Transdermal Absorption Of Drugs Research Articles

MRNA expression levels of cytochrome P450 CYP1A2, CYP3A4, and CYP3A5 in the epidermis: a focus on individual differences among Japanese individuals

Various cytochrome P450 enzymes (CYPs) that contribute to drug metabolism are expressed in the skin. However, variation among individuals in CYP expression profiles is not well-understood. To investigate CYPs related to the metabolism of transdermal preparations in Japan, multiple skin tissue specimens of individuals of Japanese descent were prepared, and the mRNA expression levels of CYP1A2, CYP3A4, and CYP3A5 were measured. Associations between the expression patterns of these CYPs and body mass index (BMI) were also investigated. There were considerable individual differences in epidermal CYP1A2 mRNA expression levels, and CYP1A2 showed a weak positive correlation with CYP3A4 mRNA expression levels. In contrast to previous results for other organs, epidermal CYP3A4 mRNA expression levels showed a weak positive correlation with BMI. CYP3A4 in the epidermis may have been locally enhanced as a defence mechanism against xenobiotics in response to impaired barrier function. These differences in mRNA expression in the skin may affect the transdermal absorption of drugs, such as lidocaine and fentanyl, which are metabolised by multiple overlapping CYPs. Our study provides new insights into drug metabolism in the skin. These results are valuable for predicting drug effects and transdermal drug transfer rates in Japanese patients.

Topical drug delivery strategies for enhancing drug effectiveness by skin barriers, drug delivery systems and individualized dosing.

Topical drug delivery is widely used in various diseases because of the advantages of not passing through the gastrointestinal tract, avoiding gastrointestinal irritation and hepatic first-pass effect, and reaching the lesion directly to reduce unnecessary adverse reactions. The skin helps the organism to defend itself against a huge majority of external aggressions and is one of the most important lines of defense of the body. However, the skin's strong barrier ability is also a huge obstacle to the effectiveness of topical medications. Allowing the bioactive, composition in a drug to pass through the stratum corneum barrier as needed to reach the target site is the most essential need for the bioactive, composition to exert its therapeutic effect. The state of the skin barrier, the choice of delivery system for the bioactive, composition, and individualized disease detection and dosing planning influence the effectiveness of topical medications. Nowadays, enhancing transdermal absorption of topically applied drugs is the hottest research area. However, enhancing transdermal absorption of drugs is not the first choice to improve the effectiveness of all drugs. Excessive transdermal absorption enhances topical drug accumulation at non-target sites and the occurrence of adverse reactions. This paper introduces topical drug delivery strategies to improve drug effectiveness from three perspectives: skin barrier, drug delivery system and individualized drug delivery, describes the current status and shortcomings of topical drug research, and provides new directions and ideas for topical drug research.

A novel natural polysaccharide dissolving microneedle capable of adsorbing pus to load EGCG for the treatment of acne vulgaris

Acne vulgaris is a common inflammatory skin disease associated with Propionibacterium acnes (P. acnes), with serious physical and psychological effects on patients. Conventional topical use of antibiotics is not effective due to the skin barrier and oral administration can adversely affect the intestinal flora. Microneedle is a novel type of localized drug delivery system that noninvasively breaks through the stratum corneum barrier and effectively enhances the transdermal absorption of drugs. Here, Bletilla striata polysaccharide (BSP)/Hyaluronic acid (HA) loaded Epigallocatechin gallate (EGCG) was used as the microneedle body to easily penetrate the epidermis and enhance antibacterial ability. Polyvinyl alcohol (PVA) and Diatomaceous earth (DE) are used as the microneedle backing to absorb pus and bacterial debris, prevent re-infection of bacteria and promote skin healing. Compared to traditional antibiotics, the excellent skin permeability of EGCG@BSP/HA MNs studied here can improve the efficacy and solve side effects and drug resistance. In vivo studies in mice models induced by P. acnes showed that this microneedle could effectively reduce skin swelling, inhibit bacterial growth and reduce the levels of TNF-α, IL-8 and MMP-2. In summary, this study provides an ideal antimicrobial drug delivery system for the treatment of acne vulgaris.

