HSPiP, Computational Modeling, and QbD-Assisted Optimized Method Validation of 5-Fluorouracil for Transdermal Products.

This study addressed the simplest and most efficient HPLC (high-performance liquid chromatography) method for the estimation of 5-fluorouracil (5-FU) from rat blood plasma by implementing the Hansen solubility parameters (HSP), computation prediction program, and QbD (quality by design) tool. The mobile phase selection was based on the HSP predictions and experimental data. The Taguchi model identified seven variables (preoptimization) to screen two factors (mobile phase ratio as A and column temperature as B) at three levels as input parameters in "CCD (central composite design)" optimization (retention time as Y1 and peak area as Y2). The stability study (freeze-thaw cycle and short- and long-term stability) was conducted in the rat plasma. Results showed that HSPiP-based HSP values and computational model-based predictions were well simulated with the experimental solubility data. Acetonitrile (ACN) was relatively suitable over methanol as evidenced by the experimental solubility value, HSP predicted parameters (δh of 5-FU - δh of ACN = 8.3-8.3 = 0 as high interactive solvent whereas δh of 5-FU - δh of methanol = 8.3-21.7 = -13.4), and instrumental conditions. CCD-based dependent variables (Y1 and Y2) exhibited the best fit of the model as evidenced by a high value of combined desirability (0.978). The most robust method was adopted at A = 96:4 and B = 40 °C to get earlier Y1 and high Y2 as evidenced by high desirability (D) = 0.978 (quadratic model with p < 0.0023). The estimated values of LLOD and LLOQ were found to be 0.11 and 0.36 µg/mL, respectively with an accuracy range of 94.4-98.7%. Thus, the adopted method was the most robust, reliable, and reproducible methodology for pharmacokinetic parameters after the transdermal application of formulations in the rat.

Impact of miconazole nitrate ferrying cationic and anionic nanoemulsion and gels on permeation profiles of across EpiDerm, artificial membrane, and skin: Instrumental evidences.

Based on our previous report, the study was extended to investigate the impact of miconazole nitrate (MCN) loaded cationic/anionic nanoemulsions and nanoemulsion gels on permeation behaviour across artificial-membrane, EpiDerm, and rat skin. Nanoemulsions and gels were evaluated for size, charge, viscosity, size-distribution, pH, and percent entrapment efficiency (%EE). In vitro drug diffusion across artificial membrane and EpiDerm were conducted to get diffusion coefficients. Permeation profiles were studied using rat skin to investigate mechanistic insight of formulated mediated permeation followed by CLSM (confocal laser scanning microscopy), SEM (scanning electron microscopy), AFM (atomic force microscopy), and irritation studies. Results showed that MCNE11-Rh (probed cationic nanoemulsion at pH âˆ¼ 7.2) and MNE11-Rh (probed anionic nanoemulsion at pH âˆ¼ 7.2) showed size values of 158 nm and 145 nm, respectively whereas MCNE11-GR (probed cationic nanoemulsion gel at pH âˆ¼ 6.8) and MNE11-GR (probed anionic nanoemulsion gel at pH âˆ¼ 6.8) exhibited size values 257 nm and 243 nm, respectively. The %EE values were found to be as 91.5 % and 89.6 % for MCNE11-Rh and MNE11-Rh, respectively. The gels (∼6000 cP) elicited relatively high viscosity than nanoemulsions (∼3300 - 3500 cP). MCNE11-GR showed the highest values of permeation flux, diffusion rate, diffusion coefficient (D), and permeation coefficient (P) across artificial membrane, EpiDerm, and rat skin which may be attributed to three potential factors (cationic charge, composition, and hydration by the hydrophilic gel) working in tandem. Transepidermal water loss (TEWL) by the MCNE11-GR was maximum (14.4 g/m2h) than control (6.1 g/m2h) indicating augmented interaction of MCNE11-Rh with skin components. Conclusively, cationic nanoemulsion gel was promising carrier for enhanced permeation and the drug access to the dermal region to treat deep seated fungal infections.

