Chemical 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.

The Study of Various Approaches for the Transdermal Patches Possess Therapeutic Potential

A non-invasive method of administering drugs through the skin's surface, transdermal delivery allows for the drug to be delivered across the dermis at a predefined rate, either locally or systemically. It might be used in place of hypodermic injections and the oral medication delivery system. Despite being more expensive than traditional formulations, transdermal dosage forms are gaining traction due to their distinct benefits. Transdermal systems have been used to formulate many medications, and more are being tested to see if this is a feasible way to administer them such as beta-blockers, calcium channel blockers, non-steroidal anti-inflammatory drugs, contraceptives, anti-arrhythmic drugs, insulin, antivirals, hormones, alpha-interferon, and cancer chemotherapeutic agents. Additionally, studies on several chemical penetration enhancers that can facilitate the delivery of medicinal compounds are still ongoing. This review article discusses personalized patch designs, transdermal patches' range of therapeutic uses in addition in-vitro and in-vivo studies.

Mechanisms of the Drug Penetration Enhancer Propylene Glycol Interacting with Skin Lipid Membranes.

Very few drugs have the necessary physicochemical properties to cross the skin's main permeability barrier, the stratum corneum (SC), in sufficient amounts. Propylene glycol (PG) is a chemical penetration enhancer that could be included in topical formulations in order to overcome the barrier properties of the skin and facilitate the transport of drugs across it. Experiments have demonstrated that PG increases the mobility and disorder of SC lipids and may extract cholesterol from the SC, but little is known about the molecular mechanisms of drug permeation enhancement by PG. In this work, we have performed molecular dynamics (MD) simulations to investigate the molecular-level effects of PG on the structure and properties of model SC lipid bilayers. The model bilayers were simulated in the presence of PG concentrations over the range of 0-100% w/w PG, using both an all-atom and a united atom force field. PG was found to localize in the hydrophilic headgroup regions at the bilayer interface, to occupy the lipid-water hydrogen-bonding sites, and to slightly increase lipid tail disorder in a concentration-dependent manner. We showed with MD simulation that PG enhances the permeation of small molecules such as water by interacting with the bilayer interface; the results of our study may be used to guide the design of formulations for transdermal drug delivery with enhanced skin permeation, as well as topical formulations and cosmetic products.

Multifunctional Ionic Hydrogel-Based Transdermal Delivery of 5-Fluorouracil for the Breast Cancer Treatment.

Transdermal drug delivery systems (TDDS) are a promising and innovative approach for breast cancer treatment, offering advantages such as noninvasiveness, potential for localized and prolonged drug delivery while minimizing systemic side effects through avoiding first-pass metabolism. Utilizing the distinctive characteristics of hydrogels, such as their biocompatibility, versatility, and higher drug loading capabilities, in the present work, we prepared ionic hydrogels through synergistic interaction between ionic liquids (ILs), choline alanine ([Cho][Ala]), and choline proline ([Cho][Pro]) with oleic acid (OA). ILs used in the study are biocompatible and enhance the solubility of 5-fluorouracil (5-FU), whereas OA is a known chemical penetration enhancer. The concentration-dependent (OA) change in morphological aggregates, that is, from cylindrical micelles to worm-like micelles to hydrogels was formed with both ILs and was characterized by SANS measurement, whereas the interactions involved were confirmed by FTIR spectroscopy. The hydrogels have excellent mechanical properties, which studied by rheology and their morphology through FE-SEM analysis. The in vitro skin permeation study revealed that both hydrogels penetrated 255 times ([Cho][Ala]) and 250 times ([Cho][Pro]) more as compared to PBS after 48 h. Those ionic hydrogels exhibited the capability to change the lipid and keratin arrangements within the skin layer, thereby enhancing the transdermal permeation of the 5-FU. Both ionic hydrogels exhibit excellent biocompatibility with normal cell lines (L-132 cells) as well as cancerous cell lines (MCF-7 cells), demonstrating over 92% cell viability after 48 h in both cell lines. In vitro, the cytotoxicity of the 5-FU-loaded hydrogels was evaluated on MCF-7 and HeLa cell lines. These results indicate that the investigated biocompatible and nontoxic ionic hydrogels enable the transdermal delivery of hydrophilic drugs, making them a viable option for effectively treating breast cancer.

