An Insight into delivery of drug through The Skin: Transdermal Drug Delivery system

 

Lakshmi Usha Ayalasomayajula*, M. Kusuma Kumari, Radha Rani Earle

Department of Pharmaceutics, Maharajah’s College of Pharmacy, Vizianagaram, A.P., India.

*Corresponding Author E-mail: alakshmiusha@gmail.com

 

ABSTRACT:

In the recent days about 75% of the drugs taken orally are does not show the desired therapeutic effect. Oral conventional dosage forms have several disadvantages such as poor bioavailability due to hepatic first pass metabolism and tendency to produce rapid blood level spikes (Both high and low). Thus, rapid drug levels in the plasma leads to a need of high and/or frequent dosing, which can be both uneconomical and inconvenient. To overcome such disadvantages transdermal drug delivery system was developed. TDDS is such a delivery system which has been explored extensively over the last two decades, with therapeutic success. Transdermal drug delivery systems (TDDS) are the drug delivery systems which involves transportation of drug to epidermal and dermal tissues of the skin for local therapeutic action while major fraction of the drug is transported into the systemic blood circulation. Topical administration of therapeutic agents offers vast advantages over conventional oral and invasive methods of drug delivery. Some of the advantages of transdermal drug delivery include limitation of hepatic first pass metabolism, enhancement of therapeutic efficiency and maintenance of steady state plasma level concentration of the drug. This study includes a brief overview of TDDS, its advantages over conventional dosage forms, drug delivery routes across human skin, permeation enhancers, and classification, formulation, methods of preparation and evaluation of transdermal patches.

 

KEYWORDS: Transdermal drug delivery system (TDDS), Bioavailability, Hepatic first pass metabolism, therapeutic efficacy.

 

 


INTRODUCTION:

Transdermal drug delivery systems (TDDS), also known as “patches,” are drug delivery systems developed to deliver a therapeutically effective amount of drug across skin. This type drug delivery system has been in existence since a long time. The most commonly applied topical dosage forms are creams and ointments for dermatological disorders. Large number of drugs has been applied topically to produce systemic treatment.

 

In a broad sense, the term transdermal delivery system includes all the formulations that are topically administered and deliver the active ingredient into the blood circulation. Conventional dosage forms, when given in multiple doses have numerous problems and complications. The design of conventional dosage form, is to deliver the right amount of drug at the target site becomes complicated if each medication were to be delivered in an optimal and preferred manner to the individual patient. Redesigning the modules and means to drug transport into the body is less demanding and more lucrative task. To address these problems, controlled release drug delivery system, a novel drug delivery approach has evolved, which facilitates the drug release into systemic circulation at a pre-determined rate. Controlled drug release can also be achieved by transdermal drug delivery systems (TDDS) which can deliver drug via the skin to systemic circulation at a predetermined rate over an extended period of time. For topical products the goal of dosage design is to maximize the flux through the skin into the systemic circulation and simultaneously minimize the retention and metabolism of the drug in the skin. Transdermal drug delivery systems (TDDS) are defined as self-contained, discrete dosage forms which, when applied to intact skin, deliver the drug (s), through the skin, at a controlled rate to systemic circulation. This route of administration is one of the most potential routes for the local and systemic delivery of drugs. Transdermal delivery sometimes leads to undesirable side effects because continuous input of drugs with short biological half-lives, eliminates pulsed entry into systemic circulation, which often. Thus, various forms of Novel drug delivery system such as Transdermal drug delivery systems, Controlled release systems, Transmucosal delivery systems etc. emerged in comparison to conventional pharmaceutical dosage forms. TDDS offer many advantages, such as elimination of first pass metabolism, enhancement of therapeutic efficiency and maintenance of steady plasma level of the drug sustained drug delivery, reduced frequency of administration, reduced side effects and improved patient compliance reduces the load that the oral route commonly places on the digestive tract and liver. Another advantage is convenience, especially notable in patches that require only once weekly application. Such a simple dosing regimen can aid in patient adherence to drug therapy.1

 

Advantages:

·       The delivery of drug is a steady infusion for a prolonged period of time therefore avoiding adverse effects and therapeutic failure frequently associated with intermittent dosing.

