Natural products as potential drug permeation enhancer in transdermal drug delivery system

Permeation enhancers are defined as substances that are capable of promoting penetration of drugs into skin and transdermal therapeutic systems offers a more reliable mean of administering drug through the skin. Skin is a natural barrier so it is necessary to employ enhancement strategies to improve topical bioavailability. This review explores that natural products have got potential to enhance the permeation of the drug through skin by reversibly reducing the skin barrier resistance. The use of natural products is the most reliable means of permeation enhancement of transdermally administered drugs and permits the delivery of broader classes of drugs through the stratum corneum. They are safe, non-toxic, pharmacologically inert, non-irritating, and non-allergenic to use as permeation enhancers. The present review initially highlights the current status of natural products on the basis of SAR studies which have shown significant enhancer activities.     

Evaluation of liposomal delivery system for topical anesthesia

Local anesthesia is an integral aspect of cutaneous surgery. Its effects provide a reversible loss of sensation in a limited area of skin, allowing dermatologists to perform diagnostic and therapeutic procedures safely, with minimal discomfort and risk to the patient. Moreover, the skin acts as a major target as well as principle barrier for topical/transdermal (TT) drug delivery. The stratum corneum (SC) plays a crucial role in barrier function for TT drug delivery. Despite the major research and development efforts in TT systems and their implementation for use of topical anesthetics, low SC permeability limits the usefulness of topical delivery, which has led to other delivery system developments, including vesicular systems such as liposomes, niosomes, and proniosomes, with effectiveness relying on their physiochemical properties. This review gives indepth coverage of liposomes and their use as a delivery route for topical anesthetics.     

Imaging the prodrug-to-drug transformation of a 5-fluorouracil derivative in skin by confocal Raman microscopy

The widespread adoption of transdermal drug delivery has been limited by the barrier properties of the outermost layer of the epidermis, the stratum corneum (SC). A variety of approaches have been developed to overcome the barrier, including the use of a prodrug form of an active therapeutic agent to enhance transdermal delivery. Once in the epidermis, the pro-molecule is converted to the active drug by endogenous enzymes or simple chemical hydrolysis. The prodrug selected for the current studies, 1-ethyloxycarbonyl-5-fluorouracil, is known to enhance transdermal delivery of 5-fluorouracil, an important systemic antitumor drug. Using confocal Raman microscopy on pigskin biopsies treated with prodrug, we are able to image the spatial distribution of both prodrug and drug in the SC and viable epidermis, thereby providing information about permeation and metabolism. This approach may readily be extended to a variety of dermatological processes.     

Sensitive and ethnic skin. A need for special skin-care agents?

Sensitive skin is a complex problem with genetic, individual, environmental, occupational, and ethnic implications. Further work is needed to rank irritants and irritant reactions to classify sensitive skin on the basis of standard models. The development of topical products designed for sensitive and ethnic skin may be advisable to optimize drug activity with minimal side effects. The availability of transdermal systems for drug delivery highlights the problem. Occlusive transdermal patch systems for delivery of clonidine show sensitization rates of 34% in white women, 18% in white men, 14% in black women, and 8% in black men. Besides ethnic differences in transcutaneous penetration, individual and ethnic skin sensitivity may play an important role in determining both patient compliance and therapeutic efficacy of drugs and cosmetics; furthermore, a drug formulation considering skin physiology may prevent unwanted local and general adverse effects.     

经皮给药新技术——微针

微针给药是一种新型的经皮给药技术,克服皮肤局部给药后角质层对药物经皮渗透的屏障作用,促进药物的经皮吸收.该技术具有使用方便、无痛和可与多种技术联用的优点.为适应不同药物的给药需求,该技术不断发展,糖制微针、膜封微针等更加安全高效的微针相继出现,应用范围更加广阔.     

