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.

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.

Development of probiotic loaded multilayer microcapsules incorporated into dissolving microneedles for potential improvement treatment of vulvovaginal candidiasis: A proof of concept study.

Vulvovaginal candidiasis (VVC) is a vaginal infection caused by abnormal growth of Candida sp., especially Candida albicans, in the vaginal mucosa. A shift in vaginal microbiota is prominent in VVC. The presence of Lactobacillus plays a vital role in maintaining vaginal health. However, several studies have reported resistance of Candida sp. against azoles drugs, which is recommended as VVC treatment. The use of L. plantarum as a probiotic would be an alternative to treat VVC. In order to exert their therapeutic activity, the probiotics needed to remain viable. Multilayer double emulsion was formulated to obtain L. plantarum loaded microcapsules (MCs), thus improving its viability. Furthermore, a vaginal drug delivery system using dissolving microneedles (DMNs) for VVC treatment was developed for the first time. These DMNs showed sufficient mechanical and insertion properties, dissolved rapidly upon insertion, facilitating probiotic release. All formulations proved non-irritating, non-toxic, and safe to apply on the vaginal mucosa. Essentially, the DMNs could inhibit the growth of Candida albicans up to 3-fold than hydrogel and patch dosage forms in ex vivo infection model. Therefore, this study successfully developed the formulation of L. plantarum-loaded MCs with multilayer double emulsion and its combination in DMNs for vaginal delivery to treat VVC.

Recent Advances in Pharmaceutical Approaches of Antimicrobial Agents for Selective Delivery in Various Administration Routes.

Globally, the increase of pathogenic bacteria with antibiotic-resistant characteristics has become a critical challenge in medical treatment. The misuse of conventional antibiotics to treat an infectious disease often results in increased resistance and a scarcity of effective antimicrobials to be used in the future against the organisms. Here, we discuss the rise of antimicrobial resistance (AMR) and the need to combat it through the discovery of new synthetic or naturally occurring antibacterial compounds, as well as insights into the application of various drug delivery approaches delivered via various routes compared to conventional delivery systems. AMR-related infectious diseases are also discussed, as is the efficiency of various delivery systems. Future considerations in developing highly effective antimicrobial delivery devices to address antibiotic resistance are also presented here, especially on the smart delivery system of antibiotics.

Development of Solid Lipid Nanoparticle-Loaded Polymeric Hydrogels Containing Antioxidant and Photoprotective Bioactive Compounds of Safflower (Carthamus tinctorius L.) for Improved Skin Delivery.

Safflower (Carthamus tinctorius L.) is a potent natural antioxidant because of active compounds such as quercetin (QU) and luteolin (LU). These components prevent damage to the skin caused by free radicals from UV rays. However, due to the poor solubility and transdermal permeation, the effectiveness of the compounds in showing their activity was limited. In this study, we develop solid lipid nanoparticle (SLN)-based hydrogel formulations to enhance the solubility and penetration of two bioactive compounds found in safflower petals extract (SPE). The hot emulsification-ultrasonication method was used to produce SLNs, and to obtain high antioxidant activity, 100% v/v ethanol was used in the extraction procedure. The results showed that this approach could encapsulate >80% of both QU and LU. Moreover, Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) spectra indicated that most of the QU and LU were trapped in a lipid matrix and dispersed homogeneously at the molecular level, increasing the solubility. Additionally, SLN-hydrogel composites are able to release two lipophilic bioactive compounds for 24 h, which also demonstrated increased skin retention and penetrability of the QU and LU up to 19-fold. In vitro blood biocompatibility showed that no hemolytic toxicity was observed below 500 µg/mL. Accordingly, the formulation was considered safe for use. Sun protective factor (SPF) test shows a value above 15, showing an excellent promising application as the photoprotective agent to prevent symptoms associated with photoinduced skin aging.

Development of thermosensitive and mucoadhesive gels of cabotegravir for enhanced permeation and retention profiles in vaginal tissue: A proof of concept study.