·       Alternative route of administration for the patients who cannot tolerate oral dosage forms such as vomiting patient.

·       Increases therapeutic value of many drugs by avoiding specific problems associated with therapeutic range.

 

Disadvantages:

·       Mostly potent drugs are suitable candidates for transdermal delivery because of the natural limits of drug entry imposed by the skin’s impermeability.

·       Some patients develop contact dermatitis at the site of application from one or more of the system components, necessitating discontinuation.

·       The delivery system cannot be used for drugs which are to be taken in high dose.

·       Transdermal delivery of drugs is uneconomical.

 

Anatomy of Skin:

The skin is the largest organ of the body, covering about 20 sqft. The skin gives us protection from micro-organisms and other elements. It also helps in regulating body temperature, and permits the sensations of touch, heat, and cold.

 

Structure of the skin:

The skin consists of three layers which include

·       The outermost layer of skin, known as Epidermis which acts as a waterproof barrier and creates our skin tone.

·       The next layer dermis, below the epidermis, is made up of tough connective tissue, hair follicles, and sweat glands.

·       The inner subcutaneous tissue hypodermis is made of fat and connective tissue.

·       The color of the skin is because of special cells called melanocytes, located in the epidermis. They produce the pigment melanin responsible for skin complexation.

 

Fig 1: Structure of the skin

 

Penetration of drug through the skin:

The drug enters potentially into the blood vasculature through the epidermis itself or diffuses through shunt pathway, mainly hair follicles with their associated sebaceous glands and the sweat ducts. Therefore, there are two major routes of penetration.

 

Transcorneal penetration:

Drug molecule passes through the cells of stratum corneum. Hydrophilic drugs are usually penetrated by this mechanism. As hydration of stratum corneum occurs, water accumulates near the outer surface of the protein filaments. Polar molecules appear to pass through this immobilized water.

 

Intercellular penetration:

Non-polar substances are transported by intercellular penetration. These molecules dissolve in and diffuse through the non- aqueous lipid matrix imbibed between the protein filaments. It is also called as shunt pathway. In this route, the drug molecule may transverse through the hair follicles, the sebaceous pathway of the pilosebaceous apparatus or the aqueous pathway of the salty sweat glands. However large polar compounds can be penetrated by this mechanism. The route through which permeation occurs is largely dependent on physico-chemical characteristics of penetrant, most importantantly being the relative ability to partition into each skin phase. The transdermal permeation can be visualized as composite of a series in sequence as:

1.     Adsorption of a penetrating molecule onto the surface layers of stratum corneum.

2.     Diffusion through stratum corneum through viable epidermis.

3.     Finally, through the papillary dermis into the microcirculation.

 

The viable tissue layer and the capillaries are relatively permeable and the peripheral circulation is sufficiently rapid. Hence diffusion through stratum corneum is the rate-limiting step. The stratum corneum acts like a passive diffusion medium2.

 

Basic Components of TDDS:

·       Polymer matrix / Drug reservoir

·       Drug

·       Permeation enhancers

·       Pressure sensitive adhesive (PSA)

·       Backing laminates

·       Release liner

·       Other excipients like plasticizers and solvents

 

Polymer matrix / Drug reservoir:

Polymer is the most important component of TDDS, which controls the drug release from the device. Polymer matrix is prepared by dispersion of drug in liquid or solid-state synthetic polymer base. Polymers used in TDDS should have good stability and compatibility with the drug and other components of the system and they should provide effective release of a drug throughout the device with safe status.

 

Molecular weight and chemical functionality of the polymer should be such that the specific drug diffuses properly and gets released through it.

 

The polymer should be stable, nontoxic, economical and easily manufactured. The polymer and its deaggration product must be nontoxic or non-antagonistic to the host.

·       Large amounts of the active agent are usually incorporated into the polymer.

 

 

Table 1: Polymers Used in Transdermal Preparations

Natural Polymers

Synthetic Elastomers

Synthetic Polymers

Cellulose derivatives

Polybutadiene

Polyvinylalcohol

Arabino

Hydrinrubber

Polyethylene

Galactan

Polysiloxane

Polyviny Chloride

Zein

Acrylonitrile

Polyacrylates

Gelatin

Neoprene

Polyamide

Proteins

Chloroprene

Acetal copolymer

Shellac

Silicon rubber

Polysyrene

Starch

 

 

 

Drug:

To develop a transdermal drug delivery system successfully, great care should be chosen while selecting a drug. The points to be kept in mind while selecting a drug for transdermal delivery are.

