Effect Of Chemical Enhancers Research Articles

Development Strategy of Dermal and Transdermal Formulation: Synergistic Effect of Chemical Penetration Enhancers

Development Strategy of Dermal and Transdermal Formulation: Synergistic Effect of Chemical Penetration Enhancers

Contribution of chemical permeation enhancers to the process of transdermal drug delivery: Adsorption, microscopic interactions, and mechanism

Transdermal drug delivery (TDD) has attracted widespread attention because of the advantage of its non-invasive nature, easy self-administration, and low side effects. The key to this pathway of drug delivery is how to overcome the barrier of the lipid matrix in the stratum corneum (SC). In this work, molecular dynamics (MD) were employed to investigate the adsorption of thyrotropin-releasing hormone (TRH) on the SC, and the effects of three different chemical permeation enhancers (ethanol (ETOH), carveol (CAV), and borneol (BOR)) on the SC were analyzed. The results showed that ETOH hardly altered the order of lipids in the SC, while CAV and BOR disrupted the morphology of the SC. The primary target of CAV was the CHOL in SC, which not only disrupted the ordered arrangement of CHOL, but also “extracted” CHOL from SC. The thickness distribution of SC became more inhomogeneous in the presence of CAV and BOR, which facilitated the penetration of drug molecules. Compared to no chemical permeation enhancers, the free energy of permeation in the presence of chemical permeation enhancers was less than 4–10 kcal mol−1, which suggested that chemical permeation enhancers were more favorable for the permeation of drugs from viewpoints of thermodynamics. All the results provided theoretical insights into the effect of chemical permeation enhancers on the transdermal permeation of drugs.

Effect of Various Herbal and Chemical Enhancers on Skin Permeability to Cetirizine: A Study of Changes in Rat Skin Cells

Background: Cetirizine is a second-generation antihistamine with anti-allergy and anti-itching properties. The topical formulation of this medicine is used in androgenic alopecia treatment. Due to the hydrophilic nature of cetirizine, its skin absorption is negligible, so to increase its absorption, various enhancers were examined to see which can be used in the design of a topical formulation. Methods: First, the skin was exposed to enhancers, including eucalyptus, menthol, Tween 80, propylene glycol, and oleic acid, for 1 or 2 hours. Then, the permeability parameters of the cetirizine solution and the structural changes of the skin after exposure to enhancers were analyzed by differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR) techniques. Results: The obtained results show that all used enhancers increased the permeability of the drug cetirizine compared to water. Various mechanisms, such as liquefaction of lipids, destruction of lipid structure, and irreversible denaturation of intracellular keratin, are involved in the increase in drug penetration caused by eucalyptus, mint, Tween 80, propylene glycol, and oleic acid. Conclusions: The results showed that among the studied absorption enhancers, eucalyptus and Tween 80 had the strongest, and propylene glycol had the weakest absorption enhancement effect after 2- and 1-hour pre-contact, respectively.

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.

Buccal Permeation of Polysaccharide High Molecular Weight Compounds: Effect of Chemical Permeation Enhancers.

The greatest achievement in the advanced drug delivery field should be the optimization of non-invasive formulations for the delivery of high molecular weight compounds. Peptides, proteins, and other macromolecules can have poor membrane permeation, principally due to their large molecular weight. The aim of this work was to explore the possibility of administering fluorescently labeled dextrans (molecular weight 4-150 kDa) across the buccal mucosa. Permeation experiments across pig esophageal mucosa were carried out using fatty acids and bile salts as penetration enhancers. The data obtained show that it is possible to increase or promote the mucosa permeation of high molecular weight dextrans by using caprylic acid or sodium taurocholate as the chemical enhancers. With these enhancers, dextrans with molecular weight of 70 and 150 kDa, that in passive conditions did not permeate, could cross the mucosa in detectable amounts. FD-70 and FD-150 showed comparable permeability values, despite the molecular weight difference. The results obtained in the present work suggest that the buccal administration of high molecular weight compounds is feasible.

Probing Pharmaceutical Strategies to Promote the Skin Delivery of Asiatic Acid from Hydrogels: Enhancement Effects of Organic Amine Counterions, Chemical Enhancers, and Microneedle Pretreatment.