Transdermal Drug Delivery Systems and Skin Sensitivity Reactions

Transdermal devices are now marketed for the delivery of systemic medication through the skin. Advantages associated with transdermal drug delivery include avoidance of first-pass metabolism and variable absorption as well as improved patient compliance. Drugs currently available by this route include scopolamine, nitroglycerin (glyceryl trinitrate), estradiol, nicotine, clonidine, fentanyl, and testosterone. This novel development has brought about a specific constellation of skin problems which vary widely in incidence between drugs. It is important to vary the site of drug administration to minimize these reactions. Any eczematous reaction can be treated with a moderately potent topical corticosteroid. Patients with topical sensitivity are usually tolerant of oral challenge but systemic sensitization has been reported and caution is still advocated before proceeding to this step. The increasing use of transdermal drug delivery systems across many specialities means that problems of skin sensitivity are of growing relevance to the dermatologist, the hospital specialist, and the primary care physician.     

A review of the effect of occlusive dressings on lamellar bodies in the stratum corneum and relevance to transdermal absorption

Transdermal drug delivery is becoming a widely used tool in the pharmaceutical industry. Many factors can influence the transdermal flux of medication from a transdermal drug delivery system. The recently described skin physiology of lamellar bodies and skin responses to occlusive dressings provide new insights into transdermal drug delivery. This paper reviews the literature on occlusive dressings and lamellar bodies as it relates to transdermal drug delivery. An understanding of the physiology of lamellar bodies is important to understand and improve transdermal drug delivery.     

Testing of controlled-release transdermal dosage forms. Product development and clinical trials

In vitro techniques have been developed that are predictive of drug permeation through skin. Methods also have been developed to determine the skin irritation potential of a drug substance during the preclinical stages of transdermal dosage form development. Clinical studies are performed to test for skin irritation, contact sensitization, plasma levels of drug, and efficacy of the dosage form. In theory, these studies should be predictive of a dosage form's performance in routine clinical use. This may not be the case, however; contact sensitization cannot be predicted with absolute certainty beforehand in animals. This article discusses various aspects of testing transdermal dosage forms and how the results of these tests correlate with what happens when a transdermal dosage form is put into routine clinical use.     

Molecular skin barrier models and some central problems for the understanding of skin barrier structure and function

A better understanding of the structure and function of the human skin barrier is a prerequisite for a more rational design of transdermal drug administration systems. The study of biological structural organisation is, however, confronted with many difficulties, and interpretations of skin barrier-related data should therefore be done with caution. The recently developed 'single gel-phase model' constitutes an attempt to interpret structural and functional skin barrier data from a biophysical standpoint.     

Transdermal therapeutic systems (TTS)

The technique, pharmacokinetics, and advantages and disadvantages of transdermal drug delivery systems (TDS) are discussed. Special emphasis is laid on the dermatological problems arising during use of the TDS, such as irritation, sensitization, and the effects of occlusion, dermatoses, skin microflora and epidermal metabolism.     

Sensitization of mice to topically applied drugs: albuterol chlorpheniramine, clonidine and nadolol

Allergic contact dermatitis from drugs is a significant obstacle to the development of transdermal drug delivers systems. Protocols for the sensitization of mice to drugs are needed to test methods for the prevention of allergic contact dermatitis. CBA/J female mice were sensitized to the drugs albuterol, chlorpheniramine, clonidine and nadolol by topical application. Sensitization was achieved by application of drug at 5% (w/v) 10 shaven dorsal skin for 5 days in a hydroxyethylcellulose vehicle. Contact serialization was determined by measuring the car swelling response to application of l%. drug in vehicle. Control mice treated by application of vehicle alone did not exhibit an ear swelling response to drug. Supplementation of the mice with vitamin A boosted the ear swelling response, as did application of drug to dorsal versus abdominal skin. Although plasma amounts of retinol were higher in vitamin A supplemented versus control mice, the rate of drug (albuterol and nadolol) permeation was not significantly different between vitamin A supplemented and control mice. Permeability of dorsal skin for nadolol was twice that of ventral skin, which may explain the differences in sensitization at these sites. This sensitization protocol should be useful in the development of hypoallergenic transdermal drug delivery systems.     

Solvent effects in permeation assessed <Emphasis Type="Italic">in vivo</Emphasis> by skin surface biopsy

Background  

Transdermal drug delivery has become an important means of drug administration. It presents numerous advantages but it is still limited by the small number of drugs with a suitable profile. The use of solvents that affect the skin barrier function is one of the classic strategies of penetration enhancement. Some of these solvents have well characterised actions on the stratum corneum, but the majority are still selected using empirical criteria. The objective of this work was to conduct a systematic study on the ability to affect skin permeation of solvents commonly used in transdermal formulations. An innovative methodology in this area was employed, consisting of the combination of skin surface biopsy with colorimetry.     

