The effect of ceramides on skin absorption by Raman spectroscopy.

INTRODUCTION: Ceramides are essential epidermal constituents that play a critical role in skin moisturization treatment as a raw material in cosmetics formulation. Recently, ceramides have been known to be frequently applied in various cosmetic formulations. Despite ceramide's beneficial characteristics, academic research regarding ceramides and their skin absorption remains insufficient. Therefore, our study conducted clinical research employing Raman spectroscopy to investigate the effects of ceramides on skin absorption to enhance the understanding of ceramides' dermatological functionality and their topical application in cosmetics science. MATERIALS AND METHODS: Twenty healthy individuals with dry skin have participated in this clinical trial. In this double-arm designed trial, the test group received an investigational product with ceramides (5000 ppm) and a control group received an investigational product without the ceramides while all other components remained identical. The subjects visited the clinical research center and acclimatized for 30 min in constant humidity and temperature for equilibrium, subsequently conducting a measurement. Before the trial, the research subject's target site (lower arm area) was kept clean, devoid of any cosmetic administering 24 h before the trial when investigational product was topically applied. RESULTS: Our findings with Raman spectroscopy statistically demonstrate that skin absorption amount, speed and depth for both groups improved overall (p < 0.05) after administration of the investigational product. Notably, the test group received an investigational product with ceramides (5000 ppm) indicating superior effectiveness across all parameters compared to a control group from comparison analysis of each parameter (p < 0.05). CONCLUSION: This study concludes that ceramide-containing cosmetics provide a beneficial effect on skin absorption via visual and statistical results of Raman spectroscopy analysis.

Skin Penetration and Permeation Properties of Transcutol® in Complex Formulations.

Percutaneous delivery is explored as alternative pathway for addressing the drawbacks associated with the oral administration of otherwise efficacious drugs. Short of breaching the skin by physical means, the preference goes to formulation strategies that augment passive diffusion across the skin. One such strategy lies in the use of skin penetration and permeation enhancers notably of hydroxylated solvents like propylene glycol (PG), ethanol (EtOH), and diethylene glycol monoethyl ether (Transcutol®, TRC). In a previous publication, we focused on the role of Transcutol® as enhancer in neat or diluted systems. Herein, we explore its' role in complex formulation systems, including patches, emulsions, vesicles, solid lipid nanoparticles, and micro or nanoemulsions. This review discusses enhancement mechanisms associated with hydroalcoholic solvents in general and TRC in particular, as manifested in multi-component formulation settings alongside other solvents and enhancers. The principles that govern skin penetration and permeation, notably the importance of drug diffusion due to solubilization and thermodynamic activity in the vehicle (formulation), drug solubilization and partitioning in the stratum corneum (SC), and/or solvent drag across the skin into deeper tissue for systemic absorption are discussed. Emphasized also are the interplay between the drug properties, the skin barrier function and the formulation parameters that are key to successful (trans)dermal delivery.

Beyond Skin Deep: Phospholipid-Based Nanovesicles as Game-Changers in Transdermal Drug Delivery.

Transdermal administration techniques have gained popularity due to their advantages over oral and parenteral methods. Noninvasive, self-administered delivery devices improve patient compliance and control drug release. Transdermal delivery devices struggle with the skin's barrier function. Molecules over 500 Dalton (Da) and ionized compounds don't permeate through the skin. Drug encapsulation in phospholipid-based vesicular systems is the most effective skin delivery technique. Vesicular carriers include bi-layered liposomes, ultra-deformable liposomes, ethanolic liposomes, transethosomes, and invasomes. These technologies enhance skin drug permeation by increasing formula solubilization, partitioning into the skin, and fluidizing the lipid barrier. Phospholipid-based delivery systems are safe and efficient, making them a promising pharmaceutical and cosmeceutical drug delivery technique. Still, making delivery systems requires knowledge about the physicochemical properties of the drug and carrier, manufacturing and process variables, skin delivery mechanisms, technological advances, constraints, and regulatory requirements. Consequently, this review covers recent research achievements addressing the mentioned concerns.

Evaluation of in vitro Skin Permeation of Clascoterone From Clascoterone Topical Cream, 1% (w/w).

