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Abstract

Background

The objective of this study was to design and assess the quality of PropoLid, a propolis-based, lidocaine-contained hydrophilic oromucosal film for the treatment of aphthous, ulcerative, and traumatic lesions in the oral cavity.

Methods

PropoLid oromucosal films containing Lidocaine (4%) and Propolis extract (1:10), known for its analgesic, antimicrobial, antifungal, and anti-inflammatory properties were obtained using solvent evaporation technique, with gelatin as the polymer and glycerin as the plasticizer (1:1.5). Rosehip syrup is added as a saliva-stimulating, flavoring and adhesive agent. The quality parameters of the PropoLid oral films, such as organoleptic properties, thickness, flexibility, dryness, surface pH, dissolution, and quantitative content of Lidocaine, were assessed.

Results

Yellow-brown translucent films with a smooth surface and an average thickness of 0.3 ± 0.03 mm were developed. The quality parameters of the obtained oral films meet the organoleptic requirements outlined in the Pharmacopoeia. The flexibility index of the films was >300 and the surface pH was 6.97. The quantitative content of lidocaine in the film was determined to be 2.5 mg/cm². Dissolution testing demonstrated that PropoLid oral films completely release active pharmaceutical substances responsible for the pharmacological effect.

Conclusion

The technology and composition developed to create mucoadhesive films that meet Pharmacopoeial requirements. The Lidocaine content per 1 cm² of the oral films is 2.5 mg, aligning with the previously calculated concentration of 4%. The PropoLid oral adhesive films can be used to treat oral ulcers with associated pain.

Keywords

Lidocaine hydrochloride propolis oromucosal films oral mucosa aphthous stomatitis ulcer

Background

Ulceration in the oral cavity can be a sign of various diseases involving different etiological factors. The majority of ulcerative lesions in the oral cavity may have an infectious (bacterial, viral, fungal), immune-related (Recurrent Aphthous Stomatitis, Lichenoid Lesions, Erythema Multiforme, Medication-Related Ulcerations, etc), traumatic (mechanical, chemical, thermal, electric), and neoplastic origin.¹ The development of aphthous ulcers can be a result of various systemic diseases, such as Behcet's disease, celiac disease, Crohn's disease, ulcerative colitis, Gilbert's syndrome, and others. In most cases, the development of oral ulcers is accompanied by pain, soreness, and other inflammatory signs.^1,2

The treatment of various oral ulcers is currently carried out using a range of drugs in different formulations, such as rinses, tablets, ointments and films. In recent decades, innovative drug delivery systems have significantly enhanced the efficacy, safety and tolerability of treatments. Since the discovery and development of new chemical compounds is a complex, expensive and time-consuming process, the latest trend in pharmaceutical manufacturing focuses on creating and improving drug delivery systems for existing drugs.

Orally dissolving films are of great interest in the modern pharmaceutical industry. These dosage forms dissolve in the mouth within a few minutes, without the need for chewing or water. This technology ensures a rapid localized effect.³ Drug delivery via the mucous membrane is considered a promising method of drug administration due to its potential for rapid absorption and localized therapeutic effects. The buccal mucosa is the most suitable for both local and systemic drug delivery.^4–6 The oral mucosa is known to have a large absorption surface, which ensures rapid absorption and high bioavailability of drugs. It is noteworthy that the permeability of the oral mucosa is several times greater than that of the skin, yet lower than that of the intestine.^7,8 It is important to highlight that more than 70% of medicinal substances can be used in the form of oral films.⁹

Given that oral ulcers are usually characterized by severe pain, microbial colonization and the risk of regular chemical or thermal trauma while eating, it is essential to develop a drug formulation that not only protects the wound from various harmful irritants but also delivers active pharmacological agents with pronounced analgesic, antimicrobial, anti-inflammatory and wound-healing effect. While various medications are used clinically to treat oral ulcerative lesions, PropoLid is the first drug to combine Lidocaine—widely used in dentistry for its anesthetic properties—and Propolis, which offers local anesthetic, antimicrobial, anti-inflammatory, antiviral, antifungal, and wound-healing benefits.^10–13 (Patent No 865Y https://old.aipa.am/search_mods/patents/view_item.php?id = 865YAM20230089Y&language = en).

