Use Of Chemical Penetration Enhancers Research Articles

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.

Chemical vs. Physical Methods to Improve Dermal Drug Delivery: A Case Study with Nanoemulsions and Iontophoresis.

So far, various approaches have been proposed to improve dermal drug delivery. The use of chemical penetration enhancers has a long history of application, while methods based on the electrical current (such as iontophoresis) stand out as promising “active” techniques. Aiming to evaluate the contribution of different approaches to dermal delivery, in this work curcumin-loaded nanoemulsions with and without monoterpenes (eucalyptol or pinene) as chemical penetration enhancers, and a custom-made adhesive dermal delivery system based on iontophoresis were designed and assessed. In an in vivo study applying skin bioengineering techniques, their safety profile was proven. Three examined iontophoresis protocols, with total skin exposure time of 15 min (continuous flow for 15 min (15-0); 3 min of continuous flow and 2 min pause (3-2; 5 cycles) and 5 min of continuous flow and 1 min pause (5-1; 3 cycles) were equally efficient in terms of the total amount of curcumin that penetrated through the superficial skin layers (in vivo tape stripping) (Q3-2 = 7.04 ± 3.21 μg/cm2; Q5-1 = 6.66 ± 2.11 μg/cm2; Q15-0 = 6.96 ± 3.21 μg/cm2), significantly more efficient compared to the referent nanoemulsion and monoterpene-containing nanoemulsions. Further improvement of an efficient mobile adhesive system for iontophoresis would be a practical contribution in the field of dermal drug application.

Potential of Sonophoresis as a Skin Penetration Technique in the Treatment of Rheumatoid Arthritis with Transdermal Patch.

Rheumatoid arthritis, a chronic disorder, limits the use of chemical penetration enhancers for a prolonged period of time. Moreover, systemic routes of administration of the first-line drug, methotrexate, have shown undesirable systemic as well as local side effects. The objective of this research was to overcome the limitations associated with treatment of rheumatoid arthritis by utilizing three physical transdermal penetration enhancement techniques namely cold-laser, electroporation, and sonophoresis to deliver methotrexate. Methotrexate patch was prepared using solvent casting method and the ex-vivo release of methotrexate in combination with three physical penetration enhancers (sonophoresis, electroporation, and cold laser) were studied. The best technique was employed in pre-clinical testing in arthritic and control groups of male Wistar rats excluding remaining two techniques. The comparative ex-vivo studies showed that the penetration enhancement of methotrexate is maximum by sonophoresis followed by electroporation and cold laser (sonophoresis > electroporation > cold laser). In pharmacodynamic studies, the reduction in diameter of injected and non-injected paw on day 5 and day 21 for group 4 (ultrasound pre-treated group) was higher as compared to group 3 (group receiving only methotrexate patch). The motility score and the reduction in pain were significantly improved for group 4 than group 3 on both day 5 and day 21 (P˂0.05) which confirmed the faster recovery of animals of group 4 due to penetration enhancement of methotrexate patch by ultrasound treatment. From the results, it can be concluded that sonophoresis along with methotrexate patch has shown a significant effect in the treatment of rheumatoid arthritis.

Chemical Penetration Enhancers Increase Hydrogen Peroxide Uptake in C. elegans for In Vivo Fast Photochemical Oxidation of Proteins.

Fast photochemical oxidation of proteins (FPOP) is a hydroxyl radical protein footprinting method that covalently labels solvent-accessible amino acids by photolysis of hydrogen peroxide. Recently, we expanded the use of FPOP for in vivo (IV-FPOP) covalent labeling in C. elegans. In initial IV-FPOP studies, 545 proteins were oxidatively modified in all body systems within the worm. Here, with the use of chemical penetration enhancers (CPEs), we increased the number of modified proteins as well as the number of modifications per protein to gain more structural information. CPEs aid in the delivery of hydrogen peroxide inside C. elegans by disturbing the highly ordered lipid bilayer of the worm cuticle without affecting worm viability. IV-FPOP experiments performed using the CPE azone showed an increase in oxidatively modified proteins and peptides. This increase correlated with greater hydrogen peroxide uptake by C. elegans quantified using a chemical fluorophore demonstrating the efficacy of using CPEs with IV-FPOP. Mass spectrometry proteomics data are available via ProteomeXchange with identifier PXD019290.