Design and Development of Functionalized Single-walled Carbon Nanotube-ethosomes for Transdermal Delivery of Ketoprofen.

The purpose of this study was to combine carbon nanotube with ethosomes in order to obtain hybrid nanocarriers for transdermal delivery of ketoprofen (KP). KP-loaded functionalized single-walled carbon nanotube (f-SWCNTs) composite ethosomes (f-SWCNTs-KP-ES) were designed and were verified by a series of characterizations. The particle size of the preparation is less than 400 nm. DSC and XRD experiments showed that KP existed in an amorphous state after it was adsorbed and loaded on f-SWCNTs. TEM experiments showed that the structure of SWCNTs remained intact after oxidation and modification by PEI. FTIR results showed that PEI were successfully modified on the surface of SWCNT-COOH, and KP was successfully loaded on f-SWCNTs. In vitro release characteristics showed that the preparation had sustained release behavior and conformed to the first-order kinetic equation model. In addition, f-SWCNTs-KP-ES gel were prepared and in vitro skin permeation and in vivo pharmacokinetics were studied. The results showed that f-SWCNTs-KP-ES gel could enhance the skin permeation rate of KP and increase the drug retention of drugs in the skin. The characterization results consistently showed f-SWCNTs is a promising drug carrier. The hybrid nanocarrier prepared by the combination of f-SWCNTs and ethosomes can enhance the transdermal absorption of drugs and improve the bioavailability of drugs, which has a certain significance for the development of advanced hybrid nano-preparations.

Influence of Types of Media and Modes of Therapeutic Ultrasound on drug absorption in phonophoresis: A Comparative Experimental study on rabbits

Although non-invasive transdermal application of various pharmaco-therapeutic drugs via phonophoresis (PH) is widely used in physical therapy, the influence of the type of medium in which the drug is prepared and mode of ultrasound on drug absorption is hardly explored. Hence, the same formed the aim of this study. In this study, serum concentration of diclofenac sodium (DS) was quantified and compared between gel and cream medium, using continuous mode (CTUS) and pulsed (PTUS) mode of Therapeutic Ultrasound (TUS) respectively. Study was conducted on eight healthy adult rabbits with 1% DS in gel and cream as topical application (TA) and PH using TUS of 1 MHz with 1 W/cm2 in CTUS and 20% PTUS respectively for 8 minutes during each session. Blood samples were analysed for drug concentration in serum by High performance liquid chromatography (HPLC) assay. Comparison of DS concentration in plasma showed a significant difference with cream than gel medium in both CTUS (p=<.001) and PTUS (p=.005) mode. For the modes of TUS, PTUS showed significance against TA in both gel (p= <.001) and cream (p=.001) and with CTUS better with TA in cream (p = 0.003) medium. The transdermal drug absorption was significantly higher in the cream than gel medium, having similar results between continuous and pulsed TUS. PH also confirmed significantly higher drug absorption than TA in both media and modes of TUS.

Skin drug delivery using lipid vesicles: A starting guideline for their development.

Lipid vesicles can provide a cost-effective enhancement of skin drug absorption when vesicle production process is optimised. It is an important challenge to design the ideal vesicle, since their properties and features are related, as changes in one affect the others. Here, we review the main components, preparation and characterization methods commonly used, and the key properties that lead to highly efficient vesicles for transdermal drug delivery purposes. We stand by size, deformability degree and drug loading, as the most important vesicle features that determine the further transdermal drug absorption. The interest in this technology is increasing, as demonstrated by the exponential growth of publications on the topic. Although long-term preservation and scalability issues have limited the commercialization of lipid vesicle products, freeze-drying and modern escalation methods overcome these difficulties, thus predicting a higher use of these technologies in the market and clinical practice.