The combination of Propolis and Lidocaine can, therefore, contribute to the development of a new drug with multiple effects suitable for the treatment of oral ulcerative lesions. Thus, the aim of the study was to develop and further assess the quality of propolis-based, lidocaine-containing hydrophilic oromucosal PropoLid oral films for the treatment of aphthous, ulcerative and traumatic lesions in the oral cavity.

Materials and Methods

Film Ingredients (Dimension)

Propolis extract (1:10) (ml), Solution of Lidocaine hydrochloride 10% (ml), Gelatin powder (g), Glycerin (g), Rosehip syrup (g), and Purified water (ml).

Commercially available 100 mg/ml (10%) lidocaine hydrochloride solution (2 ml N10, Organica LLC, Kemerovo Region, Russia) and standardized propolis extract (see section 2.2) were used as active ingredients. Propolis was collected in the Gegharkunik region of Armenia in the spring of 2022. Other formulation components: alimentary gelatin type A (from porcine skin) as the film-forming agent, chemically pure 99.5% glycerin as the plasticizer, 96% ethanol (v/v) as the co-solvent, where obtained commercially from Medisar LLC, Yerevan, Armenia and Rosehip syrup as a sweetening, flavoring, and saliva-stimulating agent was obtained from Nectarbonus LLC, Yerevan Armenia. Ultrapure water as a solvent was produced using the Adrona Crystal EX-1101 water purification system.

Preparation and Standardization of Propolis Ethanolic Extracts

Propolis was extracted using the conventional maceration method. A mixture of ethanol and water was used as an extractant since it provides a high yield of polyphenols.¹¹ Literature data suggest that 70–80% ethanol is optimal for obtaining a polyphenol-rich extract.¹⁴ An ethanol concentration of 80% was selected for the experiments since the extract showed the highest absorbance at 290 nm, indicating the maximum release of flavonoids from the propolis, particularly kaempferide, acacetin and isorhamnetin.¹⁵ Five different ratios of 1:5, 1:10, 1:15, 1:20 and 1:30 were used to compare the yield of polyphenols and obtain the optimal concentration.

After collection, propolis was stored frozen at −20 °C. Then, the frozen propolis was crushed in a cold environment, and 10 mg of accurately weighed propolis was placed into a conical flask. Ethyl alcohol was then added in volumes of 50 ml, 100 ml, 150 ml, 200 ml and 300 ml, respectively. The solutions were stored in tightly closed containers in the dark at room temperature for 14 days. The ethanolic extracts of propolis were filtered with a ‘Blue ribbon filter’ and standardized by phenolic compound contents by spectrometry using a Unicam 8625 UV/Vis spectrometer.

1 ml of the corresponding propolis extract was placed in a 100 ml volumetric tube, and 95% ethanol was added until the required volume was reached and mixed. Next, 1 ml of the obtained solution was placed in a 50 ml volumetric tube, and 95% ethanol was added repeatedly to bring the volume up to the required level, and then the mixture was mixed. The absorbance of the obtained solution was measured at a wavelength of 290 nm, with 95% ethanol used as the blank solution. The quantity of total phenolic compounds (%) was determined by the following formula:

X = \frac{A \cdot 50 \cdot 100}{V \cdot K}

Where:

A is the optical density of the solution

V is the volume of solution (ml)

K is the coefficient, which is equal to 510 in 290 nm wavelength.

Development of Oral Films

The total mass of the mixture, after the initial evaporation of the solvents and prior to film formation, should be 50 g. The quantitative content of the components was calculated to ensure that the final concentration of lidocaine would be 4%, a concentration commonly used in Lidocaine preparations for topical application.¹⁶ The amount of propolis extract was adjusted according to the quantitative content of gelatin as a polymer. The amounts of plasticizer and polymer were calculated based on the results obtained during the development of the film manufacturing technology. The optimal amount of Rosehip syrup, which provides appropriate tenacity, was determined empirically. Purified water was used in quantum satis, ie in an amount sufficient to match the quantity of gelatin, considering the volumes of the other liquid components.

