Enhancement of skin localization of ß-carotene from red fruit (Pandanus conoideus Lam.) using solid dispersion-thermoresponsive gel delivered via polymeric solid microneedles.

Red fruit (Pandanus conoideus Lam.) boasts high ß-carotene (BC) content, often consumed orally. However, absorption issues and low bioavailability due to food matrix interaction have led to transdermal delivery exploration. Nevertheless, BC has a short skin retention time. To address these limitations, this study formulates a ß-carotene solid dispersion (SD-BC) loaded thermoresponsive gel combined with polymeric solid microneedles (PSM) to enhance in vivo skin bioavailability. Characterization of SD-BC includes saturation solubility, X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), and in vitro release. Characterization of SD-BC thermoresponsive gel includes gelation temperature, viscosity, rheological behaviour, pH, bio-adhesiveness, spreadability, and extrudability. PSM's mechanical properties and insertion capability were assessed. Ex vivo and in vivo dermato-pharmacokinetic studies, drug content, hemolysis, and skin irritation assessments were conducted to evaluate overall performance. Results confirm amorphous SD-BC formation, enhancing solubility. Both SD-BC thermoresponsive gel and PSM exhibit favourable characteristics, including rheological properties and mechanical strength. In vitro release studies showed a seven-fold increase in BC release compared to plain hydrogel. SD-BC thermoresponsive gel combined with PSM achieves superior ex vivo permeation (Cmax = 305.43 ± 32.07 µg.mL-1) and enhances in vivo dermato-pharmacokinetic parameters by 200-400 %. Drug content, hemolysis, and skin irritation studies confirmed its safety and non-toxicity.

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.

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.

Hydrogel forming microneedle-mediated transdermal delivery of sildenafil citrate from polyethylene glycol reservoir: An ex vivo proof of concept study.

Erectile dysfunction (ED) is a disorder that often occurs in men worldwide. One of the drugs used as the first-line therapy for erectile dysfunction is sildenafil citrate (SC). Unfortunately, SC was commonly found in oral, injection, and transdermal dosage forms with some limitations, mainly related to low oral bioavailability caused by the occurrence of first-pass metabolism in the liver, and poor patient comfort and compliance. Therefore, it was essential to develop dosage forms to overcome these limitations. We developed hydrogel-forming microneedles (HFM) that can facilitate transdermal delivery of SC by penetrating the stratum corneum. HFM was made using polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP) as polymers and several variations of tartaric acid as crosslinking agents. The evaluation of swelling properties, mechanical resistance, and penetration ability showed that the HFM produced had good insertion properties and swelling capabilities ranging from 300% to 700%. This HFM was designed to be integrated with a polyethylene glycol (PEG) reservoir prepared using several types of PEG with different molecular weights. The ex vivo permeation study showed that up to 80% of SC (equivalent to 20.2 ± 0.29 mg/mL) was delivered transdermally from this combined dosage form. For the first time, SC has been successfully developed into an HFM that was integrated with a PEG reservoir which was non-irritating, safe, and painless. It also had promising results for increasing the effectiveness of ED therapy.

Polymeric hydrogel forming microneedle-mediated transdermal delivery of sildenafil citrate from direct-compressed tablet reservoir for potential improvement of pulmonary hypertension therapy.

Pulmonary hypertension (PH) is a cardiovascular disease affecting patient's life. Sildenafil citrate (SC), the first-line treatment, is present in oral and injectable forms with some drawbacks, primarily poor patient's comfort and low oral bioavailability. To counter these limitations, stratum corneum-penetrating hydrogel-forming microneedles (HFM) was created, making it easier to distribute SC transdermally. HFM was fabricated using polyvinyl alcohol (PVA) and two variations of polyvinyl pyrrolidone's (PVP) concentration as polymers and citric acid (CA) as crosslinking agent. The crosslinking time was also variated. The assessment of swelling, insertion characteristics, and mechanical resistance revealed that it possessed swelling capacities up to 470 % and strong insertion capabilities. This HFM was integrated with a tablet reservoir prepared using several concentrations of sodium starch glycolate (SSG) as super disintegrant. The tablet reservoir's hardness, dissolution rate, XRD, and FTIR profiles were evaluated and the results showed that 4 % of SSG was the option for enhancing SC's solubility. According to ex vivo study, this system released 24.12 ± 0.92 % of SC. For the first time, SC was successfully incorporated into a system of HFM and tablet reservoir and was non-toxic, showing promise in terms of improving PAH therapy's efficacy following comprehensive in vivo studies in the future.

Enhanced and sustained transdermal delivery of primaquine from polymeric thermoresponsive hydrogels in combination with Dermarollers®.

Primaquine (PMQ) is an effective antimalaria drug with several limitations. We report the combinatorial approach of thermoresponsive hydrogels and Dermarollers® for transdermal delivery of PMQ to overcome these limitations. The hydrogels were prepared using Pluronic F127 (PF127) and F68 (PF68). Specifically, HPMC was added into the formulation to improve the bioadhesive properties. Numerous formulations were prepared, showing that formulation comprising 15 % PF127, 3 % PF68 and 0.4 % HPMC with 1 % PMQ was selected as the optimum formulation. The formulation showed the gelation temperature around 35 °C with bioadhesive strength of 26.43 ± 2.31 dyne.cm2. Importantly, the pH of the formulation was suitable for skin application with the percentage of PMQ recovery of 99.57 ± 3.23 %. Moreover, the hydrogels exhibited free-flow liquid at storage and room temperature and high viscosities in the skin temperature. In vitro release experiments showed that the release of PMQ was sustained for 24 h. Evaluated in extensive ex vivo studies, the treatment with Dermarollers® improved the skin permeation and retention of PMQ for 3 days. In combination with Dermarollers®, the ex vivo permeation of PMQ was sustained and the localization of PMQ in the skin was improved over 72 h.

Combination of transdermal patches and solid microneedles for improved transdermal delivery of primaquine.

Malaria caused by various types of Plasmodium has become a global health problem. One of the drugs used as the first line of malaria therapy is primaquine (PMQ). PMQ is generally administered through the oral route. However, the use of PMQ orally could potentially cause some side effects and undergo the first-pass metabolism in the liver, reducing its effectiveness. Therefore, it is necessary to develop another drug administration route to avoid this effect. In this study, for the first time, PMQ was formulated into a transdermal patch for transdermal delivery, combined with solid microneedles, Dermaroller®. Following several optimizations, HPMC and glycerin were used as the main polymer and plasticizer, respectively. Specifically, the concentration of PEG 400 as a permeation enhancer was also optimized. The transdermal patches were evaluated for weight uniformity, thickness, surface pH, folding endurance, moisture content, moisture absorption ability, bioadhesive evaluation, and drug content recovery. PMQ release and permeation were also investigated through in vitro and ex vivo tests on rats' skin tissue. Importantly, the safety of the transdermal patch was also evaluated through in vitro hemolytic and in vivo irritation tests which were confirmed by histopathological examinations. The results showed that all formulations showed desired physical and bioadhesive properties with a folding endurance of >300 folds. The results exhibited that 31.31 ± 5.25% and 22.55 ± 4.35% of primaquine were released from transdermal patches following the in vitro and the ex vivo permeation studies. Combined with Dermaroller®, the ex vivo permeation study showed an improved permeation profile with 45.89 ± 5.00% of primaquine permeated after 24 h with a zero-order kinetic during the first 8 h. Hemolysis percentage was found to be <5%, indicating the non-toxic of this approach. Finally, the histopathology study showed that there was no severe tissue damage following the administration of our approach. Further in vivo evaluations should be performed.