Calcipotriol Nanosuspension-Loaded Trilayer Dissolving Microneedle Patches for the Treatment of Psoriasis: In Vitro Delivery and In Vivo Antipsoriatic Activity Studies.

Psoriasis, affecting 2-3% of the global population, is a chronic inflammatory skin condition without a definitive cure. Current treatments focus on managing symptoms. Recognizing the need for innovative drug delivery methods to enhance patient adherence, this study explores a new approach using calcipotriol monohydrate (CPM), a primary topical treatment for psoriasis. Despite its effectiveness, CPM's therapeutic potential is often limited by factors like the greasiness of topical applications, poor skin permeability, low skin retention, and lack of controlled delivery. To overcome these challenges, the study introduces CPM in the form of nanosuspensions (NSs), characterized by an average particle size of 211 ± 2 nm. These CPM NSs are then incorporated into a trilayer dissolving microneedle patch (MAP) made from poly(vinylpyrrolidone) and w poly(vinyl alcohol) as needle arrays and prefrom 3D printed polylactic acid backing layer. This MAP features rapidly dissolving tips and exhibits good mechanical properties and insertion capability with delivery efficiency compared to the conventional Daivonex ointment. The effectiveness of this novel MAP was tested on Sprague-Dawley rats with imiquimod-induced psoriasis, demonstrating efficacy comparable to the marketed ointment. This innovative trilayer dissolving MAP represents a promising new local delivery system for calcipotriol, potentially revolutionizing psoriasis treatment by enhancing drug delivery and patient compliance.

Selective Delivery of Clindamycin Using a Combination of Bacterially Sensitive Microparticle and Separable Effervescent Microarray Patch on Bacteria Causing Diabetic Foot Infection.

INTRODUCTION: Diabetic foot infection (DFI) is one of the complications of diabetes mellitus. Clindamycin (CLY) is one of the antibiotics recommended to treat DFI, but CLY given orally and intravenously still causes many side effects. METHODS: In this study, we encapsulated CLY in a bacteria sensitive microparticle system (MP-CLY) using polycaprolactone (PCL) polymer. MP-CLY was then delivered in a separable effervescent microarray patch (MP-CLY-SEMAP), which has the ability to separate between the needle layer and separable layer due to the formation of air bubbles when interacting with interstitial fluid in the skin. RESULT: The characterization results of MP-CLY proved that CLY was encapsulated in large amounts as the amount of PCL polymer used increased, and there was no change in the chemical structure of CLY. In vitro release test results showed increased CLY release in media cultured with Staphylococcus aureus bacteria and showed controlled release. The characterization results of MPCLY-SEMAP showed that the developed formula has optimal mechanical and penetration capabilities and can separate in 56 ± 5.099 s. An ex vivo dermatokinetic test on a bacterially infected skin model showed an improvement of CLY dermatokinetic profile from MP-CLY SEMAP and a decrease in bacterial viability by 99.99%. CONCLUSION: This research offers proof of concept demonstrating the improved dermatokinetic profile of CLY encapsulated in a bacteria sensitive MP form and delivered via MP-CLY-SEMAP. The results of this research can be developed for future research by testing MP-CLY-SEMAP in vivo in appropriate animal models.

Development of pH-Sensitive Nanoparticle Incorporated into Dissolving Microarray Patch for Selective Delivery of Methotrexate.

PURPOSE: Rheumatoid arthritis (RA) is a systemic autoimmune disease that attacks human joints. Methotrexate (MTX), as one the most effective medications to treat RA, has limitations when administered either orally or by injection. To overcome this limitation, we formulated MTX through a smart nanoparticle (SNP) combined with dissolving microarray patch (DMAP) to achieve selective-targeted delivery of RA. METHODS: SNP was made using the combination of polyethylene glycol (PEG) and polycaprolactone (PCL) polymers, while DMAP was made using the combination of hyaluronic acid and polyvinylpyrrolidone K-30. SNP-DMAP was then evaluated for its mechanical and chemical characteristics, ex vivo permeation test, in vivo pharmacokinetic study, hemolysis, and hen's egg test-chorioallantoic membrane (HET-CAM) test. RESULT: The results showed that the characteristics of the SNP-DMAP-MTX formulas meet the requirements for transdermal delivery, with the particle size of 189.09 ±12.30 nm and absorption efficiency of 65.40 ± 5.0%. The hemolysis and HET-CAM testing indicate that this formula was non-toxic and non-irritating. Ex vivo permeation shows a concentration of 51.50 ± 3.20 µg/mL of SNP-DMAP-MTX in PBS pH 5.0. The pharmacokinetic profile of SNP-DMAP-MTX showed selectivity and sustained release compared with oral and DMAP-MTX with values of t1/2 (4.88 ± 0 h), Tmax (8 ± 0 h), Cmax (0.50 ± 0.04 µg/mL), AUC (3.15 ± 0.54 µg/mL.h), and mean residence time (MRT) (9.13 ± 0 h). CONCLUSION: The developed SNP-DMAP-MTX has been proven to deliver MTX transdermal and selectively at the RA site, potentially avoiding conventional MTX side effects and enhancing the effectiveness of RA therapy.