Winlevi® (clascoterone) topical cream (1%, w/w) was approved by the U.S. FDA for the treatment of acne vulgaris in patients 12 years of age and older. The active ingredient, clascoterone, is not stable in physiological solutions and can hydrolyze to cortexolone at body temperature. Instability of clascoterone poses a significant challenge in accurately assessing the rate and extent of clascoterone permeation in vitro. Therefore, the purpose of this study was to develop an in vitro skin permeation test (IVPT) method, and a robust analytical method, that can minimize hydrolyzation of clascoterone during the study for quantification of clascoterone. Two IVPT methods, using either vertical diffusion cells or flow-through cells, were developed and compared to evaluate in vitro permeation of clascoterone from Winlevi. A liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was developed to monitor the level of clascoterone and cortexolone in the IVPT samples. The analytical method features a 2-min high-throughput analysis with good linearity, selectivity, and showed a lower limit of quantitation (LLOQ) of 0.5 ng/mL for both clascoterone and cortexolone. The in vitro skin permeation of clascoterone and cortexolone was observed as early as 2 h in both IVPT methods. A substantive amount of clascoterone was found to hydrolyze to cortexolone when using the vertical static diffusion cells with aliquot sampling. Conversely, degradation of clascoterone was significantly minimized when using the flow-through diffusion cells with fractional sampling. The data enhanced our understanding of in vitro permeation of clascoterone following topical application of the Winlevi topical cream, 1% and underscores the importance of IVPT method development and optimization during product development.

Transdermal drug delivery of rizatriptan using microneedles array patch: preparation, characterization and ex-vivo/in-vivo study.

Given the extensive first pass metabolism of rizatriptan in oral administration and its delayed absorption during a migraine attack as a result of gastric stasis, focus has been on transdermal delivery. The main purpose of this study is to prepare and assess transdermal formulation of rizatriptan, loaded on hydrogel microneedles delivery system, to avoid first pass metabolism and also improve its percutaneous permeation rate. Rizatriptan hydrogel microneedles were prepared using micromolding method and evaluated in terms of mechanical strength, encapsulation efficiency, permeation and in-vivo skin absorption. Different formulations of rizatriptan microneedles (F1-F5) were successfully prepared using different concentrations of carboxymethyl cellulose and gelatin type A. Rizatriptan hydrogel microneedles demonstrated favorable mechanical properties, including withstanding insertion forces, thereby enhancing its skin insertion ability. In permeation study, the percent cumulative drug released after 24 h ranged between 93.1-100% which means that microneedles were able to deliver the drug effectively. For in-vivo study, F3 formulation was selected due to its superior characteristics over other formulations as it exhibited the highest swelling capacity, and demonstrated favorable mechanical properties. Furthermore, F3 showcased the most controlled drug release over a 24-hour period. Relative bioavailability of F3 microneedles was 179.59% compared to oral administration based on the AUC0-24. The observed AUC0-24 in F3 microneedles was statistically significant and 1.80 times greater than that in oral administration. The higher rizatriptan level in the microneedle demonstrated adequate drug permeability through the rat skin, suggesting the potential of microneedles for enhanced therapeutic effectiveness.

HSPiP, Computational, and Thermodynamic Model-Based Optimized Solvents for Subcutaneous Delivery of Tolterodine Tartrate and GastroPlus­Based In Vivo Prediction in Humans: Part II.

In part I, we reported Hansen solubility parameters (HSP, HSPiP program), experimental solubility at varied temperatures for TOTA delivery. Here, we studied dose volume selection, stability, pH, osmolality, dispersion, clarity, and viscosity of the explored combinations (I-VI). Ex vivo permeation and deposition studies were performed to observe relative diffusion rate from the injected site in rat skin. Confocal laser scanning microscopy (CLSM) study was conducted to support ex vivo findings. Moreover, GastroPlus predicted in vivo parameters in humans and the impact of various critical factors on pharmacokinetic parameters (PK). Immediate release product (IR) contained 60% of PEG400 whereas controlled release formulation (CR) contained PEG400 (60%), water (10%) and d-limonene (30%) to deliver 2 mg of TOTA. GastroPlus predicted the plasma drug concentration of weakly basic TOTA as function of pH (from pH 2.0 to 9). The cumulative drug permeation and drug deposition were found to be in the order as B-VI˃ C-VI˃A-VI across rat skin. This finding was further supported with CLSM. Moreover, IR and CR were predicted to achieve Cmax of 0.0038 µg/ mL and 0.00023 µg/mL, respectively, after sub-Q delivery. Added limonene in CR extended the plasma drug concentration over period of 12 h as predicted in GastroPlus. Parameters sensitivity analysis (PSA) assessment predicted that sub-Q blood flow rate is the only factor affecting PK parameters in IR formulation whereas this was insignificant for CR. Thus, sub-Q delivery CR would be promising alternative with ease of delivery to children and aged patient.

