Charged liposomes as carriers to enhance the permeation through the skin

Introduction: In recent years, there has been increased interest in developing charged liposomes as carriers for transdermal drug delivery. It is necessary to modify the basic composition of the liposomes in order to enhance the penetration properties of the vesicles through the skin. Charged liposomes offer several advantages compared with previous drug delivery systems.

Areas covered: This paper provides a brief overview of the different drug delivery systems that exist which aim to improve the permeation of drugs through the skin, focusing on the use of charged liposomes for transdermal delivery. We propose a classification of such liposomes based on the origin of the charge given to the vesicles.

Expert opinion: Despite the advances that are occurring in the design of charged liposomes for transdermal drug delivery, the long-term stability continues to be a drawback in such systems. The presence of charge on the surface of the vesicles favors the electrostatic repulsion among them, creating a ζ potential positive or negative that prevents their aggregation and flocculation. However, there is loss of the encapsulated drug, which limits the in vivo use of these systems. It should be emphasized that charged liposomes are indeed a promising candidate for use in gene therapy and vaccine targeting, in a great diversity of diseases, for which drugs are administered by the percutaneous route.     

Erbium–Yttrium–Aluminum–Garnet Laser Irradiation Ameliorates Skin Permeation and Follicular Delivery of Antialopecia Drugs

Alopecia usually cannot be cured because of the available drug therapy being unsatisfactory. To improve the efficiency of treatment, erbium–yttrium–aluminum–garnet (Er–YAG) laser treatment was conducted to facilitate skin permeation of antialopecia drugs such as minoxidil (MXD), diphencyprone (DPCP), and peptide. In vitro and in vivo percutaneous absorption experiments were carried out by using nude mouse skin and porcine skin as permeation barriers. Fluorescence and confocal microscopies were used to visualize distribution of permeants within the skin. Laser ablation at a depth of 6 and 10 μm enhanced MXD skin accumulation twofold to ninefold depending on the skin barriers selected. DPCP absorption showed less enhancement by laser irradiation as compared with MXD. An ablation depth of 10 μm could increase the peptide flux from zero to 4.99 and 0.33 μg cm⁻² h⁻¹ for nude mouse skin and porcine skin, respectively. The laser treatment also promoted drug uptake in the hair follicles, with DPCP demonstrating the greatest enhancement (sixfold compared with the control). The imaging of skin examined by microscopies provided evidence of follicular and intercellular delivery assisted by the Er–YAG laser. Besides the ablative effect of removing the stratum corneum, the laser may interact with sebum to break up the barrier function, increasing the skin delivery of antialopecia drugs. The minimally invasive, well‐controlled approach of laser‐mediated drug permeation offers a potential way to treat alopecia. This study's findings provide the basis for the first report on laser‐assisted delivery of antialopecia drugs.     

Enhanced permeation parameters of optimized nanostructured simvastatin transdermal films: ex vivo and in vivo evaluation

Abstract

Objective: Detailed optimization process was carried out to enhance permeation parameters, and hence bioavailability, of simvastatin (SMV) transdermal films.

Methods: SMV solubility was investigated in various oils, surfactants and co-surfactants/co-solvents. Mixtures of the selected components were prepared to identify zone of nanoemulsion formation that was utilized in Extreme Vertices mixture design to develop SMV self-nanoemulsifying drug delivery systems (SNEDDS) with minimum globule size. Optimized SMV-SNEDDS were included in the preparation of transdermal films. A fractional factorial design was implemented to evaluate effects of the factors on the amount of SMV permeated. The optimized film was investigated for ex vivo skin permeation and in vivo pharmacokinetic parameters.

Results: The optimum SNEDDS formula was 0.09, 0.8 and 0.11 for Sefsol 218, tween 80 and PEG 200, respectively. Fractional factorial design depicted the optimized SMV transdermal film with 2% HPMC and 2% DMSO as permeation enhancer that showed 1.82-fold improvements in skin flux. The pharmacokinetic data showed higher C_max and almost doubled AUC compared with raw SMV-loaded films.

Conclusion: The two-step optimization implemented to optimize and control the experimental conditions for the preparation of SMV-SNEDDS-transdermal film with improved ex vivo skin permeation and enhanced in vivo parameters.     

Skin permeation behavior of elastic liposomes: role of formulation ingredients

Introduction: With the incorporation of edge activators into the lipid bilayer structure, elasticity properties are given to liposomes. Regardless of the debate over the precise permeation mechanism of elastic liposomes, these vesicles have been proven to enhance drug permeation into or through skin in most cases.

