A Review on Transdermal Drug Delivery Systems
Ch. Nagadev*, M. Durga Srinivasa Rao, P. Venkatesh, D. Hepcykalarani, R. Prema
Jagan’s Institute of Pharmaceutical Sciences, Jangalakandrika (V)- 524326, Muthukur (M),
Nellore (Dist.), A.P., India.
*Corresponding Author E-mail: nagadevchpharma@gmail.com
ABSTRACT:
Transdermal drug delivery systems (TDDS) are the dosage form of adhesive patch that is placed on the skin to deliver specific dose of medication through the skin and in to the blood stream. For the delivery of therapeutic agents through the human skin for systemic effects, the comprehensive morphological, bio physical and physicochemical properties of the skin are to be considered. An advantage of trans dermal drug delivery route over other type of medication is that a patch provides not only a controlled release, but also a constant administration of the drug and eliminates pulsed entry into the systemic circulation which often causes un desirable side effects. One of the most important novel drug delivery system is transdermal patch and it is a painless technique for administration of drug. The TDDS review article provides variable information regarding TDDS and its evaluation process details as a ready reference for a research scientist who is involved in TDDS.
KEYWORDS: Transdermal drug delivery systems, diffusion, polymer matrix, permeation enhancers, epidermis, topical, reservoir.
INTRODUCTION:
Transdermal Drug Delivery System (TDDS) are defined as self-contained, discrete dosage which is also known as patches.1-3 A transdermal patch or a skin patch is a medicated adhesion with minimal inter and intra patient variation. The main objective of transdermal drug delivery system is to deliver drugs into systemic circulation into the skin through skin at predetermined rate with minimal inter and intra patient variation.4-6 That will improve bioavailability, more uniform plasma levels, longer duration of action resulting in a reduction in dosing frequency, reduced side effects and improved therapy due to maintenance of plasma levels up to the end of the dosing interval compared to a decline in plasma levels with conventional oral dosage forms.7-9
Advantages of TDDS:10,11
· Transdermal drug delivery enables the avoidance of gastrointestinal absorption with its associated pitfalls of enzymatic and pH associated deactivation.
· Avoidance of first pass metabolism. EX: transdermal nitro glycerine
· They provided extended therapy with a single application, improving compliance over other dosage forms requiring more frequent dose administration e.g. Transdermal clonidine day
· Minimizing undesirable side effects.
· Provide utilization of drug with short biological half-lives, narrow therapeutic window.
· Avoiding in drug fluctuation drug levels.
· They can substitute for oral administration of medication when the route is unsuitable as with vomiting and diarrhoea
· Drug therapy may be terminated rapidly by removal of the application from the surface of the skin Transdermal patches are better way to deliver substances that are broken down by the stomach aids, not well observed from the gut, or extensively degraded by liver.
· Transdermal patches are cost effective.
Disadvantages of TDDS:12,13
· It cannot deliver drugs in a pulsatile fashion.
· It cannot develop if drug or formulation causes irritation to skin.
· Possibility of local irritation at site of application.
· Only potent drugs are suitable candidates for transdermal patch because of the natural limits of drug entry imposed by the skin's impermiability
· Long-time adhere is difficult.
Anatomy of skin:
The structure of human skin can be categorized into three main layers and represented in (Fig.1)14
Fig.1. Structure of skin
Epidermis:
Is a continually self-renewing, stratified squamous epithelium covering the entire outer surface of the body and primarily composed of two parts which is represented in (Fig.2). The living cells of the malpighian layer (viable epidermis) andthe dead cells of the stratum corneum (non-viable epidermis), commonly referred to as the horny layer. Viable epidermis is further classified into four distinct layers.
· Stratum lucidum
· Stratum granulose
· Stratum spinose
· Stratum basale
Stratum corneum:
This is the outermost layer of skin also called as horny layer. It is approximately 10 mm thick when dry but swells to several times this thickness when fully hydrated. It is approximately 10 mm thick when dry but swells to several times this thickness when fully hydrated. The stratum corneum is the principal barrier for penetration of drug. In this model, the keratinized cells function as protein “bricks” embedded in lipid “mortar.” Viable epidermis is situated beneath the stratum corneum and varies in thickness from 0.06 mm on the eyelids to 0.8 mm on the palms. it consists of various layers as stratum lucidum, stratum granulosum, stratum spinosum and the stratum basal.