As an effective anti-HIV drug, cabotegravir (CAB) is currently administered via oral and injection routes, leading to several drawbacks, such as poor oral bioavailability and problems in the injection application process, as well as low drug concentration in vaginal tissue of woman patients. To overcome these issues, for the first time, we formulated CAB into three types of vaginal gels, considering the benefits of vaginal tissue as a delivery route. Thermosensitive gel, mucoadhesive gel, and the combination of these gels were developed as suitable carriers for CAB. Pluronics®, hydroxy propyl methyl cellulose (HPMC), Carbomer and poly(ethylene glycol) (PEG) 400 were used as thermosensitive, mucoadhesive and permeation enhancer agents, respectively. The gels were evaluated for their thermosensitive and mucoadhesive properties, as well as their pH values, viscosities, gel erosions, drug content recovery, in vitro drug release, ex vivo permeation, ex vivo retention, hemolytic activities, Lactobacillus inhibition activities and in vivo irritation properties. The results showed that all formulations showed desired characteristics for vaginal administration. Importantly, all formulations did not show hemolytic activities and inhibitions to Lactobacillus as normal bacteria in the vagina. Furthermore, no irritation in the vaginal tissues of the rats was observed by histopathological studies. Considering the thermosensitive and mucoadhesive properties, the combination of Pluronic® F127, Pluronic F68, and HPMC in thermosensitive-mucoadhesive vaginal gels was selected as the optimum dosage form for CAB as this formulation was able to provide ease administration due to its liquid form at room temperature. The use of PEG in this formulation was able to increase the penetrability of CAB through vaginal tissue with 0.61 ± 0.05 mg and 17.28 ± 0.95 mg of CAB being able to penetrate and localize in the vagina, respectively. Essentially, the optimum formulation was retained in the vaginal mucosa for>8 h. To conclude, further extensive in vivo studies should now be conducted to evaluate the efficacy of this approach.

Standard precaution adherence among clinical medical students in HIV and non-HIV ward in Indonesia.

INTRODUCTION: Health-care workers, especially medical intern, are at risk of exposed to blood and other body fluids in the course of their work. To reduce the risk, standard precaution (SP) is introduced. Among all communicable diseases that could be transmitted, human immunodeficiency virus (HIV) is the most stigmatized disease. However, there are some government hospitals that separated adult HIV patients with other patients to prevent additional infection. This study aims to evaluate the impact of ward separation on SP adherence. MATERIALS AND METHODS: This was an observational study conducted in March 2017 in a tertiary referral hospital for the eastern part of Indonesia. The participants were 150 medical students who underwent the past year of their clinical rotation. They were given a three-part questionnaire, consisting of their background, their SP practice in the HIV ward and non-HIV wards, and their perception and attitude regarding SP. McNemar's test and Fisher's exact test were used for the statistical analysis, using SPSS version 23.0 for Windows. RESULTS: Participants were more adhered to SP (hand hygiene, wear mask as indicated, and wear glove as indicated) in the HIV ward compare to non-HIV wards (P = 0.002, P = 0.001, and P = 0.001, respectively). Almost all participants were more careful in implementing SP in the HIV ward than in non-HIV wards and were more concerned of getting needlestick injury in the HIV ward than in non-HIV ward. CONCLUSION: HIV and non-HIV ward separation negatively impact medical students' SP adherence.

Determinants of Tobacco Smoking Addiction in Rural Indonesian Communities.

Purpose: To analyze the determinants of tobacco smoking addiction in rural areas. Methods: A cross-sectional study was conducted on February 2020. The self-administered questionnaire (α = 0.908) and Perceived Stress Scale-10 were used as tobacco smoking determinants and the WHO ASSIST questionnaire V3.0 to determine its addiction risk. Their correlations were analyzed by Spearman's rank-order approach using the SPSS version 23.0. Results: Among 75 male respondents that participated in this study, those on low, moderate, and high addiction risk were 45 (60.00%), 23 (30.67%), and 7 (9.33%), respectively, and significantly correlated with the research questionnaire that consisted three parts: 1. awareness toward the health risk; 2. social control; 3. mass media role in tobacco smoking (p=0.014, 0.004, and 0.009 respectively), but there was no significant correlation with the stress level (p=0.287). Conclusion: Increased awareness toward the health risk, good social control, and mass media reporting the danger of tobacco smoking is significantly in correlation with the decreased addiction in rural areas. However, the high perceived stress has no correlation with its increase.