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The purpose of the current work was to develop and characterize ethosomes of vitamin D3 gel that could more effectively work against psoriasis. Psoriasis is a chronic immune-mediated inflammatory skin disease. Due to vitamin D3 role in proliferation and maturation of keratinocytes, it has become an important local therapeutic option in the treatment of psoriasis. In this research we have initiated worked on ethosomes gels containing vitamin D3 to treat psoriasis. Soya lecithin 1–8% (w/v), propylene glycol and ethanol were used to create the formulations, which were then tested for vesicle size, shape, surface morphology, entrapment effectiveness, and in vitro drug permeation. The drug encapsulation efficiency of ethosomes was 96.25% ± 0.3. The particle sizes of the optimized ethosomes was 148 and 657 nm, and the PDI value was 0.770 ± 0.12 along with negative charge − 14 ± 3. Fourier transform infrared (FT-IR) spectroscopy and differential scanning calorimetry (DSC) along with thermogravimetric analysis (TGA) studies confirmed the absence of interactions between vitamin D3 and other ingredients. It was determined that the total amount of medication that penetrated the membrane was 95.34% ± 3. Percentage lysis was very negligible for all strengths which were found less than 15%. Based on our research, ethosomes appear to be safe for use. The vitamin D3 ethosomal gel order, description, pH, and viscosity were all within the specified ranges, according to the findings of a 6-month investigation into the stability profile of the completed system. In this research, we successfully prepared ethosomes loaded with vitamin D3 and then converted it into gel for patients' easy applications. [ABSTRACT FROM AUTHOR]

Abstract The purpose of the current work was to develop and characterize ethosomes of vitamin D3 gel that could more effectively work against psoriasis. Psoriasis is a chronic immune-mediated inflammatory skin disease. Due to vitamin D3 role in proliferation and maturation of keratinocytes, it has become an important local therapeutic option in the treatment of psoriasis. In this research we have initiated worked on ethosomes gels containing vitamin D3 to treat psoriasis. Soya lecithin 1–8% (w/v), propylene glycol and ethanol were used to create the formulations, which were then tested for vesicle size, shape, surface morphology, entrapment effectiveness, and in vitro drug permeation. The drug encapsulation efficiency of ethosomes was 96.25% ± 0.3. The particle sizes of the optimized ethosomes was 148 and 657 nm, and the PDI value was 0.770 ± 0.12 along with negative charge − 14 ± 3. Fourier transform infrared (FT-IR) spectroscopy and differential scanning calorimetry (DSC) along with thermogravimetric analysis (TGA) studies confirmed the absence of interactions between vitamin D3 and other ingredients. It was determined that the total amount of medication that penetrated the membrane was 95.34% ± 3. Percentage lysis was very negligible for all strengths which were found less than 15%. Based on our research, ethosomes appear to be safe for use. The vitamin D3 ethosomal gel order, description, pH, and viscosity were all within the specified ranges, according to the findings of a 6-month investigation into the stability profile of the completed system. In this research, we successfully prepared ethosomes loaded with vitamin D3 and then converted it into gel for patients’ easy applications.

Nanocomposite gels consist of nanoparticles dispersed in a gel matrix. The main aim of this work was to develop nanocomposite gels for topical delivery of Flurbiprofen (FB) for humans and farm animals. Nanocomposite gels were prepared stemming from nanoparticles (NPs) freeze-dried with two different cryoprotectants, D-(+)-trehalose (NPs-TRE) and polyethylene glycol 3350 (NPs-PEG), sterilized by gamma (γ) irradiation, and gelled with Sepigel® 305. Nanocomposite gels with FB-NPs-TRE and FB-NPs-PEG were physiochemically characterized in terms of appearance, pH, morphological studies, porosity, swelling, degradation, extensibility, and rheological behavior. The drug release profile and kinetics were assessed, as well as, the ex vivo permeation of FB was assessed in human, porcine and bovine skin. In vivo studies in healthy human volunteers were tested without FB to assess the tolerance of the gels with nanoparticles. Physicochemical studies demonstrated the suitability of the gel formulations. The ex vivo skin permeation capacity of FB-NPs nanocomposite gels with different cryoprotectants allowed us to conclude that these formulations are suitable topical delivery systems for human and veterinary medicine. However, there were statistically significant differences in the permeation of each formulation depending on the skin. Results suggested that FB-NPs-PEG nanocomposite gel was most suitable for human and porcine skin, and the FB-NPs-TRE nanocomposite gel was most suitable for bovine skin. [ABSTRACT FROM AUTHOR]

Personal lubricants intended for local or systemic delivery via the vaginal route can induce vaginal irritation, damage the vaginal epithelial barrier which can enhance microbial entry, induce inflammation, and alter the microbiome of the vaginal ecosystem. Therefore, manufacturers of personal lubricants and medical devices are required to show biocompatibility and safety assessment data to support regulatory decision-making within a specified context of use. Furthermore, due to ethical concerns and the introduction of the 7th amendment of the European Council Directive which bans animal testing for cosmetic ingredients and products coupled with the Food and Drug Administration modernization Act 2.0 guidelines, there is a wave of drive to develop alternative test methods to predict human responses to chemical or formulation exposure. In this framework, there is a potential to use three-dimensional organotypic human vaginal-ectocervical tissue models as a screening tool to predict the vaginal irritation potential of personal lubricants and medicaments. To be physiologically relevant, the in vitro tissue models need to be reconstructed using primary epithelial cells of the specific organ or tissue and produce organ-like structure and functionality that recapitulate the in vivo–like responses. Through the years, progress has been made and vaginal tissue models are manufactured under controlled conditions with a specified performance criterion, which leads to a high level of reproducibility and reliability. The utility of vaginal tissue models has been accelerated in the last 20 years with an expanded portfolio of applications ranging from toxicity, inflammation, infection to drug safety, and efficacy studies. This article provides an overview of the state of the art of diversified applications of reconstructed vaginal tissue models and highlights their utility as a tool to predict vaginal irritation potential of feminine care products. [ABSTRACT FROM AUTHOR]

The pharmaceutical industry has faced significant changes in recent years, primarily influenced by regulatory standards, market competition, and the need to accelerate drug development. Model-informed drug development (MIDD) leverages quantitative computational models to facilitate decision-making processes. This approach sheds light on the complex interplay between the influence of a drug's performance and the resulting clinical outcomes. This comprehensive review aims to explain the mechanisms that control the dissolution and/or release of drugs and their subsequent permeation through biological membranes. Furthermore, the importance of simulating these processes through a variety of in silico models is emphasized. Advanced compartmental absorption models provide an analytical framework to understand the kinetics of transit, dissolution, and absorption associated with orally administered drugs. In contrast, for topical and transdermal drug delivery systems, the prediction of drug permeation is predominantly based on quantitative structure–permeation relationships and molecular dynamics simulations. This review describes a variety of modeling strategies, ranging from mechanistic to empirical equations, and highlights the growing importance of state-of-the-art tools such as artificial intelligence, as well as advanced imaging and spectroscopic techniques. [ABSTRACT FROM AUTHOR]