The films were formed by solvent evaporation technique or solvent casting method using different polymer-to-plasticizer ratios.^17,18 The solvent evaporation technique is one of the most widely used methods for preparing oromucosal films, recognized for its simplicity, low cost and ease of use in laboratory settings.¹⁹

First, a homogeneous solution of water-soluble components was prepared with continuous heating and stirring with a magnetic stirrer: a 12% polymer solution was prepared using a propolis extract at a 1:10 ratio. To prepare the solution, 15 ml of propolis extract was added to 12 g of gelatin, and the mixture was placed on a heated magnetic stirrer. The solution was gradually heated to boiling, allowing for the complete evaporation of alcohol. Afterwards, 30 ml of distilled water, preheated to 55–60 °C, was added. The mixture was stirred using a magnetic stirrer for approximately 30 min, ensuring it became homogeneous. The resulting solution was stirred for another 15 min after the addition of 18 g glycerin. Next, after obtaining a homogeneous mixture, the pharmacologically active substance, 20 ml of a 10% aqueous solution of lidocaine hydrochloride, and excipients (5 g of rosehip syrup) are gradually added to the mixture until a viscous solution forms. The final solution was mixed using a magnetic stirrer while maintaining a temperature of 40–45 °C. The above ingredient quantities are based on preliminary calculations made during the film development process, such as determining the optimal polymer-to-plasticizer ratios.

Films were prepared by pouring the final solution into Petri dishes with a diameter of 9 cm. Each dish was filled with 7.5 ± 0.1 g of the solution to achieve films of optimal thickness. If air bubbles were present, the solution was deaerated using a vacuum pump and afterward transferred into Petri dishes with a syringe to minimize the introduction of surface air bubbles into the mold.

The films were dried in a drying cabinet at 40 °C for 24 h. After drying, the films were carefully removed from the Petri dishes and weighed. The average weight of the dry films was calculated. The films were then stored in a drying cabinet at room temperature until further evaluation of the quality parameters. After carefully removing the films from the Petri dishes, they are cut to the required size and proceed to further quality control steps.

Oral Film Quality Assessment

Organoleptic Properties

The color was assessed visually and was expected to match that of the ingredients or any added colorings, while the smell was expected to correspond to the ingredients or added flavorings.^20–22

The Thickness

The film thickness was measured both at the corners and in the center using a MOB-16 pre-calibrated eyepiece micrometer. According to the requirements, the film should be of the same thickness over the entire surface to ensure dosing accuracy.²³

Tack Test (Dryness)

It is the insistence due to which the film adhered to a piece of paper (an accessory) that has been pressed into contact with the film.²³ Equal cut pieces of the films were tested on paper by this method. The tenacity with which the strip adheres to paper was assessed by the ability of the film to remain on paper after turning.

Flexibility

The film is folded at the same point until it breaks. The flexibility value is determined by the number of folds made before tearing occurs. For instance, if the film tears after the fifth fold, the value is recorded as four. To meet the requirement, the film flexibility should exceed 300.^9,23

Surface pH

Preliminarily, a film with a surface area of 1cm² was soaked in 1 ml of distilled water for 15 min. The pH was measured using a Hanna Instruments pH 209 meter, with the electrode in direct contact with the film surface. The pH value should fall within the range of 6.2 to 7.6, corresponding to the typical saliva pH.²⁰

In-Vitro Drug Release (Dissolution)

According to USP 46-NF41 In-vitro release was studied using ERWEKA DT 60 and USP Apparatus 5 paddle-over-disk dissolution tester.^21,23 A film with a diameter of 2 cm was weighed and carefully transferred onto a Plexiglas disk.

