1. INTRODUCTION:

Oral route is the popular route of drug delivery. Although it has some disadvantages including first pass metabolism, drug degradation in gastrointestinal tract due to enzymes, pH etc. To cross these problems, a novel drug delivery system was developed. In this transdermal delivery system medicated adhesive patches are prepared which deliver therapeutically effective amount of drug across the skin when it placed on skin. Medicated adhesive patches or transdermal patches are of different sizes, having more than one ingredient. Once they apply on unbroken skin they deliver active ingredients into systemic circulation passing via skin barriers.

A patch containing high dose of drug inside which is retained on the skin for prolonged period of time, which get enters into blood flow via diffusion process. Drug can penetrate through skin via three pathways-through hair follicals, through circulation passing via skin barriers. A patch containing high dose of drug inside which is retained on the skin for prolonged period of time, which get enters into blood flow via diffusion process. Drug can penetrate through skin via three pathways-through hair follicals, through sebaceous glands, through sweat duct. Transdermal drug delivery systems are used in various skin disorders, also in the management of angina pectoris, pains, smoking cessation and neurological disorders such as Parkinson’s disease¹.

1.1 Advantages of transdermal drug delivery system:

1. First pass metabolisms of drug get avoided.

2. Gastrointestinal incompatibilities get avoided.

3. Self medication is possible.

4. Duration of action gets extended and predictable.

5. Unwanted side effects get minimized.

6. Drug plasma concentration gets maintained².

7. Number of doses get reduces which improve patient compliance.

8. Therapeutic value of many drugs get increased by avoiding problems associated with drug like-lower absorption, GI irritation, decomposition due to hepatic first pass metabolism.

1.2 Disadvantages of transdermal drug delivery System:

1. Chances of allergic reactions at the site of application like itching, rashes, local edema etc.

2. Larger molecular size of drug (above 1000) creates difficulty in absorption.

3. Barrier function of skin varies from site to site on the same or different person.

4. Drug with hydrophilic character is less suitable as compare to drug with lipophilic character because of their low permeability³.

1.3 Factors affecting transdermal drug delivery⁴:

A) Physicochemical properties of permeate:

1. Partition coefficient

2. Molecular size

3. Solubility/melting point

4. Ionization

B) Physiological and pathological conditions of skin:

1. Reservoir effect of horny layer

2. Lipid film

3. Skin hydration

4. Skin temperature

5. Regional variation

6. Pathological injuries to the skin

7. Cutaneous self-metabolism

8. Skin barrier properties in the neonate and young infant

9. Skin barrier properties in aged skin

10. Race

11. Body site

12. Penetration enhancers used

A) Physicochemical properties of permeate:

1. Partition coefficient:

Water and lipid soluble drugs favorably absorbed through the skin. Intercellular route is applicable for drugs with intermediate partition coefficient (log K 1 to 3) and having high lipophilicity. The transcellular route probably predominates for more hydrophilic molecules (log K < 1).

2. Molecular size:

There is an inverse relationship existed between transdermal flux and molecular weight of the molecule. The drug molecule selected as candidates for transdermal delivery tend to lie within narrow range of molecular weight (100 - 500 Dalton).

3. Solubility/melting point:

Lipophilicity is a desired property of transdermal candidates as lipophilic molecules tend to permeate through the skin faster than more hydrophilic molecules. Drugs with high melting points have relatively low aqueous solubility at normal temperature and pressure.

4. Ionization:

According to pH-partition hypothesis, only the unionized form of the drug can permeate through the lipid barrier in significant amounts⁵.

B) Physiological and pathological conditions of skin:

1. Reservoir effect of horny layer:

The reservoir effect of horny layer which is deeper layer is due to irreversible binding of a part of the applied drug with the skin.

2. Lipid film:

The lipid film on the skin surface acts as a protective layer to prevent the removal of moisture from the skin and helps in maintaining the barrier function of stratum corneum.

