Hispidulin-rich fraction of Clerodendrum fragrans Wild. (Sesewanua) dissolving microneedle as antithrombosis candidate: A proof of concept study.

Existing conventional antithrombosis drugs have caused many side effects, opening up opportunities for the development of new thrombotic drugs. There is potential to use the hispidulin-rich fraction of sesewanua (HRFS) as a new antithrombotic. The oral route limitation of hispidulin, as a low water solubility and non-polar compound, can be addressed. This study explores the potential of HRFS in the form of dissolving microneedles (DMN). The formula was created using polymers such as polyvinyl alcohol (PVA), polyvinyl pyrrolidone K-30 (PVP), and non-ionic surfactant. Ex vivo permeation studies found that 184.95 µg/cm2 of hispidulin was released 60 h after the best formulation. After 14 days of applying HRFS-DMN, the anticoagulant and antioxidant activity in male albino rats showed higher Activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT) values and lower Inter Cellular Adhesion Molecule-1 (ICAM-1) values. No statistically significant differences were found between the effects of two and four HRFS-DMN and the injection of heparin at a dosage of 200 IU per kilogram. However, notable distinctions were observed when comparing HRFS-DMN to negative controls, oral and quercetin as positive controls at anti-ICAM activity. The findings confirmed the feasibility of HRFS-DMN for thrombosis and its effectiveness in delivering Hispidulin (HIS) into the bloodstream. This DMN is non-irritating, safe, and painless, showing promising outcomes in enhancing the efficacy of thrombosis treatment via the transdermal route.

Development of itraconazole ocular delivery system using ß-cyclodextrin complexation incorporated into dissolving microneedles for potential improvement treatment of fungal keratitis.

Itraconazole (ITZ) is one of the broad-spectrum antifungal agents for treating fungal keratitis. In clinical use, ITZ has problems related to its poor solubility in water, which results in low bioavailability when administered orally. To resolve the issue, we formulated ITZ into the inclusion complex (ITZ-IC) system using ß-cyclodextrin (ß-CD), which can potentially increase the solubility and bioavailability of ITZ. The molecular docking study has confirmed that the binding energy of ITZ with the ß-CD was -5.0 kcal/mol, indicating a stable conformation of the prepared inclusion complex. Moreover, this system demonstrated that the inclusion complex could significantly increase the solubility of ITZ up to 4-fold compared to the pure drug. Furthermore, an ocular drug delivery system was developed through dissolving microneedle (DMN) using polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA) as polymeric substances. The evaluation results of DMN inclusion complexes (ITZ-IC-DMN) showed excellent mechanical strength and insertion ability. In addition, ITZ-IC-DMN can dissolve rapidly upon application. The ex vivo permeation study revealed that 75.71% (equivalent to 3.79 ± 0.21 mg) of ITZ was permeated through the porcine cornea after 24 h. Essentially, ITZ-IC-DMN exhibited no signs of irritation in the HET-CAM study, indicating its safety for application. In conclusion, this study has successfully developed an inclusion complex formulation containing ITZ using ß-CD in the DMN system. This approach holds promise for enhancing the solubility and bioavailability of ITZ through ocular administration.

Development of dissolving microneedles loaded with fucoidan for enhanced anti-aging activity: An in vivo study in mice animal model.

Skin aging occurs naturally as essential skin components gradually decline, leading to issues such as fine lines, wrinkles, and pigmentation. Fucoidan, a natural bioactive compound, holds potential for addressing these age-related concerns. However, its hydrophilic nature and substantial molecular weight hinder its absorption into the skin. In this study, we utilized polyvinyl pyrrolidone K30 (PVP) and polyvinyl alcohol (PVA) as polymers to fabricate dissolving microneedles loaded with fucoidan (DMN-F). The DMN-F formulations were examined for physical characteristics, stability, permeability, toxicity, and efficacy in animal models. These formulations exhibited consistent polymer blends with a conical structure and uniform cone-shaped design. Microneedle structure and penetration capability gradually decreased with increasing fucoidan concentration, with storage recommended at approximately 33 % relative humidity (RH). Ex vivo studies showed that DMN-F efficiently delivered up to 95.03 ± 2.36 % of the total fucoidan concentration into the skin. In vivo investigations revealed that DMN-F effectively reduced wrinkles, improved skin elasticity, maintained moisture levels, and increased epidermal thickness. Histological images provided additional evidence of DMN-F's positive effects on these aging parameters. The results confirm that the DMN-F formulation effectively delivers fucoidan into the skin, allowing it to treat and mitigate signs of aging.