Dissolution conditions:

Medium: phosphate buffer (pH 6.8)

Medium volume: 300 ml

Temperature: 37 ± 0.5 °C

Paddle rotation speed: 25 rpm

The film was placed at the bottom of a vessel filled according to the specified buffer volume. Samples of 0.5 ml were collected at 5-min intervals, and the medium was replenished with an equivalent volume of buffer (0.5 ml) after each sampling. The process lasted for 45 min. All samples were analyzed spectrophotometrically using a Unicam 8625 UV/Vis spectrometer at a wavelength of 263 nm, with phosphate buffer (pH 6.8) serving as the reference solution. The quantitative content of active substances was determined using a calibration curve constructed from data obtained with standard Lidocaine solutions at varying concentrations (0.02, 0.05, 0.1, 0.25, and 0.5 mg/ml) (SF 1).²⁴

Determination of the Lidocaine Quantitative Content in Films

Initially, the films were weighed, and their thickness was measured at four edges and in the center. A film sample of 16 cm² was placed in a beaker and 10 ml of ultrapure water was added. The beaker was shaken for 15 min to ensure complete disintegration of the film. Afterward, the mixture was filtered, and 0.5 ml of the filtrate was transferred to a 25 ml volumetric flask and diluted to the mark with the solvent.

The HPLC method quantitatively determined the content using a Waters chromatograph with Waters 2487 UV/Vis detector and C18 column.²⁵

Chromatographic Conditions

Mobile phase: Acetonitrile/ water adjusted to pH 6–7 with ammonium hydroxide

Injection volume: 20 μL

Flow rate: 0.5 ml/min

Run length: 15 min

UV detector wavelength: 263 nm

A standard solution of lidocaine hydrochloride with a concentration of 1 mg/ml was prepared. Then, 0.5 ml of this solution was placed in a 25 ml measuring flask, and the volume was adjusted to the mark with solvent. Lidocaine hydrochloride content in the standard solution was 0.02 mg/ml.

Based on the data obtained from the chromatograph, the quantitative content of lidocaine hydrochloride per 1 cm² of the recalculated film surface was determined. The calculation was carried out considering the peak areas obtained from the standard and test solutions.

Data presentation

Data from multiple studies were presented as the mean ± standard deviation (M ± m).

Results

Preparation and Standardization of Ethanolic Propolis Extracts

Propolis extracts were prepared in five different ratios: 1:5, 1:10, 1:15, 1:20, and 1:30. These extracts were compared for their phenolic compound content to identify the concentration that provided the desired extraction yield of phenolic compounds. All five extracts were obtained under the same conditions using the traditional method (maceration). They all had a reddish-brown color and a characteristic odor. The data on the standardization of these extracts based on phenolic acid content are provided in Table 1. According to the research results, the content of phenolic compounds in the extracts in the first three concentrations meets the required specifications. The yield of polyphenols in more diluted extracts was minimal (see Table 1). The extract with a ratio of 1:5 exhibited the highest yield, with a total polyphenol content of 6.5% in the extract. The phenolic acid content in the extracts with a ratio of 1:10 and 1:15 was 2.3% and 3.5%, respectively. However, the optimal yield of the active compounds recalculated based on the unit mass of the raw material taken for extraction was observed from a 1:10 ratio extract. Thus, to avoid waste of raw material, for the preparation of our films, we used 1:10 extract. Moreover, the films also contain the pain-relieving component Lidocaine, and the selection of 1:10 extract for further research provides the necessary dosage of phenolic compounds in the final product and meets the standard requirements.

Table 1.

Total Polyphenol Content (%) in Extracts with Different Ratios of Propolis and Extragent.

	Propolis/ethanol ratio	Phenolic compound content (%)
1.	1:5	6,5%
2.	1:10	3,5%
3.	1:15	2,3%
4.	1:20	1,25%
5.	1:30	0,1%

Obtaining Films

Quantitative Composition of Film Components

Gelatin type A was used as the film-forming polymer, while glycerin acted as the plasticizer. Propolis extract in a 1:10 ratio was added for its analgesic, keratoplastic, antimicrobial, antifungal, and anti-inflammatory properties. Rosehip syrup was added to ensure film adhesion and to act as a sweetener and saliva stimulant. Lidocaine hydrochloride, which is the pharmacologically active substance of the film, was used as a solution. The final quantitative composition of the mass required for film formation, determined through research and calculations, is presented in Table 2.