 

Physicochemical properties:

·       Molecular weight: Less than 1000 Daltons.

·       Melting point: Low melting point drugs.

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

·       Drugs that are potent, those having short half life and non-irritating should be preferred.

 

Biological Properties:

·       Stability: The drug should be stable when it comes in contact with the skin and should not stimulate an immune reaction to the skin.

·       Tolerance: Tolerance to the drug must not develop under zero order release profile of transdermal delivery.

·       The drug should not get irreversibly bound to the subcutaneous tissue and should not get extensively metabolized by the skin.

 

Permeation enhancers:

Permeation enhancers are used to increase permeability of stratum corneum by interacting with structural components of stratum corneum i.e., proteins or lipids to attain higher therapeutic levels of the drug. They act by altering the protein and lipid packing of stratum corneum, thus chemically modifying the barrier functions and thus increase the permeability.

 

Some examples are: Dimethyl sulfoxide, Propylene glycol, 2-Pyrrolidone, Isopropyl myristate, Laurocapram (Azone), Sodium lauryl sulfate, Sorbitan monolaurate, Pluronic, Cardamom oil, Caraway oil, Lemon oil, Menthol, dlimonene, Linoleic acid.

 

Pressure sensitive adhesives:

The pressure-sensitive adhesive (PSA) binds the Tansdermal drug delivery system firmly to the skin. They must be compatible with the skin, causing minimal irritation or sensitization, and removable without inflicting physical trauma or leaving residue. In addition, they must be able to dissolve drug and excipient in sufficient quantity to produce desired pharmacological effect without losing their adhesive properties and skin tolerability.PSA’s used in commercially available Transdermal systems include polyacrylate, polyisobutylene, and polysiloxane.

 

Hot Melt Pressure Sensitive Adhesives (HMPSA):

HMPSA’s are melted such that their viscosity is suitable for coating, but when they are cooled, they generally do not flow. They are thermoplastic in nature. Compounded HMPSA’s are Ethylene vinyl acetate copolymers, Paraffin waxes, Low density polypropylene, Styrene-butadiene copolymers, Ethylene-ethacrylate copolymers. Uncompounded HMPSA’s are Polyesters, Polyamides and Polyurethanes3.

 

Backing laminate:

Backing materials must be flexible and possess good tensile strength. Commonly used materials are polyolefin’s, polyesters, and elastomers in clear, pigmented, or metallized form. Elastomeric materials such as low-density polyethylene provide better adhesion than less compliant materials such as polyester. Backing materials should also have low water vapor transmission rate to promote increased skin hydration and, thus, greater skin permeability. In systems containing drug within a liquid or gel, the backing material must be heat-sealable to allow fluid-tight packaging of the drug reservoir using a process known as form-fill-seal. The most comfortable backing will be the one that exhibits lowest modulus or high flexibility, good oxygen transmission and a high moisture vapor transmission rate.

 

Examples of some backing materials are vinyl polyester films, Polyester-polypropylene films, Polypropylene resin, Polyethylene resin, Polyurethylene, Co Tran 9722 film, Ethylene-vinyl acetate, Aluminized plastic laminate.

 

Release Liner:

The patch is covered by a protective liner during storage. The protective layer is removed and discharged immediately before theapplication of the patch to skin. It is therefore regarded as a part of the primary packaging material rather than a part of dosage form for delivering the drug. However, as the liner is in intimate contact with the delivery system, it should comply with specific requirements such as chemical inertness and permeation to the drug, penetration enhancer and water. Typically, release liner is composed of a base layer which may be non-occlusive (e.g. paper fabric) or occlusive (e.g. polyethylene, polyvinylchloride) and a release coating layer made up of silicon or teflon. Other materials used for TDDS release liner include polyester foil and metalized laminates4.

 

Other excipients:

Various solvents such as chloroform, methanol, acetone, isopropanol and dichloromethane are used to prepare reservoir for drug. In addition, plasticizers such as dibutylpthalate, triethylcitrate, polyethylene glycol and propylene glycol are added to provide plasticity to the transdermal patch.

