Transdermal Drug Delivery System: A Review

Bhakti R. Chorghe¹*, Swapnil T. Deshpande², Rohit D. Shah¹, Swati S. Korabu¹, Sagar V. Motarwar³

¹Sinhgad College of Pharmacy, Vadgaon (Bk.), Pune – 411 041

²SCSSS’s Sitabai Thite College of Pharmacy, Shirur, Pune – 412 210

³Smt. Kashibai Navale College of Pharmacy, Kondhwa (Bk.), Pune – 411 048

ABSTRACT:

Transdermal therapeutic systems, or transdermal patches, facilitate controlled release of active ingredients through the skin and into the systemic circulation. Drugs administered through such systems escape first pass metabolism and steady state is maintained similar to a continuous intravenous infusion for up to several days. The transdermal route of drug delivery has attracted researchers due to many biomedical advantages associated with it. However, excellent impervious nature of skin is the greatest challenge that has to be overcome for successfully delivering drug molecules to the systemic circulation by this route. This article gives a brief overview over principles behind transdermal drug delivery, as well as the advantages and disadvantages of transdermal therapeutic systems and the recent innovations in the field of transdermal drug delivery and also describes the methods of preparation of different types of transdermal patches, evaluation parameters and some available marketed products.

KEY WORDS: Transdermal drug delivery system, transdermal patches, evaluation of Transdermal system, skin.

INTRODUCTION:

Transdermal therapeutic systems have been designed to provide controlled continuous delivery of drugs via the skin to the systemic circulation. oral treatment involves attainment and maintenance of drug concentration in the body within a therapeutically effective range by introduction of fixed dose at regular intervals due to which drug concentration in the body follow a peak and trough profile leading to a greater chance of adverse effects or therapeutic failure, large amount of drug is lost in vicinity of target organ and close attention is required to monitor therapy to avoid overdosing^1-5.

Advantages of Transdermal Drug Delivery

It offers therapeutic benefits such as:

· Sustained delivery of drugs to provide a steady plasma profile, particularly for drugs with short half-lives, control input kinetics and hence reduced systemic side effects.

· Reducing the typical dosing schedule to once daily or even once weekly.

· Potential for improved patient compliance.

· Avoidance of the first-pass metabolism effect for drugs with poor oral bioavailability.

· Convenient, patient-friendly option for drug delivery with the potential for flexibility, easily allowing dose changes according to patient needs and the capacity for self-regulation of dosing by the patient.

· Transdermal drug delivery can be used in situations requiring minimal patient cooperation, in situations involving administration of drugs by someone other than the patient.

· The non-invasive character of transdermal drug delivery makes it accessible to a wide range of patient populations and a highly acceptable option for drug dosing.

Limitations for Drug Candidates

· Higher molecular weight candidates (>500 Dalton) fail to penetrate the stratum corneum.

· Drugs with very low or high partition coefficient fail to reach systemic circulation.

· High melting drugs, due to their low solubility both in water and fat.

· Barrier function of the stratum corneum^1-8.

Components of Transdermal Drug Delivery Systems

· Polymer matrix or matrices

· Drug

· Permeation enhancers

· Other excipients

Polymer Matrix

The polymer controls the release of the drug from the device. Possible useful polymers for transdermal devices are:

1. Natural Polymers:

e.g. Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Proteins, Gums and their derivatives, Natural rubber, Starch etc.

2. Synthetic Elastomers:

e.g. Polybutadiene, Hydrin rubber, Polysiloxane, Silicone rubber, Nitrile, Acrylonitrile, Butyl rubber, Styrene butadiene rubber, Neoprene etc.

3. Synthetic Polymers:

e.g. Polyvinyl alcohol, Polyvinyl chloride, Polyethylene, Polypropylene, Polyacrylate, Polyamide, Polyurea, Polyvinylpyrrolidone, Polymethylmethacrylate, Epoxy etc.

Drug

For successfully developing a transdermal drug delivery system, the drug should be chosen with great care. The desirable properties of a drug for transdermal delivery should be,

· The drug should have a molecular weight less than approximately 1000 daltons.

