Dry mouth syndrome is a risk factor for oral diseases, including microbial infections, such as dental caries, periodontitis, and candidiasis [1] . Decreased saliva secretion occurs as a symptom of disease, such as diabetes, or as an adverse effect of drug administration [2] . Aging also decreases salivation [3] and can cause difficulty swallowing in the elderly. Saliva plays an important role in cleaning the oral cavity, and has an antimicrobial activity. Oral candidiasis is a fungal infection caused by Candida strains, including Candida albicans. Candida strains are not harmful to healthy individuals, but can cause infections in immunocompromised patients. Oral candidiasis is common in patients with dry mouth [4] . Miconazole nitrate (MCZ) is an antifungal agent widely used to treat Candida infections. It is well known that systemic MCZ administration can cause drug interactionsowing to cytochrome P450 inhibition [5] . Therefore, MCZ is directly applied to the tongue to avoid side effects that occur following gastrointestinal absorption [6] . MCZ gel preparations are commonly used to topically treat oral candidiasis. The patient has to apply the gel evenly in the oral cavity with their tongue. However, this procedure is tedious for patients, and is difficult for elderly patients.

Film is an excellent dosage form for oral care. When film dosage forms (FD) are placed in a small amount of liquid, they swell quickly and release the incorporated drug. FDs prepared with natural polysaccharides, including sodium alginate (ALG) and pullulan (PUL), which are safe for ingestion were previously characterized [7] . These polysaccharides can form films using simple methods that do not require dissolution in organic solvents. For FDs incorporating MCZ, the drug dissolution rate is enhanced by the addition of a surfactant to the base solution [8] . The surfactant used to prepare FDs is selected considering safety, formability, and patient comfort.

Cyclodextrins (CDs) are cyclic oligosaccharides with cone-shaped cavities, which affect the physicochemical properties of organic compounds by forming inclusion complexes. CDs have been studied to enhance the solubility of poorly water-soluble drugs, to improve the stability of unstable compounds, and as a masking agent for medicines and foods [9] -[11] . Some natural CDs are safe for oral administration, particularly α-CD, β-CD, and γ-CD, which are widely used as food additives [12] . In the present study, FDs were modified by the addition of CD to control the MCZ dissolution rate in limited dissolution medium. Additionally, FDs modified using the adsorbent, cyclodextrin polymer (CDP), were also investigated [13] [14] .

The polysaccharides used in this study can form thin films, termed FDs, using a casting method. FDs were formed by pouring 1.5% ALG, 1.2% BPS, or 4% PUL containing MCZ (1 mg/g) into a Petri dish and evaporating the solvent. Addition of CDs to the film base solution affected FD formation. As shown in Figure 1, a circular, soft film was obtained from 1.5% ALG solutions containing 0.5% α-CD, with a thickness of 43 μm. FDs were also obtained using ALG containing 0.5% β-CD and 0.5% γ-CD, as shown in Table 1, although the film

▬ 1 cm

prepared with solution containing 0.8% γ-CD was cracked. In the case of 1.5% ALG containing CDP, the FD thickness was approximately 200 μm. MCZ and other additives were homogeneously dispersed in the FDs, as shown in Figure 2. FDs were also obtained when 4% PUL containing 0.5% γ-CD was used; however, 1.2% BPS containing 0.5% CD did not form FDs.

To use FDs incorporating MCZ in oral candidiasis therapy, they must be easy to handle, since the form is directly applied to the target region. Figure 3 shows the additive effect of CD on the rheological properties of FDs prepared with ALG. Although γ-CD or γ-CDP lowered the resistance of FDs to tearing, each FD had sufficient strength to be treated by hand.

Since the FD film matrix consists of a water-soluble polysaccharide, it immediately swells in physiological saline at 37˚C, leading to erosion and MCZ release. Figure 4 shows the MCZ dissolution profiles from FDs prepared with 1.5% ALG. FDs prepared with ALG released 8.8% ± 0.7% of the incorporated MCZ into the test solution at 5 min. The initial dissolution rate increased following addition of CDs to the film base. For example, 24% ± 8% of the MCZ was released at 5 min from FDs prepared with ALG containing 0.5% α-CD. Addition of β-CD or γ-CD to the FDs also accelerated the drug dissolution rate. This phenomenon was also observed in FDs prepared with the other alginate, IL-6G. However, addition of 0.5% CDPs to the base solution did not affect the drug dissolution profile. The MCZ dissolution rate increased when CD was added to 4% PUL. For example, the amount of MCZ dissolved at 5 min increased from 36% ± 4% to 68% ± 9% following the addition of 0.5% α-CD to the film base. In addition, the initial MCZ dissolution rate increased when CD-free FD was dipped into the test solution containing 0.15% CD.

Table 2 shows the additive effect of CD or CDP on MCZ solubility in physiological saline at 37˚C. When 0.15% α-CD was added to the test solution, the solubility increased 1.5-fold, as compared to α-CD free test solution. A similar effect was observed using β-CD and γ-CD. In contrast, MCZ solubility was not affected by the addition of α-CDP, β-CDP, or γ-CDP. CDs can form complexes with some water-insoluble compounds, thereby increasing their solubility. Therefore, the acceleration of MCZ dissolution from FD may be attributable to complex formation between the polysaccharide matrix and CDs in the base solution.

Figure 5 shows the additive effect of γ-CD on the MCZ dissolution rate from FDs. As the amount of γ-CD incorporated in the FDs increased, the MCZ dissolution rate increased. To treat oral candidiasis, FDs containing

▬ 1 mm

^*Suspension.

^*Corresponding author.

In this study, FDs were prepared with polysaccharides and CDs incorporating MCZ. All materials used are safe for oral administration. When treating oral candidiasis, the antifungal agent must be applied repeatedly to completely treat the disease [16] . Therefore, the dissolution rate of MCZ in saliva affects the antifungal activity. FD easily disintegrates upon contact with a small amount of saliva, allowing it to deliver the incorporated MCZ to the affected part of the oral cavity. The MCZ dissolution rate can be controlled by the amount of CD added to the base FD solution. Thus, FDs prepared with water-soluble polymers, such as polysaccharides, are useful for treating localized problems in the oral cavity and simplify the administration of drugs to patients. This preparation is a candidate for the treatment of oral candidiasis caused by dry mouth syndrome.

This work was supported in parts by a grant from The OTC Self-Medication Promotion Foundation (2014).