Mechanisms of penetration and diffusion of drugs and cosmetic actives across the human Stratum corneum.

Based on the structure of the Stratum corneum (SC) the potential penetration/diffusion pathways of drugs and cosmetic actives through the SC are presented and discussed. The well-known lipophilic pathway across the SC is presented and relevant examples are used to show that highly lipophilic molecules such as glucocorticoids, coenzyme Q10 etc. are accumulated in the SC and penetrate into the inner liquid like layer of the SC lipid bilayer by lateral diffusion. The diffusion into and across the SC of highly hydrophilic drugs and active substances such as urea, amino acids and peptides is still under discussion. Another diffusion pathway for the highly hydrophilic molecules via the corneocytes and the corneodesmosomes is presented and discussed, the corneocytary diffusion pathway.

Laser-mediated Solutions: Breaking Barriers in Transdermal Drug Delivery.

Skin diseases pose challenges in treatment due to the skin's complex structure and protective functions. Topical drug delivery has emerged as a preferred method for treating these conditions, offering localized therapy with minimal systemic side effects. However, the skin's barrier properties frequently limit topical treatments' efficacy by preventing drug penetration into deeper skin layers. In recent years, laser-assisted drug delivery (LADD) has gained attention as a promising strategy to overcome these limitations. LADD involves using lasers to create microchannels in the skin, facilitating the deposition of drugs and enhancing their penetration into the target tissue. Several lasers, such as fractional CO2, have been tested to see how well they work at delivering drugs. Despite the promising outcomes demonstrated in preclinical and clinical studies, several challenges persist in implementing LADD, including limited penetration depth, potential tissue damage, and the cost of LADD systems. Furthermore, selecting appropriate laser parameters and drug formulations is crucial to ensuring optimal therapeutic outcomes. Nevertheless, LADD holds significant potential for improving treatment efficacy for various skin conditions, including skin cancers, scars, and dermatological disorders. Future research efforts should focus on optimizing LADD techniques, addressing safety concerns, and exploring novel drug formulations to maximize the therapeutic benefits of this innovative approach. With continued advancements in laser technology and pharmaceutical science, LADD has the potential to revolutionize the field of dermatology and enhance patient care.

Navigating Skin Delivery Horizon: An Innovative Approach in Pioneering Surface Modification of Ultradeformable Vesicles.

In the dynamic landscape of pharmaceutical advancements, the strategic application of active pharmaceutical ingredients to the skin through topical and transdermal routes has emerged as a compelling avenue for therapeutic interventions. This non-invasive approach has garnered considerable attention in recent decades, with numerous attempts yielding approaches and demonstrating substantial clinical potential. However, the formidable barrier function of the skin, mainly the confinement of drugs on the upper layers of the stratum corneum, poses a substantial hurdle, impeding successful drug delivery via this route. Ultradeformable vesicles/carriers (UDVs), positioned within the expansive realm of nanomedicine, have emerged as a promising tool for developing advanced dermal and transdermal therapies. The current review focuses on improving the passive dermal and transdermal targeting capacity by integrating functionalization groups by strategic surface modification of drug-loaded UDV nanocarriers. The present review discusses the details of case studies of different surface-modified UDVs with their bonding strategies and covers the recent patents and clinical trials. The design of surface modifications holds promise for overcoming existing challenges in drug delivery by marking a significant leap forward in the field of pharmaceutical sciences.