· The drug should have affinity for both – lipophilic and hydrophilic phases. Extreme partitioning characteristics are not conductive to successful drug delivery via the skin.

· The drug should have low melting point.

Enhancers

These are compounds which promote skin permeability by altering the skin as a barrier to the flux of a desired penetrant.

Solvents

These compounds increase penetration possibly by swallowing the polar pathway and/or by fluidizing lipids. Examples include water, alcohols: methanol and ethanol; alkyl methyl sulfoxides: dimethyl sulfoxide (DMSO), alkyl homologs of methyl sulfoxide dimethyl acetamide and dimethyl formamide; pyrrolidones: 2-pyrrolidone, N-methyl, 2-purrolidone; laurocapram (azone), miscellaneous solvents: propylene glycol, glycerol, silicone fluids, isopropyl palmitate.

Surfactants

These compounds are proposed to enhance polar pathway transport, especially of hydrophilic drugs. The ability of a surfactant to alter penetration is a function of the polar head group and the hydrocarbon chain length.

1. Anionic Surfactants:

e.g. Dioctyl sulphosuccinate (DOSS), Sodium lauryl sulphate, Decodecylmethyl sulphoxide etc.

2. Nonionic Surfactants:

e.g. Pluronic F127, Pluronic F68, etc. Bile Salts: e.g. Sodium taurocholate, Sodium deoxycholate, Sodium tauroglycocholate.

Binary system

These systems apparently open up the heterogeneous multilaminate pathway as well as the continuous pathways. e.g. Propylene glycol-oleic acid and 1, 4-butane diol-linoleic acid.

Miscellaneous chemicals

These include urea, a hydrating and keratolytic agent; N, N-dimethyl-m-toluamide; calcium thioglycolate; anticholinergic agents. Some potential permeation enhancers have recently been described but the available data on their effectiveness sparse. These include eucalyptol, di-o-methyl-ß-cyclodextrin and soyabean casein.

Other excipients

Adhesives:

The fastening of all transdermal devices to the skin has so far been done by using a pressure sensitive adhesive which can be positioned on the face of the device or in the back of the device and extending peripherally^9-11.

Transdermal Patches^10-14

Single-layer Drug-in-Adhesive

The Single-layer Drug-in-Adhesive system is characterized by the inclusion of the drug directly within the skin-contacting adhesive. In this transdermal system design, the adhesive not only serves to affix the system to the skin, but also serves as the formulation foundation, containing the drug and all the excipients under a single backing film. The rate of release of drug from this type of system is dependent on the diffusion across the skin.

Multi-layer Drug-in-Adhesive

The Multi-layer Drug-in-Adhesive is similar to the Single layer Drug-in-Adhesive in that the drug is incorporated directly into the adhesive. However, the multi-layer encompasses either the addition of a membrane between two distinct drug-in-adhesive layers or the addition of multiple drug-in-adhesive layers under a single backing film.

Drug Reservoir-in-Adhesive

The reservoir transdermal system design is characterized by the inclusion of a liquid compartment containing a drug solution or suspension separated from the release liner by a semi-permeable membrane and adhesive. The adhesive component of the product responsible for skin adhesion can either be incorporated as a continuous layer between the membrane and the release liner or in a concentric configuration around the membrane.

Drug Matrix-in-Adhesive

The Matrix system design is characterized by the inclusion of a semisolid matrix containing a drug solution or suspension which is in direct contact with the release liner. The component responsible for skin adhesion is incorporated in an overlay and forms a concentric configuration around the semisolid matrix.

Evaluation of Transdermal Patches^12-17

Transdermal patches have been developed to improve clinical efficacy of the drug and to enhance patient compliance by delivering smaller amount of drug at a predetermined rate. This makes evaluation studies even more important in order to ensure their desired performance and reproducibility under the specified environmental conditions. These studies are predictive of transdermal dosage forms and can be classified into following types:

· Physicochemical evaluation

· In vitro evaluation

· Ex vivo evaluation

1. Physicochemical Evaluation:

Thickness:

The thickness of transdermal film is determined by traveling microscope, dial gauge, screw gauge or micrometer 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 determination:

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 test:

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% to 125% 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 desiccators 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.