 

Methods for preparation of transdermal drug delivery system:

Asymmetric TPX membrane method:

This method involves fabrication of a prototype patch by a heat sealable polyester film (type 1009, 3m) with a concave of 1cm diameter used as the backing membrane. Drug sample is dispensed into the concave membrane, covered by a TPX {poly (4-methyl-1-pentene)} asymmetric membrane, and sealed by an adhesive.

 

Asymmetric TPX membrane preparation:

These are fabricated by using the dry/wet inversion process. TPX is prepared by mixing a solvent (cyclohexane) and non solvent additives at 60°c to form a polymer solution. The polymer solution is kept at 40°C for 24 hrs and cast on a glass plate to a pre-determined thickness with a gardener knife. After that the casting film is evaporated at 50°C for 30 sec, then the glass plate is to be immersed immediately in coagulation bath [maintained at 25°C]. After 10 minutes of immersion, the membrane can be removed, air dried in a circulation oven at 50°C for 12 hrs5.

 

Fig. 2: Asymmetric TPX membrane preparation

 

Circular Teflon Mould method:

Solutions containing polymers in various ratios are used in an organic solvent. Calculated amount of drug is dissolved in half the quantity of same organic solvent. Enhancers in different concentrations are dissolved in the other half of the organic solvent and then added. Di-N-butylphthalate is added as a plasticizer into drug polymer solution. The total contents are to be stirred for 12hrs and then poured into a circular teflon mould. The moulds are placed on a leveled surface and covered with an inverted funnel to control solvent vaporization in a laminar flow hood model with speed of air 1/2 m /sec. The solvent is allowed to evaporate for 24 hrs. Before evaluation the dried films are for another 24 hrs at 25±0.5°C in a desiccator containing silica gel before to eliminate aging effects. These types of films are to be evaluated within one week of their preparation6.

 

Fig. 3: Circular Teflon Mould method

 

Mercury substrate method:

In this method drug is dissolved in polymer solution along with plasticizer. The above solution is to be stirred for 10-15 min to produce a homogeneous dispersion and poured in to a leveled mercury surface. Then the solution is covered with inverted funnel to control solvent evaporation7.

 

Fig. 4: Mercury substrate method

 

“IPM membranes” method:

In this method drug is dispersed in a mixture of water and propylene glycol containing carbomer 940 polymer and stirred for 12 hrs in magnetic stirrer. The dispersion is to be neutralized and made viscous by the addition of triethanolamine. Buffer of pH 7.4 can be used in order to obtain solution gel, if the drug solubility in aqueous solution is very poor. The formed gel will be incorporated in the IPM membrane8.

 

Fig. 5: IPA membrane method

“EVAC membranes” method:

In order to prepare the target transdermal therapeutic system, 1% carbopol reservoir gel, polyethelene (PE), ethylene vinyl acetate copolymer (EVAC) membranes can be used as rate control membranes. If the drug is not soluble in water, propylene glycol is used for the preparation of gel. Drug is dissolved in propylene glycol, carbopol resin will be added to the above solution and neutralized by using 5% w/w sodium hydroxide solution. The drug (in gel form) is placed on a sheet of backing layer covering the specified area. A rate controlling membrane will be placed over the gel and the edges will be sealed by heat to obtain a leak proof device9.

 

Aluminium backed adhesive film method:

Transdermal drug delivery system may produce unstable matrices if the loading dose is greater than 10 mg. Aluminium backed adhesive film method is a suitable one for preparation of same. Chloroform is choice of solvent, because most of the drugs as well as adhesive are soluble in chloroform. The drug is dissolved in chloroform and adhesive material will be added to the drug solution and dissolved. A custom-made aluminium former is lined with aluminium foil and the ends blanked off with tightly fitting cork blocks10.