Validation and testing of a new artificial biomimetic barrier for estimation of transdermal drug absorption

Human skin remains the most reliable model for studying the transdermal permeation of active compounds. Due to the limited source, porcine skin has been used extensively for performing penetration tests. Performing penetration studies by using human and animal skin, however, would also involve a series of ethical issues and restrictions. For these reasons, new biomimetic artificial barriers are being developed as possible alternatives for transdermal testing. If appropriately optimized, such products can be cost-effective, easily standardized across laboratories, precisely controlled in specific experimental conditions, or even present additional properties compared to the human and animal skin models such as negligible variability between replicates. In this current work we use the skin mimicking barrier (SMB) for drug permeability tests. The aim was to evaluate the suitability of the new barrier for studying the percutaneous absorption of the lipophilic extract of the plant Zingiber officinale Roscoe in vitro and compare its permeability ability with the artificial membrane Permeapad® and porcine skin. Our results showed that the permeability values obtained through the SMB are comparable are comparable to those obtained by using the porcine skin, suggesting that the new barrier may be an acceptable in vitro model for conducting percutaneous penetration experiments.

The Nanostructured lipid carrier gel of Oroxylin A reduced UV-induced skin oxidative stress damage

Oxidative stress damage caused by sun exposure damages the appearance and function of the skin, which is one of the essential inducements of skin aging and even leads to skin cancer. Oroxylin A (OA) is a flavonoid with excellent antioxidant activity and has protective effects against photoaging induced by UV irradiation. However, the strong barrier function of the skin stratum corneum prevents transdermal absorption of the drug, which limits the application of OA in dermal drug delivery. Studies have shown that nanostructured lipid carriers (NLC) can promote not only transdermal absorption of drugs but also increase drug stability and control drug release efficiency, which has broad prospects for clinical applications. In this paper, NLC loaded with OA (OA-NLC) was prepared in order to improve the skin permeability and stability of OA. In vitro studies revealed that OA-NLC had better therapeutic effects than OA solution (OA-Sol) in the cellular model of UVB radiation. OA-Sol and OA-NLC were immobilized in a hydrogel matrix to facilitate application to the dorsal skin of mice. It was found that OA-NLC-gel showed significant antioxidant and anti-apoptotic activity compared to OA-Sol-gel, which was able to protect against skin damage in mice after UV radiation. These results suggest that OA-NLC can improve the deficiencies of OA in skin delivery and show better resistance to UV-induced oxidative damage. The application of OA-NLC to skin delivery systems has good prospects and deserves further development and investigation.

Homoharringtonine is a transdermal granular permeation enhancer

Although modulation of claudin-1-based tight junction (TJ) in stratum granulosum is an option for transdermal absorption of drugs, granular permeation enhancers have never been developed. We previously found that homoharringtonine (HHT), a natural alkanoid, weakened intestinal epithelial barrier with changing expression and cellular localization of TJ components such as claudin-1 and claudin-4. In the present study, we investigated whether HHT is an epidermal granular permeation enhancer. Treatment of normal human epidermal keratinocytes (NHEK) cells with HHT decreased claudin-1 and claudin-4 but not zonula occludens-1 and E-cadherin. HHT lowered TJ-integrity in NHEK cells, accompanied by permeation-enhancement of dextran (4 kDa) in a dose-dependent manner. Transdermal treatment of mice with HHT weakened epidermal barrier. HHT treatment enhanced transdermal absorption of dextran with a molecular mass of up to 10 kDa. Together, HHT may be a transdermal absorption enhancer.

Enhancing effect and mechanism of muscone on transdermal penetration of traditional Chinese medicine ingredients with different log P value

This study aimed to investigate the enhancing effect of muscone on the transdermal penetration of traditional Chinese medicine ingredients and explore its possible mechanism of action. The Franz diffusion cells were employed to investigate the effect of muscone on the transdermal permeation of a series of model drugs with a wide range of log P values. The solubilities at saturation and the stratum corneum(SC)/vehicle partition coefficients of model drugs were measured to evaluate the effect of muscone on drug thermodynamic activities and partition of drugs into SC. Attenuated total reflectance-Fourier transform infrared spectroscopy(ATR-FTIR) was employed to explore the effect of muscone on the molecular structure of SC. The results showed that muscone significantly promoted the transdermal penetration of hydrophilic and lipophilic drugs, and the enhancement ratio(ER) increased with the decrease in the log P. Muscone could interact with the SC lipids to increase the disorder and fluidity of lipid bilayer packing, which improved skin permeability and promoted transdermal absorption of drugs. This study provides a scientific basis for the application of muscone in traditional Chinese medicine topical preparations.