Asiatic acid (AA) is a pentacyclic triterpene isolated from Centella asiatica, holding great promise for treating a variety of skin disorders. However, the dermal application of AA is limited by its poor solubility and permeability. This study aimed to identify a hydrogel formulation for AA and improve its skin penetration by various penetration enhancement methods. Four kinds of hydrogel bases were selected to prepare the AA hydrogel, in which different organic amines and chemical enhancers were incorporated in combination with microneedle pretreatment. The results showed that AA had good release profiles in the presence of hyaluronic acid as the hydrogel base and organic amines as the counter-ions. Diethylamine and Span 80 could promote drug penetration into the skin, and pretreatment with microneedles could further increase the drug permeability. In conclusion, the optimized hyaluronic acid hydrogel has great potential for use in the topical delivery of AA, and its penetration via the skin can be further improved by different pharmaceutical approaches.

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.

In vitro percutaneous absorption studies of cannabidiol using human skin: Exploring the effect of drug concentration, chemical enhancers, and essential oils

Cannabidiol, a non-psychoactive constituent of cannabis, has garnered much attention after United States Food and Drug Administration approved Epidiolex® for oral use. Although therapeutic effect of cannabidiol after systemic absorption has been investigated extensively, its therapeutic potential in treating skin disorders after local delivery still needs further exploration. Our study has investigated the effect of cannabidiol concentration, chemical enhancers, and essential oils on percutaneous absorption of cannabidiol. In vitro permeation tests were conducted on human skin. The 24 h study results suggest no significant difference in amount of drug absorbed into skin, between 5% (242.41 ± 12.17 µg/cm2) and 10% (232.79 ± 20.82 cm2) cannabidiol solutions. However, 1% delivered (23.02 ± 4.74 µg/cm2) significantly lower amount of drug into skin than 5% and 10%. Transcutol and isopropyl myristate did not enhance delivery of cannabidiol. However, oleic acid was found to be useful as chemical enhancer. Oleic acid (43.07 ± 10.11 µg/cm2) had significantly higher cannabidiol delivery into skin than the group without oleic acid (10.98 ± 3.40 µg/cm2) after a 4 h in vitro permeation study. Essential oils at concentrations tested had lower total cannabidiol delivery when compared to control. This study's findings will help guide future research on the pharmacological effect of percutaneously delivered cannabidiol on inflammatory skin disorders.

An integrated biophysical model for predicting the clinical pharmacokinetics of transdermally delivered compounds

The delivery of therapeutic drugs through the skin is a promising alternative to oral or parenteral delivery routes because dermal drug delivery systems (D3Ss) offer unique advantages, such as controlled drug release over sustained periods and a significant reduction in first-pass effects, thus reducing the required dosing frequency and the level of patient noncompliance. Furthermore, D3Ss find applications in multiple therapeutic areas, including drug repurposing. This article presents an integrated biophysical model of dermal absorption for simulating the permeation and absorption of compounds delivered transdermally. The biophysical model is physiologically/biologically inspired and combines a holistic model of healthy skin with whole-body physiology-based pharmacokinetics through the dermis microcirculation. The model also includes the effects of chemical penetration enhancers and hair follicles on transdermal transport. The model-predicted permeation and pharmacokinetics of select compounds were validated using in vivo data reported in the literature. We conjecture that the integrated model can be used to gather insights into the permeation and systemic absorption of transdermal formulations (including cosmetic products) released from novel depots and to optimize delivery systems. Furthermore, the model can be extended to diseased skin with parametrization and structural adjustments specific to skin diseases.

Enhanced skin retention and permeation of a novel peptide via structural modification, chemical enhancement, and microneedles

Hyperpigmentation is a common skin condition with serious psychosocial consequences. Decapeptide-12, a novel peptide, has been found to be safer than hydroquinone in reducing melanin content, with efficacy up to more than 50% upon 16 weeks of twice-daily treatment. However, the peptide suffers from limited transcutaneous penetration due to its hydrophilicity and high molecular weight. Therefore, decapeptide-12 was modified by adding a palmitate chain in an attempt to overcome this limitation. Molecular docking results showed that the two peptides exhibited similar biological activity towards tyrosinase. We also tested the effect of chemical penetration enhancers and microneedles to deliver the two peptides into and through skin, using an in vitro human skin permeation method. It was shown that the palm-peptide achieved the best skin retention owing to the increased lipophilicity. In addition, skin permeation of the palm-peptides was enhanced by the chemical skin penetration enhancers, namely, oleic acid and menthol. Skin permeation of the native peptide was enhanced by the microneedle patch but not the chemical skin penetration enhancers. Cutaneous absorption of the palm-peptides was estimated to have achieved its therapeutic concentration within skin. The combinatory approach of using molecular modification, chemical penetration enhancement, and microneedle patch proves to be useful to enhanceskin permeation of the peptides.