Areas covered: This article provides an overview of the formulation ingredients of elastic liposomes and their relationship with skin permeation behavior. The ingredients are divided into two categories of basic and optional ingredients. The effect of stability on permeation behavior of the vesicles is highlighted.

Expert opinion: More attention should be paid to the stability of elastic liposomes. The different stability properties of the elastic liposomes following administration can induce different skin permeation behaviors of the vesicles. It is necessary to select the optimum composition of the elastic liposomes in order to control the stability and permeation behavior of the vesicles into or through the skin. Moreover, for the development of elastic liposomes, particular attention should also be paid to the drug leakage from the vesicles during long-term storage. The application of optional ingredients to improve the stability and/or elasticity of the elastic liposomes is becoming a new trend.     

Potential targets in the discovery of new hair growth promoters for androgenic alopecia

Introduction: Androgenic alopecia (AGA) is the major type of scalp hair loss affecting 60 – 70% of the population worldwide. It is caused by two potent androgens, namely testosterone (T) and 5α-dihydrotestosterone (5α-DHT). Till date, only two FDA-approved synthetic drugs, minoxidil and finasteride, are used to cure AGA with only 35 and 48% success, respectively; therefore, a search for new drug based on the mechanism of androgens action is still needed.

Areas covered: Relevant literature was reviewed to identify current therapeutic targets and treatments for AGA. The potential targets are classified into three categories: i) 5α-reductase; ii) androgen receptor and iii) growth-factor-producing genes related to hair growth.

Expert opinion: Relevant assay systems using the right targets are required in order to obtain specific and effective drugs for AGA treatment. It is unlikely that single targeted agents will be sufficient for treating AGA, and therefore, it would be a challenge to obtain compounds with multiple activities.     

Comparative study of liposomes,transfersomes and ethosomes as carriers for improving topical delivery of celecoxib

Topical administration of celecoxib proved to be an effective mean of preventing skin cancer development and improving anticancer drugs effectiveness in skin tumors treatment. The aim of this study was the development of an effective topical formulation of celecoxib, able to promote drug skin delivery, providing its in depth penetration through the skin layers. Three kinds of vesicular formulations have been investigated as drug carriers: liposomes containing a surfactant, or transfersomes and ethosomes, containing suitable edge activators. Firstly, the effect of membrane composition variations on the system performance has been evaluated for each vesicle type. Selected formulations were characterized for particle size, polydispersity index and encapsulation efficiency. The best formulations were subjected to ex vivo permeation studies through excised human skin. All vesicular formulations markedly (p < 0.001) improved the drug amount penetrated into the skin with respect to an aqueous suspension, from 2.0 to 6.5, up to 9.0 folds for liposomes, transfersomes and ethosomes, respectively. In particular, ethosomes containing Tween 20 as edge activator not only showed the best vesicle dimensions and homogeneity, and the highest encapsulation efficacy (54.4%), but also enabled the highest increase in drug penetration through the skin, probably due to the simultaneous presence in their composition of ethanol and Tween 20, both acting as permeation enhancers. Therefore, among the various vesicular formulations examined in the study, Tween 20-ethosomes can be considered the most promising one as carrier for topical celecoxib applications aimed to prevent skin cancer development and increase the anticancer drugs effectiveness against skin tumors.     

Liposomes in topical photodynamic therapy

Introduction: Topical photodynamic therapy (PDT) refers to topical application of a photosensitizer onto the site of skin disease which is followed by illumination and results in death of selected cells. The main problem in topical PDT is insufficient penetration of the photosensitizer into the skin, which limits its use to superficial skin lesions. In order to overcome this problem, recent studies tested liposomes as delivery systems for photosensitizers.

Areas covered: This paper reviews the use of different types of liposomes for encapsulating photosensitizers for topical PDT. Liposomes should enhance the photosensitizers' penetration into the skin, while decreasing its absorption into systemic circulation. Only few photosensitizers have currently been encapsulated in liposomes for topical PDT: 5-aminolevulinic acid (5-ALA), temoporfin (mTHPC) and methylene blue.