Development of mucoadhesive microspheres for intranasal delivery of fluconazole as an alternative treatment of cryptococcal meningitis infection in patients with acquired immunodeficiency.

INTRODUCTION: Cryptococcal meningitis is a deadly disease with few treatment options. Its incidence is still high and closely linked to the HIV/AIDS epidemic. This study aimed to develop a mucoadhesive microsphere delivery system for fluconazole for the intranasal route. METHOD: Microspheres of mucoadhesive fluconazole formulation variables such as different amounts of drug concentration and polymer concentration were prepared by a simple emulsion-crosslinking method. The prepared microspheres' surface was characterised by SEM (Scanning electron microscopy) and evaluated for particle size, entrapment efficiency, production yield, infrared spectroscopic study, in-vitro muco-adhesion, and in-vitro drug release. RESULTS: The results showed that formula 1 is the optimal mucoadhesive microsphere preparation, with a particle size of 56.375m, a spherical surface shape, an entrapment efficiency of 99.96%, and a greater mucoadhesive capability during 6-hour evaluation. Furthermore, wash-off examination revealed that the mucoadhesive ability of this delivery system has a long duration and may release the active material at the right time. CONCLUSION: The result of the researches suggesting that the formulation of mucoadhesive microspheres of fluconazole could be used to treat cryptococcal meningitis infection in HIV/AIDS patients.

Application of validated UV spectrophotometric and colorimetric method to quantify minoxidil in the development of trilayer dissolving microneedle: Proof of concept in ex vivo and in vivo studies in rats.

Alopecia areata (AA) is an autoimmune-induced hair loss condition, by utilizing MNX, a hair growth-promoting compound. However, minoxidil (MNX) administration's efficacy is hindered by low bioavailability and adverse effects. To enhance its delivery, Trilayer Dissolving Microneedles (TDMN) are introduced, enabling controlled drug release. The study's primary was to establish a validated UV-Vis Spectrophotometer method for Minoxidil analysis in rat skin affected by alopecia areata. This method adheres to International Conference Harmonization (ICH) and FDA guidelines, encompassing accuracy, precision, linearity, quantification limit (QL), and detection limit (DL). The validation method was conducted through two approaches, namely UV region validation using PBS and the colorimetric method in the visible region (Vis). The validated approach is then employed for assessing in vitro release, ex vivo permeation, and in vivo pharmacokinetics. Results indicate superior MNX extraction recovery using methanol compared to acetonitrile. Method C (5mL methanol) is optimal, offering high recovery with minimal solvent usage. Precision assessments demonstrate %RSD values within MNX guidelines (≤15%), affirming accuracy and reproducibility. UV-Vis spectroscopy quantifies MNX integration into TDMN, using PVA-PVP, with concentrations aligning with ICH standards (95% to 105%). In conclusion, TDMN holds promise for enhancing MNX delivery, mitigating bioavailability and side effect challenges. The validated UV-Vis Spectrophotometer method effectively analyzes MNX in skin tissues, providing insights into AA treatment and establishing a robust analytical foundation for future studies.

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.

Solid Dispersion Incorporated into Dissolving Microneedles for Improved Antifungal Activity of Amphotericin B: In Vivo Study in a Fungal Keratitis Model.

