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.     

Percutaneous and Systemic Disposition of Hexamethylene Lauramide and Its Penetration Enhancement Effect on Hydrocortisone in a Rat Sandwich Skin-Flap Model

The percutaneous absorption and distribution profile of hexamethylene lauramide (hexahydro-1-lauroyl-lH-azepine) were examined using a rat skin-flap model. After a topical dose to the skin flap, the drug concentrations in the vasculature at the site of drug application and in the systemic blood were monitored simultaneously. Hexamethylene lauramide penetrated the skin and reached a steady state in stratum corneum, viable epidermis, dermis, and cutaneous blood in 3 hr. Its concentration in the skin was much higher than that in the blood. Its apparent concentration in the epidermis was 19 times that in the dermis and about 3000 times that in the cutaneous blood. The percutaneous absorption of ¹⁴C-hexamethylene lauramide resulted in ascending systemic blood concentrations throughout the experimental period, whereas the cutaneous blood levels remained steady. The topically absorbed hexamethylene lauramide was quantitatively recovered in urine (85%) and feces (13%). The half-lives of urinary and fecal excretion of ¹⁴C-hexamethylene lauramide were 17 and 30 hr, respectively. Hexamethylene lauramide, when topically coadministered in an experimental formulation, enhanced the skin penetration of hydrocortisone with increased drug contents in the stratum corneum (2-fold) and with increased hydrocortisone concentrations in the cutaneous blood (3.4-fold) and the systemic blood (3.5-fold). The results indicated that the high concentration and retention of hexamethylene lauramide in stratum corneum and viable epidermis may contribute to its penetration enhancement effect in the skin. A steady state in percutaneous tissues was observed before the drug reached distribution equilibrium systemically. The systemic blood concentration of a topically applied agent therefore may not reflect its percutaneous kinetic processes before a systemic distribution equilibrium is reached. Temporal profiles of a topical penetration enhancer in the skin and in the body are important information for the development of dematologic preparations for the treatment of skin disorders.     

In Vivo and in Vitro Analysis of Skin Penetration Enhancement Based on a Two-Layer Diffusion Model with Polar and Nonpolar Routes in the Stratum Corneum

In vitro and in vivo skin penetration of three drugs with different lipophilicities and the enhancing effects of l-geranylazacycloheptan-2-one (GACH) were studied in rats. In vivo drug absorption profiles obtained by deconvolution of urinary excretion profiles were compared to the corresponding in vitro data obtained with a diffusion experiment. In vivo skin penetration of lipophilic butylparaben was considerably greater than that observed in vitro, while hydrophilic mannitol and acyclovir showed low penetration in both systems without GACH pretreatment. On the other hand, GACH enhanced mannitol and acyclovir penetration, especially in the in vivo system. Analysis of absorption profiles, using a two-layer skin model with polar and nonpolar routes in the stratum corneum, suggested that the diffusion length of a viable layer (viable epidermis and dermis) was shorter in vivo than in vitro and the effective area of the polar route in the stratum corneum was larger in vitro without GACH pretreatment. GACH increased the partitioning of acyclovir into the nonpolar route to the same extent in both systems. In addition, GACH increased the effective area of the polar route in vivo, probably because of enhanced water permeability; however, this effect was smaller in vitro since the stratum corneum was already hydrated even without GACH pretreatment.     

Stratum corneum reservoir as a predictive method for in vitro percutaneous absorption

