Clotrimazole-loaded fatty acid-based in situ forming film oral spray (2023)

Materials Today: Proceedings

Volume 52, Part 5,


, Pages 2479-2484

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The lower viscosity character of fatty acid solution has been interested as in situ forming film (ISF) oral spray owing to its ease of spraying. Thus, the present experiment prepared ISF oral spray formula comprising different proportions of lauric acid (L) and palmitic acid (P) and their pH, density, viscosity, contact angle, surface tension and spray angle were determined. The higher L amount decreased density, pH, contact angle and spray angle as well as increased the gelation and matrix film formation. Although the increasing trend of viscosity was observed when L amount was increased, the viscosity in all prepared ISF was still apparently low. Clotrimazole-loaded ISF oral spray comprising 1: 1 L: P at 40% and 50% w/w exhibited a gelation at once upon contacted with phosphate buffer pH 6.8. The adhesion test proved the prominent adhesiveness on tongue tissue rather than on buccal tissue. Thus, these developed ISF oral spray solutions could be potential as ISF oral spray for treatment of oropharyngeal candidiasis.


Oropharyngeal candidiasis (OPC), commonly known as oral thrush, is a superficial mucous membrane infection which usually caused by the yeast Candida albicans [1]. It can occur in patient who received antibiotics, corticoids or those with impaired immune system such as those undergoing chemotherapy for cancer, or suffering from diabetes and immunocompromised persons [2]. The majority of oral candidiasis more than 95% are caused by C. albicans [3], [4], [5], [6], [7]. Among commonly used antifungal drugs, clotrimazole is an imidazole antifungal drug which is special interest in oral candidiasis that is used both locally and systemically [8], [9], [10]. In addition, it also appears as highly effective agent and drug of choice for the treatment of oral candidiasis. Since this drug is poorly absorbed, it is available as a 10-mg troche for localizing at oral mucosa [10]. As an alternative, it would be expected to be beneficial if the clotrimazole-based in situ forming film (ISF) oral spray is developed which in solution state initially but upon administered to the target site, it transformed into film by solvent exchange mechanism. Typically, after exposure with the environmental liquid, the solvent from ISF diffuses outward and the surrounding liquid enters into, which consequently, the phase separation of film former and formation of matrix film are presented. Hereby, the entrapped drug in this matrix film releases in a controlled manner. It has also been reported that a thin, non-sticky film enhances the contact time and the permeability of the drug and thereafter the continuous drug release. Therefore, more drug content is available to provide the therapeutic effects compared to conventional topical preparations [11]. Moreover, the film forming spray provides an even distribution and spreading at target site and the ease of use promoting the patient compliance [12]. Lauric acid is active against many oral microbes [13]. It has been reported as safe, bio-compatible and biodegradable material [14]. Because of its hydrophobic property, it was effectively used to regulate the drug release from capsules dosage form [15]. Palmitic acid (P) has been studied for gelation of the sunflower oil and several other vegetable oils [16], [17]. It is also reported that P was used in the synthesis of solid lipid nanoparticles for ocular drug delivery of antifungal drug such as itraconazole [18]. Clove oil is typically applied in various oral hygiene products owing to its antimicrobial activities. Thus, this investigation aimed to use lauric acid (L) and palmitic acid (P) as film forming agents in the preparation of the clotrimazole-loaded ISF oral spay using N-methyl pyrrolidone (NMP) as the solvent and clove oil was also added as additive.

Section snippets


Clotrimazole (batch no. 20001304, Lambrochem, Italy) was used as received. Lauric acid (Batch No. 229F150225C, Pacific Oleochemicals Sdn. Bhd., Pasir Gudang, Johor Darul Takzim, Malaysia) was used as a gelling agent. Clove oil was purchased from PC Drug, Bangkok, Thailand. NMP (lot no. A0251390; Fluka, New Jersey, USA) were used as solvent for lauric acid and CO. Agarose (Lot H7014-14) was from Vivantis Technologies Sdn, Bhd, Malaysia. Phosphate buffer pH 6.8 (PBS) was employed as the medium

Physical properties of the solutions containing different proportion of L

The physical properties of the ISF solutions with different concentrations of L are shown in Table 2. The density of the clove oil and NMP was 1.0280 ± 0.0002 (g/cm3) and 1.0406 ± 0.0001 respectively. The addition of L made the descending trend of density. The density of L is 0.82 ± 0.08 g. cm−3 at 23–24 °C [19]; thus, the replacement with the low density of L attributed to lower density of the system. The increasing amount of L decreased the pH of the system which may be attributed by the


The present study developed the ISF oral spray solution using the proper proportion of L:P where the equal proportion of L:P (20:20 and 25:25) gave the proper physical properties of ISF oral spray solution. Both clotrimazole-loaded ISF oral spray formulations showed the low viscosity which is the desire property for sprayable system. When compared, the more viscous nature with lower in spray angle were observed in ISF oral spray comprising L:P 25:25. The gelation or film-like matrix of them was

Author contributions

Please change Author contributions to "Sai Myo Thurein and Jongjan Mahadlek conceived for conceptualization of the project. Jongjan Mahadlek and Warakon Thammasut contributed to data curation and Sai Myo Thurein and Jongjan Mahadlek took the writing original draft. Jongjan Mahadlek and Thawatchai Phaechamud involved in writing-review & editing. The project administration was conducted by Thawatchai Phaechamud.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


The researchers are grateful to grant support funded by National Research Council of Thailand. The authors thank The Research and Creative Fund, Faculty of Pharmacy, Silpakorn University, Thailand and the Natural Bioactive and Material for Health Promotion and Drug Delivery System Group (NBM), Faculty of Pharmacy, Silpakorn University for their supports. The authors thank Wichai Santimaleeworagun, Napattorn Boonpae, Siriwat Num-on and Adisak Jongjit for their helps.

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