Synergistic Effect of Chemical Penetration Enhancers on Lidocaine Permeability Revealed by Coarse-Grained Molecular Dynamics Simulations.

The search for new formulations for transdermal drug delivery (TDD) is an important field in medicine and cosmetology. Molecules with specific physicochemical properties which can increase the permeability of active ingredients across the stratum corneum (SC) are called chemical penetration enhancers (CPEs), and it was shown that some CPEs can act synergistically. In this study, we performed coarse-grained (CG) molecular dynamics (MD) simulations of the lidocaine delivery facilitated by two CPEs—linoleic acid (LA) and ethanol—through the SC model membrane containing cholesterol, N-Stearoylsphingosine (DCPE), and behenic acid. In our simulations, we probed the effects of individual CPEs as well as their combination on various properties of the SC membrane and the lidocaine penetration across it. We demonstrated that the addition of both CPEs decreases the membrane thickness and the order parameters of the DPCE hydrocarbon chains. Moreover, LA also enhances diffusion of the SC membrane components, especially cholesterol. The estimated potential of mean force (PMF) profiles for the lidocaine translocation across SC in the presence/absence of two individual CPEs and their combination demonstrated that while ethanol lowers the free energy barrier for lidocaine to enter SC, LA decreases the depth of the free energy minima for lidocaine inside SC. These two effects supposedly result in synergistic penetration enhancement of drugs. Altogether, the present simulations provide a detailed molecular picture of CPEs’ action and their synergistic effect on the penetration of small molecular weight therapeutics that can be beneficial for the design of novel drug and cosmetics formulations.

Enhanced Transdermal Delivery of Bisoprolol Hemifumarate via Combined Effect of Iontophoresis and Chemical Enhancers: Ex Vivo Permeation/In Vivo Pharmacokinetic Studies.

Bisoprolol hemifumarate (BH) is an antihypertensive drug that is used as first-line treatment for chronic hypertension and angina pectoris. Our study was performed to enhance the transdermal delivery of BH, a hydrophilic drug active with high molecular weight, through differently prepared hydrogels. The synergistic effect of permeation enhancers and iontophoresis was investigated via both ex vivo and in vivo permeation studies. Ex vivo iontophoretic permeation studies were performed by using male albino Wistar rat skin. Cellosolve® hydrogel (F7) showed a 1.5-fold increase in Q180, Jss, and FER compared to F5 (lacking permeation enhancer). BH pharmacokinetic data were studied in human volunteers, following transdermal delivery of F7, using Phoresor® Unit II iontophoresis device, compared to conventional oral tablets. F7 showed 1.9- and 2-fold higher values of Cmax and AUC0–40, respectively compared to Concor® tablets, as well as a smaller Tmax (2.00 ± 2.00 h). The relative bioavailability of F7 was found to be 201.44%, relative to Concor® tablets, demonstrating the significantly enhanced transdermal permeation of BH from the selected hydrogel by iontophoresis, in human volunteers. Finally, results showed the successful utility of permeation enhancers combined with iontophoresis in significantly enhanced transdermal permeation of BH, despite its large molecular weight and hydrophilic nature. Therefore, this strategy could be employed as a successful alternative route of administration to conventional oral tablets.

Distribution by influence factors of pyrene removal in chemical enhancers assisted microbial phytoremediation of Scirpus triqueter in co-contaminated soils

The rehabilitation of soil co-contaminated by heavy metals and polycyclic aromatic hydrocarbons (PAHs) has become a serious global issue. Chemical enhancers and strains are often used to remove PAHs from contaminated soil. In this paper, the effects of chemical enhancers, strain HD-1, and Scirpus triqueter in removing pyrene from co-contaminated soil are studied. In the pot experiment, chemical enhancers and HD-1 were added to the co-contaminated soil. On the 60th day, the plants and soil were taken out for measurement. The result showed that the addition of chemical enhancers and microorganisms (Group PBC) alleviated the inhibition effect of plants on pollution. The accumulation of pyrene in plants of Group PC (chemical enhancers) and Group PBC (chemical enhancers and HD-1) were much higher than those in other groups. Plant enrichment was not the major way to remove pyrene from soil (less than 0.3%). Compared with the contributions of chemical enhancers, HD-1, and Scirpus triqueter, HD-1 had stronger effects on the removal of pyrene (17.23–22.80%). This study indicates that the combination of chemical enhancers, HD-1, and Scirpus triqueter constituted a beneficial composite system, in which the three elements interacted with each other and ultimately achieved the goal of removing pyrene from co-contaminated soil.