Interaction between drug and proteins and lipids in stratum corneum (SC) is an important pharmacokinetic parameter in early steps of absorption. Previous in vivo studies showed that the total amount of compound, regardless of properties, penetrating over a 96 h period could be predicted by the amount present in SC 30 min after application by a linear relationship. Validating this linear relationship through in vitro study would facilitate testing of transdermal drug delivery platforms. We aimed to determine in vitro penetration behavior across SC of humans by determining the relationship between quantity present in SC reservoir 30 min after application with 24 h skin absorption and penetration. In this study, use of the SC reservoir effect to predict absorption and penetration of topical compounds is reaffirmed with in vitro models involving human skin. These results indicate the amount in short‐term (30 min) SC reservoir predict long‐term (24 h) skin absorption and penetration, as characterized by statistically significant linear relationships determined via regression. This may be explained by the fact that SC is a rate‐limiting barrier to percutaneous drug transport. After molecules diffuse through SC barrier, passage into deeper dermal layers and systemic uptake occur relatively quickly. These results enable one to measure quantity in SC reservoir shortly after topical application as a proxy for absorption and penetration over longer periods. With respect to drug development and risk assessment of toxic substances, this may simplify assays attempting to quantitate penetration capacity. Further investigation with a larger range of compounds is needed to clarify the observations recorded here. Copyright © 2015 John Wiley & Sons, Ltd.     

Self Promotion of Deep Tissue Penetration and Distribution of Methylsalicylate After Topical Application

Purpose. To determine how changes in cutaneous blood flow induced in-vivo by methylsalicylate (MeSA), compared to non-rubefacient trie-thanolamine salicylate (TSA), affected topical salicylate absorption and distribution, and to assess formulation therapeutic potential by comparing tissue concentrations to published antiinflammatory concentrations. Methods. Flux of salicylate from MeS A and TSA formulations applied to full-thickness rat skin was determined using in vitro diffusion cells. Anaesthetised rats were then used to quantify salicylate concentrations in plasma and tissues underlying the application site for the two formulations over a 6h period. In vitro and in vivo absorption profiles were then compared and the effect of MeSA on cutaneous blood flow assessed. Results. In vitro flux of salicylate from the MeSA formulation was 40% higher, though after correcting for differences in formulation concentrations the ratio of permeability coefficients was reversed. Contrary to the in vitro predictions, in vivo tissue and plasma concentrations of salicylate in rats rose rapidly in the first 1 hr and were more than the predicted 1.4-fold higher for MeSA. This effect was mirrored by the increase in blood flow induced by MeSA in human cutaneous vessels and that reported in the literature. Potential therapeutic levels were not seen below superficial muscle layers. Conclusions. Direct tissue penetration of salicylate occurs below application sites from both MeSA and TSA formulations. Tissue concentrations of MeSA were higher than predicted due to its rapid distribution in the blood.     

Microemulsions mediated effective delivery of methotrexate hydrogel: more than a tour de force in psoriasis therapeutics

Methotrexate (MTX), a well known drug for the treatment of cancer and rheumatoid arthritis, has gained prominence in the treatment of psoriasis over the period of years. However, the present mode of systemic administration through oral or parenteral route has always proposition, full of compromises. The toxicity of drug to the vital organs and physiological environment is the major concern. Also, its poor skin penetration is one major problem. Hence novel system based on lipid carriers has been considered here to overcome the barriers. Microemulsions (MEs) were prepared using pseudo-ternary phase diagram (PTPD) and they were characterized for various parameters such as size, shape (cryo-SEM), PDI, zeta potential, etc. The chosen MEs system (optimized) was then incorporated into secondary vehicles and characterized for rheological behavior, texture profile analysis, in vitro release, ex vivo permeation and drug distribution into different layers of skin. The developed formulations were further evaluated in ex vivo and in vivo such as cell line study, imiquimod-induced psoriatic model, allergic contact dermatitis, rat tail model (% orthokeratosis) and safety test (Draize test). The MEs based MTX gel has shown its potential in locating the drug at the desired domain of stratum corneum, epidermal and dermal layers of skin and reducing systemic absorption. Our results are suggestive of MEs potential as a novel carrier for topical delivery of MTX in topical therapeutic and safety approaches. In conclusion, developed MEs-based hydrogel has shown promising results in achieving effective delivery of MTX.     