Fungal keratitis (FK) is a fungal infection of the cornea, which is part of the eye and causes corneal ulcers and an increased risk of permanent blindness, which is often found in Candida albicans species. Amphotericin B (AMB), which is a group of polyenes as the first-line treatment of FK, is effective in annihilating C. albicans. However, AMB preparations such as eye drops and ointments have major drawbacks, for instance, requiring more frequent administrations, loss of the drug by the drainage process, and rapid elimination in the precornea, which result in low bioavailability of the drug. An ocular dissolving microneedle containing the solid dispersion amphotericin B (DMN-SD-AMB) had been developed using a mixture of poly(vinyl alcohol) (PVA) and poly(vinylpyrrolidone) (PVP) polymers, while the solid dispersion AMB (SD-AMB) was contained in the needle as a drug. This study aims to determine the most optimal and safest DMN-SD-AMB formula for the treatment of FK in the eye as well as a solution to overcome the low bioavailability of AMB eye drops and ointment preparations. SD-AMB had been successfully developed, which was characterized by increased antifungal activity and drug release in vitro compared to other treatments. Furthermore, DMN-SD-AMB studies had also been successfully performed with the best formulation, which exhibited the best ex vivo corneal permeation profile and antifungal activity as well as being safe from eye irritation. In addition, an in vivo antifungal activity using a rabbit infection model shows that the number of fungal colonies was 0.98 ± 0.11 log10 CFU/mL (F3), 5.76 ± 0.32 log10 CFU/mL (AMB eye drops), 4.01 ± 0.28 log10 CFU/mL (AMB ointments), and 9.09 ± 0.65 log10 CFU/mL (control), which differed significantly (p < 0.05). All of these results evidence that DMN-SD-AMB is a new approach to developing intraocular preparations for the treatment of FK.

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.

Bovine Colostrum Treatment of Specific Cancer Types: Current Evidence and Future Opportunities.

Worldwide, the incidence of cancer is on the rise. Current cancer treatments include chemotherapy, radiation therapy, and surgery. Chemotherapy and radiation treatment are typically associated with severe adverse effects and a decline in patients' quality of life. Anti-cancer substances derived from plants and animals need to be evaluated therapeutically as it is cost-effective, have fewer side effects, and can improve cancer patients' quality of life. Recently, bovine colostrum (BC) has attracted the interest of numerous researchers investigating its anti-cancer potential in humans. Dressings loaded with BC are beneficial in treating chronic wounds and diabetic foot ulcers. Lactoferrin, a glycoprotein with potent anti-oxidant, anti-inflammatory, anti-cancer, and anti-microbial effects, is abundant in BC. The BC pills successfully promote the regression of low-grade cervical intraepithelial neoplasia when administered intravaginally. The biological, genetic, and molecular mechanisms driving BC remain to be determined. Oral BC supplements are generally well-tolerated, but some flatulence and nausea may happen. To evaluate the therapeutic effects, long-term safety, and appropriate dosages of BC drugs, well-designed clinical trials are necessary. The purpose of this article is to emphasize the anti-cancer potential of BC and its constituents.

Combinatorial Approach of Thermosensitive Hydrogels and Solid Microneedles to Improve Transdermal Delivery of Valsartan: an In Vivo Proof of Concept Study.

Due to the limitations of oral administration of valsartan, in this study, we aimed to develop thermosensitive hydrogel for sustained transdermal delivery and improved bioavailability of valsartan, which was further improved using solid microneedles. The thermosensitive gel formula was made using Poloxamer 407 and Poloxamer 188 in various ratios. Valsartan thermosensitive gels were evaluated for their gelation temperature, pH values, drug content, spreadability, viscosity, rheological properties, in vitro drug release, in vitro permeation, and ex vivo permeation. Finally, in vivo study was conducted, compared to oral administration. The results presented the formulations showed required characteristic for transdermal administration with desired thermosensitive properties. Based on the permeation test with and without microneedles, it was found that the use of microneedles could affect the permeation of valsartan. Specifically, the increase of microneedles' needle length also increased valsartan permeation. The combination with the highest permeation was produced by 1.55 mm MNs with the amount of drug permeated of 2.27 ± 0.01 mg. Importantly, the transdermal delivery of valsartan using this combination approach could significantly improve the bioavailability of valsartan in in vivo study. The concentration of poloxamer was able to affect the properties of the hydrogels, and the use of solid microneedles improved the transdermal delivery of valsartan. In vivo studies showed the improvement of the bioavailability of valsartan compared to oral administration, showing the effectiveness of this combination approach.

Development, Evaluation, and Pharmacokinetic Assessment of Polymeric Microarray Patches for Transdermal Delivery of Vancomycin Hydrochloride.