HSPiP and QbD Program-Based Analytical Method Development and Validation to Quantify Ketoconazole in Dermatokinetic Study.

Ketoconazole (KTZ) is the most potential azole anti-mycotic drug. The quantification of KTZ from various layers of the skin after topical application of lipidic nanocarriers is critical. We addressed a sensitive, specific, simple, rapid, reproducible, and economic analytical method to quantify KTZ from the treated skin homogenate using the Hansen solubility parameter (HSP, HSPiP software)-based modeling and experimental design. The software provided various HSP values for KTZ and solvents to compose the mobile phase. The Taguchi model identified the significant sets of factors to develop a robust bioanalytical method with reduced variability. In the optimization, acetonitrile (ACN) concentration (X1 as A) and the pH of mobile phase (X2 as B) were two factors against two responses (Y1: peak area and Y2: retention time). The HPLC (high-performance liquid chromatography) method validation was carried out based on US-FDA guidelines for the developed KTZ formulations (suspension, solid nanoparticles, and commercial product) extracted from the treated rat skin. The experimental solubility of KTZ was found to be maximum in the two solvents (ACN and ethyl acetate), based on HSP values. Surface response methodology (SRM) identified remarkable impact of ACN concentration and the mobile phase pH on the peak area and retention time. Analytical limits (0.17 and 0.50 µg/mL) were established for KTZ-SLNs (extracted from the skin). The method was implemented with high reproducibility, accuracy, and selectivity to quantify KTZ from the treated rat skin.

Hansen Solubility Parameters and QbD-Oriented HPLC Method Development and Validation for Dermatokinetic Study of a Miconazole-Loaded Cationic Nanoemulsion in Rat Model.

Miconazole (MCZ) is a potential antifungal drug to treat skin infections caused by Candida, Tinea pedis (athlete's foot fungal infection), Tinea cruris (jock itching in the groin and buttocks), and Tinea corporis (red scaly rash on the skin). The current study focused on Hansen parameter-based solvent selection (HSPiP software) and method development optimization using an experimental design tool for sensitive, accurate, reproducible, economic, rapid, robust, and precise methodology to quantify MCZ in rat plasma. Moreover, a Taguchi design was used for screening two independent factors (flow rate and ACN content). Quality by design (QbD) was employed to optimize and identify the right ratio of mobile phase composition and its impact on the peak and retention time. The elution of MCZ was achieved using methanol and acetonitrile (15:85 v/v ratio) at a retention time of 6 min and optimal flow rate (1 mL/min). Finally, the method was validated based on accuracy, precision, linearity, selectiveness, and high recovery at varied concentrations as per the International Council for Harmonization (ICH) guidelines. The method was linear (r2 = 0.999) over the explored concentration range (250-2000 ng/mL) at 270 nm detection wavelength. The optimized method was used to quantify in vivo pharmacokinetic (PK) study after transdermal application of MCZ-loaded formulations (MCNE11, MNE11, MCZ-Sol, and MCZ-MKT). HSP-oriented solvent selection and quality by design-based optimized process variables and composition in the optimized analytical methodology were quite convincing and have been a cutting-edge MCZ analysis method so far. The validated method was robust, economic, and rapid with high specificity and selectivity.

Mechanistic of Vesicular Ethosomes and Elastic Liposomes on Permeation Profiles of Acyclovir across Artificial Membrane, Human Cultured EpiDerm, and Rat Skin: In Vitro-Ex Vivo Study.