 

Fig. 6: Aluminium backed adhesive film method

 

Preparation of TDDS by using proliposomes:

The proliposomes are prepared by carrier method using film deposition technique. The proliposomes are prepared by taking 5mg of mannitol powder in a 100ml round bottom flask which is kept at 60-70 °C temperature and the flask is rotated at 80-90 rpm and dried the Mannitol using vacuum for 30 min. After drying, the temperature of the water bath is adjusted to 20- 30 °C. Drug and lecithin are dissolved in a suitable organic solvent mixture. Aliquot of 0.5 ml of organic solution is introduced into the round bottomed flask at 37 °C containing Mannitol and dried. After complete drying, second aliquot (0.5ml) of the solution is to be added. After the last loading, the flask containing proliposomes are connected to a lyophilizer and subsequently drug loaded Mannitol powders (proliposomes) is placed in desiccators overnight and then sieved through 100 mesh. The collected powder is transferred into a glass bottle and stored at freezer temperature until characterization11.

 

Free film method:

Free film of cellulose acetate is prepared by casting on mercury surface. A polymer solution 2% w/w is prepared by using chloroform. Plasticizers are incorporated at a concentration of 40% w/w of polymer weight. 5ml of polymer solution was poured in a glass ring which is placed over the mercury surface in a glass petri dish. The rate of evaporation of the solvent is controlled by placing an inverted funnel over the petri dish. The film formation is noted by observing the mercury surface after complete evaporation of the solvent. The dry film will be separated out and stored between the sheets of wax paper in desiccators until they are used. Free films of different thickness can be prepared by changing the volume of the polymer solution12.

 

Fig. 7: Free Film Method

 

Evaluation Techniques of TDDS:

The evaluation test for transdermal dosage form:

 

Interaction studies:

The drug and the excipients must be compatible with one another to produce a stable product. The interaction between drug and excipients affects the bioavailability and stability of the drug. If the excipients are new and have not been used in formulations containing the active substance, the compatibility studies play an important role in formulation development. Interaction studies are studied by Thermal analysis, FTIR, UV and chromatographic techniques for comparing their physicochemical properties like assay, melting point, wave numbers, absorption maxima.     

 

Thickness of the patch:

The thickness of the prepared patch is measured by using a digital micrometer at different points on a patch and average thickness is determined. The standard deviation for the same is calculated to ensure the thickness of the prepared patch13.

 

Weight uniformity:

The prepared patches are to be dried at 60°C for 4hrs before testing. A specified area of patch is to be cut in different parts of the patch and weighed on a digital balance. The average weight and standard deviation values are to be calculated from the individual weights.

 

Folding endurance:

A specific area of strip is cut and repeatedly folded at the same place till it breaks. The number of times the film could be folded without breaking gives the value of folding endurance14.

 

Percentage moisture content:

The prepared patches are to be weighed individually and to be kept in a desiccator containing fused calcium chloride at room temperature. After 24 hrs the films are to be reweighed and determine the percentage moisture content by using the formula.

 

               Initial weight - Finalweight

Percentage moisture content =  ×100.

         Final weight

 

Percentage moisture uptake:

The prepared patches are to be weighed individually and to be kept in a desiccator containing saturated solution of potassium chloride in order to maintain 84% RH. After 24hrs the films are to be reweighed and determine the percentage moisture uptake by using the formula.

 

               Final weight - Initial weight

Percentage moisture uptake =  ×100.

        initial weight

 

Evaluation of water vapor permeability (WVP):

Water vapor permeability can be determined by a natural air circulation oven. The WVP can be determined by the following formula.

 

WVP=W/A Where, WVP is expressed in gm/m2per 24 hrs,

W is the amount of vapor permeated through the patch expressed in gm/24 hrs

 

A is the surface area of the exposure samples expressed in m15.

 

Drug content:

A specified area of the patch is to be dissolved in a suitable solvent of specific volume. Then the solution is to be filtered through a filter medium and analyse the drug content by suitable method such as UV or HPLC. Then take the average of three different samples.

 

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 test16.

 

Uniformity of dosage unit test:

An accurately weighed portion of the patch is to be cut into small pieces and transferred to a volumetric flask, dissolved in a suitable solvent and sonicate for complete extraction of drug from the patch and made up to the mark with same. The resulting solution was allowed to settle for about an hour, and the supernatant was suitably diluted with suitable solvent to give the desired concentration. The solution was filtered using 0.2µm membrane filter and analysed by suitable analytical technique (UV or HPLC) and the drug content per piece will be calculated.