Drug nanofibers play a crucial role in ameliorating therapeutic effects, reducing toxicity, and increasing the bioavailability of drugs. This study was aimed at the fabrication of isotretinoin-loaded MMT-reinforced bi-polymeric (PAN/PU) nanofibers with varying concentrations of isotretinoin. In this study, montmorillonite (MMT)-reinforced cross-linked polyacrylonitrile and pullulan nanofibers combined with varying amounts of isotretinoin were fabricated through an electrospinning approach and investigated for their drug permeation potential. PAN-PU nanofibers were successfully integrated with the isotretinoin. The incorporation of isotretinoin into the nanofibrous structure was confirmed by FTIR and XRD. TGA study indicated the stability of the fabricated nanoparticles. The SEM results showed the beaded and smooth morphology of nanofibers. Formulation with a higher drug concentration had a non-significantly (p > 0.05) higher swelling ratio. Drug-loaded polymeric nanofiber erodes at a slower rate as compared to drug-free nanofibers. The ex-vivo permeation study of nanofibers revealed that the drug was not released all at once, but rather gradually and consistently over the period of 24 h, indicating a controlled release of the drug. In addition, the drug concentration in the nanofibers affected the permeation of the drug. According to the findings, isotretinoin-loaded MMT-reinforced bi-polymeric (PAN/PU) nanofibers with varying concentrations of isotretinoin were successfully fabricated. The fabricated nanofibers (PAN/PU) showed a promising potential for controlled permeation of drugs through rabbit skin. [ABSTRACT FROM AUTHOR]

The goal of the present study was to formulate and evaluate a topical gel of nanoparticulate andrographolide for the anti-bacterial and inflammation effect that would attenuate the first-pass metabolism following oral administration. Nanoparticulate andrographolide was fabricated by the solvent evaporation method and optimized using size, polydispersity index, and physical stability properties. The dispersion was converted into a dermal gel using three gelling agents. The optimal gel formulation based on Carbopol 934 at 0.25% concentration showed four-fold higher drug release through a mouse skin model and 26-fold higher drug retention in the skin compared to the gel formulation containing saturated suspension. The anti-inflammation activity of andrographolide suggests also that the topical gel as a promising dosage form for dermal delivery of poorly water-soluble and extensively metabolized andrographolide. [ABSTRACT FROM AUTHOR]

AbstractDrug nanofibers play a crucial role in ameliorating therapeutic effects, reducing toxicity, and increasing the bioavailability of drugs. This study was aimed at the fabrication of isotretinoin-loaded MMT-reinforced bi-polymeric (PAN/PU) nanofibers with varying concentrations of isotretinoin. In this study, montmorillonite (MMT)-reinforced cross-linked polyacrylonitrile and pullulan nanofibers combined with varying amounts of isotretinoin were fabricated through an electrospinning approach and investigated for their drug permeation potential. PAN-PU nanofibers were successfully integrated with the isotretinoin. The incorporation of isotretinoin into the nanofibrous structure was confirmed by FTIR and XRD. TGA study indicated the stability of the fabricated nanoparticles. The SEM results showed the beaded and smooth morphology of nanofibers. Formulation with a higher drug concentration had a non-significantly (p > 0.05) higher swelling ratio. Drug-loaded polymeric nanofiber erodes at a slower rate as compared to drug-free nanofibers. The ex-vivo permeation study of nanofibers revealed that the drug was not released all at once, but rather gradually and consistently over the period of 24 h, indicating a controlled release of the drug. In addition, the drug concentration in the nanofibers affected the permeation of the drug. According to the findings, isotretinoin-loaded MMT-reinforced bi-polymeric (PAN/PU) nanofibers with varying concentrations of isotretinoin were successfully fabricated. The fabricated nanofibers (PAN/PU) showed a promising potential for controlled permeation of drugs through rabbit skin.

Maltitol (MAL) is a well-known polyol with potential pharmaceutical applications. Unlike other polyols, its utilization as a carrier for solid dispersions (SDs) has not been adequately investigated. This research studied the feasibility of MAL as an SD carrier to enhance the biopharmaceutical properties of a BCS class I/III drug, isoniazid (INH). SDs of INH–MAL were prepared by the fusion method, and physicochemical characteristics were investigated to determine the solid-state habit, solubility and permeation enhancement of INH. Fourier-transform infrared (FT-IR) spectroscopy demonstrated significant peak broadening for the SDs consisting of a higher MAL concentration. Powder X-ray diffraction indicated a decrease in degree of crystallinity with increasing MAL concentration. Hot-stage microscopy (HSM) and scanning electron microscopy (SEM) revealed that INH–MAL molar ratios affect the type of SD prepared via the fusion method. Results from the equilibrium solubility studies indicated significant INH solubility improvement (p < 0.05) with SDs in comparison with the pure drug and physical mixtures. The artificial membrane permeation assay (PAMPA) of INH was positively affected by the presence of MAL. The results of the study indicated the potential for MAL as a carrier in the preparation of SDs for the solubility and/or permeability enhancement of drugs. [ABSTRACT FROM AUTHOR]

In recent years, there has been a significant increase in the registration of drugs for nasal application with systemic effects. Previous preclinical in vitro test systems for transmucosal drug absorption studies have mostly been based on primary cells or on tumor cell lines such as RPMI 2650, but both approaches have disadvantages. Therefore, the aim of this study was to establish and characterize a novel immortalized nasal epithelial cell line as the basis for an improved 3D cell culture model of the nasal mucosa. First, porcine primary cells were isolated and transfected. The P1 cell line obtained from this process was characterized in terms of its expression of tissue-specific properties, namely, mucus expression, cilia formation, and epithelial barrier formation. Using air–liquid interface cultivation, it was possible to achieve both high mucus formation and the development of functional cilia. Epithelial integrity was expressed as both transepithelial electrical resistance and mucosal permeability, which was determined for sodium fluorescein, rhodamine B, and FITC-dextran 4000. We noted a high comparability of the novel cell culture model with native excised nasal mucosa in terms of these measures. Thus, this novel cell line seems to offer a promising approach for developing 3D nasal mucosa tissues that exhibit favorable characteristics to be used as an in vitro system for testing drug delivery systems. [ABSTRACT FROM AUTHOR]