Fig.2. Structure of epidermis
Dermis:
Is the layer of skin just beneath the epidermis which is 3 to 5 mm thick layer and is composed of a matrix of connective tissues, which contains blood vessels, lymph vessels, and nerves. The cutaneous blood supply has essential function in regulation of body temperature.It also provides nutrients and oxygen to the skin while removing toxins and waste products. In terms of transdermal drug delivery, this layer is often viewed as essentially gelled water, and thus provides a minimal barrier to the delivery of most polar drugs, although the dermal barrier may be significant when delivering highly lipophilic molecules.
Hypodermis:
Is the subcutaneous fat tissue that supports the dermis and epidermis. It serves as a fat storage area. This layer helps to regulate temperature, provides nutritional support and mechanically protection. It carries principal blood vessels and nerves to skin and may contain sensory pressure organs. For transdermal drug delivery, drug has to penetrate through all three layers and reach in systemic circulation.
Components of TDDS:
Various components of a TDDS are15-17
Polymers:
The polymer controls the release of the drug from the device. Polymers are the backbone of transdermal drug delivery system. a drug polymer matrix is sand witched between two polymeric layers, an outer impervious backing layer that prevents the loss of drug through the backing surface and an inner polymeric layer that functions as an adhesive, or rate-controlled membrane.
Ideal properties of a polymer to be used in TDDS:
Molecular weight, chemical functionality of the polymer should be such that the specific drug diffuses properly and gets released through it.
· Should be stable.
· Should be nontoxic
· Should be easily of manufactured
· Should be inexpensive
· The polymer and its degradation products must be non-toxic or non-antagonistic to the host.
· Large amounts of the active agents are to be incorporated into it
Table1. Various polymers used in TDDS
Type |
Example |
Natural polymers |
Cellulose derivatives, gelatin, waxes, proteins, gums, shellac, natural rubber, starch. |
Synthetic elastomers |
Hydrin rubber, silicone rubber, nitrile, acrylonitrile, neoprene. |
Synthetic polymers |
Polyvinyl alcohol, polyvinyl chloride, polyethylene, polypropylene, polyamiode, polyurea |
Drug:
For successfully developing a TDDS, the drug should be chosen with great care. Drug solution in direct contact with release liner
Physiochemical properties of drug:
· The drug should have a molecular weight less than 1000 Daltons.
· The drug should have affinity for both lipophilic and hydrophilic phases.
· The drug should have a low melting point.
Biological properties of drug substance:
· The drug should be potent with a daily dose of the order of a few mg/day.
· The half-life (t½) of the drug should be short.
· The drug must not produce allergic response.
· Tolerance to the drug must not develop under the near zero-order release profile of transdermal
Penetration enhancers:
These are compounds which promote the skin permeability by altering the skin as barrier to the flux of a desired penetrate.
Ideal properties of penetration enhancers:
· should not cause loss of body fluids, electrolytes or other endogenous materials
· Nontoxic, nonallergic, non-irritating
· Pharmacological inertness
· Ability to act specifically for predictable duration
· Odourless, colourless, economical and cosmetically acceptable.
Other excipients:
Solvents: Such as chloroform, methanol, acetone, isopropanol, and dichloromethane, are used to prepare drug reservoir.
Plasticizers:
Such as dibutylpthalate, propylene glycol are added to provide plasticity to the transdermal patch.
Adhesives:
Such as polyacrylamates, polyacrylates, polyisobutylene, silicone-based adhesives.
Ideal properties ofAdhesives:
· The pressure sensitive adhesive can be positioned on the face of the device or in the back of the device.
· It should not be irritant
· It should be easily removed
· It should not leave an un washable residue on the skin
· It should have excellent contact with the skin.
· Physical & chemical compatibility with the drug
· Permeation of drug should not affect.
Linear:
During storage release linear prevents the loss of drug that has migrated into the adhesive layer and contamination. However, as the linear is in intimate contact with the delivery system, it should comply with specific requirements regarding chemical inertness and permeation to the drug, penetration enhancer and water.
Backing membrane:
Such asaluminium vapour coated layer, a plastic film and heat real layer
· Protect the patch from the outer environment while designing a baking layer, the consideration of chemical resistance of the material is most important.