 

Polariscopic examination:

A specific surface area of the piece is to be kept on the object slide of Polariscope and observe for the drugs crystals to distinguish whether the drug is present in crystalline form or amorphous form in the patch17.

 

Shear Adhesion test:

This test is to be performed for the measurement of the cohesive strength of an adhesive polymer. It can be influenced by molecular weight, degree of crosslinking, composition of polymer, type and amount of tackifier added. An adhesive coated tape is applied onto a stainless-steel plate; a specified weight is hung from the tape, to affect it pulling in a direction parallel to the plate. Shear adhesion strength is determined by measuring the time it takes to pull the tape off the plate. The longer the time taken for removal of the tape, greater is the shear strength18.

 

Peel Adhesion test:

In this test, the force required to remove an adhesive coating form a test substrate is referred to as peel adhesion. Molecular weight of adhesive polymer, the type and amount of additives used determine the peel adhesion properties. A single tape is applied to a stainless-steel plate or a backing membrane of choice and then tape is pulled from the substrate at a 180°C angle. The force required to remove the tape is measured19.

 

Tack properties:

It is the ability of the polymer to adhere to the substrate with little contact pressure. Tack is dependent on molecular weight and composition of the polymer as well as on the use of tackifying resins in polymer.

 

Thumb tack test:

It is a qualitative test applied for determination of tack property of adhesive. The relative tack property is detected by simply pressing on the adhesive with the thumb20.

 

Flatness test:

Three longitudinal strips are to be cut from each film at different portion like one from the center, other one from the left side, and another one from the right side and so on. The length of each strip was measured and the variation in length because of non-uniformity in flatness was measured by determining percent constriction, with 0% constriction equivalent to 100% flatness21.

 

            I1 – I2

% constriction = ----------- × 100

               L1

 

Where I1= Initial length of each strip.

I2 = Final length of each strip.

 

Percentage elongation break test:

The percentage elongation break is determined by noting the length just before the break point, the percentage elongation can be determined from the below formula.

 

        I1 – I2

Elongation percentages = ---------- ×100

           L1

 

Where I1 = is the final length of each strip.

I2= is the initial length of each strip.

 

Rolling Ball tack test:

This test measures the softness of a polymer that relates to tack. In this test, stainless steel ball of 7/16 inches in diameter is released on an inclined track so that it rolls down and comes into contact with horizontal, upward facing adhesive. The distance the ball travels along the adhesive provides the measurement of tack, which is expressed in inch22.

 

Quick stick (peel-tack) test:

In this test, the tape is pulled away from the substrate at 90ºC at a speed of 12 inches/min. The peel force required for breaking the bond between adhesive and substrate is measured and recorded as tack value, which is expressed in ounces or grams per inch width23.

 

Probe Tack test:

In this test, the tip of a clean probe with a defined surface roughness is brought into contact with adhesive, and when a bond is formed between probe and adhesive. The subsequent removal of the probe mechanically breaks it. The force required to pull the probe away from the adhesive at fixed rate is recorded as tack and it is expressed in grams24.

 

Stability studies:

Stability studies are to be conducted according to the ICH guidelines by storing the TDDS samples at 40±0.5°c and75±5% RH for 6 months. The samples were withdrawn at 0, 30, 60, 90,120 and 180 days and analyze suitably for the drug content25.

 

In vitro drug release studies:

The paddle over disc method (USP apparatus V) can be employed for assessment of the release of the drug from the prepared patches. Dry films of known thickness are to be cut into definite shape, weighed, and fixed over a glass plate with an adhesive. The glass plate was then placed in a 500 ml dissolution medium or phosphate buffer (pH 7.4), and the apparatus was equilibrated to 32± 0.5°C. The paddle was then set at a distance of 2.5 cm from the glass plate and operated at a speed of 50 rpm. Samples (5ml aliquots) are withdrawn at appropriate time intervals up to 24hrs and are analyzed by UV spectrophotometer or HPLC. The experiment is to be performed in triplicate and the mean value can be calculated26.