皮肤给药的经皮吸收与测量技术研究进展

经皮给药系统（TDDS）可避免首关效应、胃肠道破坏，为新型皮肤给药系统，可通过控制释放而延长治疗效果，成为药物制剂开发研究的热点之一。但是，药物的理化性质以及皮肤屏障影响药物的经皮吸收。综述了TDDS常用的促渗透技术，包括化学、物理、纳米、天然促渗透技术；介绍了促渗透能力的测定方法，包括体外、离体和体内评估皮肤渗透性的方法。通过对经皮药物递送系统和经皮吸收能力测定方法的归纳与总结，以期为TDDS的合理使用和快速发展提供参考。     

Formulation and in vitro/in vivo correlation of a drug‐in‐adhesive transdermal patch containing azasetron

The aim of the present study was to develop a transdermal drug delivery system for azasetron and evaluate the correlation between in vitro and in vivo release. The effects of different adhesives, permeation enhancers, and loadings of azasetron used in patches on the penetration of azasetron through rabbit skin were investigated using two‐chamber diffusion cells in vitro. For in vivo studies, azasetron pharmacokinetic parameters in Bama miniature pigs were determined according to a noncompartment model method after topical application of transdermal patches and intravenous administration of azasetron injections. The best permeation profile was obtained with the formulation containing DURO‐TAK 87‐9301 as adhesive, 5% of isopropyl myristate as penetration enhancer, and 5% of azasetron. The optimal patch formulation exhibited sustained release profiles in vivo for 216 h. The in vivo absorption curve in Bama miniature pigs obtained by deconvolution approach using WinNonlin® program was correlated well with the in vitro permeation curve of the azasetron patch. These findings indicated that the developed patch for azasetron is promising for the treatment of delayed chemotherapy‐induced nausea and vomiting, and the in vitro skin permeation experiments could be useful to predict the in vivo performance of transdermal azasetron patches. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4540–4548, 2012     

Systematically optimized topical delivery system for Loperamide hydrochloride: Formulation design,in vitro and in vivo biopharmaceutical evaluation

This study aimed to develop a suitable topical delivery system containing diethylene glycol monoethyl ether (DGME) for Loperamide hydrochloride (Lop). Two factors, three levels Central-Composite design were applied by generating a quadratic polynomial equation to form contour plots and response surface for prediction of responses as two selected independent variables with EtOH-DGME ratio and EtOH concentration. The response variables flux and skin retention were determined in in vitro hairless mouse skin model. The selected optimum formulation was evaluated for the skin transport characteristics by developing dermatokinetic analysis model and the results demonstrated DGME improved the delivery of Lop into skin deep layers, which was further confirmed by confocal laser scanning microscopy (CLSM) study. In vitro skin permeation was found to have triphasic correlation with plasma AUC in the in vivo pharmacokinetic study. The in vitro–in vivo correlation enabled the prediction of pharmacokinetic profile of Lop from in vitro permeation results. Therefore, the optimum formulation capable of enhancing Lop intracutaneous depot could be a candidate for topical delivery of Lop as analgesics.     

In vitro and in vivo evaluation of three metronidazole topical products

Abstract

Two 1% and one 0.75% metronidazole cream products were approved as bioequivalent products. These products were evaluated for their in vivo cutaneous penetration characteristics by dermatopharmacokinetic (DPK) and dermal microdialysis (DMD) sampling methodologies. The same three products were also evaluated for their rheological and in vitro drug release (IVR) properties. Structural differences were observed in the resulting flow curves. However, similar IVR profiles were obtained for the two topical semisolid dosage forms containing 1% metronidazole. For the lower strength product, a higher IVR rate was associated with the lower DPK profile. All three products exhibited similar values of area under the curve when investigated by DMD. This in vitro evaluation corroborated the divergent penetration characteristics found using in vivo methodologies.     

