Effect Of Penetration Enhancers Research Articles

Effect of chemical penetration enhancers on the transdermal delivery of olanzapine in human skin in vitro

This research study involves the development of an olanzapine (OLZ) formulation using various chemical penetration enhancers (CPEs) for transdermal delivery. The aim of this study was to obtain the initial data needed about the effects of various CPEs on the skin permeation of OLZ. The effects of the selected CPEs were examined by studying the permeation profiles of OLZ from formulations applied to human cadaver skin samples. A control formulation of OLZ in propylene glycol (PG) was prepared and compared against formulations containing chemical penetration enhancers. Five different CPEs (oleic acid (OA), cineole (Cin), isopropyl alcohol (IPA), Tween 80 (T80), and N-methyl pyrrolidone (NMP)) at 5% w/w were individually added to the formulation containing OLZ in PG. The in vitro permeation study was carried out using vertical Franz diffusion cells mounted with human cadaver skin. Samples from the receptor compartment of the cell were collected at 2 h, 4 h, 8 h, 12 h, and 24 h at room temperature. The amount (µg/cm2) of permeated drug (OLZ) was measured using a validated HPLC method, and the percentage (%) of OLZ permeated was calculated. Based on the data obtained, different CPEs were found to have a significant impact on OLZ permeability compared to the control formulation. The most effective chemical penetration enhancer was shown to be 5% w/w OA with a 3.3-fold increase in enhancement ratio (ER). The rank of order for the highest concentration of OLZ permeated from each of CPE containing formulation was as follows: OA > Cin > IPA > T80 > NMP. The most effective chemical penetration enhancer was OA but the cytotoxic study using human fibroblast cells suggests that OA may not be safe due to its cytotoxic effects.

Effect of Penetration Enhancer on the Structure of Stratum Corneum: On-Site Study by Confocal Polarized Raman Imaging.

Keratin and lipid structures in the stratum corneum (SC) are closely related to the SC barrier function. The application of penetration enhancers (PEs) disrupts the structure of SC, thereby promoting infiltration. To quantify these PE-induced structural changes in SC, we used confocal Raman imaging (CRI) and polarized Raman imaging (PRI) to explore the integrity and continuity of keratin and lipid structures in SC. The results showed that water is the safest PE and that oleic acid (OA), sodium dodecyl sulfate (SDS), and low molecular weight protamine (LMWP) disrupted the ordered structure of keratin, while azone and liposomes had less of an effect on keratin. Azone, OA, and SDS also led to significant changes in lipid structure, while LMWP and liposomes had less of an effect. Establishing this non-invasive and efficient strategy will provide new insights into transdermal drug delivery and skin health management.

Exploration and application of microbial method to enhance the effect of hydraulic fracturing on coal seam permeability enhancement and gas extraction

The efficient extraction of gas from low-permeability coal seams is an urgent problem in coal mine safety production. The traditional gas extraction technology generally suffers from problems that limited penetration enhancement or extraction effect, low construction efficiency, large workload, etc. Thus, it is especially urgent and important to explore the new technology applicable to efficient underground gas extraction. In this paper, based on the principle of hydraulic fracturing to increase permeability, we innovatively propose a technique to enhance the effect of hydraulic fracturing to increase permeability and further improve the efficiency of gas extraction using the gas desorption activity of native microorganisms in coal seams. Herein, the composition of the primary microbial community of a coal seam in Xinji No.2 mine was analyzed by bacterial and archaeal 16SrDNA amplicon sequencing, the community structure of the main functional microorganisms was clarified, the optimal combination of functional microorganisms for organic matter degradation in coal seam under anaerobic culture conditions was obtained. Besides the Biolog microplate technology was used to screen the nutrients of the excitation carbon source to stimulate the rapid decomposition of coal organic matter by microorganisms and to define the optimal ratio of the excitation carbon source to microorganisms. Finally, the effect of this technology on the application of coal seam fracturing and gas extraction was tested through field industrial tests, revealing that the extraction effect of this technology was more significant than that of the common coal seam perforation extraction technology. The results of this paper provide a new technical idea for gas extraction from low permeability coal seams, which is an important reference value for subsequent similar studies.