The pretreatment effect of chemical skin penetration enhancers in transdermal drug delivery using iontophoresis.

The transdermal drug delivery (TDD) system has largely been divided into physical, biochemical and chemical methods. Recently, combinations of these methods were introduced for more effective delivery with less side effects. We performed this study to identify the effectiveness and mechanism of TDD using the physical method, 'iontophoresis', plus the chemical method, 'pretreatment with chemical enhancer'. The action sites of chemical enhancers in the stratum corneum (SC) were observed by electron microscope. We also studied whether this combined method synergistically impaired the skin barrier. To confirm the synergistic effect on skin penetration by this combined method, we measured the blood glucose level after insulin iontophoresis following a chemical enhancer pretreatment in rabbits. The results were that (1) dilatation of the intercellular lipid layers of the SC and lacunae was prominent in pretreatment with chemical enhancers inducing high transepidermal water loss (TEWL); (2) the skin barrier impairment, with repeated treatments showing an increased TEWL and also epidermal proliferation, was increased with the chemical enhancers that showed a high TEWL immediately after treatment; (3) the combination of chemical enhancer pretreatment and iontophoresis showed no synergistic impairment of the skin barrier, and (4) the chemical enhancer pretreatment with greater impairment of the skin barrier could increase the delivery of insulin by iontophoresis. The results showed that a combination of chemical enhancer pretreatment and iontophoresis could deliver drugs more effectively than iontophoresis alone. Our proposed theory is that iontophoretic drug delivery may be easier through the dilated intercellular spaces of the SC which have a lower electrical impedance following the chemical enhancer pretreatment. Because the effect and the side effects in the combination are decided by the chemical enhancer rather than iontophoresis, the development of proper chemical enhancers is important in future plans.     

Several different ion channel modulators abrogate contact hypersensitivity in mice.

A major obstacle in transdermal delivery of drugs is the development of adverse skin sensitization reactions. We tested the concept that ion channel modulators as a class of agents suppress contact hypersensitivity in a mouse model. Mice were sensitized to several contact sensitizing chemicals including dinitrochlorobenzene (DNCB) and a sensitizing drug, nadolol. We report our successful use of several ion channel modulators in suppressing contact hypersensitivity, including amiloride, ethacrynic acid (ECA), nifedipine and verapamil. For this purpose, Balb/c female mice were sensitized with DNCB, and abrogation of induction of contact hypersensitivity reaction (CHR) was examined by topical pretreatment of the target-sensitized skin with amiloride, nifedipine and pairwise combinations of these agents with ECA, a potassium ion channel blocker. Abrogation of induction of CHR was observed in all cases. In addition, suppression of contact hypersensitivity was observed in nadolol-sensitized mice pretreated with either verapamil or nifedipine. The results indicate that ion channel inhibitors are broadly effective inhibitors of allergic contact dermatitis and may be useful for facilitating the transdermal delivery of therapeutic drugs that have sensitization potential.     

Skin irritation caused by transdermal drug delivery systems during long-term (5 days) application

We have studied the skin irritation produced by the prolonged application of transdermal therapeutic systems. The systems were applied to the skin of the back of male volunteers for 120 hours, and sweat accumulation and bacterial growth were studied. In some cases hydrogel discs were attached to the systems. The results showed that sweat accumulation contributed more to the skin irritation than the bacterial overgrowth. The incorporation of hydrogels in the transdermal delivery system may help to reduce skin irritation by absorbing water.     

Bioadhesive film for dermal and transdermal drug delivery

This paper describes an innovative transdermal drug delivery system, a monolaminated bioadhesive film in which the usual constituents of transdermal patches (backing, drug and adhesive) have been condensed in one single layer, denominated Patch-non-Patch. The main characteristics of the film is that it is not self-adhesive in the dry state but becomes adhesive only when applied on wet skin. This characteristic is due to the presence of a small amount of adhesive, unable to make the system self-adhesive, but capable of restoring the adhesiveness in contact with a small amount of water. From the results obtained to date, it appears that the technology Patch-non-Patch has the potentiality to be successfully applied to the pharmaceutical and cosmetic market. On the skin the film is flexible, invisible and adapts to all skin irregularities. The system has been shown to be highly efficient, releasing a high percentage of the active included in most cases. Additionally, the inclusion of other excipients can modulate drug delivery, thus improving the versatility of the product. Finally, the second generation Patch-non-Patch, made occlusive on the skin surface, can further broaden the potential application.     

