Types Of Penetration Enhancers Research Articles

Correlations Between Skin Barrier Integrity and Delivery of Hydrophilic Molecules in the Presence of Penetration Enhancers.

We investigated the potential correlations between skin barrier integrity and hydrophilic drugs distribution in skin in the presence of different types of penetration enhancers (PEs) and their combinations. We measured skin conductivity to evaluate skin barrier integrity before and after the topical application of different chemical PEs, physical PE, peptide PE and their combinations in vitro. We also investigated their effect on the skin distribution profiles of two hydrophilic model drugs, Fluorescein sodium (376Da) and Fluorescein isothiocyanate-dextrans 10 (10 KDa). The physical PE significantly increased the skin conductivity compared to all other PEs, while the peptide PE had no effect on it. The drug deposition in different skin layers was not only dependent on PE applied but also its own molecular weight. We further found two excellent correlations: one (R2= 0.9388) between skin barrier integrity and total skin absorption of FNa and another one(R2= 0.9212) between skin barrier integrity and the deposition of FNa in dermis and receptor in presence of chemical or physical PEs and their combinations. The total skin absorption or the deposition in dermis and receptor of small hydrophilic drug in the presence of chemical and physical PEs and their combinations show a good correlation with skin barrier integrity. However, such correlations hold true neither for large hydrophilic drug nor for peptide PE. All good relationships found in this work will allow screening suitable PEs or combinations by measuring the skin conductivity induced by corresponding PEs. Graphical Abstract The total skin absorption of small hydrophilic drug shows a good correlation with skin barrier integrity in the presence of chemical and physical penetration enhancers and their combinations. However, such a correlation hold true neither for large hydrophilic drug nor for peptide penetration enhancer.

Main features and applications of organogels in cosmetics.

Cosmetic treatments aim at improving skin appearance through vehicles of good sensory properties. Those vehicles are mainly emulsions and gels designed to deliver safe and effective compounds to skin. Creams and serums are widely used to achieve these goals, but recently a new type of formulation known as organogels triggered scientific attention, particularly in the design of both topical and cosmetic formulations. It has been established that the lipophilic nature of organogels makes it an excellent candidate for the delivery of cosmetic molecules through skin. In this review, we discuss the properties and characteristics of organogels and present the advantages of the application of these systems in cosmetics.

Solutol HS15 based binary mixed micelles with penetration enhancers for augmented corneal delivery of sertaconazole nitrate: optimization, in vitro, ex vivo and in vivo characterization

Keratomycosis is a serious corneal disease that can cause a permanent visual disability if not treated effectively. Sertaconazole nitrate (STZ), a novel broad spectrum antifungal drug, was suggested as a promising treatment. However, its utility in the ocular route is restricted by its poor solubility, along with other problems facing the ocular delivery like short residence time, and the existing corneal barrier. Therefore, the objective of this study was to formulate STZ loaded binary mixed micelles (STZ-MMs) enriched with different penetration enhancers using thin-film hydration method, based on a 31.22 mixed factorial design. Different formulation variables were examined, namely, type of auxiliary surfactant, type of penetration enhancer, and total surfactants: drug ratio, and their effects on the solubility of STZ in MMs (SM), particle size (PS), polydispersity index (PDI), and zeta potential (ZP) were evaluated. STZ-MMs enhanced STZ aqueous solubility up to 338.82-fold compared to free STZ. Two optimized formulations (MM-8 and MM-11) based on the desirability factor (0.891 and 0.866) were selected by Design expert® software for further investigations. The optimized formulations were imaged by TEM which revealed nanosized spherical micelles. Moreover, they were examined for corneal mucoadhesion, stability upon dilution, storage effect, and ex vivo corneal permeation studies. Finally, both in vivo corneal uptake and in vivo corneal tolerance were investigated. MM-8 showed superiority in the ex vivo and in vivo permeation studies when compared to the STZ-suspension. The obtained results suggest that the aforementioned STZ loaded mixed micellar system could be an effective candidate for Keratomycosis-targeted therapy.

Terbinafine hydrochloride nanovesicular gel: In vitro characterization, ex vivo permeation and clinical investigation

In this work, nanovesicular chitosan gels were prepared for dermal delivery of terbinafine hydrochloride (TBN HCl). Ethosomes and vesicles containing different types of penetration enhancers (PEs) viz. Terpenes (cineole and limonene), labrasol and transcutol were developed. The prepared vesicles were evaluated for physical characteristics as well as skin interaction. The selected vesicles were incorporated into chitosan gel. An in vivo animal study was done on rat induced superficial Candida infection model. Moreover, randomized double blind clinical study was done on patients to compare the effect of the selected nanovesicular gel against the market product. Results showed the formation of nearly spherical, mostly deformable vesicular systems with size range of 95.5–530nm, zeta potential range of −0.1 to 15mV and entrapment efficiency range of 20–96.7%. Penetration enhancer vesicles (PEVs) prepared with 4% limonene (ELI4) showed the highest percent of drug deposition in the skin (53%) and the highest local accumulation efficiency value (35.3). In vivo animal study showed that the lowest fungal burden produced with ELI4 chitosan gel. Clinical studies showed cure rate of 86% within 7days treatment in case of limonene nanovesicular gel compared to 20% for market product (Lamisil® cream).