Expert opinion: Investigated liposomes enhanced the skin penetration of 5-ALA and mTHPC, reduced their systemic absorption and reduced their cytotoxicity compared with free drugs. Their high tissue penetration should enable the treatment of deep and hyperkeratotic skin lesions, which is the main goal of using liposomes. However, liposomes still do not attract enough attention as drug carriers in topical PDT. In vivo studies of their therapeutic effectiveness are needed in order to obtain enough evidence for their potential clinical use as carriers for photosensitizers in topical PDT.     

Impacts of chemical enhancers on skin permeation and deposition of terbinafine

Abstract

Context/Objective: The addition of chemical enhancers into formulations is the most commonly employed approach to overcome the skin barrier. The objective of this work was to evaluate the effect of vehicle and chemical enhancers on the skin permeation and accumulation of terbinafine, an allylamine antifungal drug.

Methods: Terbinafine (1% w/w) was formulated as a Carbopol 934?P gel formulation in presence and absence of three chemical enhancers, nerolidol, dl-limonene and urea. Terbinafine distribution and deposition in stratum corneum (SC) and skin following 8-h ex vivo permeation study was determined using a sequential tape stripping procedure. The conformational order of SC lipids was investigated by ATR-FTIR spectroscopy.

Results and discussion: Nerolidol containing gel formulation produced significantly higher enhancement in terbinafine permeation through skin and its skin accumulation was increased. ATR-FTIR results showed enhancer induced lipid bilayer disruption in SC. Urea resulted in enhanced permeation of terbinafine across the skin and a balanced distribution to the SC was achieved. But, dl-limonene could not minimize the accumulation of terbinafine in the upper SC.

Conclusion: Nerolidol dramatically improved the skin permeation and deposition of terbinafine in the skin that might help to optimize targeting of the drug to the epidermal sites as required for both of superficial and deep cutaneous fungal infections.     

Cow ghee fortified ocular topical microemulsion; in vitro,ex vivo,and in vivo evaluation

Abstract

Aim: Utility of cow ghee (CG) as permeation enhancer in development of topical ocular microemulsion (ME) for delivery of fluocinolone acetonide (FA) to posterior eye.

Methods: For ME preparation, oil, surfactant and cosurfactant were screened based on solubility of FA. Pseudoternary phase diagrams were constructed to determine their ratios. The developed MEs were characterised for their physicochemical properties like size, polydispersity index, zeta potential, and stability etc. They were evaluated for ex vivo permeation and irritation. In vivo pharmacokinetic studies were performed on Sprague dawley rats.

Results: Lauroglycol as oil, labrasol as surfactant and Transcutol as cosurfactant were selected. The optimised ratio of oil:surfactant:cosurfactant:water was 4:23:23:50. The developed FA loaded ME fortified with CG was characterised. Ex vivo study revealed higher permeation and non-irritancy. In vivo pharmacokinetic study showed retention of CG fortified ME in posterior rat eye.

Conclusion: Present investigation established CG as permeation enhancer for ocular topical formulation.     

Texturing formulations for uranium skin decontamination

Abstract

Context: Since no specific treatment exists in case of cutaneous contamination by radionuclides such as uranium, a nanoemulsion comprising calixarene molecules, known for their good chelation properties, was previously designed. However, this fluid topical form may be not suitable for optimal application on the skin or wounds.

Objective: To develop a texturing pharmaceutical form for the treatment of wounded skins contaminated by uranium.

Materials and methods: The formulations consisted in oil-in-water (O/W) nanoemulsions, loaded with calixarene molecules. The external phase of the initial liquid nanoemulsion was modified with a combination of thermosensitive gelifying polymers: Poloxamer and HydroxyPropylMethylcellulose (HPMC) or methylcellulose (MC). These new formulations were characterized then tested by ex vivo experiments on Franz cells to prevent uranyl ions diffusion through excoriated pig ear skin explants.

Results: Despite strong changes in rheological properties, the physico-chemical characteristics of the new nanoemulsions, such as the size and the zeta potential as well as macroscopic aspect were preserved. In addition, on wounded skin, diffusion of uranyl ions, measured by ICP-MS, was limited to less than 5% for both HPMC and MC nanoemulsions.

Conclusions: These results demonstrated that a hybrid formulation of nanoemulsion in hydrogel is efficient to treat uranium skin contamination.     