Estimation of Skin Target Site Acyclovir Concentrations Following Controlled (Trans)dermal Drug Delivery in Topical and Systemic Treatment of Cutaneous HSV-1 Infections in Hairless Mice

The use of controlled transdermal delivery of acyclovir (AC V) in the treatment of cutaneous herpes simplex virus type 1 infections in hairless mice was investigated. Using an in vivoanimal model (A. Gonsho, et al. Int. J. Pharm. 65:183–194 (1990)) made it possible to quantify both, the topical and the systemic antiviral efficacy of ACV transdermal patches as a function of the drug delivery rate of the patches. Drug delivery rates required to attain systemic efficacy were found to be higher than the rates required to attain the same magnitude of topical efficacy. The ACV concentrations in the basal cell layer of the epidermis for 50% topical efficacy and 50% systemic efficacy were estimated. The basal epidermis layer was considered to be the site of antiviral drug activity (skin target site). Systemic plasma levels were obtained from pharmacokinetic studies and were used to estimate the ACV concentration achieved systemically in the basal epidermis layer. A computational model for drug permeation across skin was employed to estimate the ACV concentration achieved topically in the basal epidermis layer. Equal topical and systemic efficacies were found to correspond to equal drug concentrations at the site of antiviral activity. The length of the effective diffusion pathway of drug molecules in the dermis prior to entering the blood circulation was assumed to be approximately equal to 1/20 of the anatomical dermis thickness because of dermis vascularization.     

Effect of Concentration and Degree of Saturation of Topical Fluocinonide Formulations on In Vitro Membrane Transport and In Vivo Availability on Human Skin

Purpose. The thermodynamic acitvity of drugs in topical vehicles is considered to significantly influence topical delivery. In vitro diffusion across a synthetic membrane was shown to be correlated to the degree of saturation of the drug in the applied vehicle and therefore offers a potential for increased topical drug delivery. Fluocinonide a topical corticosteroid, was chosen as a model compound to investigate in vitro and in vivo availability from formulations with different degrees of saturation. Methods. Sub-, as well as, supersaturated drug solutions were prepared using PVP as an antinucleant agent. In vitro membrane diffusion experiments across silicone membrane and in vivo pharmacodynamic activity assessments, using the human skin blanching assay, were carried out. Results. Over the concentration range studied, the in vitro membrane transport of fluocinonide was proportional to the degree of saturation of the respective formulations. The in vivo pharmacodynamic response in the human skin blanching assay was related to the concentration of the drug in the vehicle irrespective of the degree of saturation. Conclusions. From the membrane permeation experiment it can be concluded, that the drug flux might be increased supra-proportionally with increasing donor concentration, drug (super-)saturation (proportional), beyond what would be anticipated based on ideal donor concentration and partition coefficient considerations only. These findings could not be confirmed in the in vivo investigation, probably due to additional vehicle effects (e.g., enhancement, irritation, drug binding) which have to be expected and could have altered the integrity of the stratum corneum and therewith topical bioavailability of the drug.     

A combination of a microemulsion and a phospholipid complex for topical delivery of oxymatrine

Oxymatrine (OMT), a water-soluble drug, has a very low oral bioavailability because of its low membrane permeability and its biotransformation in the gastrointestinal tract. Formulated as an oxymatrine-phospholipid complex (OMT-PLC) can improve the lipid solubility and effectiveness of OMT. The purpose of this study was to explore the utility of the combination of a microemulsion and an OMT-PLC as a topical delivery vehicle for enhancing the absorption and efficacy of OMT. The solubility of OMT-PLC was determined and phase diagrams of microemulsions were constructed. Various microemulsion formulations were developed and characterized by their physicochemical properties, and their in vitro and in vivo permeability through skin. An optimal microemulsion (ME4), which presented as spherical droplets and consisted of 10.0% OMT-PLC, 8.0% isopropyl myristate, 30.0% Cremophor RH40/polyethylene glycol 400 (1:1) and 52.0% water, was selected. It possessed an average droplet size of 32.4 nm, a low viscosity of 113.7 mPa · s, and a high cloud point of 88°C. Compared to the control solution, ME4 provided better skin permeability in vitro and a higher retention ratio of OMT in skin in vivo. Moreover, ME4 significantly enhanced the antiproliferative activity of OMT on scar fibroblasts. These results indicate that the combination of a microemulsion and a phospholipid complex represents an effective vehicle for topical delivery of OMT.     