Methicillin-resistant Staphylococcus aureus (MRSA) can cause harmful and potentially deadly infections. Vancomycin remains the first-line antibiotic treatment for MRSA-derived infections. Nevertheless, as a peptide drug, it is poorly absorbed when administered orally because of its high molecular weight and low permeability in the gastrointestinal tract and is therefore administered intravenously for the treatment of systemic diseases. In order to circumvent some of the many drawbacks associated with intravenous injection, other routes of drug delivery should be investigated. One of the strategies which has been employed to enhance transdermal drug delivery is based on microarray patches (MAPs). This work, for the first time, describes successful transdermal delivery of vancomycin hydrochloride (VCL) using dissolving MAPs (DMAPs) and hydrogel-forming MAPs (HFMAPs). VCL was formulated into DMAPs and reservoirs [film dosage forms, lyophilized wafers, and compressed tablets (CSTs)] using excipients such as poly(vinyl pyrrolidone), poly(vinyl alcohol), sodium hyaluronate, d-sorbitol, and glycerol. In this study, HFMAPs were manufactured using aqueous blends containing poly(methylvinyl ether-co-maleic acid) cross-linked by esterification with poly(ethylene glycol). The VCL-loaded CSTs (60% w/w VCL) were the most promising reservoirs to be integrated with HFMAPs based on the physicochemical evaluations performed. Both HFMAPs and DMAPs successfully delivered VCL in ex vivo studies with the percentage of drug that permeated across the neonatal porcine skin recorded at 46.39 ± 8.04 and 7.99 ± 0.98%, respectively. In in vivo studies, the area under the plasma concentration time curve from time zero to infinity (AUC0-∞) values of 162.04 ± 61.84 and 61.01 ± 28.50 µg h/mL were achieved following the application of HFMAPs and DMAPs, respectively. In comparison, the AUC0-∞ of HFMAPs was significantly greater than that of the oral administration control group, which showed an AUC0-∞ of 30.50 ± 9.18 µg h/mL (p < 0.05). This work demonstrates that transdermal delivery of VCL is feasible using DMAPs and HFMAPs and could prove effective in the treatment of infectious diseases caused by MRSA, such as skin and soft tissue infections, lymphatic-related infections, and neonatal sepsis.

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 ±â€¯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.

Development of Telmisartan Nanocrystal-Based Dissolving Microneedle for Brain Targeting via Trigeminal Pathway: A Potentially Promising Treatment for Alzheimer's with an Improved Pharmacokinetic Profile.

Telmisartan (TMN), an angiotensin receptor blocker (ARB) drug, is being considered as an alternative therapy for Alzheimer's disease (ALZ). However, when taken orally, its low water solubility leads to a low bioavailability and brain concentration. To overcome this problem, TMN was formulated as nanocrystals (NC), then incorporated into dissolving microneedles (DMN) to enhance drug delivery to the brain via the trigeminal route on the face. TMN-NC was formulated with 1% PVA using the top-down method and stirred for 12 h, producing the smallest particle size of 132 ± 11 nm and showing a better release profile, reaching 89.51 ± 7.52% (2 times greater than pure TMN). TMN-NC-DMN with a combination of 15% PVA and 25% PVP showed optimal mechanical strength and penetration ability; they could dissolve completely within 15 min, and their surface pH was safe for the skin. The permeation test of TMN-NC-DMN showed the highest concentration, reaching 285.80 ± 32.12 µg/mL, compared to TMN-DMN and patch control, which only reached 87.17 ± 11.24 and 94.00 ± 11.09 µg/mL, respectively. The TMN-NC-DMN combination showed better bioavailability and was found to be well-delivered to the brain without any irritation to the skin. Pharmacokinetic parameters had a significant difference (p > 0.05) compared to other preparations, making it a promising treatment for ALZ.

Validation of spectrophotometric and colorimetric methods to quantify clindamycin in skin tissue: application to in vitro release and ex vivo dermatokinetic studies from separable effervescent microarray patch loaded bacterially sensitive microparticle.