 

In vitro skin permeation studies:

In vitro permeation study can be carried out by using diffusion cell. Full thickness abdominal skin of male Wistar rats weighing 200 to 250 gm is taken. Hair from the abdominal region is to be removed carefully by using an electric clipper; the dermal side of the skin was thoroughly cleaned with distilled water to remove any adhering tissues or blood vessels and equilibrated for an hour in dissolution medium or phosphate buffer pH 7.4 before starting the experiment and was placed on a magnetic stirrer with a small magnetic needle for uniform distribution of the diffusant. The temperature of the cell was maintained at 32±0.5°C using a thermostatically controlled heater. The isolated rat skin piece is to be mounted between the compartments of the diffusion cell, with the epidermis facing upward into the donor compartment. Sample of definite volume is to be removed from the receptor compartment at regular intervals, and an equal volume of fresh medium is to bereplaced. Samples are to be filtered through filtering medium and can be analyzed spectrophotometrically orHPLC. Flux can be determined directly as the slope of the curve between the steady-state values of the amount of drug permeated (mg/cm2) vs time in hours and permeability coefficients were deduced by dividing flux by initial drug load (mg/cm2)27.

 

In vivo Evaluation:

In vivo evaluation is 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 lead us 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 animals28.

 

Human models:

The final stage of 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 effectiveness in patients. Phase III trials indicate the safety and effectiveness in large number of patient population and Phase IV trials include post marketing surveillance and are done for marketed patches to detect adverse drug reactions. Though human studies require considerable resources they are the best to assess the performance of the drug29.

 

Future of Transdermal therapy:

Ten years ago, the nicotine patch had revolutionized smoking cessation; patients were being treated with clonidine for hypertension, scopolamine for motion sickness and estradiol for estrogen deficiency all through patches. During the past decade, the number of drugs formulated in the patches has hardly increased and there has been little change in the composition of the patch systems30. Modifications have been mostly limited to refinements of the materials used. The reason is the only limited number of drugs fit the molecular weight, and potency requirements for transdermal absorption.

 

CONCLUSION:

Successful transdermal drug application requires numerous considerations. Keeping in mind the basic functions of the skin are protection and containment. It would seem exceptionally difficult to target the skin for drug delivery. However, with our greater understanding of the structure and function of the skin, and how to alter these properties, more and more new drug products are being developed for transdermal delivery. The properties of the drug, the characteristics of the transdermal device, selection of in-vivo model and the status of patient`s skin are all important for safe and effective drug delivery. The transdermal drug delivery system could be one of the best novel drug delivery system.

 

REFERENCES:

1.      Mahato RA. Pharmaceutical dosage forms anddrug delivery’’ Published by CRS press, Taylor and Froncrs Group, 6000 Broken Sound Parkway, Sute 300, Boca Raton, 2002, 196-197.

2.      Hadgraft J. Skin, the final frontier. Int J Pharm. 2001; 224(1–2): 1–18.

3.      Joseph R, Robinson, Vincent HL. Controlled drug delivery fundamentals and applications. Revised and Expanded: Lee. Marcel Dekker, Inc; 2005. p.524.

4.      Moser K. Passive skin penetration enhancement and its quantification in-vitro. Eur J Pharm Biopharm. 2001; 52:103-112.

5.      Aggarwal G. Development, Fabrication and Evaluation of Transdermal Drug Delivery‐ A Review. Pharmainfo.net. 2009.

6.      Hanumanaik M, Patil U, Kumar G, Patel S K, Singh I, Jadatkar K, Design, Evaluation and Recent Trends in Transdermal Drug Delivery System: A Review, IJPSR, 2012; Vol. 3(8): 2393-2406

7.      Chandrashekhar N S, Shobha Rani R H. Physicochemical and Pharmacokinetic Parameters in Drug Selection and Loading of Transdermal Drug Delivery. Indian Journal of Pharmaceutical Sciences. 2008; 70(1): 94‐96.

8.      Levin G, Kornfeld J, Patel Y R, Damon S. Transdermal Delivery: Success Through A Deep Understanding of The Skin. Corium.

9.      Shah S. Transdermal Drug Delivery Technology Revisited: Recent Advances. Pharmainfo.neGuy RH, Hadgraft J, editors. New York: Marcel Dekker; 2003. Transdermal Drug Delivery.