A recent review on transungual drug delivery system

The transungual drug delivery system refers to the administration of drugs through the nail plate to treat various nail disorders such as fungal infections, psoriasis, and nail dystrophies. The nail plate is a challenging barrier for drug penetration due to its highly keratinized and tightly packed structure, which limits the permeation of topically applied drugs. Owing to several problems associated with oral therapy, topical therapy remains a preferred treatment option for nail infections due to less side effects, and cost-effectiveness. On the other hand, the drugs that have low permeability across the nail plate highlight the need for further research in this area. Researchers working on various aspects to increase drug penetration across the nail plate, which include the use of chemical penetration enhancers, mechanical methods, and physical methods. Recent advances in transungual drug delivery systems have led to the development of antifungal nail lacquers that can penetrate the nail plate and effectively treat nail infections. Other transungual drug delivery systems under investigation include microneedles, ultrasound, and laser-assisted treatment, which can create micropores in the nail plate allowing higher drug delivery. This indicates the potential of research on transungual drug delivery systems. By understanding the anatomy of the nail, utilizing appropriate penetration-enhancing methods, and selecting appropriate drug formulations, the effectiveness of the system can be developed and utilized.

Comparative evaluation of physical and chemical enhancement techniques for transdermal delivery of linagliptin

Linagliptin is a dipeptidyl peptidase-4 inhibitor used for the management of type-2 diabetes. US FDA-approved products are available exclusively as oral tablets. The inherent drawbacks of the oral administration route necessitate exploring delivery strategies via other routes. In this study, we investigated the feasibility of transdermal administration of linagliptin through various approaches. We compared chemical penetration enhancers (oleic acid, oleyl alcohol, and isopropyl myristate) and physical enhancement techniques (iontophoresis, sonophoresis, microneedles, laser, and microdermabrasion) to understand their potential to improve transdermal delivery of linagliptin. To our knowledge, this is the first reported comparison of chemical and physical enhancement techniques for the transdermal delivery of a moderately lipophilic molecule. All physical enhancement techniques caused a significant reduction in the transepithelial electrical resistance of the skin samples. Disruption of the skin’s structure post-treatment with physical enhancement techniques was further confirmed using characterization techniques such as dye binding, histology, and confocal microscopy. In vitro permeation testing (IVPT) demonstrated that the passive delivery of linagliptin across the skin was < 5 µg/sq.cm. Two penetration enhancers - oleic acid (93.39 ± 8.34 µg/sq.cm.) and oleyl alcohol (424.73 ± 42.86 µg/sq.cm.), and three physical techniques - iontophoresis (53.05 ± 0.79 µg/sq.cm.), sonophoresis (141.13 ± 34.22 µg/sq.cm.), and laser (555.11 ± 78.97 µg/sq.cm.) exceeded the desired target delivery for therapeutic effect. This study established that linagliptin is an excellent candidate for transdermal delivery and thoroughly compared chemical penetration and physical transdermal delivery strategies.

Advancements of Polymer-Based Transdermal Drug Delivery Systems in Drug Bioavailability and Patient Compliance in United States

Transdermal drug delivery system (TDDS) helps in overcoming drug molecule barriers such as particle size, lipophilicity, permeability, and transports the medication directly to the blood circulation by employing physical and chemical penetration enhancers using polymers. The use of skin as a drug delivery route is challenging due to the stratum corneum's barrier properties that restrict the therapeutic bioavailability of the medications. Both, natural and synthetic polymers are used in TDDS to transport the medication into circulation via diffusion, and swelling control. TDDS is generally achieved by using transdermal patches containing one or more pharmaceutical active entities that are placed on unbroken skin for delivering active entities directly to the bloodstream by crossing the skin barrier. TDDS is the trendiest -delivery system as it is painless, non-invasive, self-administrative, avoids hepatic first-pass metabolism, and delivers poorly soluble drugs and increases the bioavailability. An overview of TDDS is provided in this review article, including its advantages over traditional dosage forms, limitations, different components of transdermal patches, modern techniques as well as transdermal products available in US market.

Advances in the transdermal delivery of antiretroviral drugs.

