Incorporation of Inclusion Complexes in the Dissolvable Microneedle Ocular Patch System for the Efficiency of Fluconazole in the Therapy of Fungal Keratitis.

Fluconazole (FNL) is one of the first-line treatments for fungal keratitis as it is an effective broad-spectrum antimicrobial commonly administered orally or topically. However, FNL has a very low water solubility, limiting its drug formulation, therapeutic application, and bioavailability through tissues. To overcome these limitations, this study aimed to develop FNL inclusion complexes (FNL-IC) with cyclodextrin (α-cyclodextrin, sulfobutylether-ß-cyclodextrin, and hydroxypropyl-γ cyclodextrin) and incorporate it into a dissolvable microneedle (DMN) system to improve solubility and drug penetration. FNL-IC was evaluated for saturation solubility, Fourier transform infrared spectroscopy, differential scanning calorimetry, in vitro release, minimum inhibitory concentration, minimum fungicidal concentration, and time-killing assay. DMN-FNL-IC was evaluated for mechanical and insertion properties, surface pH, moisture absorption ability, water vapor transmission, and drug content recovery. Moreover, ocular kinetic, ex vivo antimicrobial, in vivo antifungal, and chorioallantoic membrane (HET-CAM) assays were conducted to assess the overall performance of the formulation. Mechanical strength and insertion properties revealed that DMN-FNL-IC has great mechanical and insertion properties. The in vitro release of FNL-IC was significantly improved, exhibiting a 9-fold increase compared to pure FNL. The ex vivo antifungal activity showed significant inhibition of Candida albicans from 6.54 to 0.73 log cfu/mL or 100-0.94%. In vivo numbers of colonies of 0.87 ± 0.13 log cfu/mL (F2), 4.76 ± 0.26 log cfu/mL (FNL eye drops), 3.89 ± 0.24 log cfu/mL (FNL ointments), and 8.04 ± 0.58 log cfu/mL (control) showed the effectiveness of DMN preparations against other standard commercial preparations. The HET-CAM assay showed that DMN-FNL-IC (F2) did not show any vascular damage. Finally, a combination of FNL-IC and DMN was developed appropriately for ocular delivery of FNL, which was safe and increased the effectiveness of treatments for fungal keratitis.

The Formulation and Characterization of Wound Dressing Releasing S-Nitrosoglutathione from Polyvinyl Alcohol/Borax Reinforced Carboxymethyl Chitosan Self-Healing Hydrogel.

Self-healing hydrogels often lack mechanical properties, limiting their wound-dressing applications. This study introduced S-Nitrosoglutathione (GSNO) to self-healing hydrogel-based wound dressings. Self-healing hydrogel mechanical properties were improved via polymer blends. Applying this hydrogel to the wound site allows it to self-heal and reattach after mechanical damage. This work evaluated polyvinyl alcohol (PVA)-based self-healing hydrogels with borax as a crosslinking agent and carboxymethyl chitosan as a mechanical property enhancer. Three formulations (F1, F4, and F7) developed self-healing hydrogels. These formulations had borax concentrations of 0.8%, 1.2%, and 1.6%. An FTIR study shows that borate ester crosslinking and hydrogen bonding between polymers generate a self-healing hydrogel. F4 has a highly uniform and regular pore structure, as shown by the scanning electron microscope image. F1 exhibited faster self-healing, taking 13.95 ± 1.45 min compared to other formulations. All preparations had pH values close to neutrality, making them suitable wound dressings. Formula F7 has a high drug content (97.34 ± 1.21%). Good mechanical qualities included high tensile stress-strain intensity and Young's modulus. After 28 h of storage at -20 °C, 5 °C, and 25 °C, the self-healing hydrogel's drug content dropped significantly. The Korsmeyer-Peppas release model showed that the release profile of GSNO followed Fickian diffusion. Thus, varying the concentration of crosslinking agent and adding a polymer affects self-healing hydrogels' physicochemical properties.

Application of Biomaterials in the Development of Hydrogel-Forming Microneedles Integrated with a Cyclodextrin Drug Reservoir for Improved Pharmacokinetic Profiles of Telmisartan.

