Review Article Technologies in Transdermal Drug
Total Page：16
File Type：pdf, Size：1020Kb
INTERNATIONAL JOURNAL OF PHARMACEUTICAL AND CHEMICAL SCIENCES ISSN: 22775005 Review Article Technologies in Transdermal Drug Delivery System: A Review Dharmaraj Dnyneshwar Biradar* and Nikita Sanghavi MET’S Institute of Pharmacy, Bandra (west), Mumbai-400 050, India. ABSTRACT Transdermal drug delivery system is the system in which the delivery of the drug occurs through skin. It offers a convenient way to deliver drugs without the drawbacks as in case of standard hypodermic injections relating to issues such as patient acceptability and injection safety. The success of transdermal drug delivery has been severely limited due to the inability of most of the drugs to enter the skin at therapeutically useful rates. The stratum corneum acts as a barrier that limits the penetration of substances through the skin. In recent years various passive and active strategies have emerged to optimise delivery. However passive approach do not significantly improve the permeation of drugs with molecular weight > 500 Da. In contrast active methods, normally involving physical or mechanical methods of enhancing delivery has been shown to be generally superior. The delivery of drugs of differing lipophilicity and molecular weight including proteins, peptides and oligonucletides has been showed to be improved by active methods. This review covers the recent findings in various advanced techniques of enhancement of drug delivery which includes jet injectors, iontophoresis, ultrasound, thermal ablation, biodegradable microneedles. Keywords: Transdermal drug delivery system, iontophoresis, microneedles. INTRODUCTION Transdermal drug delivery systems (TDDS) To increase skin permeability, a number of are defined as self-contained discrete different approaches has been studied, dosage forms which, when applied to intact ranging from chemical/ lipid enhancers to skin, deliver the drug(s), through the skin, electric fields employing iontophoresis and at a controlled rate to systemic circulation. electroporation to pressure waves The main advantage of this approach is generated by ultrasound or photoacoustic that the drug is entered into the body effects. Although the mechanisms are all undistorted without being passed through different, these methods share a common the body’s various defense systems. In goal to disrupt stratum corneum structure contrast to oral administration the most in order to create “Holes” big enough for convenient way of drug administration, the molecules to pass through. The size of transdermal route does not suffer from disruptions generated by each of these drug degradation in the gastrointestinal methods is believed to be of nanometer tract and reduced potency through first- dimensions, which is large enough to pass metabolism ( i.e. in the liver ). In permit transport of small drugs and, in addition, oral-specific side effects like liver some cases, macromolecules, but probably damages are avoided. Transdermal patches small enough to prevent causing damage were introduced in the late 1970’s, starting of clinical significance. An alternative with a 3 day patch to treat motion approach involves creating larger transport sickness. Since then, the market for drug pathways of micron dimensions using array administration through patches has been of microscopic needles. These pathways steadily increasing. However transdermal are orders of magnitude bigger than delivery is severely limited by the inability molecular dimensions and, therefore, should of the majority of drugs to cross skin at readily permit transport of macromolecules therapeutic rates due to the barrier as well as possibly supramolecular imposed by the skin’s outer stratum complexes and microparticles. Despite their corneum layer. very large size relative to drug dimensions, Vol. 3 (2) Apr-Jun 2014 www.ijpcsonline.com 528 INTERNATIONAL JOURNAL OF PHARMACEUTICAL AND CHEMICAL SCIENCES ISSN: 22775005 on a clinical length scale they remain corneum, a 10-20μm thick layer of 15-30 small. 6, 15 stacked, dead cornified cells. The dermis represents the bulk of the skin and the Advantages of transdermal drug delivery predominant components are collagen systems fibers and a smaller amount of elastin. 