Effect of Penetration enhancers on Topical Antifungal gel

Effect of Penetration enhancers on Topical Antifungal gel

Preparation and characterization of lidocaine HCl-loaded proniosome gels with skin penetration enhancers

The present study investigated the effect of incorporating two types of skin penetration enhancers, Transcutol® and d-limonene, in a proniosome gel (PNG) containing 1% w/w lidocaine HCl as a model drug. Different PNG formulations were prepared by coacervation phase separation technique using Span 60®, soy lecithin, cholesterol as the main vesicle ingredients with varying concentrations of Transcutol® (5, 10, 20, 30%) and d-limonene (5, 10%). The PNGs obtained were light to dark brown semisolid with pseudoplastic flow behavior. The niosomes obtained from the hydration of PNGs showed almost spherical shapes under a scanning electron microscope. The vesicle size, size distribution, zeta potential, and entrapment efficiency (EE) varied depending on the types and concentrations of the enhancers. The in vitro skin permeation and disposition of all PNGs and control formulations were performed on porcine ear skin. The results showed that using 20% Transcutol® in PEG base provided the highest skin permeation flux of lidocaine HCl (81.42 ± 5.00 μg/cm2/h). However, T20 PNGs containing 20% Transcutol® provided the highest skin disposition (419.23 ± 87.52 mg/g skin) which was significantly higher than from 20% Transcutol® in PEG base. Therefore, T20 PNG could be a good carrier for enhancing the drug disposition in the skin. An inverse relationship was observed between the flux and EE of each PNG (R2 0.7749). The results indicate that the optimal concentration of Transcutol® and its effect on EE could contribute to the flux of lidocaine HCl across the skin. The skin permeation enhancing effect of hydrated T20 niosome was investigated. It could enhance lidocaine HCl permeation at a higher penetration-enhancement ratio (ER) than its precursor, PNG (ER 4.25 ± 0.54 vs 1.45 ± 0.13-fold compared with PEG base), indicating the effect of its niosome form which facilitated the skin permeation of lidocaine HCl. Furthermore, T20 PNG exhibited good stability after storage at room temperature for three months. The results suggested that the types and concentrations of the penetration enhancers in PNGs could affect their niosomal characteristics and skin penetration-enhancing effect. Thus, these should be carefully considered in formulation development.

DRUG IN ADHESIVE TRANSDERMAL SYSTEM OF FUROSEMIDE: IN VITRO IN VIVO EVALUATION

Objective: The objective of the present work aims to check the effect of penetration enhancers on release kinetics in a novel drug in the adhesive transdermal system of furosemide. Methods: The adhesive systems were evaluated for pharmacotechnical properties and in vitro permeation of the drug through the excised rat epidermis. Among the DURO-TAKs screened for in vitro permeation studies. The results were quantified using RP-HPLC. The optimized drug in the adhesive system was subjected to in vivo kinetic studies using New Zealand male rabbits. The adhesive systems were further evaluated for tack properties and skin irritation studies. Results: DURO-TAK 2510 demonstrated a best permeation profile than DURO-TAK 2852. A combination of penetration enhancers was proved to more be efficient than alone, in the case of F9 (IPM: PG 7.5:2.5) maximum permeation of the drug (314.45±5.97 µg/cm2) was observed by the end of the study with a flux of 9.2052±0.33 μg/cm2/h. The optimized drug in the adhesive system was subjected to in vivo kinetic studies using New Zealand male rabbits. The studies confirmed that controlled release of the drug for a prolonged duration with an extended AUC and MRT decreased Cmax in adhesive systems compared to the oral route, which can provide a promising pharmacological effect the in the DIA system compared to the oral route. Conclusion: The findings in the present study confirmed that drugs in adhesive systems can provide promising results and can enhance both bioavailability and patient compliance with a combination of penetration enhancers in the development of DIA systems.

Development and Evaluation of an FDM Printed Nasal Device for CPZ Solid Nanoparticles.