Transdermal Drug Transport and Metabolism. II. The Role of Competing Kinetic Events

The steady-state flux and skin tissue distribution of a topically applied diester of salicylic acid was measured in vitro in the presence and absence of an esterase inhibitor. When compared with data obtained previously under in vivo conditions, the results presented here provide insight into the role of competing diffusional and hydrolytic events in the delivery and distribution of topically applied drugs. Furthermore, these results, when combined with a theoretical analysis of topical drug delivery and metabolism, suggest that the differences in delivery and drug distribution seen under in vitro conditions are related to both altered drug removal and altered hydrolysis rates.     

Transdermal Delivery and Cutaneous Targeting of Antivirals using a Penetration Enhancer and Lysolipid Prodrugs

Purpose

In this work, we investigate prodrug and enhancer approaches for transdermal and topical delivery of antiviral drugs belonging to the 2,6-diaminopurine acyclic nucleoside phosphonate (ANP) group. Our question was whether we can differentiate between transdermal and topical delivery, i.e., to control the delivery of a given drug towards either systemic absorption or retention in the skin.

Methods

The in vitro transdermal delivery and skin concentrations of seven antivirals, including (R)- and (S)-9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine (PMPDAP), (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine ((S)-HPMPDAP), its 8-aza analog, and their cyclic and hexadecyloxypropyl (HDP) prodrugs, was investigated with and without the penetration enhancer dodecyl-6-(dimethylamino)hexanoate (DDAK) using human skin.

Results

The ability of ANPs to cross the human skin barrier was very low (0.5–1.4 nmol/cm²/h), and the majority of the compounds were found in the stratum corneum, the uppermost skin layer. The combination of antivirals and the penetration enhancer DDAK proved to be a viable approach for transdermal delivery, especially in case of (R)-PMPDAP, an anti-HIV effective drug (30.2?±?2.3 nmol/cm²/h). On the other hand, lysophospholipid-like HDP prodrugs, e.g., HDP-(S)-HPMPDAP, reached high concentrations in viable epidermis without significant systemic absorption.

Conclusions

By using penetration enhancers or lysolipid prodrugs, it is possible to effectively target systemic diseases by the transdermal route or to target cutaneous pathologies by topical delivery.     

Dermal Penetration of Fentanyl: Inter‐ and Intraindividual Variations

Abstract: Fentanyl is a potent synthetic opioid that is increasingly being used in transdermal drug delivery systems. The target organ concentration of a drug administered dermally will depend on the rate of dermal absorption and the systemic elimination. We have studied the intra‐ and interindividual variation in dermal penetration of fentanyl in an in vitro model (static diffusion cells) with human skin, and compared the absorption of fentanyl from an aqueous solution with absorption from a commercial patch. The intraindividual variation in dermal penetration of fentanyl in aqueous solution was limited (18%) and no differences in penetration characteristics were observed between breast and abdominal skin. The interindividual variation in dermal penetration of fentanyl was extensive, with maximal fluxes ranging from 21–105 ng/cm²/hr following application of an infinite dose of fentanyl to the donor chamber. Use of transdermal drug delivery systems (patches) reduced the inter‐individual variation. The permeability coefficients after application of fentanyl in aqueous solution and through patches were identical (0.0011 cm/hr). One person had a higher than average penetration rate following patch application, which may indicate that the human skin and not the patch barrier was the rate‐determining factor for the other individuals included in this study.     