Use of anticancer agents in gynecological oncology during pregnancy: a systematic review of maternal pharmacokinetics and transplacental transfer

Introduction: Cancer affects one in a thousand pregnant women and gynecological cancers are one of the most frequent malignancies. Chemotherapy remains the cornerstone treatment for gynecological cancer. Although all chemotherapeutic agents can cross the placental barrier, the extent of placental transfer varies considerably. Furthermore, the significant physiological variations observed in pregnant women may have an impact on pharmacokinetic parameters. Given the complexity of predicting placental transfer, in vivo and ex vivo studies are essential in this context. In view of the paucity of data on chemotherapy during pregnancy, the objective of the present study was to summarize all the available data on the transplacental transfer of anticancer drugs used to treat gynecological cancers.

Areas covered: In order to evaluate the in vivo and ex vivo transplacental transfer of the anticancer drugs most frequently used in gynecological malignancies, we carried out a comprehensive review of the literature published from 1967 to 2015. Lastly, we summarized recent clinical guidelines on the treatment of gynecological cancers in pregnant patients.

Expert opinion: The preclinical and scarce clinical data must now be extrapolated to define the maternofetal toxicity/efficacy profile and thus guide the physicians to choose anticancer drugs more efficiently in this complex situation.     

Topical gels of etofenamate: in vitro and in vivo evaluation

Abstract

Non-steroid anti-inflammatory drugs (NSAIDs), such as etofenamate, are among the most prescribed drugs used for their analgesic, anti-rheumatic, antipyretic and anti-inflammatory properties. Topical formulations have the main advantage of targeted delivery. However, drugs must overcome the skin due to its role as a physical and chemical barrier against the penetration of chemicals and microorganisms. This barrier must be altered to allow the permeation of drugs at a suitable rate to the desired site of activity. Permeation modulators can intercalate the skin outer layers causing structure disruption, opening an energetically favourable route for the drug to diffuse through. The aim of this work was the development of hydroalcoholic gels containing 5.0% (w/w) of etofenamate for topical administration with anti-inflammatory activity and enhanced drug delivery. The physical and chemical characterization, in vitro release and permeation studies and in vivo anti-inflammatory activity were assessed. The gel with 30% ethanol showed in vivo anti-inflammatory activity with suitable physical chemical and microbiologic characteristics. In vitro release and permeation studies revealed that the different amounts of ethanol used influenced the release profiles of etofenamate. Moreover, it was demonstrated that this formulation is an adequate vehicle for the etofenamate skin permeation.     

A method to improve the efficacy of topical eflornithine hydrochloride cream

Abstract

Context: Facial hirsutism is a cosmetic concern for women and can lead to significant anxiety and lack of self-esteem. Eflornithine cream is indicated for the treatment of facial hirsutism. However, limited success rate and overall patient's satisfaction, even with a long-term and high-frequency application, leave room for improvement.

Objective: The objective of this study is to test the effect of microneedle treatment on the in vitro skin permeation and the in vivo efficacy of eflornithine cream in a mouse model.

Materials and method: In vitro permeation study of eflornithine was performed using Franz diffusion cell. In vivo efficacy study was performed in a mouse model by monitoring the re-growth of hair in the lower dorsal skin of mice after the eflornithine cream was applied onto an area pretreated with microneedles. The skin and the hair follicles in the treated area were also examined histologically.

Results and discussion: The hair growth inhibitory activity of eflornithine was significantly enhanced when the eflornithine cream was applied onto a mouse skin area pretreated with microneedles, most likely because the micropores created by microneedles allowed the permeation of eflornithine into the skin, as confirmed in an in vitro permeation study. Immunohistochemistry data revealed that cell proliferation in the skin and hair follicles was also significantly inhibited when the eflornithine cream was applied onto a skin area pretreated with microneedles.

Conclusion: The integration of microneedle treatment into topical eflornithine therapy represents a potentially viable approach to increase eflornithine's ability to inhibit hair growth.     

Optimization of self-nanoemulsifying systems for the enhancement of in vivo hypoglycemic efficacy of glimepiride transdermal patches

Objectives: To optimize and use of glimepiride (GMD)-loaded self-nanoemulsifying delivery systems (SNEDs) for the preparation of transdermal patches.

Methods: Mixture design was utilized to optimize GMD-loaded SNEDs in acidic and aqueous pH media. Optimized GMD-loaded SNEDs were used in the preparation of chitosan (acidic) and hydroxypropyl methyl cellulose (HPMC) (aqueous) films. The prepared optimized formulations were investigated for ex vivo skin permeation, for in vivo hypoglycemic activity and for their pharmacokinetic parameters using animal model.