Application of RP-18 TLC Retention Data to the Prediction of the Transdermal Absorption of Drugs.

Several chromatographic parameters (RM0 and S obtained from RP-18 TLC with methanol—pH 7.4 phosphate buffer mobile phases by extrapolation to zero concentration of methanol; Rf and RM obtained from RP-18 TLC with acetonitrile—pH 7.4 phosphate buffer 70:30 v/v as a mobile phase) and calculated molecular descriptors (molecular weight—MW; molar volume—VM; polar surface area—PSA; total count of nitrogen and oxygen atoms—(N+O); H-bond donor count—HD; H-bond acceptor count—HA; distribution coefficient—log D; total energy—ET; binding energy—Eb; hydration energy—Eh; energy of the highest occupied molecular orbital—EHOMO; energy of the lowest unoccupied orbital—ELUMO; electronic energy—Ee; surface area—Sa; octanol-water partition coefficient—log P; dipole moment—DM; refractivity—R, polarizability—α) and their combinations (Rf/PSA, RM/MW, RM/VM) were tested in order to generate useful models of solutes’ skin permeability coefficient log Kp. It was established that neither RM0 nor S obtained in the conditions used in this study is a good predictor of the skin permeability coefficient. The chromatographic parameters Rf and Rf/PSA were also unsuitable for this purpose. A simple and potentially useful, purely computational model based on (N+O), log D and HD as independent variables and accounting for ca. 83% of total variability was obtained. The evaluation of parameters derived from RM (RM, RM/MW, RM/VM) as independent variables in log Kp models proved that RM/VM is the most suitable descriptor belonging to this group. In a search for a reliable log Kp model based on this descriptor two possibilities were considered: a relatively simple model based on 5 independent variables: (N+O), log D, RM/VM, ET and Eh and a more complex one, involving also Eb, MW and PSA.

Verification of P-Glycoprotein Function at the Dermal Barrier in Diffusion Cells and Dynamic "Skin-On-A-Chip" Microfluidic Device.

The efficacy of transdermal absorption of drugs and the irritation or corrosion potential of topically applied formulations are important areas of investigation in pharmaceutical, military and cosmetic research. The aim of the present experiments is to test the role of P-glycoprotein in dermal drug delivery in various ex vivo and in vitro platforms, including a novel microchip technology developed by Pázmány Péter Catholic University. A further question is whether the freezing of excised skin and age have any influence on P-glycoprotein-mediated dermal drug absorption. Two P-glycoprotein substrate model drugs (quinidine and erythromycin) were investigated via topical administration in diffusion cells, a skin-on-a-chip device and transdermal microdialysis in rat skin. The transdermal absorption of both model drugs was reduced by P-glycoprotein inhibition, and both aging and freezing increased the permeability of the tissues. Based on our findings, it is concluded that the process of freezing leads to reduced function of efflux transporters, and increases the porosity of skin. P-glycoprotein has an absorptive orientation in the skin, and topical inhibitors can modify its action. The defensive role of the skin seems to be diminished in aged individuals, partly due to reduced thickness of the dermis. The novel microfluidic microchip seems to be an appropriate tool to investigate dermal drug delivery.

Potential for Tight Junction Protein-Directed Drug Development Using Claudin Binders and Angubindin-1.

The tight junction (TJ) is an intercellular sealing component found in epithelial and endothelial tissues that regulates the passage of solutes across the paracellular space. Research examining the biology of TJs has revealed that they are complex biochemical structures constructed from a range of proteins including claudins, occludin, tricellulin, angulins and junctional adhesion molecules. The transient disruption of the barrier function of TJs to open the paracellular space is one means of enhancing mucosal and transdermal drug absorption and to deliver drugs across the blood–brain barrier. However, the disruption of TJs can also open the paracellular space to harmful xenobiotics and pathogens. To address this issue, the strategies targeting TJ proteins have been developed to loosen TJs in a size- or tissue-dependent manner rather than to disrupt them. As several TJ proteins are overexpressed in malignant tumors and in the inflamed intestinal tract, and are present in cells and epithelia conjoined with the mucosa-associated lymphoid immune tissue, these TJ-protein-targeted strategies may also provide platforms for the development of novel therapies and vaccines. Here, this paper reviews two TJ-protein-targeted technologies, claudin binders and an angulin binder, and their applications in drug development.