3. Skin hydration:

Skin hydration can be achieved simply by covering or occluding the skin with plastic sheeting, leading to accumulation of sweat and enhance the penetration by opening the densed, closely packed cells of the skin and increase its porosity.

4. Skin temperature:

Increase in skin temperature increases the rate of skin permeation this is due to availability of energy required for diffusivity⁶.

5. Regional variation:

Differences in nature and thickness of the barrier of skin cause variation in permeability.

6. Pathological injuries to the skin:

Injuries that disrupt the continuity of the stratum corneum, increases permeability due to increased vasodilatation caused by removal of the barrier layer⁷.

7. Cutaneous self-metabolism:

Catabolic enzymes present in the epidermis may render the drug inactive by metabolism and thus the topical bioavailability of the drug.

8. Skin barrier properties in the neonate and young infant:

The pH of skin surface of new borns is higher than those in adult skin. The skin surface of the newborn is slightly hydrophobic and relatively dry and rough when compared to that of older infants. Stratum corneum hydration stabilizes by the age of 3 months.

9. Skin barrier properties in aged skin:

There are changes in the physiology of aged skin (>65 years). The corneocytes are shown to increase in surface area which may have implications for stratum corneum function due to the resulting decreased volume of intercorneocyte space per unit volume of stratum corneum. The moisture content of human skin decreases with age⁸.

10. Race:

Racial differences between black and white skins have been shown in some anatomical and physiological functions of the skin although data is relatively sparse. In black skin, increased intracellular cohesion, higher lipid content and higher electrical skin resistance levels compared to whites have been demonstrated.

11. Body site:

Skin structure varies at different sites of body. Genital tissue usually provides the most permeable site for transdermal drug delivery. The skin of the head and neck is also relatively permeable compared to other sites of the body such as the arms and legs. Intermediate permeability for most drugs is found on the trunk of the body.

12. Penetration enhancers used:

Low permeability of drugs across the skin can be improved by the development of penetration enhancers. Penetration enhancers or promoters are agents that have no therapeutic properties of their own but can transport the sorption of drugs from drug delivery systems onto the skin and/or their subsequent transdermal permeation through skin⁹.

2. Components of Transdermal Drug Delivery System:

1. Polymer matrix/ Drug reservoir

2. Drug.

3. Permeation enhancers.

4. Pressure sensitive adhesive (PSA)

5. Backing laminate.

6. Release liner.

7. Other excipients like plasticizers and solvents

1. Polymer matrix/ Drug reservoir:

Polymers are core part of TDDS. It is prepared by dispersing the drug in liquid or solid state synthetic polymer base. Polymers used in TDDS should have biocompatibility and chemical compatibility with the drug and other components of the system such as penetration enhancers. Additionally they should provide consistent and effective delivery of a drug throughout the product’s intended shelf life and should be of safe status ¹⁰. Polymers used in TDDS are classified as:

• Natural polymers:

e.g. cellulose derivatives, zein, gelatin, shellac, waxes, gums, natural rubber and chitosan etc.

• Synthetic elastomers:

e.g. polybutadiene, hydrin rubber, silicon rubber, polyisobutylene, acrylonitrile, neoprene, butyl rubber etc.

• Synthetic polymers:

e.g. polyvinylalcohol, polyvinylchloride, polyethylene, polypropylene, polyacrylate, polyamide, polyurea, polyvinylpyrrolidone, polymethylmethacrylate etc.

2. Drug:

Some of ideal properties of drug and some factors to be consider during preparation of TDDS are as follows.