Potential of Chemical and Physical Enhancers for Transungual Delivery of Amorolfine Hydrochloride.

Topical monotherapy of nail infection is limited by poor drug permeability into the human nail plate. Numerous substances and methods are applied to improve the antifungal agent delivery across the nail plate. This work aimed to evaluate the effect of chemical and physical enhancers on the accumulation and permeation of amorolfine hydrochloride through human nail clippings. Polymeric nail lacquers with Eudragit E100 were developed as a potentially suitable delivery system for amorolfine hydrochloride. Incorporating thioglycolic acid and urea into formulations provided increased accumulation of antifungal agent in nail layers of up to 100% and 57%, respectively. Structural changes of nail barrier, induced by fractional CO2 laser, were visualized by microscopy. The permeation of amorolfine hydrochloride through the nail increased twofold when thioglycolic acid-containing formulation was applied and the nail was pretreated with a fractional CO2 laser. The results suggest that this novel combination of enhancers has the potential to be an effective option for topical drug delivery through the nail, and increased the efficacy of treatment.

Amphotericin B-Loaded Emulgel: Effect of Chemical Enhancers on the Release Profile and Antileishmanial Activity In Vitro.

Cutaneous leishmaniasis is a neglected parasitic disease. Treatment is preferably performed with pentavalent antimony associated or not with amphotericin B (AmB). This study aimed to develop an emulgel with different chemical enhancers of cutaneous release. Initially, AmB emulsions were obtained with the chemical promoters, oleic acid and geraniol and without promoter, then for the evaluation of the formulations, a preliminary stability study was carried out where the formulations were submitted to centrifugation, before and after the freeze-thaw cycle and analyzed appearance, color, pH, spreadability, viscosity, conductivity, droplet size, assay, in vitro release study, in vitro antileishmania activity in Leishmania major promastigotes, and macrophage toxicity in the MTT test. The emulsions were yellowish, with no signs of instability after the centrifugation test. The pH range corresponded to that of the skin, which is 4.6 to 5.8, before and after the freeze-thaw cycle, the formulations had good spreadability and did not present significant viscosity differences before and after the freeze-thaw cycle, presenting a non-Newtonian characteristic. AmB content was within the kinetic model of zero order release, the formulation of 3% AmB and 5% oleic acid (formulation 1) was chosen to proceed with the antileishmania activity test and showed potential activity against the in vitro parasite with significant reduction of cytotoxicity on murine macrophages, indicating that the formulation is promising for the treatment of cutaneous leishmaniasis.

Effect of Chemical Permeation Enhancers on Skin Permeability: In silico screening using Molecular Dynamics simulations

Breaching of the skin barrier is essential for delivering active pharmaceutical ingredients (APIs) for pharmaceutical, dermatological and aesthetic applications. Chemical permeation enhancers (CPEs) are molecules that interact with the constituents of skin’s outermost and rate limiting layer stratum corneum (SC), and increase its permeability. Designing and testing of new CPEs is a resource intensive task, thus limiting the rate of discovery of new CPEs. In-silico screening of CPEs in a rigorous skin model could speed up the design of CPEs. In this study, we performed coarse grained (CG) molecule dynamics (MD) simulations of a multilayer skin lipid matrix in the presence of CPEs. The CPEs are chosen from different chemical functionalities including fatty acids, esters, and alcohols. A multi-layer in-silico skin model was developed. The CG parameters of permeation enhancers were also developed. Interactions of CPEs with SC lipids was studied in silico at three different CPE concentrations namely, 1% w/v, 3% w/v and 5% w/v. The partitioning and diffusion coefficients of CPEs in the SC lipids were found to be highly size- and structure-dependent and these dependencies are explained in terms of structural properties such as radial distribution function, area per lipid and order parameter. Finally, experimentally reported effects of CPEs on skin from the literature are compared with the simulation results. The trends obtained using simulations are in good agreement with the experimental measurements. The studies presented here validate the utility of in-silico models for designing, screening and testing of novel and effective CPEs.