Propellant Free Pressurized Spray System of Etodolac to Manage Acute Pain Conditions: In Vitro and In Vivo Evaluation.

This study aimed to develop a propellant-free topical spray formulation of Etodolac (BCS-II), a potent NSAID, which could be beneficial in the medical field for the effective treatment of pain and inflammation conditions. The developed novel propellant-free spray formulation is user-friendly, cost-effective, propellant-free, eco-friendly, enhances the penetration of Etodolac through the skin, and has a quick onset of action. Various formulations were developed by adjusting the concentrations of different components, including lecithin, buffering agents, film-forming agents, plasticizers, and permeation enhancers. The prepared propellant-free spray formulations were then extensively characterized and evaluated through various in vitro, ex vivo, and in vivo parameters. The optimized formulation exhibits an average shot weight of 0.24 ± 0.30 ml and an average drug content or content uniformity of 87.3 ± 1.01% per spray. Additionally, the optimized formulation exhibits an evaporation time of 3 ± 0.24 min. The skin permeation study demonstrated that the permeability coefficients of the optimized spray formulation were 21.42 cm/h for rat skin, 13.64 cm/h for mice skin, and 18.97 cm/h for the Strat-M membrane. When assessing its potential for drug deposition using rat skin, mice skin, and the Strat-M membrane, the enhancement ratios for the optimized formulation were 1.88, 2.46, and 1.92, respectively against pure drug solution. The findings from our study suggest that the propellant-free Etodolac spray is a reliable and safe topical formulation. It demonstrates enhanced skin deposition, and improved effectiveness, and is free from any skin irritation concerns.

Evaluation of Emulgel and Nanostructured Lipid Carrier-Based Gel Formulations for Transdermal Administration of Ibuprofen: Characterization, Mechanical Properties, and Ex-Vivo Skin Permeation.

In transdermal applications of nonsteroidal anti-inflammatory drugs, the rheological and mechanical properties of the dosage form affect the performance of the drug. The aim of this study to develop emulgel and nanostructured lipid carrier NLC-based gel formulations containing ibuprofen, evaluate their mechanical properties, bioadhesive value and ex-vivo rabbit skin permeability. All formulations showed non-Newtonian pseudoplastic behavior and their viscosity values are suitable for topical application. The particle size of the nanostructured lipid carrier system was found to be 468 ± 21 nm, and the encapsulation efficiency was 95.58 ± 0.41%. According to the index of viscosity, consistency, firmness, and cohesiveness values obtained as a result of the back extrusion study, E2 formulation was found to be more suitable for transdermal application. The firmness and work of shear values of the E2 formulation, which has the highest viscosity value, were also found to be the highest and it was chosen as the most suitable formulation in terms of the spreadability test. The work of bioadhesion values of NLC-based gel and IBU-loaded NLC-based gel were found as 0.226 ± 0.028 and 0.181 ± 0.006 mJ/cm2 respectively. The percentages of IBU that penetrated through rabbit skin from the Ibuactive-Cream and the E2 were 87.4 ± 2.11% and 93.4 ± 2.72% after 24 h, respectively. When the penetration of ibuprofen through the skin was evaluated, it was found that the E2 formulation increased penetration due to its lipid and nanoparticle structure. As a result of these findings, it can be said that the NLC-based gel formulation will increase the therapeutic efficacy and will be a good alternative transdermal formulation.

Development and comparison of machine learning models for in-vitro drug permeation prediction from microneedle patch.