Table No – 1: Ideal properties of drug and some factors to be consider during preparation of TDDS

Parameters	Properties
Dose	Should be low (less than 20 mg/day)
Half life	10/less (hrs)
Molecular weight	<400 da
Skin permeability coefficient	>0.5×10^-3cm/h
Skin reaction	Non irritating non sensitizing
Oral bioavailability	Low

Table No – 2: Factors to be considered for transdermal dose calculation

Physicochemical	Pharmacokietic	Biological
Solubility	Half life	Skin toxicity
Crystallinity	Volume of Distribution	Site of application
Molecular weight	Total body clearance	Allergic reaction
Polarity	Therapeutic plasma concentration	Skin metabolism
Melting point	Bioavailability factor	--

3. Permeation enhancers:

Chemical compounds that increase permeability of stratum corneum so as to attain higher therapeutic levels of the drug candidate ^[11]. They improve the permeability by interacting with structural components of stratum corneum.

Ideal properties of permeation enhancers are

1. They should be non-irritating, non toxic and nonallergic.

2. They should not bind to receptor site i.e. not showing any pharmacological activity.

3. They should be cosmetically acceptable with an appropriate skin feel.

4. Pressure sensitive adhesive (PSA):

Pressure sensitive adhesive helps to adhere transdermal patch to the skin surface. It can easily remove from the smooth surface without leaving a residue on it.

Ex-Polyacrylates, polyisobutylene and silicon based adhesives are widely used in TDDS.

5. Backing laminate:

Backing laminates are supportive material which is impermeable to drugs and also to permeation enhancers. They should chemically compatible with the drug, enhancer, adhesive and other excipients¹².

Ex-vinyl, polyethylene and polyester films

6. Release liner:

Release liner is the primary packaging material that can protect the patch which will remove during application of patch to the skin. Release liner is made up of 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. Release liner should be chemically inert and it should be permeable to drug, penetration enhancers and water¹³.

7. Other excipients like plasticizers and solvents:

Solvents used are chloroform, methanol, acetone, isopropanol and dichloromethane. Plasticizers used dibutylpthalate, triethylcitrate, polyethylene glycol and propylene glycol¹⁴.

3. Types of Transdermal Drug Delivery System:

A. Reservoir System:

In drug this System the drug reservoir is kept in between backing layer and a rate controlling membrane. Drug releases through microporous rate controlled membrane. Drug can be in the form of a solution, suspension, or gel or dispersed in a solid polymer matrix in the reservoir compartment¹⁵.

B. Matrix System:

1. Drug-in-adhesive system:

For the formation of drug reservoir drug dispersed in an adhesive polymer and then spreading the medicated polymer adhesive by solvent casting or by melting the adhesive (in the case of hot-melt adhesives) onto an impervious backing layer¹⁶.

2. Matrix-dispersion system:

In matrix-dispersion system the drug is dispersed homogeneously in a hydrophilic or lipophilic polymer matrix. Then this containing polymer along with drug is fixed onto an occlusive base plate in a compartment fabricated from a drug-impermeable backing layer. Adhesive is spread along the circumference instead of applying on the face of drug reservoir to form a strip of adhesive rim.

C. Micro-Reservoir System:

This system is a combination of reservoir and matrix-dispersion systems. Here drug is suspended in an aqueous solution of water-soluble polymer and then dispersing the solution homogeneously in a lipophilic polymer to form thousands of unleachable, microscopic spheres of drug reservoirs.

4. Methods of Preparation of Transdermal Drug Delivery System:

1. Asymmetric TPX membrane method

2. Circular Teflon mould method

3. Mercury substrate method

4. By using “IPM membranes” method

5. By using “EVAC memb6ranes” method

6. Preparation of TDDS by using Proliposomes

7. By using free film method

4.1 Asymmetric TPX membrane method:

By this method prototype patch can be prepared by using heat sealable polyester film (type 1009, 3m) with a concave of 1cm diameter as the backing membrane. Drug dispersed on concave membrane, covered by a TPX {poly (4-methyl-1- pentene)} asymmetric membrane, and sealed by an adhesive¹⁷.

Asymmetric TPX membrane preparation:

These are prepared by using the dry/wet inversion process. Here TPX is dissolved in a mixture of solvent (cyclohexane) and nonsolvent 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. Then casting film is evaporated at 50°C for 30 sec, then the glass plate is to be immersed immediately in coagulation bath [maintained the temperature at 25°C]. After 10 minutes of immersion, the membrane can be removed, air dry in a circulation oven at 50°C for 12 hrs.