Table 2.

Quantitative and Qualitative Film Composition.

Component name	Concentration	Quantity (g/ml)
Propolis extract	(1:10)	15 ml
Lidocaine hydrochloride	10%	20 ml
Gelatin type A	-	12 g
Glycerin	-	18 g
Rosehip syrup	-	5 g
Purified water	-	25 ml

Film Preparation and Assessment

Nowadays, there are a lot of methods for obtaining oral films, including classic solvent casting or hot-melt extrusion methods. Modern techniques such as printing (3D, flexographic or ink-jet printing) or electrospinning nanotechnologies, or their combination, also seem to be useful and promising.^16,26,27 Nevertheless, аmong all these techniques, the solvent casting method is feasible, preferable, easily reproducible, and undoubtedly a widely used method, approved by USP 46-NF41,²¹ mainly due to the straightforward manufacturing process and low cost of processing.¹⁸

Films with varying quantitative polymer-to-plasticizer ratios were initially achieved. The optimal ratio for the final films was determined based on their mechanical properties. Among the options considered, there were five different ratios of polymer to plasticizer. As shown in Table 3, the films with a gelatin-to-glycerin ratio of 1:1.5 exhibited the best properties. Films with lower glycerol content lacked elasticity, which is a crucial film property (see Table 3). Films with a 1:1 ratio were elastic but did not meet the flexibility requirements.

Table 3.

Film Characteristics Obtained with Different Polymer-to-Plasticizer Ratio.

Film composition				Film Properties
N	Ratio	Gelatin (g)	Glycerin (g)	Film Properties
F1	1:0,33	12	4	transparent, smooth, inelastic, flexibility = 0
F2	1:0,5	12	6	transparent, smooth, inelastic, flexibility = 0
F3	1:0,83	12	10	transparent, smooth, of low elasticity, flexibility <50
F4	1:1	12	12	transparent, smooth, elastic, flexibility >100
F5	1:1,5	12	18	transparent, smooth, elastic, flexibility >300

During the preparation process, the polymer solution was gently heated to 40°C to improve the solubility of gelatin, which is insoluble in cold water. The solid gelatin particles became more fragile under the influence of ethanolic propolis extract, which increased their dissolution rate. The pharmacologically active substance was added to the homogeneous base solution, followed by the addition of rosehip syrup to create a more viscous mixture, as it dried more effectively compared to diluted solutions. The solution was poured into Petri dishes using a syringe to minimize the introduction of air bubbles, as these can compromise the quality of the film, particularly by increasing the risk of film rupture. The films were dried in a drying chamber at a temperature of 35–40 °C for 24 h, which provided the optimal conditions for producing films of good quality. Films stored at 50–60 °C in the drying chamber broke more easily, while those dried at room temperature were more rigid and less elastic.

Each Petri dish was filled with 7.5 ± 0.1 g of solution. The resulting dry films weighed 3.3 ± 0.2 g. Following solvent evaporation, sufficiently flexible, uniform films with a thickness of 0.2–0.3 mm and good physical properties were obtained.

Oral Film Quality Assessment

Organoleptic Properties

A visual assessment of the film color was conducted. It corresponded to the color of the components added. Yellow-brown translucent films with a smooth, homogeneous surface were developed. The resulting films exhibited a slight odor characteristic of propolis extract. The inclusion of rosehip syrup effectively masked the bitter taste of lidocaine and propolis extract, imparting a sweet flavor to the films (Table 3).

Thickness

Four measurements were taken in the center and at the edges of each film using an eyepiece micrometer. The film thickness was determined to be 0,3 ± 0,03 mm.