Nasal drug delivery has been a focus of scientific interest for decades. A number of drug delivery systems and devices are available and have been highly successful in providing better and more comfortable therapy. The benefits of nasal drug delivery are not in question. The nasal surface provides an excellent context for the targeted delivery of active substances. In addition to the large nasal surface area and intensive absorption, the active substances delivered through the nose overcome the blood-brain barrier and can be delivered directly to the central nervous system. Formulations for nasal administration are typically solutions or liquid dispersed systems such as emulsions or suspensions. Formulation techniques for nanostructures have recently undergone intensive development. Solid-phase heterogeneous dispersed systems represent a new direction in pharmaceutical formulations. The wide range of possible examples and the variety of excipients allow for the delivery of a wide range of active ingredients. The aim of our experimental work was to develop a solid drug delivery system that possesses all of the above-mentioned advantageous properties. In developing solid nanosystems, we not only exploited the advantages of size but also the adhesive and penetration-enhancing properties of excipients. During formulation, several amphiphilic compounds with adhesion properties and penetration enhancing effects were incorporated. We used chlorpromazine (CPZ), which is mainly used in the treatment of psychotic disorders such as schizophrenia and bipolar disorder. Chlorpromazine has been previously investigated by our team in other projects. With the availability of previous methods, the analytical characterization of the drug was carried out effectively. Due to the frequent and severe side effects of the drug, the need for therapeutic dose reduction is indisputable. In this series of experiments, we succeeded in constructing drug delivery systems. Finely divided Na nanoparticles were formed using a Büchi B90 nanospray dryer. An important step in the development of the drug carrier was the selection of suitable inert carrier compounds. Particle size determination and particle size distribution analysis were performed to characterize the prepared nanostructures. As safety is the most important aspect of any drug formulation, all components and systems were tested with different biocompatibility assays. The tests performed demonstrated the safe applicability of our systems. The bioavailability of chlorpromazine was studied as a function of the ratio of the active ingredient administered nasally and intravenously. As described above, most nasal formulations are liquids, but our system is solid, so there is currently no tool available to accurately target this system. As a supplement of the project, a nasal dosing device was developed, corresponding to the anatomical structure; a prototype of the device was made using 3D FDM technology. Our results lay the foundation for the design and industrial scaling of a new approach to the design and production of a high-bioavailability nasal medicinal product.

The Effect of Herbal Penetration Enhancers on the Skin Permeability of Mefenamic Acid Through Rat Skin.

Mefenamic acid (MA) is a strong non-steroidal anti-inflammatory drug, but because of its limited oral bioavailability and the side effects that come with taking it systemically, it is better to apply it topically. The major goal of this study was to see how certain permeation enhancers affected MA is in vitro skin permeability. In manufactured Franz diffusion cells, MA permeability tests using rat skin pretreatment with several permeation enhancers such as corn oil, olive oil, clove oil, eucalyptus oil, and menthol were conducted and compared to hydrate rat skin as a control. The steady-state flux (Jss), permeability coefficient (Kp), and diffusion coefficient are among the permeability metrics studied. The permeability enhancement mechanisms of the penetration enhancer were investigated using fourier transform infrared spectroscopy (FTIR) to compare changes in peak position and intensities of asymmetric and symmetric C-H stretching, C=O stretching, C=O stretching (amide I), and C-N stretching of keratin (amide II) absorbance, as well as differential scanning calorimetry (DSC) to compare mean transition temperature and their enthalpies. Clove oil, olive oil, and eucalyptus oil were the most effective enhancers, increasing flux by 7.91, 3.32, and 2.6 times, as well as diffusion coefficient by 3.25, 1.34, and 1.25, respectively, when compared to moist skin. FTIR and DSC data show that permeation enhancers caused lipid fluidization, extraction, disruption of lipid structures in the SC layer of skin, and long-term dehydration of proteins in this area of the skin. According to the findings, the permeation enhancers used improved drug permeability through excised rat skin. The most plausible mechanisms for greater ERflux, ERD, and ERP ratios were lipid fluidization, disruption of the lipid structure, and intracellular keratin irreversible denaturation in the SC by eucalyptus oil, menthol, corn oil, olive oil, and clove oil.