A simple,noninvasive and efficient method for transdermal delivery of siRNA

Effective delivery of therapeutic agents is the most challenging hurdle in the use of RNA interference for research and in the clinic. Here, we assessed whether a short synthetic peptide, ACSSSPSKHCG (TD-1), could be transported through rat footpad (follicle-free) skin and efficiently deliver small interfering RNA (siRNA) to knock down a target gene. Fluorescence microscopy revealed that topical co-administration of FITC-labeled TD-1 and FAM-labeled siRNA distributed uniformly from the epidermis to the subcutaneous tissue of rat footpad skin. Transmission electron microscopy revealed the absence of cell–cell junctions and enlarged spaces between epithelial cells in the TD-1-treated footpad skin. TD-1 delivery of anti-GAPDH siRNA significantly reduced the level of GAPDH in 72 h. TD-1 can create a transient opening in non-follicle rat skin for delivery of siRNA and reveal a novel mechanism of transdermal delivery of TD-1 and siRNA into the epidermis for gene knockdown. The system might have potential for siRNA delivery in skin for drug therapy.     

Vehiculización de fármacos asistida por láser

Absorption of topical products through the epidermis is limited by the skin's barrier function. Numerous techniques and agents such as microneedling, dermabrasion, radiofrequency, and lasers have been used to increase penetration within an approach known as transdermal drug delivery. One of these techniques is laser-assisted drug delivery (LADD), which often uses ablative fractional lasers (CO₂ or erbium:YAG lasers) because of their capacity to produce microscopic ablated channels. The parameters in LADD need to be adjusted to the patient, the skin condition and its location, and the drug. LADD has been used with various topical products, such as corticosteroids, photosensitizers, and immunotherapy agents (imiquimod or 5-fluorouracil) to treat numerous conditions, including scars, nonmelanoma skin cancer, and photodamage. LADD is a promising technique that enhances the absorption of topical molecules while adding the synergic effect of the laser.     

Delivering drugs by the transdermal route: review and comment

Background: There are many advantages to administering drugs by routes that bypass the gastrointestinal tract. One such route is the transdermal in which the drug agent is applied to the skin in a patch or device of some type so that sufficient quantity penetrates the skin to exert a systemic effect. There are several theoretical advantages to this approach not the least of which is that the drug avoids being metabolized by the liver after absorption and that gastrointestinal irritation is avoided.
Aims: To discuss the various ways in which drugs can be persuaded to cross the skin barrier and also to discuss the adverse effects of transdermal administration. Technical advances have permitted an increasing number of drugs to be offered in the transdermal format.     

Interfacial kinetics effects on transdermal drug delivery: a computer modeling

Background/purpose: Percutaneous permeation is a frequently used approach in drug delivery, but the detailed physics process in the patch – stratum corneum (SC) – viable epidermis system remains unclear: the influence of the interphases in the multilayered structure has been little studied.
Methods: This paper applied the finite-element method to develop a contact algorithm with an interphase element to account for the interphase barrier on drug diffusion and chemical absorption during a transdermal drug delivery process. A more realistic multilayer structure, including the patch, SC and viable epidermis, are incorporated into the algorithm. Both interphases between the patch and SC, and between SC and viable epidermis are considered.
Results: Our study confirms that the interphase transfer coefficients have a direct connection with drug concentration and flux distribution along the diffusion paths. The simulation results suggested a potential for the optimal control of drug diffusion. The partition coefficients and other interphase barrier factors can be incorporated into the model.
Conclusions: The algorithm can deal with complicated geometrical conditions, which is difficult using classical analytical approaches. Furthermore, calibrated against experiments, the model may predict more realistically the drug delivery process and drug distribution profiles so as to assist in the patch and even drug design.