To assess the probability of bioequivalence (BE) between orally disintegrating tablets (ODTs) taken without water and conventional tablets (CTs) taken with water, an in vitro biorelevant methodology was developed using the BE Checker, which reproduces fluid shifts in the gastrointestinal tract and drug permeation. In addition to the fluid shift from the stomach to the small intestine, the process of ODT disintegration in a small amount of fluid in the oral cavity and the difference in gastric emptying caused by differences in water intake were incorporated into the evaluation protocol. Assuming a longer time to maximum plasma concentration after oral administration of ODTs taken without water than for CTs taken with water due to a delay in gastric emptying, the fluid shift in the donor chamber of the BE Checker without water was set longer than that taken with water. In the case of naftopidil ODTs and CTs, the values of the f2 function, representing the similarity of the permeation profiles, were 50 or higher when the fluid shift in ODTs taken without water was set at 1.5 or 2 times longer than that of the CTs taken with water. The values of the f2 function in permeation profiles of pitavastatin and memantine ODTs were both 62 when the optimized experimental settings for naftopidil formulations were applied. This methodology can be useful in formulation studies for estimating the BE probability between ODTs and CTs. [ABSTRACT FROM AUTHOR]

Nanocomposite gels consist of nanoparticles dispersed in a gel matrix. The main aim of this work was to develop nanocomposite gels for topical delivery of Flurbiprofen (FB) for humans and farm animals. Nanocomposite gels were prepared stemming from nanoparticles (NPs) freeze-dried with two different cryoprotectants, D-(+)-trehalose (NPs-TRE) and polyethylene glycol 3350 (NPs-PEG), sterilized by gamma (γ) irradiation, and gelled with Sepigel® 305. Nanocomposite gels with FB-NPs-TRE and FB-NPs-PEG were physiochemically characterized in terms of appearance, pH, morphological studies, porosity, swelling, degradation, extensibility, and rheological behavior. The drug release profile and kinetics were assessed, as well as, the ex vivo permeation of FB was assessed in human, porcine and bovine skin. In vivo studies in healthy human volunteers were tested without FB to assess the tolerance of the gels with nanoparticles. Physicochemical studies demonstrated the suitability of the gel formulations. The ex vivo skin permeation capacity of FB-NPs nanocomposite gels with different cryoprotectants allowed us to conclude that these formulations are suitable topical delivery systems for human and veterinary medicine. However, there were statistically significant differences in the permeation of each formulation depending on the skin. Results suggested that FB-NPs-PEG nanocomposite gel was most suitable for human and porcine skin, and the FB-NPs-TRE nanocomposite gel was most suitable for bovine skin.

The blood–brain barrier (BBB) is the bottleneck in the development of new drugs to reach the brain. Due to the BBB, toxic substances cannot enter the brain, but promising drug candidates also pass the BBB poorly. Suitable in vitro BBB models are therefore of particular importance during the preclinical development process, as they can not only reduce animal testing but also enable new drugs to be developed more quickly. The aim of this study was to isolate cerebral endothelial cells, pericytes, and astrocytes from the porcine brain to produce a primary model of the BBB. Additionally, as primary cells are well suited by their properties but the isolation is complex and better reproducibility with immortalized cells must be ensured, there is a high demand for immortalized cells with suitable properties for use as a BBB model. Thus, isolated primary cells can also serve as the basis for a suitable immortalization technique to generate new cell lines. In this work, cerebral endothelial cells, pericytes, and astrocytes were successfully isolated and expanded using a mechanical/enzymatic method. Furthermore, in a triple coculture model, the cells showed a significant increase in barrier integrity compared with endothelial cell monoculture, as determined by transendothelial electrical resistance measurement and permeation studies using sodium fluorescein. The results demonstrate the opportunity to obtain all three cell types significantly involved in BBB formation from one species, thus providing a suitable tool for testing the permeation properties of new drug candidates. In addition, the protocols are a promising starting point to generate new cell lines of BBB-forming cells as a novel approach for BBB in vitro models. [ABSTRACT FROM AUTHOR]

Oral transmucosal administration, where drugs are absorbed directly through the non-keratinized, lining mucosa of the mouth, represents a solution to drug delivery with several advantages. Oral mucosal equivalents (OME) developed as 3D in vitro models are of great interest since they express the correct cell differentiation and tissue architecture, simulating the in vivo conditions better than monolayer cultures or animal tissues. The aim of this work was to develop OME to be used as a membrane for drug permeation studies. We developed both full-thickness (i.e., connective plus epithelial tissue) and split-thickness (i.e., only epithelial tissue) OME using non-tumor-derived human keratinocytes OKF6 TERT-2 obtained from the floor of the mouth. All the OME developed here presented similar transepithelial electrical resistance (TEER) values, comparable to the commercial EpiOral™. Using eletriptan hydrobromide as a model drug, we found that the full-thickness OME had similar drug flux to EpiOral™ (28.8 vs. 29.6 µg/cm2/h), suggesting that the model had the same permeation barrier properties. Furthermore, full-thickness OME showed an increase in ceramide content together with a decrease in phospholipids in comparison to the monolayer culture, indicating that lipid differentiation occurred due to the tissue-engineering protocols. The split-thickness mucosal model resulted in 4–5 cell layers with basal cells still undergoing mitosis. The optimum period at the air–liquid interface for this model was twenty-one days; after longer times, signs of apoptosis appeared. Following the 3R principles, we found that the addition of Ca2+, retinoic acid, linoleic acid, epidermal growth factor and bovine pituitary extract was important but not sufficient to fully replace the fetal bovine serum. Finally, the OME models presented here offer a longer shelf-life than the pre-existing models, which paves the way for the further investigation of broader pharmaceutical applications (i.e., long-term drug exposure, effect on the keratinocytes' differentiation and inflammatory conditions, etc.). [ABSTRACT FROM AUTHOR]

Diverse neurological symptoms have been reported in patients with SARSCoV-2 disease (COVID-19), including stroke, ataxia, meningitis, encephalitis, and cognitive impairment. These alterations can cause serious sequelae or death and are associated with the entry of SARS-CoV-2 into the Central Nervous System (CNS). This mini-review discusses the main proposed mechanisms by which SARS-CoV-2 interacts with the blood-brain barrier (BBB) and its involvement in the passage of drugs into the CNS. We performed a search in PubMed with the terms "COVID-19" or "SARS-CoV-2" and "blood-brain barrier injury" or "brain injury" from the year 2019 to 2022. We found proposed evidence that SARS-CoV-2 infects neurovascular cells and increases BBB permeability by increasing the expression of matrix metalloproteinase-9 that degrades type IV collagen in the basement membrane and through activating RhoA, which induces restructuring of the cytoskeleton and alters the integrity of the barrier. The breakdown of the BBB triggers a severe inflammatory response, causing the cytokine storm (release of IL-1b, IL-6, TNF-a, etc.) characteristic of the severe phase of COVID-19, which includes the recruitment of macrophages and lymphocytes and the activation of astrocytes and microglia. We conclude that the increased permeability of the BBB would allow the passage of drugs that would not reach the brain in a normal physiological state, thus enhancing certain drugs' beneficial or adverse effects. We hope this article will encourage research on the impact of drugs on patients with COVID-19 and recovered patients with sequelae, focusing mainly on possible dose adjustments and changes in pharmacokinetic parameters. [ABSTRACT FROM AUTHOR]