4.2 Circular Teflon mould method:

Polymeric solution in various ratios is used as an organic solvent. Then that solution is divided in two halfs. In one half calculated amount of drug is dissolved and in another half enhancers in different concentration are dissolved, and then two halves mixed together. Plasticizer (e.g., Di-Nbutylphthalate) is added into the drug polymer solution. The total contents are to be stirred for 12 hrs and then poured into a circular Teflon mould. The moulds are to be placed on a leveled surface and covered with inverted funnel to control solvent vaporization in a laminar flow hood model with an air speed of 0.5m/s. The solvent is allowed to evaporate for 24 h. The dried films are to be stored for another 24 h at 25±0.5°C in a desiccators containing silica gel before evaluation to eliminate aging effects¹⁸.

4.3 Mercury substrate method:

In the polymeric solution drug and plasticizer get dissolved. It is kept for 10-15min stirring to produce homogenous dispersion then it is poured into leveled mercury surface, covered with inverted funnel to control solvent evaporation.

4.4 By using “IPM membranes” method:

In the mixture of water and polymer (propylene glycol containing Carbomer 940 polymer) drug get dispersed and stirred for 12 hrs in magnetic stirrer. The dispersion is to be neutralized and made viscous by the addition of triethanolamine. If the drug solubility in aqueous solution is very poor then solution gel is obtained by using Buffer pH 7.4. The formed gel will be incorporated in the IPM membrane.

4.5 By using “EVAC membranes” method:

For the preparation of 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 insoluble in water then use propylene glycol for gel preparation. 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 device¹⁹.

4.6 Preparation of TDDS by using Proliposomes:

By carrier method using film deposition technique proliposomes are prepared. Drug and lecithin ratio should be 0.1:2.0 taken as an optimized one from previous references. For the preparation of proliosome in 100ml round bottom flask take 5mg of mannitol powder, then it is kept at 60-70°C temperature and the flask is rotated at 80-90rpm and dried the mannitol at vacuum for 30 minutes. 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, a 0.5ml aliquot of the organic solution is introduced into the round bottomed flask at 37°C, after complete drying second aliquots (0.5ml) of the solution is to be added. After the last loading, the flask containing proliposomes are connected in a lyophilizer and subsequently drug loaded mannitol powders (proliposomes) are placed in a desiccator over night and then sieved through 100 mesh. The collected powder is transferred into a glass bottle and stored at the freeze temperature until characterization²⁰.

4.7 By using free film method:

Cellulose acetate free film can prepared by casting on mercury surface. 2% w/w polymer solution is prepared by using chloroform. Plasticizers are to be incorporated at a concentration of 40% w/w of polymer weight. Five ml 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 a desiccator until use. Free films of different thickness can be prepared by changing the volume of the polymer solution²¹.

5. Evaluation of transdermal drug delivery system:

A. Interaction Studies

B. Thickness of the patch

C. Weight of uniformity

D. Folding endurance

E. Percentage moisture content

F. Water vapour permeability (WVP) evaluation

G. Drug content

H. Uniformity of dosage unit test

I. Polaroscope evaluation

J. Shear adhesion test

K. Peel adhesion test

L. Thumb tack test

M. Flatness test

N. Percentage elongation break test

O. Rolling ball tack test

P. Quick stick (peel tack) test

Q. Probe tack test

R. In vitro drug release studies

S. In vitro skin permeation studies

T. Skin irritation test

U. Stability studies

A. Interaction Studies:

To produce stable product the drug and excipient must be compatible with each other. Drug-excipient interaction will affect the stability and bioavailability of the final formulation²². When excipients are new, firstly used with the active substance in the formulation in that condition compatibility or interaction study is very much important. Interaction studies are carried out by Thermal analysis, Fourier transform infrared spectroscopy (FTIR), ultra violet (UV) and chromatographic techniques by comparing their physicochemical properties like assay, melting point, wave numbers, and absorption maxima.