· Excipient compatibility should also be considered because the prolonged contact between the backing layer and the excipients may causes the additives to leach out of the backing layer or may lead to diffusion of excipients drug or penetration enhancer through the layer. However, an over overemphasis on the chemical resistance may lead to stiffness and high occlusivity to moisture vapor and air, causing patches to lift and possibly irritate the skin during long wear. Or high flexibility. Good oxygen transmission and high moisture vapor transmission rate.
Desirable features for TDDS:18, 19
· Composition relatively invariant in use.
· System size reasonable.
· Defined site for application.
· Application technique highly reproducible.
· Delivery is zero order.
· Delivery is efficient.
Conditions in which transdermal patches are to be used:
· When the patient has intolerable side effects (including constipation) and who is unable to take oral medication (dysphagia) and is requesting an alternative method of drug delivery.
· Where the pain control might be improved by reliable administration. This might be useful in patients with cognitive impairment or those who for other reasons are not able to self-medicate with their analgesia.
· It can be used in combination with other enhancement strategies to produce synergistic effects.
Conditions in which transdermalpatches are not to be used:
· Cure for acute pain is required.
· Where rapid dose titration is required.
· Where requirement of dose is equal to or less than 30 mg /24 h.
Types of TDDS:20-22
Single-layer drug-in-adhesive:
The adhesive layer of this system also contains the drug. In this type of patch the adhesive layer not only serves to adheres the various layers together, along with the entire system to the skin, but is also responsible for the releasing of the drug. The adhesive layer is surrounded by a temporary liner and a backing.
Multi-layer drug-in-adhesive:
The multi-layer drug inadhesive patch is similar to the single-layer system in that both adhesive layers are also responsible for the releasing of the drug. The multi-layer system is different however that it adds another layer of drug-inadhesive, usually separated by a membrane (but not in all cases). This patch also has a temporary liner-layer and a permanent backing.
Reservoir:
Unlike the single-layer and multi-layer drug-inadhesive systems the reservoir transdermal system has a separate drug layer. The drug layer is a liquid compartment containing a drug solution or suspension separated by the adhesive layer. This patch is also backed by the backing layer. In this type of system the rate of release is zero order.
Matrix:
The Matrix system has a drug layer of a semisolid matrix containing a drug solution or suspension. The adhesive layer in this patch surrounds the drug layer partially overlaying it.
Vapour patch:
In this type of patch the adhesive layer not only serves to adheres the various layers together but also to release vapour. The vapour patches are new on the market and they release essential oils for up to 6 hours. The vapours patches release essential oils and are used in cases of decongestion mainly. Other vapour patches on the market are controller vapour patches that improve the quality of sleep. Vapour patches that reduce the quantity of cigarettes that one smokes in a month are also available on the market.
Evaluation of TDDS:
The transdermal patches can be characterized in terms of following parameters
· Physicochemical evaluation23-27
· In vitro evaluation28-32
· In vivo evaluation33-35
Physicochemical evaluation:
Transdermal patches can be physio-chemically evaluated in terms of these parameters
Thickness:
The thickness of transdermal film is determined by travelling microscope, dial gauge, screw gauge or micro meter at different points of the film.
Uniformity of weight:
Weight variation is studied by individually weighing 10 randomly selected patches and calculating the average weight. The individual weight should not deviate significantly from the average weight.
Drug content:
An accurately weighed portion of film (about 100 mg) is dissolved in 100 mL of suitable solvent in which drug is soluble and then the solution is shaken continuously for 24 h in shaker incubator. Then the whole solution is sonicated. After sonication and subsequent filtration, drug in solution is estimated spectrophotometrically by appropriate dilution.
Content uniformity:
10 patches are selected and content is determined for individual patches. If 9 out of 10 patches have content between 85% to 115% of the specified value and one has content not less than 75% to125% of the specified value, then transdermal patches pass the test of content uniformity. But if 3 patches have content in the range of 75% to 125%, then additional 20 patches are tested for drug content. If these 20 patches have range from 85% to 115%, then the transdermal patches pass the test.
Moisture content:
The prepared films are weighed individually and kept in a desiccator containing calcium chloride at room temperature for 24 h. The films are weighed again after a specified interval until they show a constant weight. The percent moisture content is calculated using following formula.
content Initial weight - Final weight
% Moisture = ------------------------------------------X 100
Final weight
Eq. No. 1
Moisture uptake:
Weighed films are kept in a desiccator at room temperature for 24 h. These are then taken out and exposed to 84% relative humidity using saturated solution of Potassium chloride in a desiccator until a constant weight is achieved. % moisture uptake is calculated as given below.35
uptake Final weight – Initial weight
% Moisture = ------------------------------------------- X 100
Initial weight Eq. No. 2
Flatness:
A transdermal patch should possess a smooth surface and should not constrict with time. This can be demonstrated with flatness study. For flatness determination, one strip is cut from the centre and two from each side of patches. The length of each strip is measured and variation in length is measured by determining percent constriction. Zero percent constriction is equivalent to 100 percent flatness.
