Specific delivery of metronidazole using microparticles and thermosensitive in situ hydrogel for intrapocket administration as an alternative in periodontitis treatment.

Periodontitis is a common chronic inflammatory disease primarily caused by the prevalence of bacterial overgrowth resulting in the development of an inflammatory condition that destroys the tooth's supporting tissues and eventual tooth loss. Comparatively, to other treatment methods, it is difficult for topical antibacterial drugs to effectively permeate the biofilm's physical barrier, making conventional therapy for periodontitis more challenging. This novel study combines thermosensitive in situ hydrogel with microparticles (MPs) to enhance the targeted delivery of metronidazole (MET) to the periodontal pocket. Polycaprolactone (PCL) polymer was utilized to produce bacteria-sensitive MPs. Additionally, the study assessed the attributes of MPs and demonstrated an enhancement in the in vitro antibacterial efficacy of MPs towards Staphylococcus aureus (SA) and Escherichia coli (EC). Subsequently, we incorporated MET-MPs into thermosensitive in situ hydrogel formulations using chitosan. The optimized formulations exhibited stability, appropriate gelation temperature, mucoadhesive strength, and viscosity. In vitro permeation tests showed selective and prolonged drug release against SA and EC. Ex vivo experiments demonstrated no significant differences between in situ hydrogel containing pure MET and MET-MPs in biofilm quantity, bacterial counts, and metabolic activity in biofilms. According to in vitro tests and the effectiveness of the antibacterial activity, this study has exhibited a novel methodology for more efficacious therapies for periodontitis. This study aims to utilize MET in MPs to improve its effectiveness, enhance its antibacterial activity, and improve patient treatment outcomes. In further research, the efficacy of the treatment should be investigated in vivo using an appropriate animal model.

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.

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.

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.

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 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 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.

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.

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.

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.

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.

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 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.

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.

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.

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.

Development of chitosan-hyaluronic acid based hydrogel for local delivery of doxycycline hyclate in an ex vivo skin infection model.

Doxycycline hyclate (DOXY) is a tetracycline derivative known as the broad-spectrum bacteriostatic drug. DOXY has been suggested as the first-line antibiotic for diabetic foot ulcers (DFU). Unfortunately, the long-term availability of DOXY in both oral and conventional topical dosage forms reduces its therapeutic effectiveness, which is closely linked to gastrointestinal side effects and acute pain during therapy, as well as uncontrolled DOXY release at the wound site. To address these shortcomings, we present for the first time a DOXY hydrogel system (DHs) built on crosslinks between carboxymethyl chitosan (CMC) and aldehyde hyaluronic acid (AHA). Three formulations of DHs were developed with different ratios of CMC and AHA, consisting of F1 (3:7, w/w), F2 (5:5, w/w), and F3 (7:3, w/w). Viscosity, rheology, gel strength, pH, swelling, gel fraction, wettability, stability, in vitro drug release, ex vivo antibacterial, and dermatokinetic studies were used to evaluate the DHs. According to the in vitro release study, up to 85% of DOXY was released from DHs via the Fickian diffusion mechanism in the Korsmeyer-Peppas model (n < 0.45), which provides controlled drug delivery. Because of its excellent physicochemical characteristics, F2 was chosen as the best DHs formulation in this study. Essentially, the optimum DHs formulation could greatly improve DOXY's ex vivo dermatokinetic profile while also providing excellent antibacterial activity. As a consequence, this study had promising outcome as a proof of concept for increasing the efficacy of DOXY in clinical therapy. Further extensive in vivo studies are required to evaluate the efficacy of this approach.

Solid implantable devices for sustained drug delivery.

Implantable drug delivery systems (IDDS) are an attractive alternative to conventional drug administration routes. Oral and injectable drug administration are the most common routes for drug delivery providing peaks of drug concentrations in blood after administration followed by concentration decay after a few hours. Therefore, constant drug administration is required to keep drug levels within the therapeutic window of the drug. Moreover, oral drug delivery presents alternative challenges due to drug degradation within the gastrointestinal tract or first pass metabolism. IDDS can be used to provide sustained drug delivery for prolonged periods of time. The use of this type of systems is especially interesting for the treatment of chronic conditions where patient adherence to conventional treatments can be challenging. These systems are normally used for systemic drug delivery. However, IDDS can be used for localised administration to maximise the amount of drug delivered within the active site while reducing systemic exposure. This review will cover current applications of IDDS focusing on the materials used to prepare this type of systems and the main therapeutic areas of application.

Docking Studies and Molecular Dynamics Simulations of Potential Inhibitors from the Brown Seaweed Sargassum polycystum (Phaeophyceae) against PLpro of SARS-CoV-2.

The COVID-19 disease is a major problem affecting human health all over the world. Consequently, researchers have been trying to find solutions to treat this pandemic-scale disease. Even if there are vaccines and approved drugs that could decrease the spread of this pandemic, multidisciplinary approaches are still needed to identify new small molecules as alternatives to combat COVID-19, especially those from nature. In this study, we employed computational approaches by screening 17 natural compounds from the tropical brown seaweed Sargassum polycystum known to have anti-viral properties that benefit human health. This study assessed some seaweed natural products that are bound to the PLpro of SARS-CoV-2. By employing pharmacophore and molecular docking, these natural compounds from S. polycystum showed remarkable scores for protein targets with competitive scores compared to X-ray crystallography ligands and well-known antiviral compounds. This study provides insightful information for advanced study and further in vitro examination and clinical investigation for drug development prospects of abundant yet underexploited tropical seaweeds.

Natural products targeting inflammation-related metabolic disorders: A comprehensive review.

Currently, the incidence of metabolic disorders is increasing, setting a challenge to global health. With major advancement in the diagnostic tools and clinical procedures, much has been known in the etiology of metabolic disorders and their corresponding pathophysiologies. In addition, the use of in vitro and in vivo experimental models prior to clinical studies has promoted numerous biomedical breakthroughs, including in the discovery and development of drug candidates to treat metabolic disorders. Indeed, chemicals isolated from natural products have been extensively studied as prospective drug candidates to manage diabetes, obesity, heart-related diseases, and cancer, partly due to their antioxidant and anti-inflammatory properties. Continuous efforts have been made in parallel to improve their bioactivity and bioavailability using selected drug delivery approaches. Here, we provide insights on recent progress in the role of inflammatory-mediated responses on the initiation of metabolic disorders, with particular reference to diabetes mellitus, obesity, heart-related diseases, and cancer. In addition, we discussed the prospective role of natural products in the management of diabetes, obesity, heart-related diseases, and cancers and provide lists of potential biological targets for high throughput screening in drug discovery and development. Lastly, we discussed findings observed in the preclinical and clinical studies prior to identifying suitable approaches on the phytochemical drug delivery systems that are potential to be used in the treatment of metabolic disorders.