Telmisartan (TEL) is a promising antihypertensive agent among other angiotensin receptor blockers. However, its oral application is limited by its poor water solubility. This study presents the successful utilization of biomaterial-based hydrogel-forming microneedles integrated with a direct compressed tablet reservoir (HFMN-DCT) for the transdermal delivery of telmisartan in the treatment of hypertension. The combination of PVP, PVA, and tartaric acid was used in the HFMN formulation. A range of cross-linking temperatures and times were employed to optimize the characteristics of the HFMN. The HFMN exhibited excellent swelling capacity, mechanical strength, and insertion properties. Additionally, the poorly soluble characteristic of TEL was improved by the inclusion complex formulation with ß-cyclodextrin (ßCD). Phase solubility analysis showed an Ap-type diagram, indicating a higher-order complex between TEL and ßCD, with respect to ßCD. A ratio of TEL:ßCD of 1:4 mM demonstrates the highest solubility enhancement of TEL. The inclusion complex formation was confirmed by FTIR, XRD, DSC, and molecular docking studies. A significantly higher release of TEL (up to 20-fold) from the inclusion complex was observed in the in vitro release study. Subsequently, a DCT reservoir was developed using various concentrations of sodium starch glycolate. Essentially, both the HFMN and DCT reservoir exhibit hemocompatibility and did not induce any skin irritation. The optimized combination of the HFMN-DCT reservoir showed an ex vivo permeation profile of 83.275 ± 2.405%. Notably, the proposed system showed superior pharmacokinetic profiles in the in vivo investigation using male Wistar rats. Overall, this study highlights the potential of HFMN-DCT reservoir systems as a versatile platform for transdermal drug delivery applications.

Dual delivery systems combining nanocrystals and dissolving microneedles for improved local vaginal delivery of fluconazole.

Fluconazole (FLZ) has been widely used in the treatment of infection caused by Candida albicans, including the treatment of vulvovaginal candidiasis (VVC). However, when delivered orally, FLZ faces numerous limitations due to its poor solubility and undergoes the symptoms of first-pass metabolism. In this study, we developed the combinatorial approach of nanocrystals (NCs) and dissolving microneedles (DMNs) for effective local vaginal delivery of FLZ. The formulation containing 1.0% w/v PVA as stabilizer with 12 h of milling time process was found to be an optimal combination to fabricate FLZ as NCs (FLZ-NCs) with optimum size particle and PDI value (less than 0.25). Furthermore, the in vitro release study also showed a superior percentage of FLZ release up to 89.51 ± 7.52%. In combination with the DMNs, the FLZ recovery was 96.45 ± 2.38% with the insertion percentage in average of 76.14 ± 2.28% and height decreased percentage was only 7.53 ± 0.56%. Moreover, the ex vivo investigation and anti-candidiasis activity of DMNs-FLZ-NCs in vaginal model showed better results compared to other conventional preparations, such as film patch and hydrogel containing FLZ.

Effectiveness of Combination of Chitosan Gel and Hydroxyapatite from Crabs Shells (Portunus pelagicus) Waste as Bonegraft on Periodontal Network Regeneration through IL-1 and BMP-2 Analysis.

Background: Periodontitis can be treated by regenerating periodontal tissue using a bone graft. Several natural materials such as chitosan and minerals such as hydroxyapatite can be developed to increase periodontal tissue regeneration. Chitosan has a high potential in healing wounds. Hydroxyapatite has excellent properties such as biocompatibility, osteoconductive, osteoinductive, and osteogenesis, making it an ideal material for soft and hard tissue regeneration. Chitosan and hydroxyapatite can be obtained from the shells of crustaceans, such as crabs shells (Portunus pelagicus). Objective: To assess the effectiveness of the combination of chitosan gel and hydroxyapatite powder as a bone graft on periodontal tissue regeneration in experimental animals. Periodontal tissue regeneration was assessed by expressing inflammatory cytokine gene indicators IL-1 and BMP-2. Methods: Experimental laboratory research and clinical trials with posttest only control group design. Twenty-seven Wistar rats were divided into three groups. Then the femoral bone defect was made, the positive control group was given placebo gel, the positive control group was given BATAN hydroxyapatite, and the test group was given a combination of chitosan gel and hydroxyapatite crab shells. Wistar rats were sacrificed on days 7, 14, and 21, and the femur bone was then taken for immunohistochemical analysis to determine the levels of IL-1 and BMP-2. The Kolmogorov-Smirnov test, Levene test, and one-way ANOVA analyzed the data. Results: On days 7, 14, and 21, the expression levels of IL-1 and BMP2 were significantly different between the three groups. The group added with chitosan gel and crab shell HA showed a faster decrease in IL-1 expression than the control group. BMP-2 expression increased in the test group compared to the control group. Conclusion: The combination of chitosan gel and hydroxyapatite inhibited the production of proinflammatory cytokines and increased the production of BMP-2.

