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.

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.

Glucose-Responsive Microparticle-Loaded Dissolving Microneedles for Selective Delivery of Metformin: A Proof-of-Concept Study.

Diabetes mellitus (DM) is a metabolic disorder that is one of the most common health problems in the world, primarily type 2 DM (T2DM). Metformin (MTF), as the first-line treatment of DMT2, is effective in lowering glucose levels, but its oral administration causes problems, including gastrointestinal side effects, low bioavailability, and the risk of hypoglycemia. In this study, we formulated MTF into microparticles incorporating a glucose-responsive polymer (MP-MTF-GR), which could potentially increase the bioavailability and extend and control the release of MTF according to glucose levels. This system was delivered by dissolving microneedles (MP-MTF-GR-DMN), applied through the skin, thereby preventing gastrointestinal side effects of orally administered MTF. MP-MTF-GR was formulated using various concentrations of gelatin as a polymer combined with phenylboronic acid (PBA) as a glucose-responsive material. MP-MTF-GR was encapsulated in DMN using polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA) as DMN polymers. The physicochemical evaluation of MP-MTF-GR showed that MTF could be completely entrapped in MP with the percentage of MTF trapped increasing with increasing gelatin concentration without changing the chemical structure of MTF and producing stable MP. In addition, the results of the physicochemical evaluation of MP-MTF-GR-DMN showed that DMN had adequate mechanical strength properties and penetration ability and was stable to environmental changes. The results of the in vitro release and ex vivo permeation study on media with various concentrations of glucose showed that the release and permeation of MTF from the formula increased with increasing glucose levels in the media. The MP-MTF-GR-DMN formula successfully delivered MTF through the skin at 11.30 ± 0.29, 23.31 ± 1.64, 36.12 ± 3.77, and 53.09 ± 3.01 µg from PBS, PBS + glucose 1%, PBS + glucose 2%, and PBS + glucose 4%, respectively, at 24 h, which indicates glucose-responsive permeation and release behavior. The formula developed was also proven to be nontoxic based on hemolysis tests. Importantly, the in vivo study on the rat model showed that this combination approach could provide a better glucose reduction compared to other routes, reducing the blood glucose level to normal levels after 3 h and maintaining this level for 8 h. Furthermore, this approach did not change the skin moisture of the rats. This MP-MTF-GR-DMN is a promising alternative to MTF delivery to overcome MTF problems and increase the effectiveness of T2DM therapy.

Improved transdermal delivery of valsartan using combinatorial approach of polymeric transdermal hydrogels and solid microneedles: an ex vivo proof of concept investigation.

Valsartan (VAL) is used as a first-line agent to treat hypertension. However, VAL exhibits poor absorption and low bioavailability when administrated orally. To overcome these issues, VAL transdermal gel was developed in this study, where Carbopol was used as the gel matrices. Additionally, solid microneedles (Dermaroller®) with various needle lengths were combined with transdermal gel to improve its permeation across the stratum corneum as a skin barrier. Developed formulations were further evaluated for various parameters, including pH, viscosity, spreadability, extrudability, gel strength, drug content, ex vivo permeation, in vitro release, occlusivity, and hemolysis. The results showed that all formulations exhibited desired physical characteristics without any potential to cause toxicity. Moreover, this approach showed that using microneedles could significantly enhance the permeation of VAL up to 3 folds compared to untreated skin. The use of microneedles 1.5 mm was found to be the optimum combination to improve VA permeation without affecting skin integrity. As much as 1.69 ± 0.004 mg of VAL permeated after 8 h. Finally, it could be concluded that this work had successfully developed a new approach for VALS drug delivery and could potentially show a significant impact on the treatment of hypertension. Further in vivo work should be considered.

HPLC-UV method validation for quantification of ß-carotene in the development of sustained release supplement formulation containing solid dispersion-floating gel in situ.

Despite the health benefits of ß-carotene, its activity has been hampered by poor aqueous solubility and low oral bioavailability. Therefore, it is crucial to develop a new approach to overcome these problems. In this study, we developed a dry powder supplement comprising a combination approach of solid dispersion and floating gel in situ of ß-carotene to enhance the solubility and achieve sustained release behavior. Here, we validated an HPLC method to quantify ß-carotene as per the guidelines from ICH. The analytical method was validated in methanol and Fasted-State Simulated Gastric Fluid (FaSSGF) to determine ß-carotene in recovery and in vitro release studies, respectively. A simple HPLC method using Xselect CSH™ C18 column (Waters, 3.0 × 150 mm) with the particle size of 3.5 µm was validated with 100% acetonitrile as the mobile phase. The calibration curves were found to be linear with LLOQ values < 3 ng/mL. Importantly, the method was accurate and precise without a carry over effect and successfully applied to determine the ß-carotene concentration in the content analysis of the compound and in vitro drug release from floating gel in situ laden with solid dispersion formulations. The sensitivity of the method obtained here offers a wide potential use in various applications in drug delivery systems.

Validation of spectrophotometric method to quantify cabotegravir in simulated vaginal fluid and porcine vaginal tissue in ex vivo permeation and retention studies from thermosensitive and mucoadhesive gels.

Cabotegravir (CAB) is an antiretroviral therapy (ARV) used for Human Immunodeficiency Virus (HIV) treatment. CAB has low solubility, which affects its bioavailability in oral therapy. Moreover, the injection form of CAB has difficulty in the administration process. Therefore, it is essential to develop a new drug delivery system for CAB. Vaginal drug delivery system offers many advantages such as a large surface area, increased drug bioavailability, and improved drug delivery. CAB was developed in thermosensitive and mucoadhesive vaginal gel preparations that provided optimal distribution in the vaginal mucosa. To support the process of formulation development, in this study, UV-visible spectrophotometry method was validated in methanol, simulated vaginal fluid (SVF) and vaginal tissue to quantify the amount of CAB in the gel preparations, in vitro, and ex vivo studies, respectively. The developed analytical method was subsequently validated according to ICH guidelines. The calibration curves in these matrices were found to be linear with correlation coefficient values (R2) ≥ 0.998. The LLOQ values in methanol, SVF and vaginal tissue were 2.15 µg/mL, 2.22 µg/mL, and 5.13 µg/mL, respectively. The developed method was found to be accurate and precise without being affected by dilution integrity. These methods were successfully applied to quantify the amount of CAB in gel preparations, in vitro, and ex vivo studies, showing uniformity of drug content and controlled release manner in the permeation profile for 24 h for both thermosensitive and mucoadhesive vaginal gels. Further analytical method is required to be developed for the quantification of CAB in in vivo studies.

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.