In vitro and ex vivo experimental models for evaluation of intranasal systemic drug delivery as well as direct nose-to-brain drug delivery

The intranasal route of administration provides a noninvasive method to deliver drugs into the systemic circulation and/or directly into the brain. Direct nose-to-brain drug delivery offers the possibility to treat central nervous system diseases more effectively, as it can evade the blood–brain barrier. In vitro and ex vivo intranasal models provide a means to investigate physiological and pharmaceutical factors that could play a role in drug delivery across the nasal epithelium as well as to determine the mechanisms involved in drug absorption from the nose. The development and implementation of cost-effective pharmacokinetic models for intranasal drug delivery with good in vitro-in vivo correlation can accelerate pharmaceutical drug product development and improve economic and ecological aspects by reducing the time and costs spent on animal studies. Special considerations should be made with regard to the purpose of the in vitro/ex vivo study, namely, whether it is intended to predict systemic or brain delivery, source and site of tissue or cell sampling, viability window of selected model, and the experimental setup of diffusion chambers. The type of model implemented should suit the relevant needs and requirements of the project, researcher, and interlaboratory. This review aims to provide an overview of in vitro and ex vivo models that have been developed to study intranasal and direct nose-to-brain drug delivery.     

Assessment of Subconjunctival Delivery with Model Ionic Permeants and Magnetic Resonance Imaging

No HeadingPurpose. The objective was to assess the permeation and clearance of model ionic permeants after subconjunctival injection with nuclear magnetic resonance imaging (MRI).Methods. New Zealand white rabbit was the animal model and manganese ion (Mn²⁺) and manganese ethylenediaminetetraacetic acid complex (MnEDTA^2–) were the model permeants. The current study was divided into three parts: in vitro, postmortem, and in vivo. Transscleral passive permeation experiments were conducted with excised sclera in side-by-side diffusion cells in vitro. Subconjunctival delivery experiments were conducted with rabbits postmortem and in vivo. The distribution and elimination of the probe permeants from the subconjunctival space after subconjunctival injections were determined by MRI.Results. The data of excised sclera in vitro suggest large effective pore size for transscleral transport and negligible pore charge effects upon the permeation of the ionic permeants. The permeability coefficients of Mn²⁺ and MnEDTA^2- across the sclera in vitro were 3.6 × 10^-5 cm/s and 2.4 × 10^-5 cm/s, respectively. Although relatively high sclera permeability was observed in vitro, subconjunctival injections in vivo did not provide significant penetration of Mn²⁺ and MnEDTA^2- into the globe; permeant concentrations in the eye were below the detection limit, which corresponds to less than 0.05% of the concentration of the injection solution (e.g., less than 0.02 mM when 40 mM injection solution was used). The volume of the subconjunctival pocket and the concentration of the permeants in the pocket were observed to decrease with time after the injection, and this could contribute to the lower than expected subconjunctival absorption in vivo. Different from the results in vivo, experiments with rabbits postmortem show significant penetration of Mn²⁺ and MnEDTA^2- into the globe with the permeants primarily delivered into the anterior segment of the eye. This difference suggests blood vasculature clearance as a main barrier for passive transscleral transport. The data also show that the pars plicata/pars plana is the least resistance pathway for passive transscleral drug delivery of the polar permeants, and there are indications of the presence of another barrier, possibly the retinal epithelium and/or Bruchs membrane, at the back of the eye.Conclusions. Subconjunctival delivery of the ionic permeants in vivo cannot be quantitatively predicted by the in vitro results. MRI is a noninvasive complementary technique to traditional pharmacokinetic methods. It can provide insights into ocular pharmacokinetics without permeant redistribution that can occur in surgical procedure postmortem in traditional pharmacokinetic studies when the blood vasculature barrier is absent.     

Niosomes as a propitious carrier for topical drug delivery

Introduction: Topical delivery is defined as drug targeting to the pathologic sites of skin with the least systemic absorption. Drug localization in this case is a crucial issue. For these purposes vesicular drug delivery systems including niosomes, proniosomes, liposomes and transferosomes have been developed.

Areas covered: This review first highlights the role of niosome in dermatology focusing on localized skin delivery and then reviews the most recent literatures regarding specific applications of niosomal drug delivery systems in clinics.

Expert opinion: Niosomes are becoming popular in the field of topical drug delivery due to their outstanding characteristics like enhancing the penetration of drugs, providing a sustained pattern of drug release, increasing drug stability and ability to carry both hydrophilic and lipophilic drugs.