[Display omitted] The retinal pigment epithelial (RPE) cell monolayer forms the outer blood–retinal barrier and has a crucial role in ocular pharmacokinetics. Although several RPE cell models are available, there have been no systematic comparisons of their barrier properties with respect to drug permeability. We compared the barrier properties of RPE secondary cell lines (ARPE19, and ARPE19mel) and both primary (hfRPE) and stem-cell derived RPE (hESC-RPE) cells by investigating the permeability of nine drugs (aztreonam, ciprofloxacin, dexamethasone, fluconazole, ganciclovir, ketorolac, methotrexate, voriconazole, and quinidine) across cell monolayers. ARPE19, ARPE19mel, and hfRPE cells displayed a narrow P app value range, with relatively high permeation rates (5.2–26 × 10−6 cm/s). In contrast, hESC-RPE cells efficiently restricted the drug flux, and displayed even lower P app values than those reported for bovine RPE-choroid, with the range of 0.4–32 cm−6/s. Therefore, ARPE19, ARPE19mel, and hfRPE cells failed to form a tight barrier, whereas hESC-RPE cells restricted the drug flux to a similar extent as bovine RPE-choroid. Therefore, hESC-RPE cells are valuable tools in ocular drug discovery. [ABSTRACT FROM AUTHOR]

[Display omitted] Skin pharmacokinetics (SPK) of permeation enhancers can answer the question of why enhancement effects different at the kinetic level. Herein, SPK of permeation enhancers were classified into two categories, namely, lateral elimination (elimination to surrounding stratum corneum (SC)) and longitudinal elimination (elimination to deep epidermal (EP)). They were evaluated with a specific parameter for permeation enhancers, diffusion ratio (DR SC-EP), according to results of tissue-distribution test, molecular dynamic (MD) simulation, and confocal laser scanning microscopy (CLSM). The linear relationship between k e-enahcer and Δ C max-drug (R 2 = 0.92), MRT enhancer and Δ T max-drug (R 2 = 0.97), AUC t - enhancer and Δ AUC t-drug (R 2 = 0.90) suggesting that SPK of permeation enhancers precisely controlled dynamic process of drug permeation in vivo. The molecular mechanisms of the dynamic effect of SPK process on drug transdermal behaviors were characterized by modulated-temperature differential scanning calorimetry (MTDSC), dielectric spectroscopy, small-angle X-ray scattering (SAXS), solid-state NMR. Permeation enhancers with high molecular weight (M.W.) and high polar surface area (P.S.A.) had good compatibility and strong interaction strength with SC, leading their lateral-elimination behavior, causing their low DR SC-EP and resulting in low k e-enhancer , long MRT enhancer , and large AUC t-enhancer. Consequently, skin barrier can be rapidly opened fast and to a great extent. In summary, compared with SPK of permeation enhancers with longitudinal elimination, SPK of permeation enhancers with lateral elimination can enable more sustainable and greater drug permeation. The information about SPK of permeation enhancers offered a criterion to estimate its permeation-enhancement effect on the drug and its subsequent application in transdermal formulations. [ABSTRACT FROM AUTHOR]

The pharmaceutical industry has faced significant changes in recent years, primarily influenced by regulatory standards, market competition, and the need to accelerate drug development. Model-informed drug development (MIDD) leverages quantitative computational models to facilitate decision-making processes. This approach sheds light on the complex interplay between the influence of a drug’s performance and the resulting clinical outcomes. This comprehensive review aims to explain the mechanisms that control the dissolution and/or release of drugs and their subsequent permeation through biological membranes. Furthermore, the importance of simulating these processes through a variety of in silico models is emphasized. Advanced compartmental absorption models provide an analytical framework to understand the kinetics of transit, dissolution, and absorption associated with orally administered drugs. In contrast, for topical and transdermal drug delivery systems, the prediction of drug permeation is predominantly based on quantitative structure–permeation relationships and molecular dynamics simulations. This review describes a variety of modeling strategies, ranging from mechanistic to empirical equations, and highlights the growing importance of state-of-the-art tools such as artificial intelligence, as well as advanced imaging and spectroscopic techniques.

Diverse neurological symptoms have been reported in patients with SARS-CoV-2 disease (COVID-19), including stroke, ataxia, meningitis, encephalitis, and cognitive impairment. These alterations can cause serious sequelae or death and are associated with the entry of SARS-CoV-2 into the Central Nervous System (CNS). This mini-review discusses the main proposed mechanisms by which SARS-CoV-2 interacts with the blood-brain barrier (BBB) and its involvement in the passage of drugs into the CNS. We performed a search in PubMed with the terms “COVID-19” or “SARS-CoV-2” and “blood-brain barrier injury” or “brain injury” from the year 2019 to 2022. We found proposed evidence that SARS-CoV-2 infects neurovascular cells and increases BBB permeability by increasing the expression of matrix metalloproteinase-9 that degrades type IV collagen in the basement membrane and through activating RhoA, which induces restructuring of the cytoskeleton and alters the integrity of the barrier. The breakdown of the BBB triggers a severe inflammatory response, causing the cytokine storm (release of IL-1β, IL-6, TNF-α, etc.) characteristic of the severe phase of COVID-19, which includes the recruitment of macrophages and lymphocytes and the activation of astrocytes and microglia. We conclude that the increased permeability of the BBB would allow the passage of drugs that would not reach the brain in a normal physiological state, thus enhancing certain drugs’ beneficial or adverse effects. We hope this article will encourage research on the impact of drugs on patients with COVID-19 and recovered patients with sequelae, focusing mainly on possible dose adjustments and changes in pharmacokinetic parameters.

Vitamin D3 is available in oral and injectable dosage forms. Interest in the transdermal route as an alternative to the oral and parenteral routes has grown recently. In this study, several film-forming solutions for the transdermal delivery of vitamin D3 were prepared. They contained 6000 IU/mL of vitamin D3 that formed a dry and acceptable film in less than 5 min after application. The formulations consisted of ethanol and acetone 80:20, and one or more of the following ingredients: Eudragit L100-55, PVP, PG, limonene, oleic acid, camphor, and menthol. Vitamin D3 release was studied from both the film-forming solution and pre-dried films using a Franz diffusion cell. The film-forming solution released a significant amount of vitamin D3 compared to the dry film, which is attributed mostly to the saturation driving force due to the evaporation of volatile solvents. In vitro permeation studies through artificial skin Strat M® membrane revealed that the cumulative amount of vitamin D3 permeated after 24 h under the experimental conditions was around 800 IU across 3.14 cm2. The cumulative permeation curve showed faster permeation in earlier stages. Young's modulus, viscosity, and pH of the formulations were determined. Most of the formulations were stable for 3 weeks. [ABSTRACT FROM AUTHOR]

