Oral candidiasis is a common disease in patients with dry mouth. In this study, film dosage forms (FD) incorporating miconazole nitrate, an antifungal agent, were prepared with water-soluble polysaccharide and cyclodextrin (CD). The dissolution profiles of the drug from the FDs were investigated in limited dissolution medium. Soft films were obtained from sodium alginate containing 0.5% α-CD, β-CD, or γ-CD. Most FDs were easy to handle, though the film tearing resistance was lower than that of CD-free FDs. Addition of CD to the FD accelerated the drug dissolution rate. Interestingly, this phenomenon was also observed in FDs prepared with pullulan. In contrast, acceleration of the drug dissolution rate was not observed when CD polymer was added to the base solution. The initial drug dissolution rate was controllable by the amount of CD added to the FD. Therefore, FDs prepared with these materials are useful to treat oral candidiasis in patients with dry mouth syndrome.
Dry mouth syndrome is a risk factor for oral diseases, including microbial infections, such as dental caries, periodontitis, and candidiasis [
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 [
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 [
ALG was obtained from NacalaiTesque Inc. (300 cps, Kyoto, Japan), and 1.5% (w/w) ALG was prepared in deionized water as thefilm base solution. Guluronicacid-rich ALG (IL-6G) was supplied by Kimica Co. (Tokyo, Japan). PUL was supplied by Hayashibara Biochemical Laboratories (Okayama, Japan), and polysaccharides produced by Bifidobacteriumlongum JBL05 (BPS) were supplied by Morishita Jintan (Osaka, Japan). MCZ (C18H14Cl4N2O HNO3, M.W. 479.14), the three CDs (α-CD, β-CD, γ-CD), and the three CDPs (α-CDP, β-CDP, γ-CDP) were obtained fromWako Pure Chemicals (Osaka, Japan). All other chemicals were of reagent grade.
A CD or CDP was added with agitationto 10 g of the film base solution.The mixture was thoroughly mixed with sonication, and 3.0 g of each solution was poured into individual plastic Petri dishes (diameter: 54 mm). After 24 h at 37˚C, the circular films formed on each dish were transferred to a desiccator. Film formation was considered to have failed if a circular film was not obtained, the film had cracks, or the film could not be removed from the bottom of the dish. In the present method, 3 mg of MCZ was theoretically incorporated into each FD.
Film thickness was measured at 10 points on each film using a micrometer (CLM1-15QM; Mitutoyo, Kawasaki, Japan) with a set pressure of 0.5 N. Measurements were made on 3 films, and the mean thickness was calculated for each type. The rheological properties of each film were determined using a rheometer (SUN RHEO TEX SD-700#; Sun Scientific Co., Tokyo, Japan) at room temperature. The film was fixed on a vial (inner diameter: 1.4 mm; outer diameter: 18.8 mm) using a rubber band (Kyowa Co., Osaka, Japan), and was probed with a cylindrical adapter (diameter: 5.0 mm). Stress and strain were measured at the point at which the adapter broke through the film. The tests were performed in triplicate.
The solubility of MCZ was measured in physiological saline containing CD or CDP. MCZ was added to the test solution and shaken at 37˚C for 24 h. The suspension was removed using a pre-heated plastic syringe (Terumo Co., Tokyo, Japan) at 37˚C and filtered using asyringe driven filter unit (Millex-HV, pore size: 0.45 μm, Millipore Co., Danvers, MA, USA). The solution was diluted with physiological saline and injected onto a high performance liquid chromatography (HPLC) column.
The HPLC system (Hitachi Co., Tokyo, Japan) consisted of a pump (L-2130), UV-detector (L-2400), autosampler (L-2200), and chromate-integrator (D-2500) connected to a packed column (150 mm × 4.6 mm, Cosmosil 5C18-MS-II, NacalaiTesque, Kyoto, Japan). To determine the concentration of MCZ, HPLC was conducted at ambient temperature using an eluent consisting of 10 mM KH2PO4 and acetonitrile (1:4) at a flow rate of 0.8 ml/min [
The FD was placed in a plastic dish, and 10 ml dissolution medium (physiological saline preheated to 37˚C) was added. The dish was shaken at 300 rpm in a shaker incubator (SI-300; As One Co., Osaka, Japan) at 37˚C. After 1, 3, 5, 10, 15, 20, 30, 45, or 60 minutes, 0.3 ml of the medium was removed using a plastic syringe and filtered through a syringe driven filter unit (pore size: 0.45 μm). Aliquots of the filtered solution (80 μl) were placed into micro-test tubes (1.5 ml), and 720 μl of methanol was added to precipitate the polysaccharide dissolved from the FD. Samples were mixed and centrifuged (7700 × g, 5 min; H-1300; Kokusan Co., Saitama, Japan), and the supernatants were injected onto the HPLC column. All tests were performed in triplicate.
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
▬ 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
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.
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.
Additive | Thickness (μm) |
---|---|
α-CD | 43 ± 5 |
β-CD | 45 ± 6 |
γ-CD | 71 ± 4 |
α-CDP | 217 ± 5 |
β-CDP | 220 ± 3 |
γ-CDP | 209 ± 22 |
▬ 1 mm
Additive | Solubility (mM) |
---|---|
additive free | 1.2 |
α-CD | 1.8 |
β-CD | 1.8 |
γ-CD | 1.9 |
α-CDP* | 1.1 |
β-CDP* | 1.2 |
γ-CDP* | 1.1 |
*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 [
This work was supported in parts by a grant from The OTC Self-Medication Promotion Foundation (2014).