Seed Oils in Treatment of Skin Aging and Photoaging

Background: Seed oils have been exploited for an array of purposes with their addition to dietary, cosmetics, or therapeutic products. The process of skin aging is a natural and complex phenomenon in living beings. Skin aging is classified into two independent processes, i.e., chronological aging and premature aging. Aging is observed as a loss of strength and elasticity of the skin, leading to wrinkles on the skin. It is due to a decrease in various components of the skin matrix, like elastin, collagen, and hyaluronic acid. Furthermore, aging is potentiated by excessive exposure to UV radiation (Photoaging) and can be prevented or reduced by using products that combat photoaging. Objective: Anti-aging and antiwrinkle agents are in demand for maintaining skin tone. Seed oils composed of polyunsaturated fatty acids are traditionally used in cosmetic products as moisturizers and emollients, while palmitic acid and oleic acid are known for their penetration-enhancing effect. With the changing trend for extraction of oils like cold pressed methods, seed oils enriched with polyphenols, flavonoids, carotenoids, and phytosterols are good antioxidants and antimicrobials and therefore have an ever-growing demand for their usage in the treatment of skin diseases. In this review, an attempt will be made to brief the phytoconstituents present in various seed oils and their utilization against skin ailments. Furthermore, a mechanistic approach towards the benefit of oils in skin barrier repair, antiaging, and photo-aging with the help of extensive well-designed clinical trials carried out in the recent past is elaborated. Methods: A literature search in the Scopus database, Pubmed, and Medline was carried out using the terminology “aging, photoaging, antioxidant, UV-protection, sunscreens, skin barrier repair, and fatty acids, formulations” in the study. Data were retrieved over the last twenty years. Results: The review summarises the mechanistic approach and beneficial application of seed oils for healthy and glowing skin. The oils obtained from olives, sesame, borage, grape seeds, and carrot seeds have multitargeted effects. However, the variation in pharmacological effect may vary based on geographically differing varieties, skin type, and person-to-person variation. The need to standardize the varieties for their phytoactive ingredients and the composition of formulation used for skin care can help utilize the seeds as a potential source of actives against skin diseases. Conclusion: The potential of seed oils can be increased with appropriate analytical tools, validation protocols, and systematic experimental studies at preclinical and clinical trials for their application to skin care products.

Promotion of glyoxylic acid penetration into human hair by glycolic acid.

Glyoxylic acid (GA) is widely used as a straight perming agent for hair care products, however, advanced GA penetration-enhancing agents are desired due to the peculiar odour and hair colour fading caused by the continuous use of GA products. Hence, it is important to develop a penetration-enhancing agent that helps minimize the GA concentration. We have found that the combined use of GA and glycolic acid (GCA) has a strong hair straightening effect. Straightening hair test was carried out to the evaluation of the effect of additives. Liquid chromatography-mass spectrometry (LC/MS) was performed to quantify the GA penetration amount into human hair. Attenuated total reflection (ATR) Fourier transform-infrared spectroscopy (FT-IR) and FT-IR microscope were implemented to estimate the localization of GA in the hair. Straightening hair tests indicated that the hair straightening effect by GA was enhanced by the presence of GCA. LC/MS results showed that the addition of GCA enhanced the amount of GA that penetrated human hair by about four times. ATR FT-IR and FT-IR microscope measurements indicated that GA was localized more in the innermost region of hair (medulla) than the cortex and cuticle. The GA accumulated in the medulla disappeared after a hair straightener treatment at 180°C due to the chemical reaction. The GA penetration-enhancing effect of GCA is worth investigating to reduce the GA concentration in products for more comfortable use.

Effect of Penetration Enhancers on Transdermal Delivery of Oxcarbazepine, an Antiepileptic Drug Using Microemulsions.

Oxcarbazepine (OXC) is an anticonvulsant drug, indicated for the treatment of the neurological disorder, epilepsy. The objective of the present study was to evaluate the transdermal delivery of OXC from microemulsions using different penetration enhancers. Transcutol® P (TRC), oleic acid (OA), cineole (cin), Labrasol (LS), Tween 80 (T80) and N-Methyl-Pyrrolidone (NMP) were used as penetration enhancers as well as microemulsion components. Simple formulations of OXC in propylene glycol (PG) incorporating various penetration enhancers and combination of penetration enhancers were also evaluated for transdermal delivery. Drug delivery and penetration enhancement were studied using human cadaver skin on Franz diffusion cells. The results showed that all penetration enhancers improved the rate of permeation of OXC compared to the control. The flux of drug delivery from the various formulations was found to be, in decreasing order, cin > OA + TRC > NMP > TRC > OA. Overall, microemulsions prepared using cineole, Tween 80 and Transcutol® P (TRC) were shown to be provide the best penetration enhancement for OXC.

Skin permeability prediction with MD simulation sampling spatial and alchemical reaction coordinates

A molecular-level understanding of skin permeation may rationalize and streamline product development, and improve quality and control, of transdermal and topical drug delivery systems. It may also facilitate toxicity and safety assessment of cosmetics and skin care products. Here, we present new molecular dynamics simulation approaches that make it possible to efficiently sample the free energy and local diffusion coefficient across the skin’s barrier structure to predict skin permeability and the effects of chemical penetration enhancers. In particular, we introduce a new approach to use two-dimensional reaction coordinates in the accelerated weight histogram method, where we combine sampling along spatial coordinates with an alchemical perturbation virtual coordinate. We present predicted properties for 20 permeants, and demonstrate how our approach improves correlation with ex vivo/in vitro skin permeation data. For the compounds included in this study, the obtained log KPexp-calc mean square difference was 0.9 cm2 h−2.