Results: The optimized formulations showed flux value of (2.88 and 4.428 μg/cm²/h) through rat skin for chitosan and HPMC films, respectively. The pattern of GMD release from both formulations was in favor of Higuchi and approaching zero order models. The n values for Korsmeyer–Peppas equation were characteristic of anomalous (non-Fickian) release mechanism. Moreover, HPMC patches have shown significant reductions (p < 0.05) in blood glucose levels; (213.33 ± 15.19) mg/100 ml from the base-line measurement after 12 h of application.

Conclusions: Optimized GMD SNEDs patches were found to improve GMD skin permeability and the essential pharmacokinetic parameters. Further extensive pre/clinical studies are necessary prior to use transdermal GMD as a valuable alternative to peroral dosage forms with improved bioavailability, longer duration of action and more patient convenience.     

Low-frequency sonophoresis: application to the transdermal delivery of macromolecules and hydrophilic drugs

Importance of the field: Transdermal delivery of macromolecules provides an attractive alternative route of drug administration when compared to oral delivery and hypodermic injection because of its ability to bypass the harsh gastrointestinal tract and deliver therapeutics non-invasively. However, the barrier properties of the skin only allow small, hydrophobic permeants to traverse the skin passively, greatly limiting the number of molecules that can be delivered via this route. The use of low-frequency ultrasound for the transdermal delivery of drugs, referred to as low-frequency sonophoresis (LFS), has been shown to increase skin permeability to a wide range of therapeutic compounds, including both hydrophilic molecules and macromolecules. Recent research has demonstrated the feasibility of delivering proteins, hormones, vaccines, liposomes and other nanoparticles through LFS-treated skin. In vivo studies have also established that LFS can act as a physical immunization adjuvant. LFS technology is already clinically available for use with topical anesthetics, with other technologies currently under investigation.

Areas covered in this review: This review provides an overview of mechanisms associated with LFS-mediated transdermal delivery, followed by an in-depth discussion of the current applications of LFS technology for the delivery of hydrophilic drugs and macromolecules, including its use in clinical applications.

What the reader will gain: The reader will gain an insight into the field of LFS-mediated transdermal drug delivery, including how the use of this technology can improve on more traditional drug delivery methods.

Take home message: Ultrasound technology has the potential to impact many more transdermal delivery platforms in the future due to its unique ability to enhance skin permeability in a controlled manner.     

Solid lipid nanoparticles-loaded topical gel containing combination drugs: an approach to offset psoriasis

Aim: The primary aim of present work was to develop effective combination drug therapy for topical treatment of psoriasis.

Methods: Betamethasone dipropionate and calcipotriol loaded solid lipid nanoparticles (CT-BD-SLNs) were prepared by hot melt high shear homogenization technique, which were then incorporated in Carbopol gel matrix. The anti-psoriatic potential was tested by sequential in vitro (skin permeation and dermal distribution, anti-proliferative effect in HaCaT cells) and in vivo (Draize patch irritation, transepidermal water loss (TEWL) and anti-psoriatic mouse tail studies) experiments.

Results: A negligible amount in receptor compartment, yet confined distribution of drugs to epidermal and dermal region of skin was observed in case of SLNs, which is essential for safe and effective anti-psoriatic therapy. Draize patch test and TEWL demonstrated negligible skin irritation and better skin tolerability of SLNs. The in vitro HaCaT cell line study demonstrated that SLNs delayed the abrupt growth of keratinocytes, while in vivo mouse tail model showed that SLNs gel significantly decreased the epidermal thickness and increased melanocyte count in comparison to commercial Daivobet® ointment.

Conclusions: The developed SLNs gel is expected to be potential strategies for treatment of psoriasis and other topical diseases.     

Solid lipid nanoparticles as a drug delivery system for the treatment of neurodegenerative diseases

ABSTRACT

Introduction: The failure of many molecules as CNS bioactive compounds is due to many restrictions: poor water solubility, intestinal absorption, in vivo stability, bioavailability, therapeutic effectiveness, side effects, plasma fluctuations, and difficulty crossing physiological barriers, like the brain blood barrier (BBB), to deliver the drug directly to the site of action.

Area covered: Nanotechnology-based approaches with the employment of liposomes, micelles, dendrimers, and solid lipid nanoparticles (SLN) as drug delivery systems, are used to overcome the above reported limitations. Here, we focus on the delivery of drugs based on SLN formulation to treat neurodegenerative diseases. Notably, SLN have the ability to protect drugs from chemical and enzymatic degradation, direct the active compound towards the target site with a substantial reduction of toxicity for the adjacent tissues, and pass physiological barriers increasing bioavailability without resorting to high dosage forms.