Combined Use of N-Palmitoyl-Glycine-Histidine Gel and Several Penetration Enhancers on the Skin Permeation and Concentration of Metronidazole.

N-Palmitoyl-Glycine-Histidine (Pal-GH) is a novel low molecular weight gelator. In our previous report, ivermectin, a lipophilic drug, was effectively delivered to skin tissue after topical application with Pal-GH as a spray gel formulation, and a much higher skin concentration was confirmed than with the administration of a conventional oral formulation. The objective of this study was to increase the skin permeation of metronidazole (MTZ), a hydrophilic drug, after the topical application of Pal-GH gel. An evaluation of the combined effect of chemical penetration enhancers (CPEs), such as isopropyl myristate (IPM), propylene glycol (PG), ethanol, diethylene glycol monoethyl ether, and dimethyl sulfoxide (DMSO), on skin permeation was also conducted. We found that a 5% Pal-GH gel containing 1% MTZ (F5MTZ) exhibited a 2.7-fold higher MTZ permeation through excised hairless rat skin than its solution. Furthermore, F5PG-MTZ and F5IPM-MTZ further increased the skin permeation of MTZ when compared to F5MTZ. Interestingly, F5PG-MTZ enhanced the skin penetration of MTZ, although no enhancement effect was observed for an MTZ solution containing PG. Thus, a Pal-GH formulation containing PG and IPM may enhance the skin permeation of MTZ.

1105 The effect of chemical penetration enhancers and dosage form on in vitro skin permeation

1105 The effect of chemical penetration enhancers and dosage form on in vitro skin permeation

Effect of Permeation Enhancers on the Buccal Permeability of Nicotine: Ex vivo Transport Studies Complemented by MALDI MS Imaging.

The purpose of this study was to assess the effect of several chemical permeation enhancers on the buccal permeability of nicotine and to image the spatial distribution of nicotine in buccal mucosa with and without buccal permeation enhancers. The impact of sodium taurodeoxycholate (STDC), sodium dodecyl sulphate (SDS), dimethyl sulfoxide (DMSO) and Azone® on the permeability of [3H]-nicotine and [14C]-mannitol (a paracellular marker) across porcine buccal mucosa was studied ex vivo in modified Ussing chambers. The distribution of nicotine, mannitol and permeation enhancers was imaged using using matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MSI). Despite STDC significantly increasing permeability of [14C]-mannitol, no enhancing effect was seen on [3H]-nicotine permeability with any of the permeation enhancers. Rather, SDS and DMSO retarded nicotine permeability, likely due to nicotine being retained in the donor compartment. The permeability results were complemented by the spatial distribution of nicotine and mannitol determined with MALDI MSI. The buccal permeability of nicotine was affected in an enhancer specific manner, suggesting that nicotine primarily diffuses via the transcellular pathway. MALDI MSI was shown to complement ex vivo permeability studies and tobe a useful qualitative tool for visualizing drug and penetration enhancer distribution in buccal mucosa.

An insight into the molecular mechanism of the temporary enhancement effect of isopulegol decanoate on the skin

Chemical enhancers are widely used to facilitate drug permeation in transdermal drug delivery system (TDDS) and the effect of chemical enhancers is desired to be temporary. Though temporary enhancement effect of chemical enhancers has been widely discussed, there is still a lack of knowledge about the molecular mechanism of temporary enhancement effect. Using the skin permeation of flurbiprofen as a probe, the temporary enhancement effect of isopulegol decanoate (ISO-10) was evaluated with in vitro permeation experiment and confocal laser scanning microscopy (CLSM). In addition, molecular mechanism of skin recovery was explored with skin retention of ISO-10, attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), molecular dynamic (MD) simulation and transepidermal water loss (TEWL). Temporary enhancement effect of ISO-10 was observed by the permeation of flurbiprofen after the treatment of 180min. Furthermore, temporary enhancement effect of ISO-10 on the diffusion of intercellular lipid in the stratum cornuem (SC) was observed by ATR-FTIR, molecular dynamic (MD) simulation. The SC barrier function recovered with the existence of ISO-10 in the lipid bilayer as indicated by the retention study and TEWL. In conclusion, the lipid bilayer accepted the enhancer as a new component to form a new stable arrangement, resulted the recovery of the skin barrier function. This work processed a novel mechanism of the recovery of skin barrier function after the addition of chemical enhancers.