Bioavailability enhancement of sildenafil citrate via hydrogel-forming microneedle strategy in combination with cyclodextrin complexation.

Sildenafil citrate (SIL) as a first-line treatment for erectile dysfunction is currently reported to have poor solubility and bioavailability. Moreover, SIL undergoes first-pass metabolism when taken orally and its injection can lead to discomfort. In this study, we introduce a novel transdermal delivery system that integrates hydrogel-forming microneedles with the inclusion complex tablet reservoir. The hydrogel-forming microneedle was prepared from a mixture of polymers and crosslinkers through a crosslinking process. Importantly, the formulations showed high swelling capacity (>400 %) and exhibited adequate mechanical and penetration properties (needle height reduction < 10 %), penetrating up to five layers of Parafilm® M (assessed to reach the dermis layer). Furthermore, to improve the solubility of SIL in the reservoir, the SIL was pre-complexed with ß-cyclodextrin. Molecular docking analysis showed that SIL was successfully encapsulated into the ß-cyclodextrin cavity and was the most suitable conformation compared to other CD derivatives. Moreover, to maximize SIL delivery, sodium starch glycolate was also added to the reservoir formulation. As a proof of concept, in vivo studies demonstrated the effectiveness of this concept, resulting in a significant increase in AUC (area under the curve) compared to that obtained after administration of pure SIL oral suspension, inclusion complex, and Viagra® with relative bioavailability > 100 %. Therefore, the approach developed in this study could potentially increase the efficacy of SIL in treating erectile dysfunction by being non-invasive, safe, avoiding first-pass metabolism, and increasing drug bioavailability.

Anti-inflammatory effects of banana (Musa balbisiana) peel extract on acne vulgaris: In vivo and in silico study.

Objective: Acne vulgaris (AV) is a common problem with a relatively high incidence rate among Asian people. The potential antimicrobial and anti-inflammatory properties of banana peels have been demonstrated in previous studies but have not been studied in cases of AV. Therefore, this study was aimed at investigating the protective effects of banana (Musa balbisiana) peel extract (MBPE) against AV. Methods: Thirty rats were divided into five groups (n = 6 rats per group): an AV group, AV group treated with 0.15% MBPE, AV group administered 0.30% MBPE, AV group administered 0.60% MBPE, and AV group administered clindamycin (the standard drug treatment). We assessed nodule size, bacterial count, histopathology, and cytokine levels (IL-1α, IFN-γ, tumor necrosis factor (TNF)-α, and IL-8). Enzyme linked immunoassays were used to measure the cytokine levels. In addition, we performed molecular docking studies to determine the interactions between phytochemicals (trigonelline, vanillin, ferulic acid, isovanillic acid, rutin, and salsolinol) via the Toll-like receptor 2 (TLR2) and nuclear factor-kappa B (NF-κB) pathways. Results: All MBPE treatment groups, compared with the AV group, showed suppression of both bacterial growth and proinflammatory cytokine production, as well as resolved tissue inflammation. The nodule size was significantly suppressed in the groups receiving the two highest doses of MBPE, compared with the AV group. However, the pharmacological action of MBPE remained inferior to that of clindamycin. Docking studies demonstrated that rutin was the phytocompound with the most negative interaction energy with TLR2 or NF-κB. Conclusions: Our results indicated that MBPE has anti-inflammatory effects against AV, by suppressing nodule formation, inhibiting bacterial growth, and decreasing proinflammatory cytokine production.