Effects of Sting Plant Extracts as Penetration Enhancers on Transdermal Delivery of Hypoglycemic Compounds.

Background and objectives: The percutaneous route is an interesting and inventive investigation field of drug delivery. However, it is challenging for drug molecules to pass through the skins surface, which is a characterized by its permeability barrier. The purpose of this study is to look at the effect of some penetration enhancers on in vivo permeation of insulin and insulin sensitizers (curcumin and rutin) through diabetes-induced mouse skin. Materials and Methods: Sting crude extracts of Dendrocnide meyeniana, Urtica thunbergiana Sieb. and Zucc, and Alocasia odora (Lodd.) Spach were used as the penetration enhancers. Mouse skin irritation was tested by smearing the enhancers for the measurements at different time points and the cell viability of the HaCaT human skin keratinocytes, which was determined by Trypan blue exclusion and MTT assays to evaluate human biosafety for these extracts after the mouse skin permeation experiments. Results: All enhancers induced a slight erythema without edema on the mouse skin that completely recovered after 6 h from the enhancer smears as compared with normal mouse skin. Furthermore, no damaged cells were found in the HaCaT keratinocytes under sting crude extract treatments. The blood sugar level in the diabetic mice treated with the insulin or insulin sensitizers, decreased significantly (p < 0.05) in the presence of enhancers. The area under the curve (AUC) values of transdermal drug delivery (TDD) ranged from 42,000 ± 5000 mg/dL x min without enhancers, to 30,000 ± 2000 mg/dL x min in the presence of enhancers. Conclusions: This study exhibited that natural plant extracts could be preferred over the chemically synthesized molecules and are safe and potent penetration enhancers for stimulating the transdermal absorption of drugs.

Phase Diagram of a Stratum Corneum Lipid Mixture.

Computational modeling of lipid ternary mixtures is challenging because of their complicated and segmented phase diagram, the long timescales required for mixing the system components, and the necessity to sufficiently sample the three-dimensional phase space. Here, we investigate a ternary system, which mimics the lipid matrix of the stratum corneum, the outermost layer of the epidermis and the primary barrier for transdermal drug absorption. Our system consists of ceramide, cholesterol, and lignoceric acid at 23 different composition ratios, which we study at two different temperatures using coarse-grained molecular dynamics (CG MD) simulations. As CG MD simulations heavily depend on the choice of parameters, first an improved set of ceramide CG parameters was developed that reproduces experimental and all-atom simulation data. Second, the performance of the recently updated MARTINI 2015 cholesterol force field was systematically evaluated and compared to the 2007 model. We provide a detailed analysis of the structural and dynamic properties of the ternary system, such as area per lipid, area compressibility modulus, lipid order parameters, bilayer thickness, lipid tail interdigitation, and lateral self-diffusion. Based on the analysis of these properties, we devise a phase diagram of the ternary system, where three different phases, namely, liquid-disordered, gel, and liquid-ordered, are observed. The individual occurrence of a certain phase not only depends on the component molar ratio and the temperature but also decisively on the employed cholesterol force field.

Expression of drug transporters in the human skin: comparison in different species and models and its implication for drug development

&lt;p class="ADMETabstracttext"&gt;It is clear that many drug transporters (both ABCs and SLCs) are present in the human skin. Different in vitro skin models can be used to investigate the role of drug transporters in the skin despite quantitative differences in expression profile across species. P-gp was shown to have an important influence on transdermal drug absorption in the skin and to function in “absorptive” transport, carrying substrate drugs from the skin surface to the dermis. This observation might be used to modulate drug distribution inside the skin. If drugs can be retained in the epidermis compartment by inhibition of the transporters, such property of the drug would be beneficial for treatment of dermatological diseases. Therefore, it might be feasible to control transdermal delivery of drugs to specific locations in the skin, by modulating the function of the transporters in the skin. We are at the dawn of an exciting period where drug transporters might be novel targets for improvement of drug delivery to the skin and for pharmacological intervention.&lt;/p&gt;

Advanced Analgesic Drug Delivery and Nanobiotechnology.