Antiretroviral therapy regimens are successful in stopping the advancement of human immunodeficiency virus infection to acquired immunodeficiency syndrome, and other opportunistic infections. However, they do have significant disadvantages, including long-term treatment, limited oral bioavailability, inaccessibility to organs, non-adherence by patients, and the development of medication resistance. Because of the listed drawbacks of available routes and the availability of curative medicines for human immunodeficiency virus/acquired immunodeficiency syndrome, advanced solutions are required. Antiretroviral therapy transdermal delivery is one of the current strategies that have attracted much attention from many researchers. In this narrative review, various in vitro, in vivo, and ex vivo transdermal antiretroviral therapy delivery strategies were reviewed, such as transdermal patches and films, lipid-based nano-delivery systems, microneedles, chemical penetration enhancers, and iontophoresis, which showed promising results. Although the majority of studies on Antiretroviral transdermal delivery have produced hopeful findings, additional in-depth research on passive and physical enhancement techniques, both existing and new, is necessary to fully understand the potential of this route and to make it accessible to human immunodeficiency virus patients.

Recent advances in delivery of transdermal nutrients: A review.

Nutrients provide vital functions in the body for sustained health, which have been shown to be related to the incidence, prevention and treatment of disease. However, limited bioavailability, loss of targeting specificity and the increased hepatic metabolism limit the utilization of nutrients. In this review, we highlight transdermal absorption of nutrients, which represents an opportunity to allow great use of many nutrients with promising human health benefits. Moreover, we describe how the various types of permeation enhancers are increasingly exploited for transdermal nutrient delivery. Chemical penetration enhancers, carrier systems and physical techniques for transdermal nutrient delivery are described, with a focus on combinatorial approaches. Although there are many carrier systems and physical techniques currently in development, with some tools currently in advanced clinical trials, relatively few products have achieved full translation to clinical practice. Challenges and further developments of these tools are discussed here in this review. This review will be useful to researchers interested in transdermal applications of permeation enhancers for the efficient delivery of nutrients, providing a reference for supporting the need to take more account of specific nutritional needs in specific states.

Overcoming the barrier of skin to drug permeation for localized dermatological therapies

Background. The skin’s uppermost layer, the stratum corneum is a very effective barrier against the penetration of compounds including pharmaceuticals and cosmetic actives. To deliver higher amounts of drugs into the skin layers or to deliver drugs deeper into the skin (e.g., into the dermis), several enhancement techniques have been established. These techniques include chemical penetration enhancers as well as physical techniques such as iontophoresis and microneedles. In addition, one of the newer approaches includes the use of nano-based carriers such as metallic nanoparticles and polymeric self-assembling nanospheres. Methods. This mini-review explores this new approach of using nano-based drug carriers for skin penetration enhancement. In particular we will explore the use of gold nanoparticles as well as biocompatible tyrosine-derived polymeric nanoparticles known as Tyrospheres. Results. The most investigated carriers in the class of metallic carriers are gold nanoparticles that can be used for both medical as well as diagnostic uses. Many investigators have reported that gold nanoparticles are able to enhance the skin transport and delivery of macromolecular and hydrophilic drugs. Meanwhile, for challenging highly lipophilic and/or unstable compounds such as adapalene and Vitamin D3 packaging them into polymeric nanocarriers such as Tyrospheres enables drug delivery to hair follicles, significantly increased aqueous solubility and resulted in elevated amounts of drug in targeted skin layers. Conclusions. The relatively new approach of using nanotechnological approaches as a way of enhancement of drug delivery to skin shows significant promise over some other established techniques such as the addition of chemical penetration enhancers to formulations used for topical/transdermal uses.

Development of Procaine Loaded Transdermal Patches Based on Biopolymer Pectin, Castor Oil, and Polyethylene Glycol for Controllable Drug Release Studies and Their Characterizations