Diabetes mellitus can cause diabetic foot infection (DFI) complications. DFI is generally caused by infection from bacteria and Methicillin-Resistant Staphylococcus aureus (MRSA) which is resistant to several antibiotics. Application therapy of clindamycin (CLY) administration with the oral route has low bioavailability and non-selective distribution of antibiotics towards bacteria intravenously. In this research, CLY was developed into bacterially sensitive microparticles (MPs) which were further incorporated into a separable effervescent microarray patch (SEMAP) system to increase the selective and responsive to DFI-causing bacteria of CLY. To support this formulation, we explore the potential of silver nanoparticles (AgNPs) towards the UV-Vis spectrophotometry method. The analytical method was validated in phosphate-buffered saline (PBS), tryptic soy broth (TSB), and skin tissue to quantify CLY, CLY loaded in microparticle, and SEMAP system. The developed analytical method was suitable for the acceptance criteria of ICH guidelines. The results showed that the correlation coefficients were linear ≥ 0.999. The values of LLOQ towards PBS, TSB, and skin tissue were 2.02 µg/mL, 4.29 µg/mL, and 2.31 µg/mL, respectively. These approaching methods were also found to be accurate and precise without being affected by dilution integrity. The presence of Staphylococcus aureus bacteria culture can produce lipase enzymes that can lysing the microparticle matrix. Drug release studies showed that bacterial infection in the high drug release microparticle sensitive bacteria and high drug retention in ex vivo dermatokinetic in rat skin tissue media. In addition, in vivo studies were required to quantify the CLY inside in further analytical validation methods.

Trilayer dissolving microneedle for transdermal delivery of minoxidil: a proof-of-concept study.

Alopecia areata (AA) is a chronic autoimmune disease characterized by bald patches in certain areas of the body, especially the scalp. Minoxidil (MNX), as a first-line treatment of AA, effectively induces hair growth. However, oral and topical administration pose problems, including low bioavailability, risk of uncontrolled hair growth, and local side effects such as burning hair loss, and scalp irritation. In the latest research, MNX was delivered to the skin via microneedle (MN) transdermally. The MNX concentration was distributed throughout the needle so that drug penetration was reduced and had the potential to irritate. In this study, we formulated MNX into three-layer dissolving microneedles (TDMN) to increase drug penetration and avoid irritation. Physicochemical evaluation, parafilm, was used to evaluate the mechanical strength of TDMN and showed that TDMN could penetrate the stratum corneum. The ex-vivo permeation test showed that the highest average permeation result was obtained for TDMN2, namely 165.28 ± 31.87 ug/cm2, while for Minoxidil cream it was 46.03 ± 8.5 ug/cm2. The results of ex vivo and in vivo dermatokinetic tests showed that the amount of drug concentration remaining in the skin from the TDMN2 formula was higher compared to the cream preparation. The formula developed has no potential for irritation and toxicity based on the HET-CAM test and hemolysis test. TDMN is a promising alternative to administering MNX to overcome MNX problems and increase the effectiveness of AA therapy.

Formulation and evaluation of dissolving microneedle for transdermal delivery of piperine: the effect of polymers concentration.

This research aims to develop the formulation of Dissolving Microneedle Piperine (DMNs PIP) and evaluate the effect of polymer concentration on characterisation and permeation testing results in ex vivo. DMNs PIP were prepared from varying concentrations of piperine (PIP) (10, 15, and 20% w/w) and polymers of polyvinyl alcohol (PVA): Polyvinyl pyrrolidone (30:60 and 60:25), respectively. Then the morphological evaluation of the formula was carried out, followed by mechanical strength testing. Furthermore, the density, LOD, and weight percentage of piperine in the dried microneedle were calculated and the determination of volume, needle weight and piperine weight and analysed. Ex vivo testing, X-Ray Diffraction, FTIR and hemolysis tests were carried out. PIP with PVA and PVP (F1) polymers produced DMN with mechanical strength (8.35 ± 0.11%) and good penetration ability. In vitro tests showed that the F1 polymer mixture gave good penetration (95.02 ± 1.42 µg/cm2), significantly higher than the F2, F3, F4, and F5 polymer mixtures. The DMNs PIP characterisation results through XRD analysis showed a distinctive peak in the 20-30 region, indicating the presence of crystals. The FTIR study showed that the characteristics of piperine found in DMNs PIP indicated that piperine did not undergo interactions with polymers. The results of the ex vivo study through DMNs PIP hemolytic testing showed no hemolysis occurred, with the hemolysis index below the 5% threshold reported in the literature. These findings indicate that DMNs PIP is non-toxic and safe to use as alternative for treating inflammation.

Implantable trilayer microneedle transdermal delivery system to enhance bioavailability and brain delivery of rivastigmine for Alzheimer treatment: A proof-of-concept study.