Tack Test (Dryness)

Preliminary tack test - studies on paper determined the optimum amount of rosehip syrup (5 g). After assessing of the resulting film, it was confirmed that it exhibited the appropriate ability to adhere to paper.

Flexibility

The flexibility of the films, assessed using the folding method, is detailed in Table 3. The flexibility index for the oral films with the selected composition exceeds 300.

Film pH

The pH of the film surface, measured by bringing the pH meter electrode in direct contact with the film surface previously wetted with distilled water, was 6.97.

In-Vitro Drug Release (Dissolution)

The dissolution testing was performed following the method outlined in section 2.4.6. A calibration curve was constructed based on the optical density values of five different lidocaine concentrations, demonstrating a linear relationship (R² = 0.09908) (SF 1). This calibration curve was used during the dissolution testing to calculate the concentration of active substances in the samples being studied.

The dissolution profile of the oral films was constructed based on the time-course results (Figure 1), which show that 70% of the active substance is released within 5 min.

Figure 1.

Dissolution Profile of Oral Films (n = 12).

Notably, the dissolution rate remains consistent at approximately 95.5% starting from the 25^th minute, confirming that the film has fully dissolved and released its active ingredient at this point.

Quantitative Determination of Lidocaine

The chromatographic retention time of Lidocaine for both standard and test solutions, determined using the quantitative HPLC method, was 9.32 ± 0.04 min (SF 2). According to chromatographic data, the lidocaine content in the sample is 0.08 mg/ml. Recalculation shows that a 16 cm² film contains 40 mg of lidocaine, equating to 2.5 mg per 1cm², which corresponds to a 4% lidocaine content in the films obtained.

Discussion

As previously mentioned, aphthous stomatitis has different pathogenic forms, all of which are characterized by severe pain. Pain is one of the persistent symptoms of aphthous ulcers, which is a significant concern for patients of all age groups. In mouth ulcers, etiologic treatment aims to eliminate the underlying factor affecting the oral cavity, while symptomatic treatment focuses on alleviating or eliminating pain.²⁸ A recent literature review has shown that used or developed oral mucosal films are usually one-, rare, two- or three-compartment and contain mostly pain relief component, such as lidocaine,²⁴ or its combination with synthetic drugs: NSADs and chlorhexidine.²⁹ Considering the need for a local anesthetic and the multifactorial nature of aphthous lesions, lidocaine hydrochloride and propolis were selected as the active pharmacological ingredients based on a number of advantages and their proven efficacy in dental practice. Lidocaine hydrochloride exhibits excellent local anesthetic properties, with a rapid onset of action and a moderate duration of effect.³⁰ Due to its rich chemical composition, particularly the presence of phenolic compounds, the hydroalcoholic extract of propolis exhibits local anesthetic, antimicrobial, antifungal, anti-inflammatory, antiviral, and wound healing effects.^31,32 On the other hand, R.B. Bodini et al showed that ethanol-propolis extract can effectively be incorporated in gelatin-based films without any changes in mechanical and physical properties, moreover, the obtained film possesses antimicrobial activity.³³ The main advantage of propolis compared to other synthetic drugs is its natural origin and rich composition of active compounds.

Since phenolic compounds and phenolic acids are the primary bioactive constituents of propolis, the extracts were standardized according to their total phenolic content. Ethyl alcohol was used as the solvent for propolis extracts obtained by maceration. From one perspective, literature data indicate that organic polar solvents ensure a high yield of both polar and non-polar compounds present in propolis.¹¹ From another perspective, evidence suggests that such solvents enhance the dissolution of gelatin by “loosening” its particles, making the structure more friable.

Through the standardization of hydroalcoholic extracts of propolis with different ratios (1:5, 1:10, 1:15, 1:20, 1:30) based on their phenolic compound content, it was determined that the more concentrated solutions with 1:5, 1:10, and 1:15 ratio fully met pharmacopoeial requirements, with phenolic acid concentrations exceeding 2% (PA.3.4.0037.22). Specifically, these concentrations were 6.5%, 3.5%, and 2.3%, respectively. For further research, the 1:10 ratio alcoholic extract was selected.