AbstractTransdermal drug delivery systems have considerable attention in clinical and point‐of‐care applications due to their superior advantages such as non‐invasive properties and keeping drug efficiency. To overcome the skin barrier, penetration enhancers are employed in the patch design. Chemical penetration enhancers are the most frequently applied way to improve drug diffusion through the barrier. Transdermal patches are designed as a drug‐loaded thin‐film hydrogel. Since the patch material must be biocompatible and eco‐friendly, in this study, pectin‐based transdermal patches are designed, and procaine, a painkiller drug is chosen as a model drug. Benzyl alcohol, polyethylene glycol, and castor oil are selected as chemical penetration enhancers. Drug diffusion experiments are carried out by using Franz diffusion cells at 37 °C. Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) are used to characterize the chemical structure and thermal properties of the patches. The patches are evaluated by the contact angle measurement and the swelling test in terms of their hydrophilicity and water uptake. Regarding in vitro drug release experiments by Franz diffusion cells, drug‐loaded patches were examined (CxPy‐PC; C‐castor oil, P‐PEG, x‐y amounts (mg)). It is found that the most promising results come from C10‐P5‐PC (12.7 mg drug/g film) and C30‐P5‐PC (11.4 mg drug/ g film) which can be attributed to the synergetic and optimum amount of polyethylene glycol and castor oil.

A Study of Microemulsion Systems for Transdermal Delivery of Risperidone Using Penetration Enhancers

The aim of this study was to develop and characterize microemulsion formulations using penetration enhancers as potential transdermal delivery systems for risperidone. Initially, a simple formulation of risperidone in Propylene Glycol (PG) was prepared as a control formulation, together with formulations incorporating various penetration enhancers, alone and/or in combination, and also microemulsion formulations with various chemical penetration enhancers, were prepared and all were evaluated for risperidone transdermal delivery. An ex-vivo permeation study was carried out using human cadaver skin and vertical glass Franz diffusion cells to compare all the microemulsion formulations. The microemulsion prepared from oleic acid as the oil (15%), Tween 80 (15%) as the surfactant and isopropyl alcohol (20%) as the co-surfactant, and water (50%) showed higher permeation with a flux value of 32.50±3.60 ug/hr/sq.cm, a globule size of 2.96±0.01 nm, a polydispersity index of 0.33±0.02 and pH of 4.95. This novel in vitro research disclosed that an optimized microemulsion formulated using penetration enhancers was able to increase permeation of risperidone by 14-fold compared to the control formulation. The data suggested that microemulsions may be useful in the delivery of risperidone via the transdermal route.

Emulsion-Based Gel Loaded with Ibuprofen and Its Derivatives

The aim of this study was to evaluate the effect of vehicle and chemical modifications of the structure of active compounds on the skin permeation and accumulation of ibuprofen (IBU). As a result, semi-solid formulations in the form of an emulsion-based gel loaded with ibuprofen and its derivatives, such as sodium ibuprofenate (IBUNa) and L-phenylalanine ethyl ester ibuprofenate ([PheOEt][IBU]), were developed. The properties of the obtained formulations were examined, including density, refractive index, viscosity, and particle size distribution. The parameters of release and permeability through the pig skin of the active substances contained in the obtained semi-solid formulations were determined. The results indicate that an emulsion-based gel enhanced the skin penetration of IBU and its derivatives compared to two commercial preparations in the form of a gel and a cream. The average cumulative mass of IBU after a 24 h permeation test from an emulsion-based gel formulation through human skin was 1.6-4.0 times higher than for the commercial products. Ibuprofen derivatives were evaluated as chemical penetration enhancers. After 24 h of penetration, the cumulative mass was 1086.6 ± 245.8 for IBUNa and 948.6 ± 87.5 µg IBU/cm2 for [PheOEt][IBU], respectively. This study demonstrates the perspective of the transdermal emulsion-based gel vehicle in conjunction with the modification of the drug as a potentially faster drug delivery system.

Skin penetration of caffeine from commercial eye creams and eye creams designed and optimized based on Hansen solubility parameters

Computer-aided formulation design can streamline and speed up product development. In this study, ingredient screening and optimizing software, Formulating for Efficacy® (FFE), was used to design and optimize creams for the topical delivery of caffeine. FFE was set up to optimize lipophilic active ingredients, therefore, this study challenged the program’s capabilities. The effect of two chemical penetration enhancers, including dimethyl isosorbide (DMI) and ethoxydiglycol (EDG), were studied based on their favorable Hansen Solubility Parameter physicochemical input parameters for the skin delivery of caffeine in the FFE® software application. Four oil-in-water emulsions containing 2% caffeine were formulated, one without a chemical penetration enhancer, one with five percent of DMI, one with five percent of EDG, and one with 2.5% of DMI and EDG each (DMI + EDG). Additionally, three commercial products were used as reference products. The cumulative amount of caffeine released and permeated, and the flux across Strat-M® membranes were determined using Franz diffusion cells. The eye creams had skin-compatible pH, excellent spreadability for the application area, were opaque emulsions with 14–17 μm droplet size, and were stable at 25 °C for 6 months. All four eye creams formulated released over 85% of caffeine in 24 h, outperforming the commercial products. DMI + EDG cream provided the highest permeation in vitro in 24 h, which was significantly higher than the commercial products (p < 0.05). FFE proved to be a valuable and quick tool to aid in the topical delivery of caffeine.