Acyclovir (ACV) controls cutaneous herpes, genital herpes, herpes keratitis, varicella zoster, and chickenpox. From previously reported ACV formulations, we continued to explore the permeation behavior of the optimized ACV loaded optimized ethosome (ETHO2R) and elastic liposome (ELP3R) and their respective carbopol gels across artificial membrane, cultured human EpiDerm, and rat skin. Transepidermal water loss (TEWL), scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM), and atomic force microscopy (AFM) were used to investigate the mechanistic perspective of permeation behavior. The size values of reformulated ELP3-R and ETHO2-R were observed as 217 and 128 nm, respectively (close to previous report), whereas their respective gels showed as 231 and 252 nm, respectively. ETHO2R showed high elasticity, %EE, and low vesicle size. These were investigated for the diffusion rate of the drug permeation (3 h) across the artificial membrane, cultured human EpiDerm, and rat skin. ETHO2GR showed the highest permeation flux (78.42 µg/cm2/h), diffusion coefficient (8.24 × 10-5 cm2/h), and permeation coefficient (0.67 × 10-3 cm/h) of ACV across synthetic membrane, whereas diffusion coefficient (2.4 × 10-4 cm2/h) and permeation coefficient (0.8 × 10-3 cm/h) were maximum across EpiDerm for ETHO2GR. ETHO2R suspension showed maximized permeation flux (169.58 µg/cm2/h) and diffusion rate (0.293 mg/cm2/h1/2), suggesting the rapid internalization of vesicles with cultured skin cells at low viscosity. A similar observation was revealed using rat skin, wherein the permeation flux (182.42 µg/cm2/h), permeation coefficient (0.3 × 10-2 cm/h), and diffusion rate (0.315 mg/cm2/h1/2) of ETHO2R were relatively higher than ELP3R and ELP3GR. Relative small size (128 nm), low viscosity, ethanol-mediated ultra-deformability, high drug entrapment (98%), and elasticity (63.2) are associated with ETHO2R to provide remarkable permeation behavior across the three barriers. The value of TEWL for ETHO2R (21.9 g/m2h) was 3.71 times higher than untreated control (5.9 g/m2h), indicating ethanol-mediated maximized surficial skin lipid perturbation at 3 h of application, whereas the respective ETHO2GR-treated rat skin had TEWL value (18.6 g/m2h) slightly lower than ETHO2R due to gel-based hydration into the skin. SEL, CLSM, and AFM provided a mechanistic perspective of ETHO2R and ELP3R-mediated permeation across rat skin and carrier-mediated visualization (skin-vesicle interaction). AFM provided detailed nanoscale surface roughness topographical parameters of treated and untreated rat skin as supportive data to SEM and CLSM. Thus, ethosomes ETHO2R and respective gel assisted maximum permeation of ACV across rat skin and cultured human EpiDerm to control cutaneous herpes infection and herpes keratitis.

GastroPlus- and HSPiP-Oriented Predictive Parameters as the Basis of Valproic Acid-Loaded Mucoadhesive Cationic Nanoemulsion Gel for Improved Nose-to-Brain Delivery to Control Convulsion in Humans.

Oral and parenteral delivery routes of valproic acid (VA) are associated with serious adverse effects, high hepatic metabolism, high clearance, and low bioavailability in the brain. A GastroPlus program was used to predict in vivo performance of immediate (IR) and sustained release (SR) products in humans. HSPiP software 5.4.08 predicted excipients with maximum possible miscibility of the drug. Based on the GastroPlus and HSPiP program, various excipients were screened for experimental solubility, nanoemulsions, and respective gel studies intended for nasal-to-brain delivery. These were characterized by size, size distribution, polydispersity index, zeta potential, morphology, pH, % transmittance, drug content, and viscosity. In vitro drug release, ex vivo permeation profile (goat nasal mucosa), and penetration studies were conducted. Results showed that in vivo oral drug dissolution and absorption were predicted as 98.6 mg and 18.8 mg, respectively, from both tablets (IR and SR) at 8 h using GastroPlus. The predicted drug access to the portal vein was substantially higher in IR (115 mg) compared to SR (82.6 mg). The plasma drug concentration-time profile predicted was in good agreement with published reports. The program predicted duodenum and jejunum as the prime sites of the drug absorption and no effect of nanonization on Tmax for sustained release formulation. Hansen parameters suggested a suitable selection of excipients. The program recommended nasal-to-brain delivery of the drug using a cationic mucoadhesive nanoemulsion. The optimized CVE6 was associated with the optimal size (113 nm), low PDI (polydispersity index) (0.26), high zeta potential (+34.7 mV), high transmittance (97.8%), and high strength (0.7% w/w). In vitro release and ex vivo permeation of CVE6 were found to be substantially high as compared to anionic AVE6 and respective gels. A penetration study using confocal laser scanning microscopy (CLSM) executed high fluorescence intensity with CVE6 and CVE6-gel as compared to suspension and ANE6. This might be attributed to the electrostatic interaction existing between the mucosal membrane and nanoglobules. Thus, cationic nanoemulsions and respective mucoadhesive gels are promising strategies for the delivery of VA to the brain through intransal administration for the treatment of seizures and convulsions.