Antibiotics effective against Gram‐negative ESKAPE pathogens are a critical area of unmet need. Infections caused by these pathogens are not only difficult to treat but finding new therapies to overcome Gram‐negative resistance is also a challenge. There are not enough antibiotics in development that target the most dangerous pathogens and there are not enough novel drugs in the pipeline. The major obstacle in the antibiotic discovery pipeline is the lack of understanding of how to breach antibiotic permeability barriers of Gram‐negative pathogens. These barriers are created by active efflux pumps acting across both the inner and the outer membranes. Overproduction of efflux pumps alone or together with either modification of the outer membrane or antibiotic‐inactivating enzymes and target mutations contribute to clinical levels of antibiotics resistance. Recent efforts have generated significant advances in the rationalization of compound efflux and permeation across the cell envelopes of Gram‐negative pathogens. Combined with earlier studies and novel mathematical models, these efforts have led to a multilevel understanding of how antibiotics permeate these barriers and how multidrug efflux and permeation contribute to the development of antibiotic resistance and heteroresistance. Here, we discuss the new developments in this area. [ABSTRACT FROM AUTHOR]

The barrier imposed by the outer layer of the skin, the stratum corneum, creates an almost impermeable environment for exogenous substances. Few lipophilic drugs with low molecular mass can passively diffuse through this layer, highlighting the need to develop methods to enable the delivery of more drugs via the transdermal route. The prodrug approach involves modifying the structure of a drug molecule to enhance its permeability across the skin, but it is often difficult to predict how exactly changes in chemical structure affect permeation. This study uses molecular dynamics simulations to predict permeability values and adequately characterise the molecular mechanism of permeation of the prodrugs Me-5ALA and its parent compound 5ALA across a molecular model of the lipid bilayers of the human stratum corneum. The influence of increased hydrophobicity in Me-5ALA on its permeation revealed a reduction in hydrogen bonding capability that enables it to interact more favourably with the hydrophobic region of the bilayer and diffuse at a faster rate with less resistance, thus making it a better permeant compared to its more hydrophilic parent compound. This molecular simulation approach offers a promising route for the rational design of drug molecules that can permeate effectively across the stratum corneum. [ABSTRACT FROM AUTHOR]

[Display omitted] Arbutin, a typical optical isomer, has garnered widespread acclaim in the whitening cosmetics for its favorable efficacy and safety. However, the molecular mechanisms underlying α-arbutin and β-arbutin permeating across the skin have not elucidated clearly yet. Herein we aimed to unveil how α-arbutin and β-arbutin interacted with keratin or SC lipids, further demonstrating their relationship with their drug permeability. We found that α-arbutin displayed significantly higher drug accumulation into the porcine skin than β-arbutin within 24 h through in vitro permeation test. Moreover, α-arbutin predominantly induced the alternations of secondary structure of amide II during the drug permeation, which was favorable for α-arbutin permeation. On the contrary, β-arbutin exhibited an observable effect on the stretching vibration of SC lipids, possessing a significantly stronger mixing energy, binding energy and compatibility with ceramide (Cer) than that of α-arbutin, which ultimately restricted its permeation. Interestingly, free fatty acids and ceramides of the SC lipids specifically utilized its oxygen atom of carboxyl group to dock the arbutin molecules, enhancing their affinity with β-arbutin, as confirmed by molecular simulation and 13Carbon Nuclear Magnetic Resonance. Nevertheless, a favorable compatibility between α-arbutin and keratin was observed. It was emphasized that the distinct spatial configuration and opposite optical rotation of arbutin was the leading factor impacting the intermolecular force between arbutin and the SC, and resulted in a diverse drug permeation. In cellular and in vivo skin pharmacokinetic studies, α-arbutin also possessed a higher cellular uptake and topical bioavailability than β-arbutin. This study revealed the transdermal permeation mechanisms of optical isomer arbutin at the molecular levels, providing methodological reference for the investigations of permeation behaviors of other isomers with similar spatial configuration. [ABSTRACT FROM AUTHOR]

Maltitol (MAL) is a well-known polyol with potential pharmaceutical applications. Unlike other polyols, its utilization as a carrier for solid dispersions (SDs) has not been adequately investigated. This research studied the feasibility of MAL as an SD carrier to enhance the biopharmaceutical properties of a BCS class I/III drug, isoniazid (INH). SDs of INH–MAL were prepared by the fusion method, and physicochemical characteristics were investigated to determine the solid-state habit, solubility and permeation enhancement of INH. Fourier-transform infrared (FT-IR) spectroscopy demonstrated significant peak broadening for the SDs consisting of a higher MAL concentration. Powder X-ray diffraction indicated a decrease in degree of crystallinity with increasing MAL concentration. Hot-stage microscopy (HSM) and scanning electron microscopy (SEM) revealed that INH–MAL molar ratios affect the type of SD prepared via the fusion method. Results from the equilibrium solubility studies indicated significant INH solubility improvement (p < 0.05) with SDs in comparison with the pure drug and physical mixtures. The artificial membrane permeation assay (PAMPA) of INH was positively affected by the presence of MAL. The results of the study indicated the potential for MAL as a carrier in the preparation of SDs for the solubility and/or permeability enhancement of drugs.

Otic disorders, such as otitis media and hearing loss, affect a substantial portion of the global population. Despite this, oto-therapeutics, in particular those intended to treat hearing loss, have seen limited development and innovation. A significant factor to this is likely a result of the inherent costs and complexities of drug discovery and development. With in vitro 3D tissue models seeing increased utility for the rapid, high-throughput screening of drug candidates, it stands to reason that the field of otology could greatly benefit from such innovations. In this study, we propose and describe an in vitro 3D model, designed using a physiologically based approach, which we suggest can be used to estimate drug permeability across human tympanic membranes (TM). We characterize the permeability properties of several template drugs in this model under various growth and storage conditions. The availability of such cost-effective, rapid, high-throughput screening tools should allow for increased innovation and the discovery of novel drug candidates over the currently used animal models. In the context of this TM permeation model, it may promote the development of topical drugs and formulations that can non-invasively traverse the TM and provide tissue-targeted drug delivery as an alternative to systemic treatment, an objective which has seen limited study until present. [ABSTRACT FROM AUTHOR]

Hearing loss and balance disorders are highly common disorders, and the development of effective oto-therapeutics remains an area of intense research. Drug development and screening in the hearing research field heavily rely on the use of preclinical models with often ambiguous translational relevance. This often leads to failed advancement in the market of effective therapeutics. In this context, especially for inner ear-specific pathologies, the availability of an in vitro, physiologically relevant, round window membrane (RWM) model could enable rapid, high-throughput screening of potential topical drugs for inner ear and cochlear dysfunctions and could help accelerate the advancement to clinic and market of more viable drug candidates. In this study, we report the development and evaluation of an in vitro model that mimics the native RWM tissue morphology and microenvironment as shown via immunostaining and histological analyses. The developed three-dimensional (3D) in vitro model was additionally assessed for barrier integrity by transepithelial electrical resistance, and the permeability of lipophilic and hydrophilic drugs was determined. Our collective findings suggest that this in vitro model could serve as a tool for rapid development and screening of topically deliverable oto-therapeutics. [ABSTRACT FROM AUTHOR]