Transdermal Delivery of Insulin Using Combination of Iontophoresis and Deep Eutectic Solvents as Chemical Penetration Enhancers: In Vitro and in Vivo Evaluations

A serious challenge in transdermal iontophoresis (IP) delivery of insulin (INS) is the low permeability of the drug across the skin. In this paper, we introduced deep eutectic solvent (DESs) as novel chemical penetration enhancers (CPEs) for transdermal IP of INS across rat skin, both in vitro and in vivo. Three different DESs based on choline chloride (ChCl), namely, ChCl/UR (ChCl and urea), ChCl/GLY (ChCl and glycerol), and ChCl/EG (ChCl and ethylene glycol) in the 1:2 molar ratios have been prepared. To evaluate the capability of studied DESs as CPEs for IP delivery of INS, the rat skin sample was treated with each DES. The effects of different experimental parameters (current density, formulation pH, INS concentration, NaCl concentration, and treatment time) on the in vitro transdermal iontophoretic delivery of INS were investigated. The in vitro permeation studies exhibited that INS was easily delivered employing ChCl/EG, and ChCl/GLY treatments, compared with ChCl/UR: the cumulative amount of permeated INS at the end of the experiment (Q24h) was found to be 131.0, 89.4, and 29.6 µg cm−2 in the presence of ChCl/EG, ChCl/GLY, and ChCl/UR, respectively. The differences in Q24h values of INS are due to the different capabilities of the studied DESs to treat the epidermis layer of skin. In vivo experiments revealed that the blood glucose level in diabetic rats could be decreased using ChCl/EG, and ChCl/GLY as novel CPEs in the IP delivery of INS. The presented work will open new doors towards searching for novel CPEs in the development of transdermal IP of INS.

Current Development of Chemical Penetration Enhancers for Transdermal Insulin Delivery.

The use of the transdermal delivery system has recently gained ample recognition due to the ability to deliver drug molecules across the skin membrane, serving as an alternative to conventional oral or injectable routes. Subcutaneous insulin injection is the mainstay treatment for diabetes mellitus which often leads to non-compliance among patients, especially in younger patients. Apart from its invasiveness, the long-term consequences of insulin injection cause the development of physical trauma, which includes lipohypertrophy at the site of administration, scarring, infection, and sometimes nerve damage. Hence, there is a quest for a better alternative to drug delivery that is non-invasive and easily adaptable. One of the potential solutions is the transdermal delivery method. However, the stratum corneum (the top layer of skin) is the greatest barrier in transporting large molecules like insulin. Therefore, various chemical enhancers have been proposed to promote stratum corneum permeability, or they are designed to increase the permeability of the full epidermis, such as the use of ionic liquid, peptides, chemical pre-treatment as well as packaging insulin with carriers or nanoparticles. In this review, the recent progress in the development of chemical enhancers for transdermal insulin delivery is discussed along with the possible mechanistic of action and the potential outlook on the proposed permeation approaches in comparison to other therapeutical drugs.

A theoretical investigation on the synergetic effect of hydrogen-bonding interactions and thermodynamic property in the 1: 2 (azacyclopentane-2-one: N-methylolacetamide) ternary complex.