Alzheimer's disease (ALZ) is a neurological disorder characterized by cognitive decline. Rivastigmine (RV), an acetylcholinesterase inhibitor, is commonly used to treat ALZ. Unfortunately, RV is availablein capsule form, which is associated with low drug bioavailability, and in patch form, which can lead to skin irritation upon repeated use. This study successfully fabricated a trilayer dissolving microneedle (TDMN) containing RV with adequate mechanical strength by using the molding method. In vitro release and ex vivo permeation showed that the release and permeation of RV were significantly sustained compared to control without PCL. The release and permeation percentages were 91.34 ± 11.39 % and 13.76 ± 1.49 µg/cm2, respectively. In addition, the concentration of RV in plasma and brain after 168 h was measured to be 0.44 ± 0.09 µg/mL and 1.23 ± 0.26 µg/g, respectively, which reached the minimum concentration to inhibit AcHE and BuChe. Pharmacokinetic testing revealed higher AUC values after administration of TDMN, indicating better bioavailability and RV concentrations in the brain were twice as high as those achieved with oral administration. This study suggests TDMN may enhance the bioavailability and brain delivery of RV.

Validation of UV-Vis spectrophotometric and colorimetric methods to quantify methotrexate in plasma and rat skin tissue: Application to in vitro release, ex vivo and in vivo studies from dissolving microarray patch loaded pH-sensitive nanoparticle.

This research transformed MTX into smart nanoparticles that respond to the acidic conditions present in inflammation. These nanoparticles were then incorporated into a patch that dissolves over time, aiding their penetration. A method using UV-Vis spectrophotometry was validated to support the development of this new delivery system. This method was used to measure the quantity of MTX in the prepared patches in various scenarios: in laboratory solutions with pH 7.4 and pH 5.0, in skin tissue, and plasma. This validation was conducted in laboratory studies, tissue samples, and live subjects, adhering to established guidelines. The resulting calibration curve displayed a linear relationship (correlation coefficient 0.999) across these scenarios. The lowest quantity of MTX that could be accurately detected was 0.6 µg/mL in pH 7.4 solutions, 1.46 µg/mL in pH 5.0 solutions, 1.11 µg/mL in skin tissue, and 1.48 µg/mL in plasma. This validated method exhibited precision and accuracy and was not influenced by dilution effects. The method was effectively used to measure MTX levels in the developed patch in controlled lab settings and biological systems (in vitro, ex vivo, and in vivo). This showed consistent drug content in the patches, controlled release patterns over 24 h, and pharmacokinetic profiles spanning 48 h. However, additional analytical approaches were necessary for quantifying MTX in studies focused on the drug's effects on the body's functions.

UV-Vis spectrophotometry for rapid and specific quantification of amphotericin B: analytical method validation for ex vivo and in vivo studies in the development of nanoemulsion-incorporated thermosensitive gel.

Amphotericin B (AmB) is the first-line drug used for the treatment of cryptococcal meningitis (CM). AmB has poor gastrointestinal permeability due to its large molecular weight. In addition, AmB in injectable form has the disadvantages of high systemic side effects and low bioavailability in the brain because it cannot cross the blood-brain barrier (BBB). Therefore, it is important to develop new drugs with a more optimized delivery system. The nose-to-brain drug delivery system offers many advantages such as high bioavailability in the brain as it does not need to cross the BBB. AmB was developed in nanoemulsion (NE) system which provides controlled release and to avoid nasal clearance system, it was combined with thermosensitive gel (TG). To support the formulation development process, analytical method validation was conducted for AmB in methanol (MeOH) solvent, release media, nasal mucosal tissue and brain tissue. It was conducted to measure the concentration of AmB in TG-NE, in vitro, ex vivo and in vivo studies. The developed method was then validated based on ICH guidelines. The results obtained showed that the linear coefficient was ≥ 0.9998. The LLOQ values in MeOH, PBS + 2% SLS, nasal mucosa tissue and brain tissue were 1.63 µg/mL, 1.99 µg/mL, 1.55 µg/mL, 1.62 µg/mL, respectively. The accuracy and precision of the developed analytical method were found to be precise without the influence of dilution. Therefore, the method was successfully applied to measure the amount of AmB in TG-NE. The validated method was reported to be successful for measuring the amount of AmB in gel preparations, in vitro, ex vivo and in vivo studies showing uniformity of drug content, release profile and pharmacokinetic profile.

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.