Biogenic nanoparticles from waste fruit peels: Synthesis, applications, challenges and future perspectives.

Nanotechnology is a continually growing field with a wide range of applications from food science to biotechnology and nanobiotechnology. As the current world is grappling with non-biodegradable waste, considered more challenging and expensive to dispose of than biodegradable waste, new technologies are needed today more than ever. Modern technologies, especially nanotechnology, can transform biodegradable waste into products for human use. Researchers are exploring sustainable pathways for nanotechnology by utilizing biodegradable waste as a source for preparing nanomaterials. Over the past ten years, the biogenic production of metallic nanoparticles (NPs) has become a promising alternative technique to traditional NPs synthesis due to its simplicity, eco-friendliness, and biocompatibility in nature. Fruit and vegetable waste (after industrial processing) contain various bioactives (such as flavonoids, phenols, tannins, steroids, triterpenoids, glycosides, anthocyanins, carotenoids, ellagitannins, vitamin C, and essential oils) serving as reducing and capping agents for NP synthesis and they possess antibacterial, antioxidant, and anti-inflammatory properties. This review addresses various sources of biogenic NPs including their synthesis using fruit/vegetable waste, types of biogenic NPs, extraction processes and extracted biomaterials, the pharmacological functionality of NPs, industrial aspects, and future perspectives. In this manner, this review will cover the most recent research on the biogenic synthesis of NPs from fruit/vegetable peels to transform them into therapeutic nanomedicines.

Preferential Solvation Study of Rosuvastatin in the {PEG400 (1) + Water (2)} Cosolvent Mixture and GastroPlus Software-Based In Vivo Predictions.

Rosuvastatin (RST) is a poorly water-soluble drug responsible for limited in vivo dissolution and subsequently low oral systemic absorption (poor bioavailability). The mole fraction solubility values of RST in various ratios of binary mixtures "{PEG400 (1) + water (2)}" at 298.15 K were employed to investigate the preferential solvation (PS) of RST (3) by the binary components. Moreover, the GastroPlus program predicted the drug dissolution/absorption rates, plasma drug concentration, and compartmental regional drug absorbed from a conventional tablet as compared to the RST-loaded (PEG400 + water) mixture (at x 1 = 0.5) in healthy subjects (considering the fast condition). Fedors' method was adopted to estimate the values of molar volume (314.8 cm3·mol-1) and Hildebrand solubility parameter (28.08 MPa1/2) of RST. The results of inverse Kirkwood-Buff integrals showed the PS of RST by PEG400 as observed in all studied ratios of the binary mixture. The highest PS value (δx 1,3 = 1.65 × 10-2) for RST by PEG400 was attained at x 1 = 0.5. Finally, the GastroPlus program predicted the maximum dissolution rate [20 mg within 15 min as compared to pure RST (1.5 mg within 15 min)]. Moreover, the program predicted increased in vivo oral absorption (1.2 µg/mL) and enhanced regional absorption (95.3%) of RST from upper segments of the gastrointestinal tract for the RST-loaded PEG400 + water mixture in humans as compared to conventional tablets (87.5% as total regional absorption and 0.88 µg/mL as in vivo absorption). Hence, the present binary system ferrying RST can be a promising strategy to control systemic dyslipidemia after oral or subcutaneous administration.