Molecular Docking of Phytochemical Compounds of Momordica charantia as Potential Inhibitors against SARS-CoV-2.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has been recently declared as a global public health emergency, where the infection is caused by SARS-CoV-2. Nowadays, there is no specific treatment to cure this infection. The main protease (Mpro) of SARS-CoV-2 and SARS spike glycoprotein- human ACE2 complex have been recognized as suitable targets for treatment, including COVID-19 vaccines. OBJECTIVE: In our current study, we identified the potential of Momordica charantia as a prospective alternative and a choice in dietary food during a pandemic. MATERIALS AND METHODS: A total of 16 bioactive compounds of Momordica charantia were screened for activity against 6LU7 and 6CS2 with AutoDockVina. RESULTS: We found that momordicoside B showed the lowest binding energy compared to other compounds. In addition, kuguaglycoside A and cucurbitadienol showed better profiles for drug-like properties based on Lipinski's rule of five. CONCLUSION: Our result indicates that these molecules can be further explored as promising candidates against SARS-CoV-2 or Momordica charantia can be used as one of the best food alternatives to be consumed during the pandemic.

Characterization and Biological Evaluation of Solid Dispersed Nanoparticles of Synthetic Epoksilignan Targeting Pancreatic Cancer Cell as an Anticancer Agent.

MMEO (3'-methoxy-3',4″(methylenedioxy)-2,5-epoksilignan-4'ol-6-on) is a derivative of DMEO (3'-methoxy-3″,4″(methylenedioxy)-2,5-epoksilignan-4',6-diol) synthesized through demethylation using dimethylsulfoxide-acetic anhydride reagent. MMEO inhibits Hedgehog signaling at a concentration of 4.1 µM. The current study aimed to formulate MMEO as solid dispersed nanoparticles and determine their physicochemical properties and inhibitory activities. XRD (X-ray diffraction) analysis showed that the crystalline particles of the pure compound MMEO was smaller than MMEO nanoparticles. Image J software showed that at concentrations of 25 mg/mL and 50 mg/mL, the average nanoparticle sizes were 852.26 nm and 178.65 nm, respectively. Therefore, the MMEO solid dispersion system with the PEG 4000 polymer increases the solubility of MMEO. The higher the concentration of PEG 4000 the greater the solubility of MMEO. Treating pancreatic cancer cell lines with MMEO silenced the smoothened function by downregulating mRNA Ptch expression. This study suggests that MMEO may inhibit pancreatic cancer disease.

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.

Characterization and stability evaluation of nanoencapsulated epoxylignans.

3',6-dimethoxy-3'',4''-(methylenedioxy)-2,5-epoxylignan-4'-ol (DMEO), an epoxylignan isolated from Piper nigrum, has currently captured attention for its potential antitumor effect. However, low stability is limiting its therapeutic application. The application of nanocapsulation would be the main strategy for overcoming this problem. DMEO-loaded nanocapsules were prepared by an emulsion-diffusion method using Eudragit RL 100 (at concentrations of 1, 1.5 and 2%) and polyvinyl alcohol. As the polymer content increased, the encapsulation efficiency and mean particle size also increased. After 6 months of storage at 25°C (0% RH), no crystalline peaks were observed in the diffraction patterns of all nanocapsules, thereby suggested that the physical stability of nanoencapsulated DMEO was not affected by the concentration ratio of the polymer-stabilizer combinations.

Synthesis, Molecular Mechanism and Pharmacokinetic Studies of New Epoxy Lignan-Based Derivatives.

The oxidative demethylation procedure for a new epoxy lignan isolated from Piper nigrum was applied to the synthesis of 3'-methoxy-3",4"-(methylenedioxy)-2,5-epoxylignan-4'-ol-6'-one. This compound inhibited the mRNA expression of the protein patched homolog (Ptch) in human pancreatic cancer cells (PANC1) and therefore might be valuable as a probe for tumor-related disease. The pharmacokinetic profile of 3'-methoxy-3",4"-(methylenedioxy)-2,5-epoxylignan-4'-ol-6'-one was rapidly determined using ultra-fast liquid chromatography. The compound was rapidly absorbed in blood.