% Moisture content = Initial weight – Final weight X 100

Moisture uptake:

Weighed films were 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 desiccators until a constant weight is achieved. Percent moisture uptake is calculated as given below.

% moisture uptake = Final weight – Initial weight X 100

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

Where, I₂ is the final length of each strip and I₁ is the 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 break. 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. The tensile strength can be calculated using the following equation.

Tensile strength= F/a.b (1+L/l)

Where, F is the force required to break; a is width of film; b is thickness of film; L is length of film; l is elongation of film at break point.

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.

2. In vitro release studies:

Drug release mechanisms and kinetics are two characteristics of the dosage forms which play an important role in describing the drug dissolution profile from a controlled release dosage forms and hence there in vivo performance. The dissolution data is fitted to these models and the best fit is obtained to describe the release mechanism of the drug. There are various methods available for determination of drug release rate of TDDS.

Paddle over Disc:

(USP apparatus 5/ PhEur 2.9.4.1) This method is identical to the USP paddle dissolution apparatus, except that the transdermal system is attached to a disc or cell resting at the bottom of the vessel which contains medium at 32 ±5°C.

Cylinder modified USP Basket:

(USP apparatus 6 / PhEur 2.9.4.3) This method is similar to the USP basket type dissolution apparatus, except that the system is attached to the surface of a hollow cylinder immersed in medium at 32 ±5°C.

Reciprocating Disc:

(USP apparatus 7) In this method patches attached to holders are oscillated in small volumes of medium, allowing the apparatus to be useful for systems delivering low concentration of drug. In addition paddle over extraction cell method (PhEur 2.9.4.2) may be used.

3. Ex vivo permeation studies:

The amount of drug available for absorption to the systemic pool is greatly dependent on drug released from the polymeric transdermal films. The drug reached at skin surface is then passed to the dermal microcirculation by penetration through cells of epidermis, between the cells of epidermis through skin appendages. Usually permeation studies are performed by placing the fabricated transdermal patch with rat skin or synthetic membrane in between receptor and donor compartment in a vertical diffusion cell such as franz diffusion cell or keshary-chien diffusion cell. The transdermal system is applied to the hydrophilic side of the membrane and then mounted in the diffusion cell with lipophillic side in contact with receptor fluid. The receiver compartment is maintained at specific temperature (usually 32±5°C for skin) and is continuously stirred at a constant rate. The samples are withdrawn at different time intervals and equal amount of buffer is replaced each time. The samples are diluted appropriately and absorbance is determined spectrophotometrically. Then the amount of drug permeated per centimeter square at each time interval is calculated. Design of system, patch size, surface area of skin, thickness of skin and temperature etc. are some variables that may affect the release of drug. So permeation study involves preparation of skin, mounting of skin on permeation cell, setting of experimental conditions like temperature, stirring, sink conditions, withdrawing samples at different time intervals, sample analysis and calculation of flux i.e., drug permeated per cm² per second.

Preparation of skin for permeation studies:

Hairless animal skin and human cadaver skin are used for permeation studies. Human cadaver skin may be a logical choice as the skin model because the final product will be used in humans. But it is not easily available. So, hairless animal skin is generally favored as it is easily obtained from animals of specific age group or sex.

Intact full thickness skin:

Hair on dorsal skin of animal are removed with animal hair clipper, subcutaneous tissue is surgically removed and dermis side is wiped with isopropyl alcohol to remove residual adhering fat. The skin is washed with distilled water. The skin so prepared is wrapped in aluminum foil and stored in a freezer at -20^oC till further use. The skin is defrosted at room temperature when required.

Separation of epidermis from full thickness skin: The prepared full thickness skin is treated with 2M sodium bromide solution in water for 6 h. The epidermis is separated by using a cotton swab moistened with distilled water. Then epidermis sheet is cleaned by washing with distilled water and dried under vacuum. Dried sheets are stored in desiccators until further use.

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Received on 03.03.2013

Modified on 22.03.2013

Accepted on 03.04.2013

© A&V Publication all right reserved

Research Journal of Pharmaceutical Dosage Forms and Technology. 5(2): March- April, 2013, 65-69