Improved Subcutaneous Delivery of Ketoconazole Using EpiDerm and HSPiP Software-Based Simulations as Assessed by Cell Viability, Cellular Uptake, Permeation, and Hemolysis In Vitro Studies.

Ketoconazole (KETO) is the drug of choice to control local, systemic, and resistant types of fungal infections. Subcutaneous (sub-Q) delivery offers several benefits. The present study investigated the sub-Q delivery of KETO using HSPiP software based on optimized concentrations of dimethylacetamide (DMA) in binary solvents (DMA + water), in vitro cellular uptake (J774A.1) assays, cellular toxicity (L929), and in vitro hemolysis studies. Results showed that the estimated permeation coefficient (9.6 × 10-3 cm/h) and diffusion coefficient (3.9 × 10-3 cm2/h) of KETO (22.3 mg) in KF3 (300 mg of DMA + water) across EpiDerm were relatively higher as compared to the other formulations [KF1 (11.2 and 150 mg as KETO and DMA, respectively) and KF2 [(22.3 and 300 mg as KETO and DMA, respectively)] due to the increased content of DMA and KETO. HSPiP simulated and predicted the impact of constant and variable diffusion coefficients on the percent drug absorption across EpiDerm and the time needed to achieve equilibrium. The concentration-dependent diffusion coefficient fed into HSPiP predicted that the drug absorption and permeation values were linearly dependent on the square root of time. The HSPiP predicted permeation flux values from KF3, KF2, and KF1 across the EpiDerm were 4.07 × 10-6, 4.01 × 10-6, and 1.1 × 10-6 g/cm2/s, respectively, at respective D range values. The selected K30G (324 mOsm/Kg) showed an optimal pH (6.9) and minimum drug loss (0.01%) over a period of 1 month at room temperature. KG30 was found to be less toxic to normal L292 cells and caused maximum cytotoxicity to candida cells residing within infected macrophage cells (J774A.1 incubated for 24 h), which was attributed to the slow diffusion of K30G compared to DS (the drug solution with an equivalent concentration). KG30 elicited substantial internalization with candida albicans (MTCC 4748) compared to the control group (24 h). Lastly, in vitro hemolysis studies (1 and 5 µg/mL) corroborated the safety of K30G for sub-Q delivery. Therefore, this new formulation and approach for delivering KETO is a promising alternative to conventional products to control fungal infections and, thus, should be further studied in vivo.

Impact of Composition and Morphology of Ketoconazole-Loaded Solid Lipid Nanoparticles on Intestinal Permeation and Gastroplus-Based Prediction Studies.

Ketoconazole (KTZ) is a potential oral antifungal agent to control systemic and local infections. This study addresses the impact of composition (tween 80 and compritol as CATO) and morphology on permeation (stomach, jejunum, and ileum) profiles of KTZ-loaded solid lipid nanoparticles (SLNs) in rats followed by in vivo pharmacokinetic prediction and simulation using GastroPlus. The selected formulations were characterized for size, size distribution, zeta potential, entrapment efficiency, total drug content, morphology, in vitro drug release, ex vivo permeation and drug deposition, penetration potential, and GastroPlus-based in vivo prediction in rats. The results showed that there was considerable impact of pH, composition (CATO and tween 80), size, total drug content, and entrapment efficiency on in vitro drug release and permeation across the stomach, jejunum, and ileum. Ex vivo findings suggested pH, composition, size, and permeability coefficient-dependent permeation of SLNs across the stomach, jejunum, and ileum. Confocal laser scanning microscopy (CLSM) confirmed a relatively high degree of penetration of the optimized formulation "K-SLN4" (66.1% across the stomach, 51.5% across the jejunum, and 47.9% across the ileum) as compared to KSUS (corresponding values of 21.7%, 18.2%, and 17.4%). Finally, GastroPlus predicted in vivo dissolution/absorption as 0.012 µg/mL of K-SLN4 as compared to KSUS (the drug suspension with 0.0058 µg/mL) and a total regional absorption of 80.0% by K-SLN4 as compared to 60.1% of KSUS. There was only an impact of dose on C max (maximum plasma concentration) and area under the curve (AUC) in rats. Thus, the present strategy could be a promising alternative to parenteral and topical delivery systems for long-term therapy against systemic and local mycoses with high patient compliance.