Formulation development and optimization of transungual drug delivery system of terbinafine hydrochloride for the treatment of onychomycosis.

The aim of present investigation was to develop transungual drug delivery system (nail lacquer) of terbinafine hydrochloride for treatment of onychomycosis. Different types of penetration enhancers, viz. 2-mercaptoethanol, n-acetyl-L-cysteine and thioglycolic acid, were evaluated to determine their effect on drug permeation. Various types of polymers, both hydrophobic (Eudragit® RL 100 and Eudragit® RS 100) and hydrophilic polymers (hydroxypropyl methyl cellulose (HPMC) E15), were evaluated for their film-forming and drug permeation characteristics. The nail lacquer was optimised statistically by applying 3(2) full factorial design. Polymer ratio (Eudragit® RL 100/HPMC E15; X 1) and solvent ratio (ethanol/water; X 2) were selected as independent variable, and viscosity (cPs), nail plate hydration (%) and invitro drug permeated at the end of 24h (μg/cm(2)) were selected as dependent variable. The optimised batch comprises of polymer ratio (70:30) and solvent ratio (75:25). Ex vivo drug permeation study was performed using human cadaver toe nail plate. The results revealed that the amount of drug permeated at the end of 24h was 61.55 ± 3.2μg/cm(2), which was found to be higher than the minimum inhibitory concentration of drug. This study confirms that the developed drug-loaded nail lacquer could be used as a promising tool for the effective treatment of onychomycosis.

Synergistic effect of iontophoresis and chemical enhancers on transdermal permeation of tolterodine tartrate for the treatment of overactive bladder

The objective of the study was to evaluate the synergistic transdermal permeation effect of chemical enhancers and iontophoresis technique on tolterodine tartrate (TT) transdermal gel and to evaluate its pharmacokinetic properties. Taguchi robust design was used for optimization of formulations. Skin permeation rates were evaluated using the Keshary-chein type diffusion cells in order to optimize the gel formulation. In-vivo studies of the optimized formulation were performed in a rabbit model and histopathology studies of optimized formulation were performed on rats. Transdermal gels were formulated successfully using Taguchi robust design method. The type of penetration enhancer, concentration of penetration enhancer, current density and pulse on/off ratio were chosen as independent variables. Type of penetration enhancer was found to be the significant factor for all the responses. Permeation parameters were evaluated when maximum cumulative amount permeated in 24 hours (Q24) was 145.71 ± 2.00µg/cm² by CIT4 formulation over control (91.89 ± 2.30µg/cm²). Permeation was enhanced by 1.75 fold by CIT4 formulation. Formulation CIT4 containing nerolidol (5%) and iontophoretic variables applied (0.5mA/cm² and pulse on/off ratio 3:1) was optimized. In vivo studies with optimized formulation CIT4 showed increase in AUC and T1/2 when compared to oral suspension in rabbits. The histological studies showed changes in dermis indicating the effect of penetration enhancers and as iontophoresis was continued only for two cycles in periodic fashion so it did not cause any skin damage observed in the slides. Results indicated that iontophoresis in combination with chemical enhancers is an effective method for transdermal administration of TT in the treatment of overactive bladder.

An insight into the role of barrier related skin proteins

It is well-known that intercellular lipids in the stratum corneum (SC) of the skin play an important role in maintaining barrier function, and many types of penetration enhancers affecting lipids are used in topical products to improve transdermal drug permeability. Recently, it was reported that functional proteins in tight junctions of the epidermis are important for barrier function. In this study, the effects of penetration enhancers such as fatty esters, amines/amides, and alcohols on the barrier function of the skin were evaluated in rat skin and normal human-derived epidermal keratinocytes (NHEK). All penetration enhancers decreased the electrical impedance (EI), however, the potencies of some penetration enhancers were not equal between rat skin and NHEK. The differences were clarified by immunohistochemical studies: some fatty esters decreased the immunoreactivity of involucrin and keratin 10 in the upper layer of the epidermis, while alcohols decreased the immunoreactivity of desmoglein-1, claudin-1, and E-cadherin located in the lower layer of the epidermis. From these results, it is suggested that penetration enhancers show new action mechanisms disturbing barrier-related proteins in epidermis, which are classified into two categories depending on their action sites.