Transdermal administration of analgesic medications offers several benefits over alternative routes of administration, including a decreased systemic drug load with fewer side effects, and avoidance of drug degradation by the gastrointestinal tract. Transdermal administration also offers a convenient mode of drug administration over an extended period of time, particularly desirable in pain medicine. A transdermal administration route may also offer increased safety for drugs with a narrow therapeutic window. The primary barrier to transdermal drug absorption is the skin itself. Transdermal nanotechnology offers a novel method of achieving enhanced dermal penetration with an extended delivery profile for analgesic drugs, due to their small size and relatively large surface area. Several materials have been used to enhance drug duration and transdermal penetration. The application of nanotechnology in transdermal delivery of analgesics has raised new questions regarding safety and ethical issues. The small molecular size of nanoparticles enables drug delivery to previously inaccessible body sites. To ensure safety, the interaction of nanoparticles with the human body requires further investigation on an individual drug basis, since different formulations have unique properties and side effects.

Medical Micro-Needling

Microneedles are a modestly invasive technique that gained mass popularity, and is utilized to break the top skin layer into tiny holes which self regenerate and rejuvenate the skin and facilitate the delivery of certain nutrients, proteins, drugs, antiageing, products and vitamins on the skin surface and underneath in the form of mesotherapy, being a form of controlled intradermal (transdermal drug absorption) applications. It has been an extensively researched topic in the field of cosmetology and aesthetic dermatology and has grabbed great attention all over the world. It stimulates elastin and collagen production through a controlled cascade of inflammation initiation, and then followed by production and remodeling of collagen and elastin the skin dermis. Eventually it helps in thickening of the skin, improving its texture and appearance and by combating skin aging process.

NANOVECTORS FOR TRANSDERMAL ADMINISTRATION: WHERE ARE WE?

The skin is the most important barrier of human body to prevent the absorption of exogenous substances. Its ability to limit the absorption of exogenous substances is exercised by the most superficial layer of the epidermis, the stratum corneum, which consists of about 15-20 layers of corneocytes supported by keratin fibres. The extracellular spaces are filled with a very dense lipid matrix organized in periodic lamellae, whereas the interlamellar spaces are constituted by a more fluid lipid matrix. In addition, where the corneocytes are not perfectly overlapped, pores with a higher water content are created. This complex organization allows only the passive diffusion of small molecules with peculiar chemical-physical properties. In all the other cases, it is necessary to improve the transdermal absorption of drugs using techniques able to alter reversibly the functionality of the stratum corneum, such as chemical skin penetration enhancers, iontophoresis or sonophoresis. In the era of nanotechnology, an intense effort has been made to design nanocarriers able to permeate the skin (e.g., polymeric nanoparticles, metal or solid-lipid, micro- and nanoemulsions, lipid vesicles). Nevertheless, the results are contradictory and there is scepticism in the scientific community about the real benefits of these systems compared to other traditional approaches. In fact, assuming the stratum corneum as a nanoporous membrane with openings of about 20-40 nm, the size of most of the nanocarriers is too big for permitting theoretically the skin penetration and diffusion. However, despite this consideration, on the market there are some medicinal products consisting of lipid vesicles. Starting from the critical analysis of the published information on possible permeation mechanisms of different types of nanocarriers, this review outlines lights and shadows on the (trans-)dermal administration of these drug delivery systems.

Effect of microplasma irradiation on skin barrier function

In this paper, we introduce the feasibility of atmospheric-pressure argon microplasma irradiation (AAMI) to promote percutaneous absorption. A hairless Yucatan micropig skin was used for this ex vivo study. After AAMI, the disturbance in the stratum corneum (SC) lipids was observed using attenuated total reflectance-Fourier transform infrared spectroscopy. Also, an increase in transepidermal water loss and no physical damage on pig skins were confirmed by microscopic observation. These results of AAMI were compared with those of a plasma jet irradiation (PJI) and a tape stripping test (TST) leading to the conclusion that AAMI reduces the barrier function of the skin and could also enhance the transdermal absorption of drugs.