The field of machine learning (ML) is advancing to a larger extent and finding its applications across numerous fields. ML has the potential to optimize the development process of microneedle patch by predicting the drug release pattern prior to its fabrication and production. The early predictions could not only assist the in-vitro and in-vivo experimentation of drug release but also conserve materials, reduce cost, and save time. In this work, we have used a dataset gleaned from the literature to train and evaluate different ML models, such as stacking regressor, artificial neural network (ANN) model, and voting regressor model. In this study, models were developed to improve prediction accuracy of the in-vitro drug release amount from the hydrogel-type microneedle patch and the in-vitro drug permeation amount through the micropores created by solid microneedles on the skin. We compared the performance of these models using various metrics, including R-squared score (R2 score), root mean squared error (RMSE), and mean absolute error (MAE). Voting regressor model performed better with drug permeation percentage as an outcome feature having RMSE value of 3.24. In comparison, stacking regressor have a RMSE value of 16.54, and ANN model has shown a RMSE value of 14. The value of permeation amount calculated from the predicted percentage is found to be more accurate with RMSE of 654.94 than direct amount prediction, having a RMSE of 669.69. All our models have performed far better than the previously developed model before this research, which had a RMSE of 4447.23. We then optimized voting regressor model's hyperparameter and cross validated its performance. Furthermore, it was deployed in a webapp using Flask framework, showing a way to develop an application to allow other users to easily predict drug permeation amount from the microneedle patch at a particular time period. This project demonstrates the potential of ML to facilitate the development of microneedle patch and other drug delivery systems.

Dissolvable microneedles in the skin: Determination the impact of barrier disruption and dry skin on dissolution.

Dissolvable microneedles (DMNs), fabricated from biocompatible materials that dissolve in both water and skin have gained popularity in dermatology. However, limited research exists on their application in compromised skin conditions. This study compares the hyaluronic acid-based DMNs penetration, formation of microchannels, dissolution, and diffusion kinetics in intact, barrier-disrupted (tape stripped), and dry (acetone-treated) porcine ear skin ex vivo. After DMNs application, comprehensive investigations including dermoscopy, stereomicroscope, skin hydration, transepidermal water loss (TEWL), optical coherence tomography (OCT), reflectance confocal laser scanning microscopy (RCLSM), confocal Raman micro-spectroscopy (CRM), two-photon tomography combined with fluorescence lifetime imaging (TPT-FLIM), histology, and scanning electron microscopy (SEM) were conducted. The 400 µm long DMNs successfully penetrated the skin to depths of ≈200 µm for dry skin and ≈200-290 µm for barrier-disrupted skin. Although DMNs fully inserted into all skin conditions, their dissolution rates were high in barrier-disrupted and low in dry skin, as observed through stereomicroscopy and TPT-FLIM. The dissolved polymer exhibited a more significant expansion in barrier-disrupted skin compared to intact skin, with the smallest increase observed in dry skin. Elevated TEWL and reduced skin hydration levels were evident in barrier-disrupted and dry skins compared to intact skin. OCT and RCLSM revealed noticeable skin indentation and pronounced microchannel areas, particularly in barrier-disrupted and dry skin. Additional confirmation of DMN effects on the skin and substance dissolution was obtained through histology, SEM, and CRM techniques. This study highlights the impact of skin condition on DMN effectiveness, emphasizing the importance of considering dissolvability and dissolution rates of needle materials, primarily composed of hyaluronic acid, for optimizing DMN-based drug delivery.

Development of a novel human stratum corneum mimetic phospholipid -vesicle-based permeation assay models for in vitro permeation studies.

OBJECTIVES: To develop and evaluate a novel human stratum corneum (SC) mimetic phospholipid vesicle-based permeation assay (PVPASC) model for in vitro permeation studies. SIGNIFICANCE: Due to the increasing restrictions on the use of human and animal skins, artificial skin models have attracted substantial interest in pharmaceuticals and cosmetic industries. In this study, a modified PVPASC model containing both SC lipids and proteins was developed. METHODS: The PVPASC model was optimized by altering the lipid composition and adding keratin in the formulation of large liposomes. The barrier properties were monitored by measuring the electrical resistance (ER) and permeability of Rhodamine B (RB). The modified PVPASC model was characterized in terms of the surface topography, solvent influence and storage stability. The permeation studies of the active components in Compound Nanxing Zhitong Plaster (CNZP) were performed to examine the capability of PVPASC in the application of skin penetration. RESULTS: The ER and Papp values of RB obtained from the optimized PVPASC model indicated a similar barrier property to porcine ear skin. Scanning electron microscope analysis demonstrated a mimic 'brick-and-mortar' structure. The PVPASC model can be stored for three weeks at -20 °C, and withstand the presence of different receptor medium for 24 h. The permeation studies of the active components demonstrated a good correlation (r2 = 0.9136) of Papp values between the drugs' permeation through the PVPASC model and porcine ear skin. CONCLUSION: Keratin contained composite phospholipid vesicle-based permeation assay models have been proven to be potential skin tools in topical/transdermal permeation studies.