Surfactants from itaconic acid: Toxicity to HaCaT keratinocytes in vitro, micellar solubilization, and skin permeation enhancement of hydrocortisone

One of the most widely used approaches for improving drug permeation across the stratum corneum barrier of the skin is the use of chemical penetration enhancers, such as surfactants. In this study, two anionic surfactants, named C12-OPK and C18-OPK, were synthesized via condensation of itaconic acid and fatty amines, with C12 and C18 alkyl chains, respectively. Assessment of impacts on HaCaT keratinocyte cell viability was used as indicator of their potential to cause skin irritation 24h post exposure (Alamar Blue assay). The LC50 values of C12-OPK and C18-OPK (144 and 85mg/L, respectively) were lower than LC50 values of the most used commercial surfactants (e.g. SDS). The effect of different surfactant concentrations (up to ten times the critical micellar concentration, CMC) on hydrocortisone (HC) solubility and permeation through porcine skin was also evaluated. Results showed that drug solubility increased linearly with increasing concentrations of both surfactants, as a consequence of the association between drug and micelles. In vitro permeation results showed that the permeability coefficient increased at surfactant concentrations lower than the CMC. In particular, a higher enhancement effect on drug permeation was obtained with C18-OPK, due to its hydrophobic properties that ensured a more effective HC permeation in comparison to C12-OPK.

The synergistic effect of ultrasound and chemical penetration enhancers on chorioamnion mass transport

In our previous study we proposed the use of chemical penetration enhancers for noninvasive detection of fetus abnormalities that can also be utilized for direct fetal drug delivery. In an attempt to further increase the mass transport rate across the amniotic membrane, thus shortening the procedure and improving the applicability of the proposed procedure, the effect and mechanism of combining ultrasound exposure with chemical penetration enhancers' application were assessed. The combined effect was evaluated in vitro on post-delivery human amniotic membrane and ex vivo on rat's whole amniotic sac. Ultrasound effect has been assessed by dye experiments using a customized image analysis program. Additional insights of ultrasound effect's mechanism on biological membranes are presented. Previously we have determined that chemical penetration enhancers affect the fetal membranes via two mechanisms termed as ‘extractors’ and ‘fluidizers’. In this study, we found that combining ultrasound with a ‘fluidizer’ CPE (e.g. bupivacaine) results in a synergistic enhancement (90-fold) of fetal membrane's mass transport, while combining ultrasound with ‘extractors’ (e.g. ethanol and NMP) results in an antagonistic effect. The combined procedure is faster and gain greater accuracy than the applications of sole chemical penetration enhancers.

Enhancing the buccal mucosal delivery of peptide and protein therapeutics.

With continuing advances in biotechnology and genetic engineering, there has been a dramatic increase in the availability of new biomacromolecules, such as peptides and proteins that have the potential to ameliorate the symptoms of many poorly-treated diseases. Although most of these macromolecular therapeutics exhibit high potency, their large molecular mass, susceptibility to enzymatic degradation, immunogenicity and tendency to undergo aggregation, adsorption, and denaturation have limited their ability to be administered via the traditional oral route. As a result, alternative noninvasive routes have been investigated for the systemic delivery of these macromolecules, one of which is the buccal mucosa. The buccal mucosa offers a number of advantages over the oral route, making it attractive for the delivery of peptides and proteins. However, the buccal mucosa still exhibits some permeability-limiting properties, and therefore various methods have been explored to enhance the delivery of macromoleculesvia this route, including the use of chemical penetration enhancers, physical methods, particulate systems and mucoadhesive formulations. The incorporation of anti-aggregating agents in buccal formulations also appears to show promise in other mucosal delivery systems, but has not yet been considered for buccal mucosal drug delivery. This review provides an update on recent approaches that have shown promise in enhancing the buccal mucosal transport of macromolecules, with a major focus on proteins and peptides.

Pretreatment with Skin Permeability Enhancers: Importance of Duration and Composition on the Delivery of Diclofenac Sodium

The use of chemical penetration enhancers (CPEs) is one of the most common approaches to improve the dermal and transdermal delivery of drugs. However, often, incorporation of CPEs in the formulation poses compatibility and stability challenges. Moreover, incorporation of enhancers in the formulation leads to prolonged exposure to skin increasing the concern of causing skin reactions. This study was undertaken to assess whether pretreatment with CPEs is a rational approach to enhance the permeation of diclofenac sodium. In vitro experiments were performed across porcine epidermis pretreated with propylene glycol or oleic acid or their combinations for 0.5, 2, and 4 h, respectively. Pretreatment with combination of oleic acid in propylene glycol was found to enhance the permeation of diclofenac sodium significantly only at 10% and 20% (v/v) level, and only when the pretreatment duration was 0.5 h. Longer durations of pretreatment and higher concentration of oleic acid in propylene glycol did not enhance the permeation of diclofenac sodium. In vivo dermatokinetic studies were carried out on Sprague-Dawley rats. A twofold increase in AUC and Cmax was observed in case of rats pretreated with enhancers over the group that was pretreated with buffer. In conclusion, this study showed that composition of the enhancers and duration of pretreatment are crucial in determining the efficacy of CPEs.