Lidocaine hydrochloride was selected as the analgesic agent for the formulation of the dosage form, with its final concentration calculated to be 4%. The extract of propolis was also incorporated into the composition to ensure a multifactorial pharmacological effect and to potentiate the analgesic properties of lidocaine.

The components selected for the film formulation are as follows. Gelatin was employed as the membrane-forming polymer. It is a biocompatible, biodegradable and commercially available natural polymer derived from the partial hydrolysis of collagen. Gelatin exhibits excellent film-forming and mucoadhesive properties.³⁴ Furthermore, it is listed in the FDA recommendations for inactive substances and is recognized as a safe material, devoid of irritating, carcinogenic or toxic properties.³⁵ Additionally, literature data suggest that, compared to other polymers commonly used in film production technology, gelatin films exhibit a slower release of lidocaine. As a result, the release of the active substance from the formulated films will be prolonged, enabling an extended local anesthetic effect.

Glycerin, used as a plasticizer, is compatible with all the components employed, enhancing the flexibility of the film and reducing its frailty. Evidence suggests that glycerin also has an impact on the absorption of the drug to some extent.³⁶ The results of our study revealed that films with low glycerol content lack elasticity, which is a crucial property of the films. This underscores the importance of the plasticizer as a key component in the formulation. Thus, the addition of glycerol increases the flexibility and elasticity of the films, the fluidity of the base solution, as well as decreases the film fragility.

Among the excipients, rosehip syrup serves multiple functions. It enhances adhesion, stimulates salivation and effectively disguises the bitter taste typical of propolis extract and lidocaine. Rosehip syrup is a rich source of vitamin C, which promotes collagen synthesis and connective tissue maturation.

An optimal 1:1.5 ratio of polymer to plasticizer was determined after obtaining films with different quantitative ratios of the components and quality assessment. The results indicated that films produced with low glycerin content exhibited insufficient flexibility. However, when the plasticizer content in the gelatin-glycerin matrix exceeded that of the polymer, it enabled the formation of elastic and flexible films. Consequently, the flexibility index of the films F1 and F2 was determined to be 0. The film F3 exhibited reduced elasticity, with a flexibility index of <50. Films F4 and F5 demonstrated favorable properties, exhibiting both elasticity and flexibility. Among them, film F5, with a gelatin-to-glycerin ratio of 1:1.5 and a flexibility index exceeding 300, was selected for the development of the final dosage form. As a result of evaluating the adhesion properties of the films, the optimal amount of rosehip syrup was identified as 5 g, which ensures the necessary adhesive characteristics of the films.

Thus, the components selected for the formulation of oral films effectively serve the intended purpose. The quantitative composition of these components, as presented in Table 2, ensures the production of films with the required properties.

The solvent evaporation technique is appropriate for producing films with the required properties under laboratory conditions. Incorporating gelatin into the ethanolic extract of propolis and gently heating the solution to 45 °C significantly enhances the complete and rapid polymer dissolution.

Combining water-soluble excipients, polymers, and drugs is a widely used method in film production technology. Reproducibility under laboratory conditions is another advantage of the method selected. As was revealed by the research results, the addition of propolis extract to a polymer solution contributed significantly to its higher dissolution. Therefore, the method of evaporating film-forming solvents is easy-to-use, simple, and accessible and allows for obtaining high-quality films even under laboratory conditions. Heating a polymer solution while preparing as well as “loosening” the gelatin particles with alcohol, thus making the structure more friable, significantly facilitating the technological process of dissolving gelatin in water.³³

The pH value of the films, measured using the pH-metric method, was 6.97, closely matching the slightly alkaline environment of the oral cavity. This indicates that the films are likely to dissolve completely under the specified conditions.

The release of active substances from the dosage form was determined using dissolution testing. The results showed that the film fully releases the active substance in a phosphate-buffered medium (pH 6.8, v = 300 ml) within 25 min. Notably, a significant release of 70% of the active substance was observed as early as the fifth minute. These findings confirm that the films can completely release the active substances in the oral cavity.