Formulation of Polymers-Based Methotrexate Patches and Investigation of the Effect of Various Penetration Enhancers: In Vitro, Ex Vivo and In Vivo Characterization.

The present study aimed to prepare methotrexate-loaded transdermal patches with different blends of hydrophobic and hydrophilic polymers (Eudragit S-100 and hydroxypropyl methylcellulose) at different concentrations. The polymers employed in transdermal patches formulations served as controlled agent. Transdermal patches were prepared using the solvent casting technique. The suitable physicochemical properties were obtained from the formulation F5 (HPMC and Eudragit S-100 (5:1). Various penetration enhancers were employed in different concentrations to investigate their potential for enhancing the drug permeation profile from optimized formulations. A preformulation study was conducted to investigate drug–excipient compatibilities (ATR-FTIR) and the study showed greater compatibility between drug, polymers and excipients. The prepared patches containing different penetration enhancers at different concentrations were subjected for evaluating different physicochemical parameters and in vitro drug release studies. The obtained data were added to various kinetic models, then formulated patch formulations were investigated for ex vivo permeation studies, in vivo studies and skin drug retention studies. The prepared patches showed elastic, smooth and clear nature with good thickness, drug content, % moisture uptake and weight uniformity. The prepared transdermal patches showed % drug content ranging from 91.43 ± 2.90 to 98.37 ± 0.56, % swelling index from 36.98 ± 0.19 to 75.32 ± 1.21, folding endurance from 61 ± 3.14 to 78 ± 1.54 and tensile strength from 8.54 ± 0.18 to 12.87 ± 0.50. The formulation F5, containing a greater amount of hydrophilic polymers (HPMC), showed increased drug release and permeation and drug retention when compared to other formulated transdermal patch formulations (F1-F9). No significant change was observed during a stability study for a period of 60 days. The rabbit skin samples were subjected to ATR-FTIR studies, which revealed that polymers and penetration enhancers have affected skin proteins (ceramides and keratins). The pharmacokinetic profiling of optimized formulation (F5) as well as formulations with optimized concentrations of penetration enhancers revealed Cmax ranged 167.80 ng/mL to 178.07 ± 2.75 ng/mL, Tmax was 8 h to 10 h, and t1/2 was 15.9 ± 2.11 to 21.49 ± 1.16. From the in vivo studies, it was revealed that the formulation F5-OA-10% exhibited greater skin drug retention as compared to other formulations. These results depicted that prepared methotrexate transdermal patches containing different blends of hydrophobic and hydrophilic polymers along with different penetration enhancers could be safely used for the management of psoriasis. The formulated transdermal patches exhibited sustained release of drug with good permeations and retention profile. Hence, these formulated transdermal patches can effectively be used for the management of psoriasis.

Particle-Assisted Dermal Penetration-A Simple Formulation Strategy to Foster the Dermal Penetration Efficacy.

(1) Background: The study systematically investigated the influence of dispersed particles within a topical formulation on the dermal penetration efficacy of active compounds that are dissolved in the water phase of this formulation. The aim was to prove or disprove if particle-assisted dermal penetration can be used for improved dermal drug delivery. (2) Methods: Fluorescein was used as a surrogate for a hydrophilic active ingredient (AI). It was dissolved in the water phase of different formulations with and without particles. Two different types of particles (titanium dioxide and nanostructured lipid carriers (NLC)) were used. The influence of particle size and number of particles and the influence of skin hydrating excipients was also investigated. (3) Results demonstrate that the addition of particles can strongly increase the dermal penetration efficacy of AI. The effect depends on the size of the particles and the number of particles in the formulation, where smaller sizes and higher numbers resulted in higher penetration parameters. Formulations with NLC that contained 20% w/w or 40% w/w particles resulted in an about 2-fold higher amount of penetrated AI and increased the penetration depth about 2.5-fold. The penetration-enhancing effect was highly significant (p < 0.001) and allowed for an efficient delivery of the AI in the viable dermis. In contrast, the penetration-enhancing effect of excipients that increase the skin hydration was found to be very limited and not significant (≤5%, p > 0.05). (4) Conclusions: Based on the results, it can be concluded that particle-assisted dermal penetration can be considered to be a simple but highly efficient and industrially feasible formulation principle for improved and tailor-made dermal drug delivery of active compounds.