Pre-treatment with chemical penetration enhancers in dermal/transdermal drug delivery

Delivery of drugs through skin is an alternative route of drug administration. However dermal/transdermal delivery of drugs is limited by the exceptional barrier function of the stratum corneum which forms the outermost layer of the skin. Various active and passive techniques have been successfully employed to breach this barrier function thereby allowing permeation of therapeutic levels of drug across and into the skin. One such approach has been the use of chemical penetration enhancers (CPEs). CPEs are often incorporated in the semisolid formulations and patches intended for application on the skin. Often, incorporation of CPEs in the formulation is limited by their potential for interaction with the API and other excipients in the formulation. Moreover, prolonged contact of CPEs increases the risk of significant damage to the skin structure as well as could potentially lead to skin reactions. Pre-treatment of the skin with these CPEs allows for a reversible modulation of the stratum corneum barrier without getting in contact with the formulation. This avoids any possible incompatibility and instability issues. Thus, pre-treating the skin with CPEs followed by application of drug formulation can be considered as a practical alternative to achieve enhancement into and across the skin .

Novel Penetration Enhancers for Skin Applications: A Review

The use of topical formulation is popular over the past decade due to extensive researches made in the field of transdermal drug delivery. As a result, an increasing number of drugs are being added to the list of therapeutic agents that can be delivered to systemic circulation through the skin. Commonly available dosage forms for the topical application are creams, ointments, gels, patches etc. The therapeutic benefits of the above topical formulations are limited due to barrier property of stratum corneum (SC). The use of chemical penetration enhancers (CPEs) is one of the long standing approach to overcome the barrier property of SC. Numerous class of novel compounds have been evaluated for penetration enhancement activity, including soft enhancement for percutaneous absorption (SEPA), for example, 2 N-nonyl-1,3- dioxolanes, N-acetyle prolinate esters (such as pentyl- and octyl-N-acetyle prolinate), alkyldiloxanes (e.g., 1-Alkyl-3-b-D glucopyranosyl-1,1,3,3-tetramethyl disiloxanes), transcarbam (such as 5-(dodecyloxycarbonyl) pentylammonium-5- (dodecyloxycarbonyl) pentylcarbamate), iminosulfurane (like N-hexyl,N-benzoyl-S,S-dimethylimino-sulfuranes), capsaicin derivatives (e.g., Nonivamide), cinnamene compounds (such as cinnamic acid, cinnamaldehyde etc), terpenes (like clove and basil oil) and synergestic combination of penetration enhancers (SCOPE). We briefly describe about the anatomy of skin. Potential mechanisms of action of above novel PEs along with adverse reactions associated with traditional PEs are also considered in this review.

A Review on Terpenes as Skin Penetration Enhancers in Transdermal Drug Delivery

The skin itself hinders the widespread use of transdermal drug delivery (TDD) for administration of medication. Despite the different strategies devised and employed to reversibly overcome the skin barrier, this non-invasive delivery mode is restricted to potent, low molar mass therapeutic agents. The use of chemical penetration enhancers is the conventional approach to modify the skin structure and lower its resistance for increased drug permeation. Over the years, extensive screening and testing have identified different classes of chemicals as potential adjuvants. Among these, terpenes (constituents of plant essential oils) have been widely investigated as skin penetration enhancers for both hydrophilic and hydrophobic drugs. In particular, monoterpenes were generally more effcacious probably due to their small molecular sizes. The main mechanisms of action of terpenes on the skin as determined by several analytical techniques were lipid extraction and phase separation. Terpenes such as limonene and menthol in experimental patch formulations were demonstrated to be safe on the skin and effective in improving drug delivery across the skin.

Role of complexes formation between drugs and penetration enhancers in transdermal delivery

The use of chemical penetration enhancers (CPE) is growing due to their ability to improve drug delivery through the skin. A possible mechanism of penetration enhancement could involve the complex formation between drug and components in the pharmaceutical formulation, thus altering the physicochemical properties of the active substance. Here, modelling studies indicate that hydrocarbon and oxygen-containing terpenes (penetration enhancers) could form complexes with drugs. Satisfactory correlations have been obtained between the predicted molecular properties of enhancers and their enhancement effects.

Innovative Strategies for Enhancing Topical and Transdermal Drug Delivery

Abstact: Historically, the skin was thought to be a simple homogenous barrier. However, it is now known to be a highly specialised organ, and plays a key role in homeostasis. The protective properties of the skin are provided by the outermost layer, the epidermis, which safeguards against chemical, microbial, and physical attack. The exceptional barrier properties of the skin result in it being a challenging route for the delivery of therapeutic agents. This article reviews strategies developed to enhance the skin penetration of drugs, ranging from conventional approaches, for example the use of chemical penetration enhancers to those in early-stage development, such as microscissioning.