Using chemical penetration enhancers to improve the penetration effect is one kind of important strategies in transdermal drug delivery system. Azone is a widely used transdermal absorption enhancer for transdermal drug delivery. To shed light on the permeation-promoting mechanism of azone, we selected ternary systems formed by azacyclopentane-2-one and N-methylolacetamide (1: 2) and explored the synergetic effect of hydrogen-bonding interactions among them and their thermodynamic properties. The findings indicate that the synergetic effects can enhance the ability of azone to change the original conformation of ceramides and even break the original hydrogen bonds, which is more beneficial for azone to destroy the 3D network structure of ceramides. When azone interacts with ceramide, the order of action tends to interact with one molecule of ceramide first and then with another molecule of ceramide. The synergetic effects of hydrogen-bonding interactions in ternary systems were computed at the B3LYP/6-311 + + G** and MP2(full)/6-311 + + G** levels. Thermodynamic parameters for two ternary-complex routes were worked out at the B3LYP/aug-cc-pVDZ level. The shift of the electron density occurring simultaneously with trimer formation was analyzed at the MP2(full)/6-311 + + G** level. The above calculations were carried out using the Gaussian 03 program packages. Atoms in molecules (AIM) method and the AIMPAC program showed the topological charge density at the MP2(full)/6-311 + + G** level. The synergetic effects of hydrogen-bonding interactions and thermodynamic property in the 1: 2 (azacyclopentane-2-one: N-methylolacetamide) ternary systems were investigated using the B3LYP and MP2(full) methods.

Oromucosal delivery of macromolecules: Challenges and recent developments to improve bioavailability.

Owing to their biological diversity, high potency, good tolerability, low immunogenicity, site-specific activity, and great efficacy, macromolecular drugs (i.e., proteins and peptides, antibodies, hormones, nucleic acids, vaccines, etc.) are extensively used as diagnostics, prophylactics, and therapeutics in various diseases. To overcome drawbacks associated with parenteral (invasive) delivery of macromolecules as well as to preserve their therapeutic integrity, oromucosal route (sublingual and buccal) has been proven efficient alternate port of delivery. This review aims to summarize challenges associated with oromucosal route and overtime developments in conventional delivery systems with special emphasis on most recent delivery strategies. Over the past few decades, significant efforts have been made for improving the oromucosal absorption of macromolecules by employing chemical penetration enhancers (CPE), enzyme inhibitors, chemical modification of drug structure (i.e., lipidation, PEGylation, etc.), and mucoadhesive materials in the form of buccal tablets, films (or patches), sprays, fast disintegrating tablets, and microneedles. Adaptation of adjunct strategies (e.g., iontophoresis in conjunction with CPE) has shown significant improvement in oromucosal absorption of macromolecules; however, these approaches were also associated with many drawbacks. To overcome these shortcomings and to further improve therapeutic outcomes, specialized delivery devices called "hybrid nanosystems" have been designed in recent times. This newer intervention showed promising potential for promoting oromucosal absorption and absolute bioavailability of macromolecules along with improved thermostability (cold chain free storage), enabling self-administration, site-specific activity, improving therapeutic efficacy and patient compliance. We anticipate that tailoring of hybrid nanosystems to clinical trials as well as establishing their short- and long-term safety profile would substantiate their therapeutic value as pharmaceutical devices for oromucosal delivery of macromolecules.

Emulsion-induced polymersomes taming tetrodotoxin for prolonged duration local anesthesia.

Injectable local anesthetics that can provide a continuous nerve block approximating the duration of a pain state would be a life-changing solution for patients experiencing post-operative pain or chronic pain. Tetrodotoxin (TTX) is a site 1 sodium channel blocker that is extremely potent compared to clinically used local anesthetics. Challengingly, TTX doses are limited by its associated systemic toxicity, thus shortening the achievable duration of nerve blocks. Here, we explore emulsion-induced polymersomes (EIP) as a drug delivery system to safely use TTX for local anesthesia. By emulsifying hyperbranched polyglycerol-poly (propylene glycol)-hyperbranched polyglycerol (HPG-PPG-HPG) in TTX aqueous solution, HPG-PPG-HPG self-assembled into micrometer-sized polymersomes within seconds. The formed polymersomes have microscopically visible internal aqueous pockets that encapsulate TTX with an encapsulation efficiency of up to 94%. Moreover, the polymersomes are structurally stable, enabling sustained TTX release. In vivo, the freshly prepared EIP/TTX formulation can be directly injected and increased the tolerated dose of TTX in Sprague-Dawley rats to 11.5 μg without causing any TTX-related systemic toxicity. In the presence of the chemical penetration enhancer (CPE) sodium octyl sulfate (SOS), a single perineural injection of EIP/TTX/SOS formulation produced a reliable sciatic nerve block for 22 days with minimal local toxicity.

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.