Effect of Penetration Enhancers and Safety on the Transdermal Delivery of Apremilast in Skin.

The poor water solubility of apremilast (APR) is the main impediment to the penetration of the drug through the skin barrier. The objective of this study was to evaluate the permeability of APR in different solutions enriched with penetration promoters in ex vivo samples of human skin, and additionally assess its tolerance in vivo. To this end, APR solutions with 5% promoter were developed, and the drug’s ability to penetrate human abdominal skin samples was evaluated; the coefficients of permeability, cumulated amounts permeated, and flow were some of the parameters evaluated; likewise, the in vitro and in vivo tolerance of the solutions was evaluated. The results obtained showed that the solutions containing squalene as a promoter improved the penetration of APR compared to the other promoters evaluated; in the same way, on an in vitro scale in HaCaT cells, the promoters were not toxic, finding a cell viability greater than 80% at the different dilutions evaluated. In the in vivo tests carried out with the solution that presented the best results (APR-Squalene solution), it was observed that it does not cause irritation or erythema on the skin after its colorimetric and histological evaluation of the dorsal region of rats after its application. Squalene becomes an excellent candidate to improve the permeability of the drug in the case of the development of a topical formulation; in addition, it was confirmed that this penetration enhancer is neither toxic nor irritating when in contact with the skin in in vivo tests.

Altered Skin Permeation of Finasteride Using Clove Oil, Urea, and Lyophilized Powder of Grape Seed Extract.

Purpose: Finasteride is a 5-alpha reductase inhibitor used to treat hair loss and acne. The skin permeation of finasteride is one of the main challenges associated with dermal drug delivery. One way to overcome the skin barrier is to use penetration enhancers. The purpose of this study was to investigate the effect of some penetration enhancers on finasteride permeability on the skin, as well as the effect of pretreatment time on their efficacy. Methods: In order to determine the effect of penetration enhancers on the skin permeability of finasteride, the skin was exposed to clove oil, urea, and lyophilized powder of grape seed extract (LPGSE) at different pretreatment times (2, 4 h), and then the permeability parameters were determined by passing the drug through the skin. Results: The results of this study showed that clove oil, urea, and LPGSE increased the transfer of finasteride from the skin. The highest rate of permeation was observed with clove oil (4 h), and the least permeability was observed with urea (4 h). Conclusion: Increasing the pretreatment time with clove oil and LPGSE increases the permeability of finasteride. Meanwhile, the increase in pretreatment time with urea reduces the penetration of finasteride from the skin due to reversible effects.

Influence of Massage and Skin Hydration on Dermal Penetration Efficacy of Nile Red from Petroleum Jelly-An Unexpected Outcome.

The study aimed at comparing the influence of direct and indirect skin hydration as well as massage on the dermal penetration efficacy of active compounds. Nile red was used as a lipophilic drug surrogate and was incorporated into Vaseline (petroleum jelly). The formulation was applied with and without massage onto either dry skin or pre-hydrated, moist skin. It was expected that the occlusive properties of Vaseline in combination with massage and enhanced skin hydration would cause a superposition of penetration-enhancing effects, which should lead to a tremendous increase in the dermal penetration efficacy of the lipophilic drug surrogate. Results obtained were diametral to the expectations, and various reasons were identified for causing the effect observed. Firstly, it was found that Vaseline undergoes syneresis after topical application. The expulsed mineral oil forms a film on top of the skin, and parts of it penetrate into the skin. The lipophilic drug surrogate, which is dissolved in the mineral oil, enters the skin with the mineral oil, i.e., via a solvent drag mechanism. Secondly, it was found that massage squeezes the skin and causes the expulsion of water from deeper layers of the SC. The expulsed water can act as a water barrier that prevents the penetration of lipophilic compounds and promotes the penetration of hydrophilic compounds. Based on the data, it is concluded that dermal penetration is a complex process that cannot only be explained by Fick’s law. It is composed of at least three different mechanisms. The first mechanism is the penetration of active ingredients with their solvents into the skin (convection, solvent drag), the second mechanism is the penetration of the active ingredient via passive diffusion, and the third mechanism can involve local penetration phenomena, e.g., the formation of liquid menisci and particle-associated penetration enhancement, which occur upon the evaporation of water and/or other ingredients from the formulation on top of the skin.

