solubility profile revealed that it dissolves in ethanol, methanol, and diluted hydrochloric acid (HCl) but not in water. These properties imply that the gum might find use in situations where solubility in organic solvents and water is preferred.

Figure 4: Percentage Of Drug Content

The Drug content percentage indicates the proportion of the active pharmaceutical ingredient (API) present in each formulation, a critical parameter in evaluating the consistency and effectiveness of the drug. Among the three formulations, Furthermore, the gum base's solubility profile revealed that it dissolves in ethanol, methanol, and diluted hydrochloric acid (HCl) but not in water.

Figure.5: Percentage Dug Release

Stability Studies