Expert opinion: We believe that SLN could represent a suitable tool to pass the BBB and permit drugs to reach damaged areas of the CNS in patients affected by neurodegenerative pathologies, such as Alzheimer’s and Parkinson’s diseases.     

Effect of massage on percutaneous penetration and skin decontamination: man and animal

Context: At least 15 factors of percutaneous penetration exist that should be considered when investigating dermal absorption profiles of chemicals. Rubbing is one variable that has been understudied, but may play an important role in understanding overall exposure rates, chemical toxicity, dermal absorption and skin's barrier abilities.

Objective: This reviews current data related to the role of massage in enhancing percutaneous penetration and skin decontamination as well as highlights the need for further investigation of its role.

Results: An in vivo study in rhesus monkeys and guinea pigs measuring amount of drug excreted after being topically applied showed no effect with massage. However, studies measuring permeation rates directly through human and animal skin ex vivo showed rubbing increased flux, reduced skin impedance and increased drug retention in skin. Rubbing also increased effectiveness of reactive skin decontamination lotion (RSDL).

Conclusion: Massage sometimes influences chemical penetration rates and should be studied thoroughly to clarify the mechanisms and factors involved in the possible enhancing effect. This will also reveal more insight regarding the skin's ability to act as a barrier to exogenous substances and its role in risk assessment. How ex vivo results translate to in vivo behaviors still requires further investigation.     

An investigation into the combination of low frequency ultrasound and liposomes on skin permeability

Antigen application onto skin that has been pre-treated with low frequency ultrasound leads to immunisation, and it was hypothesised that immunisation could be enhanced if antigens were entrapped within liposomes, the latter being known vaccine adjuvants. However, it has been suggested that liposomes can repair skin damage, which could limit antigen permeation and transcutaneous immunisation. The aim of the present work was therefore to investigate the influence of liposome application on subsequent: (i) in vitro antigen permeation through, and (ii) in vivo barrier properties of, ultrasound-treated skin. Sonication was conducted using either phosphate buffered saline (PBS) or an aqueous solution of sodium dodecyl sulphate (SDS) as the coupling medium, and rats were used as the animal models. Liposome application to sonicated skin reduced antigen penetration and transepidermal water loss (TEWL, used as an indication of skin integrity) when the skin had been sonicated using PBS coupling medium. The influence of liposome was evident within 5 min of its application, and smaller liposomes were more effective at repairing skin disruption caused by sonication. Such skin repair did not, however, take place when the skin had been sonicated in the presence of SDS (which caused greater skin disruption), and changes in in vitro antigen permeation and in vivo TEWL were negligible. Skin repair by liposomes seems to depend on the extent of the disruption caused by ultrasound application.     

Nanogel for dermal application of the triterpenoids isolated from Ganoderma lucidum (GLT) for frostbite treatment

Abstract

Objective: The purpose of this study was to formulate stable Ganoderma lucidum (GLT) nanogels suitable for topical delivery with a view to improve the therapeutic effect for frostbite.

Methods: GLT nanosuspensions were formulated using the high-pressure homogenization technique and then suitably gelled for characterized. In order to confirm the advantages of GLT nanogel for dermal application, skin permeation studies in vitro and pharmacodynamic evaluation in vivo were studied and compared with GLT–carbopol gel.

Results: The particle size analysis and SEM studies revealed that GLT nanosuspensions were still stably kept their particle size after suitably gelled by carbopol preparation. The drug content, pH, and spreadability of the GLT nanogel was found to be 99.23?±?1.8%, 6.07?±?0.1, and 26.42 (g·cm)/s, which were within acceptable limits. In vitro permeation studies through rat skin indicated that the amount of GLT permeated through skin of GLT nanogel after 24?h was higher than GLT–carbopol gel, and GLT nanogel increased the accumulative amount of GLT in epidermis five times than GLT–carbopol gel. No oedema and erythema were observed after administration of GLT nanogel on the rabbits' skin. Pharmacodynamic study showed that GLT nanogel was more effective than GLT–carbopol gel in treatment of frostbite.

Conclusion: The GLT nanogel possess superior therapeutic effect for frostbite compared with the GLT–carbopol gel, which indicates that nanogels are eligible for the use as a suitable nanomedicine for dermal delivery of poorly soluble drugs such as GLT.