Coupling Effect of Temperature, Gas, and Viscoelastic Surfactant Fracturing Fluid on the Microstructure and its Fractal Characteristics of Deep Coal

The study of the microstructure evolution law of coal in a natural reservoir environment for the extraction of coalbed methane mining (ECBM), especially deep ECBM, is of major significance. We treated coal samples from Qinshui Basin under combined temperature–gas–fracturing fluid conditions and analyzed the evolution of the microstructure and its fractal characteristics to study the microstructural evolution of coal under natural hydraulic fracturing conditions. In the temperature range of 303.15 to 343.15 K and the gas-pressure range of 0.5–4.5 MPa, our data demonstrate that the pore structure is more susceptible to the temperature influence, compared with microfracture. The treatment of viscoelastic surfactant fracturing fluid (VES-FF) can effectively increase the permeation pore and fracture ratio by more than 300% and reduce the adsorption pore by more than 200% through dissolution, gas wedge, and other effects, which is favorable to ECBM. At the same temperature, as the gas pressure increases, the pore decreases, whereas the fracture ratio increases. The pore fractal dimension ranges from 2.90 to 2.99, which is significantly higher than that of microfractures. The temperature has a minor effect on the fracture fractal dimension, but it causes a decrease in the pore fractal dimension. The treatment of VES-FF induces an increase in the fracture fractal dimension, implying an increase in the fractal complexity. In contrast, the pore fractal characteristics show a contrary trend. At a gas pressure of 4.5 MPa, the negative effect of VES-FF on the pore structure reaches its maximum, whereas the effect on the fracture drops to its minimum. The results document that high temperature and high gas pressure can severely limit the penetration enhancement effect of VES-FF.

Effect of the combination of permeation enhancer and ion-pairs strategies on transdermal delivery of tofacitinib

The aim of the present study was to develop a tofacitinib (TOF) transdermal patch by the combination of ion-pairs and chemical permeation enhancer strategies. And a theory of controlled release of chemical permeation enhancers by counterion was proposed on the basis of in vitro skin permeation and skin retention study. Through the in vitro skin permeation study, the formulation factors such as counterion, pressure sensitive adhesive (PSA), drug loading and patch thickness were investigated, and the optimized patch (6.5% LA-TOF, 15% POCC and thickness = 50 μm) was evaluated by the pharmacokinetic study. The AUC0-t of the optimized patch was 529.89 ± 45 h ng/mL. Special attention has been paid to the molecular mechanism of the effects of counterion concentration on the release and permeation enhancement effect of penetration enhancer. FTIR study, 13C NMR, XPS and molecular modeling were conducted to investigate the molecular interaction between POCC and LA. Raman Imaging and ATR-FTIR were used to explore the POCC content in the skin and the interference degree to lipid. The results revealed that a strong hydrogen bond appeared between LA and the hydroxyl group of POCC, which inhibited the release of POCC, thus reducing the lipid disturbance and permeation enhancement effect of POCC. In conclusion, this TOF patch was successfully developed. The effect of counterion on permeation enhancers was clarified at molecular level, and these results provided references for the development of TOF patch.

Impact of Alkanediols on Stratum Corneum Lipids and Triamcinolone Acetonide Skin Penetration.

Alkanediols are widely used as multifunctional ingredients in dermal formulations. In addition to their preservative effect, considering their possible impact on drug penetration is also essential for their use. In the present study, the influence of 2-methyl-2,4-pentanediol, 1,2-pentanediol, 1,2-hexanediol and 1,2-octanediol on the skin penetration of triamcinolone acetonide from four different semisolid formulations was investigated. Furthermore, confocal Raman spectroscopy measurements were performed to examine the influence of the alkanediols on stratum corneum lipid content and order. Alkanediols were found to increase the penetration of triamcinolone acetonide. However, the extent depends strongly on the formulation used. In certain formulations, 1,2-pentanediol showed the highest effect, while in others the penetration-enhancing effect increased with the alkyl chain length of the alkanediol used. None of the tested alkanediols extracted lipids from the stratum corneum nor reduced its thickness. Notwithstanding the above, the longer-chained alkanediols cause the lipids to be converted to a more disordered state, which favors drug penetration. This behavior could not be detected for the shorter-chained alkanediols. Therefore, their penetration-enhancing effect is supposed to be related to an interaction with the hydrophilic regions of the stratum corneum.