Objective: The study aimed to address the limitations of oral delivery and enhance the bioavailability of Cilnidipine (often prescribed as antihypertensive drug) (CND) through the development of transdermal patches containing ultra-deformable transferosomes., Methods: CND, known for its low oral bioavailability and adverse effects, was encapsulated in transferosomes using a thin film hydration method. Seventeen formulations were made (using Box Behnken Design), varying Soya lecithin, Tween-80, and rotary evaporator's speed, and evaluated for vesicle size, polydispersity index (PDI), and entrapment efficiency (EE %). The better formulation was selected based on these parameters and incorporated into transdermal patches. Physicochemical properties, in-vitro and ex-vivo permeation, and skin irritancy studies were conducted on the patches. Pharmacokinetic studies were conducted using male Wistar albino rats., Results: The study found that the developed transferosomal formulations had vesicle sizes between 185 nm and 401 nm, entrapment efficiency (EE%) between 63% and 92%, and zeta potential ranging from -52 mV to -20 mV. Both in-vitro and ex-vivo permeation studies showed that transferosomal formulations provided significantly better drug permeation than plain Cilnidipine patches, with increased permeation linked to higher PEG-400 concentrations. The transferosomal patches did not cause skin irritation. The optimized formulation exhibited a higher % drug release (85.7±1.5%). In pharmacokinetic studies using male Wistar albino rats, the transferosomal patch CTP-17 demonstrated a higher maximum concentration (Cmax) of 1565.068 mcg/ml and a greater area under the curve (AUC) of 13225.352 μg h/ml compared to oral administration., Conclusion: The study concludes that the transferosomal patches of CND offer a promising approach for effective transdermal delivery, potentially improving hypertension management for prolonged periods in a controlled manner., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

To assess the probability of bioequivalence (BE) between orally disintegrating tablets (ODTs) taken without water and conventional tablets (CTs) taken with water, an in vitro biorelevant methodology was developed using the BE Checker, which reproduces fluid shifts in the gastrointestinal tract and drug permeation. In addition to the fluid shift from the stomach to the small intestine, the process of ODT disintegration in a small amount of fluid in the oral cavity and the difference in gastric emptying caused by differences in water intake were incorporated into the evaluation protocol. Assuming a longer time to maximum plasma concentration after oral administration of ODTs taken without water than for CTs taken with water due to a delay in gastric emptying, the fluid shift in the donor chamber of the BE Checker without water was set longer than that taken with water. In the case of naftopidil ODTs and CTs, the values of the f2 function, representing the similarity of the permeation profiles, were 50 or higher when the fluid shift in ODTs taken without water was set at 1.5 or 2 times longer than that of the CTs taken with water. The values of the f2 function in permeation profiles of pitavastatin and memantine ODTs were both 62 when the optimized experimental settings for naftopidil formulations were applied. This methodology can be useful in formulation studies for estimating the BE probability between ODTs and CTs.

Oral transmucosal administration, where drugs are absorbed directly through the non-keratinized, lining mucosa of the mouth, represents a solution to drug delivery with several advantages. Oral mucosal equivalents (OME) developed as 3D in vitro models are of great interest since they express the correct cell differentiation and tissue architecture, simulating the in vivo conditions better than monolayer cultures or animal tissues. The aim of this work was to develop OME to be used as a membrane for drug permeation studies. We developed both full-thickness (i.e., connective plus epithelial tissue) and split-thickness (i.e., only epithelial tissue) OME using non-tumor-derived human keratinocytes OKF6 TERT-2 obtained from the floor of the mouth. All the OME developed here presented similar transepithelial electrical resistance (TEER) values, comparable to the commercial EpiOral™. Using eletriptan hydrobromide as a model drug, we found that the full-thickness OME had similar drug flux to EpiOral™ (28.8 vs. 29.6 µg/cm2/h), suggesting that the model had the same permeation barrier properties. Furthermore, full-thickness OME showed an increase in ceramide content together with a decrease in phospholipids in comparison to the monolayer culture, indicating that lipid differentiation occurred due to the tissue-engineering protocols. The split-thickness mucosal model resulted in 4–5 cell layers with basal cells still undergoing mitosis. The optimum period at the air–liquid interface for this model was twenty-one days; after longer times, signs of apoptosis appeared. Following the 3R principles, we found that the addition of Ca2+, retinoic acid, linoleic acid, epidermal growth factor and bovine pituitary extract was important but not sufficient to fully replace the fetal bovine serum. Finally, the OME models presented here offer a longer shelf-life than the pre-existing models, which paves the way for the further investigation of broader pharmaceutical applications (i.e., long-term drug exposure, effect on the keratinocytes’ differentiation and inflammatory conditions, etc.).

[Display omitted] 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. [ABSTRACT FROM AUTHOR]

Our goal was to prepare Span 60-based elastic nanovesicles (spanlastics (SPLs)) of tacrolimus (TCR) using the adapted ethanol injection method, characterize them, and evaluate their ability to improve the transdermal permeation of the active substance. The impact of two different concentrations of penetration enhancers, namely, propylene glycol and oleic acid, on the entrapment efficiency, vesicle size, and zeta potential was assessed. Moreover, in vitro release through a semipermeable membrane and ex vivo penetration through hairless rat skin were performed. Morphological examination and pharmacokinetics were performed for one selected formulation (F3OA1). TCR-loaded SPLs were effectively formulated with two different concentrations of permeation enhancers, and the effect of these enhancers on their physicochemical properties differed in accordance with the concentration and kind of enhancer used. The results of in vitro release displayed a considerable (p < 0.05) enhancement compared to the suspension of the pure drug, and there was a correlation between the in vitro and ex vivo results. The selected TCR-loaded nanovesicles incorporated into a gel base showed appreciable advantages over the oral drug suspension and the TCR-loaded gel. Additionally, the pharmacokinetic parameters were significantly (p < 0.05) improved based on our findings. Moreover, the AUC0–7 ng·h/mL form F3 OA1 was 3.36-fold higher than that after the administration of the TCR oral suspension. [ABSTRACT FROM AUTHOR]

The inclusion of a chemical permeation enhancer in a dosage form is considered an effective approach to improve absorption across the nasal mucosa. Herein we evaluated the possibility of exploiting biosurfactants (BS) produced by Lactobacillus gasseri BC9 as innovative natural excipients to improve nasal delivery of hydrocortisone (HC). BC9-BS ability to improve HC solubility and the BS mucoadhesive potential were investigated using the surfactant at a concentration below and above the critical micelle concentration (CMC). In vitro diffusion studies through the biomimetic membrane PermeaPad® and the same synthetic barrier functionalized with a mucin layer were assessed to determine BC9-BS absorption enhancing properties in the absence and presence of the mucus layer. Lastly, the diffusion study was performed across the sheep nasal mucosa using BC9-BS at a concentration below the CMC. Results showed that BC9-BS was able to interact with the main component of the nasal mucosa, and that it allowed for a greater solubilization and also permeation of the drug when it was employed at a low concentration. Overall, it seems that BC9-BS could be a promising alternative to chemical surfactants in the nasal drug delivery field. [ABSTRACT FROM AUTHOR]