Ion-pair compounds of diacerein for enhancing skin permeability in vitro: the compatibility-permeability relationship of counter ion and diacerein.

This research aimed to investigate how the relationship between counter ion and diacerein (DCN) exerts an effect on the skin penetration of DCN ion-pair compounds. After the ion-pair compounds were formed by DCN and organic amines with different functional groups, the hydrogen bond of these compounds was confirmed by Fourier-transform infrared (FTIR) spectroscopy and molecular docking. The skin of porcine ears was employed to conduct the in vitro skin penetration, DCN - triethanolamine was the most potential candidate with the Q24h of 7.89 ± 0.38 µg/cm2 among organic amines with different functional groups. Whereas among the homologous fatty amine, the most permeable compound was DCN - lauryl amine with the Q24h of 11.28 ± 0.48 µg/cm2. Molecular simulation was employed to explore the relationship between counter ion and DCN. It was revealed by the bind energy curve that DCN had the strongest compatibility with triethanolamine among organic amines and laurylamine (N12) among fatty amines. It was amazingly found that the in vitro permeation fluxes of DCN ion-pair compounds would increase with enhancing the compatibility of counter ion and DCN. These findings broadened our understanding of how the relationship between drug and counter ion affects the skin penetration of ion-pair compounds.

Preparation of topical bimatoprost with enhanced skin infiltration and in vivo hair regrowth efficacy in androgenic alopecia.

To prepare a topical formulation of bimatoprost (BIM) with high skin permeability, we designed a solvent mixture system composed of ethanol, diethylene glycol monoethyl ether, cyclomethicone, and butylated hydroxyanisole, serving as a volatile solvent, nonvolatile co-solvent, spreading agent, and antioxidant, respectively. The ideal topical BIM formulation (BIM-TF#5) exhibited 4.60-fold higher human skin flux and a 529% increase in dermal drug deposition compared to BIM in ethanol. In addition, compared to the other formulations, BIM-TF#5 maximally activated human dermal papilla cell proliferation at a concentration of 5 µM BIM, equivalent to 10 µM minoxidil. Moreover, BIM-TF#5 (0.3% [w/w] BIM) significantly promoted hair regrowth in the androgenic alopecia mouse model and increased the area covered by hair at 10 days by 585% compared to the vehicle-treated mice, indicating that entire telogen area transitioned into the anagen phase. Furthermore, at day 14, the hair weight of mice treated with BIM-TF#5 (5% [w/w] BIM) was 8.45- and 1.30-fold greater than in the 5% (w/w) BIM in ethanol and 5% (w/v) minoxidil treated groups, respectively. In the histological examination, the number and diameter of hair follicles in the deep subcutis were significantly increased in the BIM-TF#5 (0.3 or 5% [w/w] BIM)-treated mice compared to the mice treated with vehicle or 5% (w/w) BIM in ethanol. Thus, our findings suggest that BIM-TF#5 is an effective formulation to treat scalp alopecia, as part of a novel therapeutic approach involving direct prostamide F2α receptor-mediated stimulation of dermal papilla cells within hair follicles.

Ethylene oxide derived glycol ethers: A review of the alkyl glycol ethers potential to cause endocrine disruption.

The 'ethylene glycol ethers' (EGE) are a broad family of solvents and hydraulic fluids produced through the reaction of ethylene oxide and a monoalcohol. Certain EGE derived from methanol and ethanol are well known to cause toxicity to the testes and fetotoxicity and that this is caused by the common metabolites methoxy and ethoxyacetic acid, respectively. There have been numerous published claims that EGE fall into the category of 'endocrine disruptors' often without substantiated evidence. This review systematically evaluates all of the available and relevant in vitro and in vivo data across this family of substances using an approach based around the EFSA/ECHA 2018 guidance for the identification of endocrine disruptors. The conclusion reached is that there is no significant evidence to show that EGE target any endocrine organs or perturb endocrine pathways and that any toxicity that is seen occurs by non-endocrine modes of action.