1. Easy elimination of drug delivery This fibrous network gives tensile strength during toxicity. and elasticity to the skin and also provides 2. Avoidance of first pass metabolism support for nerve and vascular networks. of drugs In the upper, papillary, region of the 3. Reductions of fluctuations in plasma dermis the collagen fibers are small and levels of drugs, Utilization of drug loosely distributed. The deep reticular candidates region contains densely packed, bundled with short half-life and low collagen fibers mainly running parallel to therapeutic index the skin surface and along certain 4. Reduction of dosing frequency directions, called Langer’s lines. The hence increased patient compliance. dermis rests on the hypodermis which is 5. Self administration is possible with composed of loose fatty connective tissue. these systems. Its thickness varies considerably over the 6. Simplified medication regimen leads surface of the body as well as between to increased patient compliance. individuals.9, 14 7. Avoidance of gastrointestinal incompatibility. Drug delivery routes across human skin 8. When oral route is unsuitable as Drug molecules in contact with the skin with vomiting and diarrhoea then surface can penetrate by three potential transdermal route is an alternative pathways : through the sweat ducts, via to deliver the drug candidate. the hair follicles and sebaceous glands ( collectively called the shunt or appendageal Limitations of transdermal drug delivery route ), or directly across the stratum systems corneum ( fig 2 ). The relative importance of 1. Only potent drugs are suitable shunt or appendageal route versus candidates for transdermal delivery. transport across the stratum corneum has 2. This system is uneconomical. been debated by scientists over the years 3. Skin irritation may occur in some and is further complicated by the lack of patients at the site of application. suitable experimental model to permit 4. The system is not suitable for separation of the three pathways. drugs that require high blood Scheuplein and colleagues19, proposed that levels. a follicular shunt route was responsible for 5. The barrier function of the skin the pre-steady permeation of polar changes from site to site in the molecules and flux of large polar same person, person to person and molecules or ions that have difficulty also with age. diffusing across the intact stratum corneum. However it is generally accepted that as Anatomy of skin the appendages comprise a fractional area The skin is the largest organ of the for permeation of approximately 0.1 % their human body and has several functions. It contribution to steady state flux of most is a physical barrier towards the drugs is minimal. This assumption has environment, it regulates body temperature resulted in the majority of skin penetration and fluid loss, it conveys sensory enhancement techniques being focused on information to the nervous system, and it increasing transport across the stratum processes immunologic information to the corneum rather than via the appendages. immune system. The skin has a surface Exceptions are iontophoretic drug delivery area of about 1.5 to 2 m2 in adults and it which uses an electric charge to drive contains glands, hair and nails. molecules into the skin primarily via the The skin can be divided into three layers : shunt routes as they provide less electrical the superficial epidermis, dermis and charge, and vesicular delivery.5, 9 hypodermis (fig 1). The epidermis is approximately 50-150 μm thick and consists 1. Transappendageal route of constantly renewing, outward moving This is also called as the shunt pathway. cells called keratinocytes. The outermost In this route the drug molecule may layer of the epidermis is the stratum transverse through the hair follicles, the Vol. 3 (2) Apr-Jun 2014 www.ijpcsonline.com 529 INTERNATIONAL JOURNAL OF PHARMACEUTICAL AND CHEMICAL SCIENCES ISSN: 22775005 sebaceous pathway of the pilosebaceous phospholipid bilayer of the cell one more apparatus or the aqueous pathway of the time. This series of steps is repeated salty sweat glands. The transappendageal numerous times to traverse the full pathway is considered to be of minor thickness of the stratum corneum. importance because of its relative smaller area ( less than 0.1 % of total surface ). Intercellular penetration Non polar substances follow the route of 2. Transcorneal penetration intercellular penetration. These molecules Intracellular penetration dissolve in and diffuse through the non- Drug molecule passes through the cells of aqueous lipid matrix imbibed between the the stratum corneum. It is generally seen protein filaments. Although the thickness of in case of hydrophilic drugs. Although this the stratum corneum is about 20μm, the is the path of shortest distance, the drugs actual diffusional path of most molecules encounter significance resistance to crossing the skin is on the order of permeation. This is because the drugs 400μm. The 20-fold increase in the actual must cross the lipophilic membrane of path of permeating molecules greatly each cell, then the hydrophilic cellular reduces the rate of drug penetration. contents containing keratin, and then the Table 1: Regional variations in water permeability of stratum corneum 2 Diffusivity S.No. Skin region Thickness (μm) Permeation