Effectiveness of turmeric (Curcuma Longa Linn) Gel Extract (GE) on wound healing: Pre-clinical test.

OBJECTIVE: This research was basic research to identify the effect of turmeric extract tested by the in vivo method. The purpose of this study was to identify differences in the length of the wound at each concentration of gel preparations on days 3, 7, and 14, as well as differences in wound healing time at each concentration of gel preparations and, identify the most effective gel preparations for wound healing. METHOD: This study is an experimental laboratory study with experimental animals using post-test only with control groups, the type of research used is a pre-clinical test (pre-clinical trial) on female rabbits. The sample size in this study was 12 rabbits grouped randomly. The length of each group's wounds was measured and observed on days 3, 7, and 14. Gel application was carried out twice a day in the morning and evening for 14 days. In this study, the experimental data were tested using Kruskal Wallis. RESULTS: There were differences in wound length in each group treated with turmeric extract gel and base gel. Based on the mean wound length of each group, they experienced a reduction in wound length on days 3, 7, and 14. There were also differences in wound healing time in each group. In each group, wherein this case, the treatment group that was given 5% turmeric extract gel experienced a faster healing time <14 days than the other groups. CONCLUSION: In general, turmeric extract gel at each concentration is effective against wound healing. Turmeric extract gel concentration is the most effective gel with a concentration of 5%, then followed by concentrations of 10% and 15%.

Effects of Centella asiatica (L.) Urban extract in TNF-α levels.

OBJECTIVE: This study aimed to determine the effectiveness of Centella asiatica leaf extract to TNF-α levels. METHODS: There were four treatment groups (each group consisted of five rats). Group I was given 0.5% Na CMC, group II was given Cefadroxil 45mg/kg WB, Group III C. asiatica leaf extract 100mg/kg BW, and group IV combination Cefadroxil and Centella leaf extract. Each group was given treatment twice for 12h a day for five days. RESULTS: TNF-α levels between groups did not significantly affect day three and differed significantly after day 6. On day 3, the control group had a higher TNF-α level of 25.13pg/ml than the group given antibiotics and C. asiatica. While when compared to the group given only C. asiatica leaf extract, the control group was more height of 17.1pg/ml. On the 6th day, this condition was changed. The most significant difference was found in the group given C. asiatica, in which the control group had higher levels of TNF-α 72.34pg/ml than the group receiving C. asiatica. Then, the control group is higher than 66.46pg/ml than those given antibiotics and C. asiatica. CONCLUSION: C. asiatica leaf extract effectively reduces TNF both given alone and given along with antibiotics. It is potential to be explored into alternative and complementary treatments in mastitis cases with human trials.

Molecular modeling and phenoloxidase inhibitory activity of arbutin and arbutin undecylenic acid ester.

Excessive melanin formation has been linked to various skin disorders such as hyperpigmentation and skin cancer. Tyrosinase is the most prominent target for inhibitors of melanin production. In this study, we investigated whether arbutin and its prodrug, arbutin undecylenic acid ester, might inhibit phenoloxidase (PO), a tyrosinase-like enzyme. Molecular docking simulation results suggested that arbutin and arbutin undecylenic acid ester can bind to the substrate-binding pocket of PO. Arbutin undecylenic acid ester with an IC50 6.34 mM was effective to inhibit PO compared to arbutin (IC50 29.42 mM). In addition, arbutin undecylenic acid ester showed low cytotoxicity in Drosophila S2 cells and the compound inhibited the melanization reaction. Therefore, the results of this study have demonstrated that arbutin undecylenic acid ester as a potential inhibitor of PO. We successfully designed a new platform utilizing Drosophila melanogaster and Bombyx mori as animal models propounding fast, cheap, and high effectiveness in method to screen tyrosinase inhibitors.