Transdermal Drug Delivery Enhancement by Compounds of Natural Origin

The transdermal route of administration offers an alternative pathway for systemic drug delivery with numerous advantages over conventional routes. Regrettably, the stratum corneum forms a formidable barrier that hinders the percutaneous penetration of most drugs, offering an important protection mechanism to the organism against entrance of possible dangerous exogenous molecules. Different types of penetration enhancers have shown the potential to reversibly overcome this barrier to provide effective delivery of drugs across the skin. Although certain chemical and physical skin penetration enhancers are already employed by the pharmaceutical industry in commercially available transdermal products, some skin penetration enhancers are associated with irritating and toxic effects. This emphasizes the need for the discovery of new, safe and effective skin penetration enhancers. Penetration enhancers from natural origin have become popular as they offer several benefits over their synthetic counterparts such as sustainable mass production from a renewable resource and lower cost depending on the type of extraction used. The aim of this article is to give a comprehensive summary of the results from scientific research conducted on skin penetration enhancers of natural origin. The discussions on these natural penetration enhancers have been organized into the following chemical classes: essential oils, terpenes, fatty acids and polysaccharides.

Development of the loratadine gel for enhanced transdermal delivery

Background: The oral administration of loratadine, an antihistamine, can have a variety of adverse side effects, such as headache, fatigue, and nausea, because of the transient high blood concentration. To avoid these effects, loratadine can be administered using a transdermal drug delivery system. Method: This study examined the effects of the drug concentration on drug release from prepared hydroxypropyl methylcellulose gels using a synthetic cellulose membrane at 37°C. The drug concentrations tested were 0.1%, 0.2%, 0.3%, 0.4%, and 0.5% (w/w). The effect of temperature on drug release from the 0.3% loratadine gels was evaluated at 27°C, 32°C, 37°C, and 42°C. Various types of penetration enhancers, such as glycols, glycerides, propylene glycol derivatives, nonionic surfactants, and fatty acids, were incorporated in the gel formulation to increase the level of drug permeation. Results: The rate of drug release increased with increasing drug concentration or temperature. The activation energy for the release of the drug was 5.714 kcal/mol for 0.3% loratadine gel. Among all the enhancers used in this study, polyoxyethylene 2-stearyl ether showed the best enhancing effect. The enhancement factor of the loratadine gel containing the polyoxyethylene 2-stearyl ether was 2.03 compared with that of the loratadine system containing no enhancer. Conclusions: These results suggest that the topical gel formulation of loratadine containing a penetration enhancer could be developed to enhance the penetration of loratadine.

Studying the effectiveness of penetration enhancers to deliver retinol through the stratum cornum by in vivo confocal Raman spectroscopy

The purpose of this study is to monitor in vivo the effect of chemical penetration enhancers on the delivery of trans-retinol into human skin. Chemical penetration enhancers reversibly alter barrier properties of the SC by disruption of the membrane structures or maximising drug solubility with the skin. So far, most of permeation or penetration experiments are performed in vitro. Raman spectroscopy is uniquely placed to be able to measure biological processes in vivo and this paper shows for the first time that the effect of penetration enhancer on the delivery of trans-retinol can successfully be measured in vivo using this technique. Here, the volar forearm of volunteers was treated with four formulations. One formulation is a highly effective model delivery system identified from ex vivo experiments: trans-retinol in Propylene Glycol (PG)/ethanol, with PG being a well-known and efficient penetration enhancer. The other three formulations are based on 0.3% trans-retinol in Caprylic/Capric Acid Triglyceride (MYRITOL ®318), an oil commonly used in skin creams but in two of them a specific penetration enhancer is added. One contains a lipid extractor, Triton X 100, whereas another formulation contains a lipid fluidiser, Oleic Acid. Solutions were applied once and measurements were performed up to 6 h after treatment. Remarkable differences in the delivery of trans-retinol between formulation with or without penetration enhancer can clearly be seen. Moreover, the type of penetration enhancer is also shown to influence the delivery. While using the Oleic Acid, which is a lipid fluidiser, a better delivery of trans-retinol in the skin can be detected. For the first time, the effect of penetration enhancer on the delivery of trans-retinol has been monitored, non invasively in vivo, with time.

Evaluation of In-vitro Percutaneous Absorption across Human Skin and in Animal Models

The in-vitro permeability characteristics of human skin have been examined and compared with results in laboratory animals using various types of penetration enhancers. The study was focused on evaluation of predictable validity of the data obtained in animals mostly used in permeation studies. The results in man using the same penetration enhancers were about 30% of the value in the rat. The least potent enhancer was dimethylsulphoxide and the maximum efficacy was observed with sodium laurylsulphate in the rat experiments while in man the results were approximately equal when using any of the studied enhancers. Comparison of the results of experiments performed with N-methyl-2-pyrrolidone in several laboratory animals and man showed that the skin permeability in man is approximately 4 times lower than with the rat. Man and guinea-pig were not significantly different in these experiments. There were no significant differences in laurocapram penetration enhancing effect in the concentration range 0.1 to 0.5%, but there was an optimum concentration of laurocapram of 1%. The results showed quantitative differences in percutaneous absorption in various animal species in comparison with man. These differences should be considered in selecting a suitable model for preclinical drug evaluation. The guinea-pig skin penetration seems to be most similar to that in man.