In silico predictions of absorption of MDI substances after dermal or inhalation exposures to support a category based read-across assessment.

Methylenediphenyl diisocyanate (MDI) substances used polyurethane production can range from their simplest monomeric forms (e.g., 4,4'-MDI) to mixtures of the monomers with various homologues, homopolymer, and prepolymer derivatives. The relative dermal or inhalation absorption of 39 constituents of these substances in human were predicted using the GastroPlus® program. Predicted dermal uptake and absorption of the three MDI monomers from an acetone vehicle was 84-86% and 1.4-1.5%, respectively, with lower uptake and absorption predicted for the higher MW analogs. Lower absorption was predicted from exposures in a more lipophilic vehicle (1-octanol). Modeled inhalation exposures afforded the highest pulmonary absorption for the MDI monomers (38-54%), with 3-27% for the MW range of 381-751, and <0.1% for the remaining, higher MW derivatives. Predicted oral absorption, representing mucociliary transport, ranged from 5 to 10% for the MDI monomers, 10-25% for constituents of MW 381-751, and ≤3% for constituents with MW > 900. These in silico evaluations should be useful in category-based, worst-case, Read-Across assessments for MDI monomers and modified MDI substances for potential systemic effects. Predictions of appreciable mucociliary transport may also be useful to address data gaps in oral toxicity testing for this category of compounds.

Combination anesthetic therapy: co-delivery of ropivacaine and meloxicam using transcriptional transactivator peptide modified nanostructured lipid carriers in vitro and in vivo.

Combination therapy combining two drugs in one modified drug delivery system is used to achieve synergistic analgesic effect, and bring effective control of pain management, especially postoperative pain management. In the present study, a combination of drug delivery technologies was utilized. Transcriptional transactivator (TAT) peptide modified, transdermal nanocarriers were designed to co-deliver ropivacaine (RVC) and meloxicam (MLX) and anticipated to achieve longer analgesic effect and lower side effect. TAT modified nanostructured lipid carriers (TAT-NLCs) were used to co-deliver RVC and MLX. RVC and MLX co-loaded TAT-NLCs (TAT-NLCs-RVC/MLX) were evaluated through in vitro skin permeation and in vivo treatment studies. NLCs-RVC/MLX showed uniform and spherical morphology, with a size of 133.4 ± 4.6 nm and a zeta potential of 20.6 ± 1.8 mV. The results illustrated the anesthetic pain relief ability of the present constructed system was significantly improved by the TAT modification through the enhanced skin permeation efficiency and the co-delivery of MLX along with RVC that improved pain management by reducing inflammation at the injured area. This study provides an efficient and facile method for preparing TAT-NLCs-RVC/MLX as a promising system to achieve synergistic analgesic effect.

Design and Optimization of Cationic Nanocapsules for Topical Delivery of Tretinoin: Application of the Box-Behnken Design, In Vitro Evaluation, and Ex Vivo Skin Deposition Study.

Cationic nanocapsules represent a promising approach for topical delivery purposes. We elaborated on a novel formulation based on the cationic nanocapsules to enhance the pharmacodynamic efficacy, user compliance, and photostability of tretinoin (TTN). To achieve this goal, TTN nanocapsules were prepared by the nanoprecipitation method. In order to statistically optimize formulation variables, a Box-Behnken design, using Design-Expert software, was employed. Three independent variables were evaluated: total weight of the cationic acrylic polymer (X 1), oil volume (X 2), and TTN amount (X 3). The particle size and encapsulation efficiency percent (EE%) were selected as dependent variables. The optimal formulation demonstrated spherical morphology under scanning electron microscopy (SEM), optimum particle size of 116.3 nm, and high EE% of 83.2%. TTN-loaded nanocapsules improved photostability compared to its methanolic solution. The in vitro release study data showed that tretinoin was released in a sustained manner compared to the free drug. The ex vivo skin permeation study demonstrated that greater drug deposition into the epidermal region rather than the deep skin was observed with a gel containing TTN-loaded nanocapsules than that of drug solution, respectively. The skin irritation test revealed that the nanoencapsulation of the drug decreased its irritancy compared to the free drug. These results revealed the promising potential of cationic nanocapsules for topical delivery of tretinoin.