Ketoconazole-Loaded Cationic Nanoemulsion: In Vitro-Ex Vivo-In Vivo Evaluations to Control Cutaneous Fungal Infections.

An attempt has been made to optimize ketoconazole (KTZ)-loaded cationic nanoemulsion for topical delivery followed by in vitro, ex vivo, and in vivo evaluations. Central composite design suggested a total of 13 outcomes at 3 factors and 2 levels against 6 responses. Formulations were characterized for globular size, polydispersity index, pH, ζ potential, % entrapment efficiency (% EE), and drug content. Moreover, the optimized KTZ-CNM13 was compared against drug suspension (KTZ-SUS), commercial cream, and anionic nanoemulsion for in vitro drug release, ex vivo permeation, in vitro hemolysis, antifungal assay, in vivo dermal irritancy, and long-term stability. KTZ-CNM13 was found to have a low size (239 nm), an optimal ζ potential (+22.7 mV), a high % EE (89.1%), a spherical shape, a high drug content (98.9%), and a high numerical desirability value (1.0). In vitro drug release behavior of KTZ from KTZ-CNM13 was 7.54- and 1.71-folds higher than those of KTZ-ANM13 and KTZ-SUS, respectively, at 24 h. The permeation rate values were ordered as KTZ-CNM13 > KTZ-ANM13 > KTZ-MKT > KTZ-SUP due to various studied factors. High values of zone of inhibition for KTZ-CNM13 were observed against Candida albicans, Candida glabrata, Candida tropicalis, and Candida krusei as compared to KTZ-SUS. In vitro hemolysis and in vivo irritation studied confirmed the safety concern of the nanoemulsion at the explored composition. Long-term stability result revealed a stable product at the explored temperature for a year. Conclusively, cationic nanoemulsion is a promising approach to deliver KTZ for high permeation and therapeutic efficacy.

Antifungal Cationic Nanoemulsion Ferrying Miconazole Nitrate with Synergism to Control Fungal Infections: In Vitro, Ex Vivo, and In Vivo Evaluations.

This study aimed to deliver a cationic nanoemulsion carrying miconazole nitrate (MCN) to control fungal infections using excipients for synergism. Peceol (oil) and labrasol (surfactant) were selected based on maximum solubility and zone of inhibition values against Candida albicans and Aspergillus niger. Optimized MCNE11 was evaluated [size, zeta potential, % entrapment efficiency (%EE), % transmittance, viscosity, refractive index, extrudability, polydispersity (PDI), morphology, and pH]. An in vitro drug release study was conducted for comparison between DS (drug suspension) and MNE11. In vitro hemolysis was studied at two different concentrations (0.625 and 2.5 µg/mL). Permeation profiles were generated using rat skin. A Draize test was conducted using rabbit to negate irritability issues. Finally, a stability test of MCNE11 was conducted for 12 months. The results showed that MCNE11 (cationic) was the most optimized in term of size, %EE, and PDI. The drug release from MCNE11 was higher compared to DS but comparable to MNE11 (anionic), suggesting no impact of the imposed cationic charge on the release behavior. Moreover, permeation parameters of MCNE11 were significantly (p < 0.05) greater than MNE11, which may be attributed to the combined impact of size (low), surfactant (for reversible changes), and electrostatic interaction (nanoglobules-skin surface). Thus, stable MCN11 possessing high %EE (89.8%), low size (145 nm), maximum flux (5.7 ± 0.1 µg/cm2/h), high drug deposition (932.7 ± 41.6 µg/cm2), optimal viscosity (44.17 ± 0.8 cP), low PDI (0.21), optimal zeta potential (+28.1 mV), and low hemolysis can be promising alternatives to conventional cream to control resistant and recurring types of fungal infections.