Understanding the composition and function of the blood brain barrier (BBB) enables the development of novel, innovative techniques for administering central nervous system (CNS) medications and technologies for improving the existing models. Scientific and methodological interest in the pathology of the BBB resulted in the formation of numerous in vitro BBB models. Once successfully studied and modelled, it would be a valuable tool for elucidating the mechanism of action of the CNS disorders prior to their manifestation and the pathogenic factors. Understanding the rationale behind the selection of the models as well as their working may enable the development of state-of-the-art drugs for treating and managing neurological diseases. Hence, to have realistic simulation of the BBB and test its drug permeability the microfluidics-based BBB-on-Chip model has been developed. To summarise, we aim to evaluate the advanced, newly developed and frequently used in vitro BBB models, thereby providing a brief overview of the components essential for in vitro BBB formation, the methods of chip fabrication and cell culturing, its applications and the recent advances in this technological field. This will be critical for developing CNS treatments with improved BBB penetrability and pharmacokinetic properties. [Display omitted] • Blood Brain Barrier (BBB) maintains the homeostasis of the brain microenvironment. • Working of in-vitro BBB models and the rationale behind its selection are discussed. • Reasons for validation and testing the functions of BBB-on-chip fabrication are elaborated. • Applications span drug delivery, nanoparticle permeation, metastatic brain tumor study etc. [ABSTRACT FROM AUTHOR]

Qihong Zhang,1 Carol R Flach,1 Richard Mendelsohn,1 Leanne Page,2 Susan Whitson,2 Mila Boncheva Bettex3 1Department of Chemistry, Rutgers University, Newark, NJ 07102, USA; 2Charles River Laboratories Edinburgh Ltd., Tranent, East Lothian, UK; 3GSK Consumer Healthcare S.A., Nyon 1 1260, SwitzerlandCorrespondence: Mila Boncheva BettexGSK Consumer Healthcare S.A., Route de l’Etraz 2, Case Postale 1279, Nyon 1260, SwitzerlandTel +41 79 700 9281Email mila.x.boncheva-bettex@gsk.comPurpose: This work investigated whether topical pain relief diclofenac gels can form a diclofenac reservoir in the epidermal and dermal layers of human skin.Methods: Excised human skin samples were treated with three topical diclofenac gels ex vivo and examined using Raman microscopy of transversally microtomed sections. The relative diclofenac concentration in the skin layers was calculated as the ratio of the integrated areas of bands characteristic of diclofenac (∼ 445 cm− 1) and skin (Amide I). A customized masking algorithm ensured that only diclofenac-specific signal was mapped in the resulting Raman images.Results: A heterogenous spatial distribution of diclofenac was clearly visible in both the epidermis and the dermis in all samples, with a markedly higher diclofenac relative content and number of pixels above the detection limit in the epidermis compared to the dermis.Conclusion: The Raman images evidenced that the studied topical gels deliver diclofenac through the stratum corneum skin barrier and form a drug depot localized in the epidermis. The data are in line with earlier clinical findings that this depot acts like a true reservoir and enables sustained drug release.Keywords: diclofenac, drug permeation, epidermal reservoir, Raman microscopy, skin depot, topical pain relief

The barrier imposed by the outer layer of the skin, the stratum corneum, creates an almost impermeable environment for exogenous substances. Few lipophilic drugs with low molecular mass can passively diffuse through this layer, highlighting the need to develop methods to enable the delivery of more drugs via the transdermal route. The prodrug approach involves modifying the structure of a drug molecule to enhance its permeability across the skin, but it is often difficult to predict how exactly changes in chemical structure affect permeation. This study uses molecular dynamics simulations to predict permeability values and adequately characterise the molecular mechanism of permeation of the prodrugs Me-5ALA and its parent compound 5ALA across a molecular model of the lipid bilayers of the human stratum corneum. The influence of increased hydrophobicity in Me-5ALA on its permeation revealed a reduction in hydrogen bonding capability that enables it to interact more favourably with the hydrophobic region of the bilayer and diffuse at a faster rate with less resistance, thus making it a better permeant compared to its more hydrophilic parent compound. This molecular simulation approach offers a promising route for the rational design of drug molecules that can permeate effectively across the stratum corneum.

Vitamin D3 is available in oral and injectable dosage forms. Interest in the transdermal route as an alternative to the oral and parenteral routes has grown recently. In this study, several film-forming solutions for the transdermal delivery of vitamin D3 were prepared. They contained 6000 IU/mL of vitamin D3 that formed a dry and acceptable film in less than 5 min after application. The formulations consisted of ethanol and acetone 80:20, and one or more of the following ingredients: Eudragit L100-55, PVP, PG, limonene, oleic acid, camphor, and menthol. Vitamin D3 release was studied from both the film-forming solution and pre-dried films using a Franz diffusion cell. The film-forming solution released a significant amount of vitamin D3 compared to the dry film, which is attributed mostly to the saturation driving force due to the evaporation of volatile solvents. In vitro permeation studies through artificial skin Strat M® membrane revealed that the cumulative amount of vitamin D3 permeated after 24 h under the experimental conditions was around 800 IU across 3.14 cm2. The cumulative permeation curve showed faster permeation in earlier stages. Young’s modulus, viscosity, and pH of the formulations were determined. Most of the formulations were stable for 3 weeks.

Hearing loss and balance disorders are highly common disorders, and the development of effective oto-therapeutics remains an area of intense research. Drug development and screening in the hearing research field heavily rely on the use of preclinical models with often ambiguous translational relevance. This often leads to failed advancement in the market of effective therapeutics. In this context, especially for inner ear-specific pathologies, the availability of an in vitro, physiologically relevant, round window membrane (RWM) model could enable rapid, high-throughput screening of potential topical drugs for inner ear and cochlear dysfunctions and could help accelerate the advancement to clinic and market of more viable drug candidates. In this study, we report the development and evaluation of an in vitro model that mimics the native RWM tissue morphology and microenvironment as shown via immunostaining and histological analyses. The developed three-dimensional (3D) in vitro model was additionally assessed for barrier integrity by transepithelial electrical resistance, and the permeability of lipophilic and hydrophilic drugs was determined. Our collective findings suggest that this in vitro model could serve as a tool for rapid development and screening of topically deliverable oto-therapeutics.