As a result of determining the quantitative content of lidocaine hydrochloride using the HPLC method, it was confirmed that a film with an area of 1 cm² contains 2.5 mg of lidocaine hydrochloride. This finding aligns with the previously calculated concentration of 4%.

The study has certain limitations. Notably, microbiological testing, which is a key aspect of quality control, was not conducted. However, it is important to highlight that the raw materials used were sterile, and the films were prepared under controlled conditions to prevent microbial contamination. Additionally, the drug has not yet undergone clinical trials, which are planned to be conducted after the final formulation of the dosage form.

The results of the study lay the groundwork for future research in the field. We propose further modifications to the components of the oromucosal film, particularly by application of sugar-free substitutes, which would broaden the indications for administration. Additionally, we suggest alternative anesthetic components, which may also expand the indications for use and minimize potential side effects. Further clinical trials are required to assess the comparative effectiveness of this formulation against other similar drugs currently available on the market.

Conclusion

The PropoLid oromucosal films proposed for the treatment of aphthous, ulcerative, and traumatic lesions can be effective for both managing symptoms and targeting the underlying causes, owing to the properties of their active pharmacological components. The use of gelatin as a polymer and glycerin as a plasticizer in a 1:1.5 ratio for oral films ensures the production of films with the required quality characteristics. An increased amount of plasticizer enhances the elasticity and flexibility of the film. Additionally, the inclusion of rosehip syrup at a concentration of 7.5% improves the film adhesion and contributes to adjusting its taste and aroma, making the dosage form more palatable. The quality assessment criteria of the obtained oral films comply with the pharmacopoeial requirements for organoleptic properties, mechanical properties, pH value, solubility, and quantitative content. The oral film fully releases its active substances within 25 min in a phosphate buffer, which simulates the oral cavity environment. The lidocaine content per 1 cm² of the resulting oral films is 2.5 mg, aligning with the previously calculated concentration of 4%.

Supplemental Material

sj-docx-1-npx-10.1177_1934578X251336120 - Supplemental material for Development of New Combined PropoLid Oromucosal Films for the Treatment of Oral Ulcerative Lesions

Supplemental material, sj-docx-1-npx-10.1177_1934578X251336120 for Development of New Combined PropoLid Oromucosal Films for the Treatment of Oral Ulcerative Lesions by Arusyak G. Zhamharyan, Shushanik G. Afrikyan, Anna A. Avetisyan, Hakob V. Topchyan, Marine G. Balasanyan, Bagrat J. Yenokyan, Kima A. Petrosyan, Marina M. Markaryan, Lazar K. Yessayan, Lusine A. Sharimanyan and Artak Heboyan in Natural Product Communications

Footnotes

ORCID iDs

Arusyak G. Zhamharyan

Artak Heboyan

Author Contributions/CRediT

Conceptualization, A.G.Zh., A.A.A., Sh.G.A., and A.H.; methodology, A.G.Zh., A.V.T. and B.J.Y.; software, L.A.Sh., M.M.M. and L.K.Y.; validation, A.G.Zh., A.A.A., Sh.G.A. and A.H.; formal analysis, M.G.B., A.V.T.; investigation, A.G.Zh. and K.A.P.; resources, A.G.Zh. and A.V.T.; data curation, A.G.Zh., and Sh.G.A.; writing—original draft preparation A.A.A. and Sh.G.A.; writing—review and editing, A.G.Zh. and A.H.; visualization, A.H., Sh.G.A., A.G.Zh.; supervision, A.H.; project administration, H.V.T., L.K.Y. and M.M.M. All authors have read and agreed to the published version of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability

The data supporting this study's findings are available from the corresponding author upon reasonable request.

Patent

The patent was registered in the Intellectual Property Office of the Republic of Armenia (Patent No 865Y https://old.aipa.am/search_mods/patents/view_item.php?id = 865YAM20230089Y&language = en).

Supplemental Material

Supplemental material for this article is available online.

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