% Constriction = (I1 – I2) X 100 Eq. No. 3
Where:
I2 = Final length of each strip and I1 = Initial length of each strip
Folding endurance:
Evaluation of folding endurance involves determining the folding capacity of the films subjected to frequent extreme conditions of folding. Folding endurance is determined by repeatedly folding the film at the same place until it breaks. The number of times the films could be folded at the same place without breaking is folding endurance value.
Tensile strength:
To determine tensile strength, polymeric films are sandwiched separately by corked linear iron plates. One end of the films is kept fixed with the help of an iron screen and other end is connected to a freely movable thread over a pulley. The weights are added gradually to the pan attached with the hanging end of the thread. A pointer on the thread is used to measure the elongation of the film. The weight just sufficient to break the film is noted.
Tack properties:
It is the ability of the polymer to adhere to substrate with little contact pressure. Tack is dependent on molecular weight and composition of polymer as well as on the use of tackifying resins in polymer.
· Thumb tack test:
The force required to remove thumb from adhesive is a measure of tack.
· Rolling ball test:
This test involves measurement of the distance that stainless steel ball travels along an upward facing adhesive. The less tacky the adhesive, the further the ball will travel.
· Quick stick (Peel tack) test:
The peel force required breaking the bond between an adhesive and substrate is measured by pulling the tape away from the substrate at 90 at the speed of 12 inch/min.
· Probe tack test:
Force required to pull a probe away from an adhesive at a fixed rate is recorded as tack.
In vitro release studies:
Transdermal patches can be in vitro evaluated in terms of Franz diffusion cell the cell is composed of two compartments: donor and receptor. The receptor compartment has a volume of 5-12 mL and effective surface area of 1-5 cm2. The diffusion buffer is continuously stirred at 600rpm by a magnetic bar. The temperature in the bulk of the solution is maintained by circulating thermostated water through a water jacket that surrounds the receptor compartment. The drug content is analysed using suitable method, maintenance of sink condition is essential.
In vivo studies:
Transdermal patches can be in vivo evaluated in terms of in vivo evaluations are the true depiction of the drug performance. The variables which cannot be taken into account during in vitro studies can be fully explored during in vivo studies. In vivo evaluation of TDDS can be carried out using animal models human volunteers.
· Animal models:
Considerable time and resources are required to carry out human studies, so animal studies are preferred at small scale. The most common animal species used for evaluating transdermal drug delivery system are mouse, hairless rat, hairless dog, hairless rhesus monkey, rabbit, guinea pig etc. Various experiments conducted leads to a conclusion that hairless animals are preferred over hairy animals in both in vitro and in vivo experiments. Rhesus monkey is one of the most reliable models for in vivo evaluation of transdermal drug delivery in man.
· Human model:
The final stage of the development of a transdermal device involves collection of pharmacokinetic and pharmacodynamic data following application of the patch to human volunteers. Clinical trials have been conducted to assess the efficacy, risk involved, side effects, patient compliance etc. Phase-I clinical trials are conducted to determine mainly safety in volunteers and phase II clinical trials determine short term safety and mainly effectiveness in patients. Phase III trials indicate the safety and effectiveness in large number of patient population and phase IV trials at post marketing surveillance are done for marketed patches to detect adverse drug reactions. Though human studies require considerable resources best to assess the performance of the drug release.
CONCLUSION:
The fore going shows that TDDS have great potential being able to use for both hydrophobic and hydrophilic active substance into promising deliverable drugs. TDDS is a realistic practical application as the next generation of drug delivery system. This article provides a valuable information regarding the TDDS and their evaluation process details, as a ready reference for the research scientists who wantupdated information regarding TDDS.
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Received on 31.10.2019 Modified on 01.12.2019
Accepted on 30.12.2019 ©Asian Pharma Press All Right Reserved
Asian J. Res. Pharm. Sci. 2020; 10(2):109-114.
DOI: 10.5958/2231-5659.2020.00021.1