Otic disorders, such as otitis media and hearing loss, affect a substantial portion of the global population. Despite this, oto-therapeutics, in particular those intended to treat hearing loss, have seen limited development and innovation. A significant factor to this is likely a result of the inherent costs and complexities of drug discovery and development. With in vitro 3D tissue models seeing increased utility for the rapid, high-throughput screening of drug candidates, it stands to reason that the field of otology could greatly benefit from such innovations. In this study, we propose and describe an in vitro 3D model, designed using a physiologically based approach, which we suggest can be used to estimate drug permeability across human tympanic membranes (TM). We characterize the permeability properties of several template drugs in this model under various growth and storage conditions. The availability of such cost-effective, rapid, high-throughput screening tools should allow for increased innovation and the discovery of novel drug candidates over the currently used animal models. In the context of this TM permeation model, it may promote the development of topical drugs and formulations that can non-invasively traverse the TM and provide tissue-targeted drug delivery as an alternative to systemic treatment, an objective which has seen limited study until present.

Colonic mucus is a key factor in the colonic environment because it may affect drug absorption. Due to the similarity of human and canine gastrointestinal physiology, dogs are an established preclinical species for the assessment of controlled release formulations. Here we report the development of an artificial colonic mucus model to mimic the native canine one. In vitro models of the canine colonic environment can provide insights for early stages of drug development and contribute to the implementation of the 3Rs (refinement, reduction, and replacement) of animal usage in the drug development process. Our artificial colonic mucus could predict diffusion trends observed in native mucus and was successfully implemented in microscopic and macroscopic assays to study macromolecular permeation through the mucus. The traditional Transwell set up was optimized with the addition of a nylon filter to ensure homogenous representation of the mucus barrier in vitro. In conclusion, the canine artificial colonic mucus can be used to study drug permeation across the mucus and its flexibility allows its use in various set ups depending on the nature of the compound under investigation and equipment availability. [Display omitted] [ABSTRACT FROM AUTHOR]

Our goal was to prepare Span 60-based elastic nanovesicles (spanlastics (SPLs)) of tacrolimus (TCR) using the adapted ethanol injection method, characterize them, and evaluate their ability to improve the transdermal permeation of the active substance. The impact of two different concentrations of penetration enhancers, namely, propylene glycol and oleic acid, on the entrapment efficiency, vesicle size, and zeta potential was assessed. Moreover, in vitro release through a semipermeable membrane and ex vivo penetration through hairless rat skin were performed. Morphological examination and pharmacokinetics were performed for one selected formulation (F3OA1). TCR-loaded SPLs were effectively formulated with two different concentrations of permeation enhancers, and the effect of these enhancers on their physicochemical properties differed in accordance with the concentration and kind of enhancer used. The results of in vitro release displayed a considerable (p < 0.05) enhancement compared to the suspension of the pure drug, and there was a correlation between the in vitro and ex vivo results. The selected TCR-loaded nanovesicles incorporated into a gel base showed appreciable advantages over the oral drug suspension and the TCR-loaded gel. Additionally, the pharmacokinetic parameters were significantly (p < 0.05) improved based on our findings. Moreover, the AUC0–7 ng·h/mL form F3 OA1 was 3.36-fold higher than that after the administration of the TCR oral suspension.

The inclusion of a chemical permeation enhancer in a dosage form is considered an effective approach to improve absorption across the nasal mucosa. Herein we evaluated the possibility of exploiting biosurfactants (BS) produced by Lactobacillus gasseri BC9 as innovative natural excipients to improve nasal delivery of hydrocortisone (HC). BC9-BS ability to improve HC solubility and the BS mucoadhesive potential were investigated using the surfactant at a concentration below and above the critical micelle concentration (CMC). In vitro diffusion studies through the biomimetic membrane PermeaPad® and the same synthetic barrier functionalized with a mucin layer were assessed to determine BC9-BS absorption enhancing properties in the absence and presence of the mucus layer. Lastly, the diffusion study was performed across the sheep nasal mucosa using BC9-BS at a concentration below the CMC. Results showed that BC9-BS was able to interact with the main component of the nasal mucosa, and that it allowed for a greater solubilization and also permeation of the drug when it was employed at a low concentration. Overall, it seems that BC9-BS could be a promising alternative to chemical surfactants in the nasal drug delivery field.

Hansen Solubility Parameters (HSP) of human stratum corneum (SC) represent its polarity and are very important for design and optimization of dermatological formulations. However, there is no directly measured data available in the literature for such a crucial property, which is the subject of the present investigation. HSP of the SC was measured by solvent uptake here. 18 solvents/mixtures with different HSP values were selected and their uptake by the SC was measured at 32 °C. The solvents were then divided into good and bad solvents according to their uptake into the SC. The HSP discrete parts of “atomic dispersion forces (δD)”, “dipolar intermolecular forces (δP)”, and “hydrogen bonding (δH)” were then calculated using uptake data and HSPiP software. Results showed that δD, δP, and δH values of the SC at 32 °C are 16.5, 12, 7.7 respectively. The obtained HSP values, which were measured for the first time here, were then used to interpret enhancement effects of permeation enhancers and the uptake of vehicles by the SC using Relative Energy Difference (RED), with good correlations. SC HSP values can be further used in transdermal drug delivery, cosmetic formulations, safety issues, etc. [ABSTRACT FROM AUTHOR]

Purpose: Heat therapy is widely used for pain relief and may unintentionally be used in conjunction with pain relieving topical formulations. The purpose of this study was to evaluate the influence of heat on the permeation of diclofenac through porcine and human skin, comparing four marketed products. Methods: In vitro permeation tests (IVPT) were performed on porcine skin from a single miniature pig and human skin from three donors. Skin temperature was maintained at either 32 ± 1°C or 42 ± 1°C to mimic normal and elevated skin temperature conditions, respectively. Results: IVPT studies on porcine and human skin were able to demonstrate heat-induced enhancement in flux and cumulative amount of drug permeated from the four diclofenac products. The pivotal data showed the most significant heat-induced enhancement for the solution, followed by the patch and two gels in decreasing order of significance based on p values. Diclofenac solution showed the highest flux and cumulative amount permeated at both baseline and elevated skin temperature compared to the patch and gels. Conclusions: The studies demonstrated that exposure to heat can alter drug permeation from topical formulations, but the increased levels are not expected to lead to systemic concentrations that are of concern. Formulation design and excipients can influence drug permeation at elevated skin temperature. [ABSTRACT FROM AUTHOR]

The permeability of crisaborole was investigated via ex vivo Franz diffusion chambers with dorsal skin of ICR mice. Positive control (2% w/w in USP ointment, PC), 1.5% and 2.0% w/w crisaborole nanoemulsion (CN) were tested and crisaborole accumulation in skin layers was measured using the tape stripping method. The cumulative drug permeation (Qt) for PC and CN2.0% were significantly higher compared to CN1.5% at 95% confidence level. The apparent permeability coefficients (Kp) showed no significant differences in all formulations (p<0.05). CN1.5% and CN2.0% showed significantly higher accumulations in stratum corneum compared to PC (p<0.05). There was no significant difference observed in crisaborole accumulation between all formulations in epidermis. [ABSTRACT FROM AUTHOR]