10.   Williams A. London: Pharmaceutical Press; 2003. Transdermal and Topical Drug Delivery.

11.   Prausnitz MR, Mitragotri S, Langer R. Current status and future potential of transdermal drug delivery. Nat Rev Drug Discov. 2004; 3: 115–124.

12.   Bronaugh RL, Maibach HI, editors. Edn. 4th. New York: Marcel Dekker; 2005. Percutaneous Absorption.

13.   Miller MA, Pisani E. The cost of unsafe injections. Bull World Health Organ. 1999; 77: 808–811.

14.   Foldvari M, Babiuk S, Badea I. DNA delivery for vaccination and therapeutics through the skin. Curr Drug Devil. 2006; 3: 17–28.

15.   Glenn GM, Kenney RT. Mass vaccination: solutions in the skin. Curr Top Microbiol Immunol. 2006; 304: 247–268.

16.   Valenta, C. and Almasi-Szabo, I. (1995). In vitro diffusion studies of ketoprofen transdermal therapeutic system. Drug Dev.Ind. Pharm, 21: 1799-1805.

17.   Krishna, R. and Pandit, J.K. (1994). Transdermal delivery of propranolol. Drug Dev.Ind. Pharm, 20: 2459- 2465.

18.   Aqil, M., Zafar, S., Ali, A. and Ahmad, S. (2005). Transdermal drug delivery of labetolol hydrochloride: system development, in vitro; ex vivo and in vivo characterization. Curr Drug Deliv, 2(2): 125-31.

19.   Shin, S. and Lee, H. (2002). Enhanced transdermal delivery of triprolidine from the ethylene-vinyl acetate matrix. Eur. J. Pharm. Biopharm, 54: 161-164.

20.   Sweetman S.C. (2005). Martindale – The Complete Drug Reference. Foco A, Hadziabdic J, Becic Transdermal drug deliverysystems. Med. Arch 2004; 58: 230-4.

21.   Khatun M, Islam ASM, Akter P, Quadir AM, Reza SM. Controlled release of naproxen sodium from eudragit RS100 transdermal film, Dhaka University. J. Pharm. Sci. 2004; 3(1-2).

22.   Rao PR, Diwan PY. Permeability studies of cellulose acetate free films for transdermal use: Influence of plasticizers. Pharm. Acta. Helv. 1997; 72: 47-51.

23.   Gondaliya D, Pundarikakshudu K. Studies in formulation and pharmacotechnical evaluation of controlled releasetransdermal delivery system of bupropion. AAPS. Pharm.Sci. Tech. 2003; 4: Article3.

24.   Swarbrick J, Boylan J. Encyclopedia of Pharmaceutical Technology: “Transdermal drug delivery devices: systemdesign and composition”: 309-37.

25.   Singh J, Tripathi KT, Sakia TR. Effect of penetration enhancers on the in vitro transport of ephedrine throughrate skin and human epidermis from matrix basedTransdermal formulations. Drug. Dev. Ind. Pharm. 1993; 19: 1623-8.

26.   Wade A, Weller PJ. Handbook of pharmaceutical Excipients. Washington, DC: American Pharmaceutical Publishing Association; 1994. p.362-366.

27.   Reddy RK, Muttalik S, Reddy S. Once daily sustainedrelease matrix tablets of nicorandil: formulation and in vitro evaluation. AAPS. Pharm. Sci. Tech. 2003; 4: 4.

28.   Shaila L, Pandey S, Udupa N. Design and evaluation of matrix type membrane controlled Transdermal drug delivery system of nicotin suitable for use in smoking cessation. Indian. Journ. Pharm. Sci. 2006; 68: 179-84.

29.   Aarti N, Louk ARMP, Russsel OP, Richard HG. Mechanism of oleic acid induced skin permeation enhancement invivo in humans. Jour. control. Release. 1995; 37: 299-306.

30.   Lec ST, Yac SH, Kim SW, Berner B. One way membrane for transdermal drug delivery systems/system optimization.Int. J. Pharm. 1991; 77: 231-7.

 

 

 

Received on 20.05.2020            Modified on 19.08.2020           

Accepted on 25.11.2020              ©A&V Publications all right reserved

Research J. Topical and Cosmetic Sci. 2021; 12(1):4-12.

DOI: 10.52711/2321-5844.2021.00002