In vitro release, ex vivo penetration, and in vivo dermatokinetics of ketoconazole-loaded solid lipid nanoparticles for topical delivery.

The study focused to evaluate and investigate optimized (using QbD) and novel ketoconazole (KTZ)-loaded solid lipid nanoparticles (KTZ-SLNs; 2% w/v KTZ) for enhanced permeation across skin. KTZ-SLNs were evaluated for size, distribution, zeta potential (ZP), percent entrapment efficiency (%EE), drug release, morphology (HRTEM and FESEM), thermal behaviour (DSC), spectroscopic (FTIR), and solid-state/diffraction characterization (X-ray diffraction, XRD). Moreover, ex vivo permeation and drug deposition into rat skin were conducted using Franz diffusion cell. The same was confirmed using human dermatome skin and fluorescence, confocal Raman, and vibrational ATR-FTIR microscopic methods. An in vivo dermatokinetics study was performed in rats to assess the extent of KTZ permeation into the skin. Stability including accelerated and photostability studies were conducted at different temperatures (2-8, 30, and 40 °C) for 12 months. The spherical, optimized KTZ-SLN formulation (KOF1) showed particle size of 293 nm and high EE of 88.5%. Results of FTIR, DSC, and XRD confirmed formation of KTZ-SLNs and their amorphous nature due to presence of KTZ in a dissolved state in the lipid matrix. In vitro release was slow and sustained whereas ex vivo permeation parameters were significantly high in KTZ-SLNs as compared to free drug suspension (KTZ-SUS) and marketed product (Nizral®; 2% KTZ w/v). Drug retention was 10- and five-fold higher than KTZ-SUS and marketed product, respectively. In vivo dermatokinetics parameters improved significantly with SLN formulation (410-900% enhanced). Confocal Raman spectroscopy experiment showed that KTZ-SLNs could penetrate beyond the human stratum corneum into viable epidermis. Fluorescent microscopy also indicated improved penetration of KTZ-SLNs. KTZ-SLNs were photostable and showed long-term stability over 12 months under set conditions.

Lipo-PEG nano-ocular formulation successfully encapsulates hydrophilic fluconazole and traverses corneal and non-corneal path to reach posterior eye segment.

The present study describes a special lipid-polyethylene glycol matrix solid lipid nanoparticles (SLNs; 138 nm; -2.07 mV) for ocular delivery. Success of this matrix to encapsulate (entrapment efficiency - 62.09%) a hydrophilic drug, fluconazole (FCZ-SLNs), with no burst release (67% release in 24 h) usually observed with most water-soluble drugs, is described presently. The system showed 164.64% higher flux than the marketed drops (Zocon®) through porcine cornea. Encapsulation within SLNs and slow release did not compromise efficacy of FCZ-SLNs. Latter showed in vitro and in vivo antifungal effects, including antibiofilm effects comparable to free FCZ solution. Developed system was safe and stable (even to sterilisation by autoclaving); and showed optimal viscosity, refractive index and osmotic pressure. These SLNs could reach up to retina following application as drops. The mechanism of transport via corneal and non-corneal transcellular pathways is described by fluorescent and TEM images of mice eye cross sections. Particles streamed through the vitreous, crossed inner limiting membrane and reached the outer retinal layers.