B. Thickness of the patch:

At different points the thickness of the patch is measured by using digital mirometer and determine average thickness and standard deviation of the same²³.

C. Weight of uniformity:

Before testing the patch is dried at 60°C for 4 hrs. Cut that patch in different parts and weighed in digital balance. Take average weight and calculate standard deviation from individual weight.

D. Folding endurance:

A strip is cut with specific area. Fold that strip repeatedly at specific point till it get break. The number of times strip film get break gives the value of folding endurance²⁴.

E. Percentage moisture content:

Patch or film is weighed first then it is kept in desiccator containing calcium chloride at room temperature. Taken it out after 24hrs again reweighed and percentage moisture content is calculated by following formula:

Percentage moisture content (%) = [Initial weight – Final weight / Final weight] ×100

F. Water vapour permeability (WVP) evaluation:

The WVP can be determined by the following formula

WVP = W/A

Where, WVP is expressed in g/m² per 24 h,

W is the amount of vapour permeated through the patch expressed in g/24 h,

A is the surface area of the exposure samples expressed in m².

G. Drug content:

Take the patch with specific area dissolve it in specific volume of solvent. Solution is then filtered and the drug content analyzed with the suitable method (UV or HPLC technique). Then take the average of three different samples²⁵.

H. Uniformity of dosage unit test:

Take ten patches and content 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 test²⁶.

I. Polaroscope evaluation:

This examination determines whether drug is present as amorphous or crystalline form in the final formulation by using polaroscope. Patch with specific surface area is kept on the object slide and observed for drug crystals²⁷.

J. Shear adhesion test:

This test determines cohesive strength of adhesive polymer. Factors affecting are type and composition of polymers, its molecular weight, the degree of cross linking 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 direction parallel to the plate. Shear adhesion test is determined by measuring the time it takes to pull the tape off the plate. The longer the time takes for removal, greater is the shear strength²⁸.

K. Peel adhesion test:

Here peel adhesion is the force required to remove an adhesive coating from a substrate. A single tape is applied to a stainless steel plate then tape is pulled from the substrate at a 180° angle, and the required to pull the tape is measured²⁹.

L. Thumb tack test:

This test determines the tack property of adhesive. Thumb is pressed on adhesive and tack property is determined.

M. Flatness test:

Three longitudinal strips are cut from different portions of the films. The length of the each strip is measured and the variation in length because of non-uniformity in flatness is measured by determining percentage constriction, with 0% constriction equivalent to 100% flatness³⁰.

N. Percentage elongation break test:

Percentage elongation can be determine by using following formula

Elongation percentage = L₁-L₂*100/L₂

Where

L₁ is the final length of each strip and

L₂ is the initial length of each strip.

O. Rolling ball tack test:

This test determines the softness of the polymer that relates the tack. Here the stainless steel ball of size 7/16 inches in diameter is released on an inclined track so that it rolls down and comes in contact with horizontal, upward facing adhesive³¹. Distance travelled by ball along adhesive track gives the measurement of tack expressed in inch.

P. Quick stick (peel tack) test:

Here the tape is pulled away from the substrate at 90°C at a speed of 12 inches/min. The peel force required to break the bond between adhesive and substrate is measured and recorded as tack value, which is expressed in ounces or gms per inch width³².

Q. Probe tack test:

Here the probe with specific surface kept in contact with adhesive so as to form bond between them. Then probe is remove so that it mechanically break it. The force required to pull the probe is the tack measured in terms of grams.

R. In vitro drug release studies:

For the assessment of the release of the drug from the patches the paddle over disc method (USP apparatus V) can be used. Here the film with defined thickness, shape taken, weigh it, fixed over glass plate attached with adhesive. It is kept in 500ml phosphate buffer (pH7.4) as dissolution media and set the apparatus at 32±0.5°C. Keep the paddle at a distance 2.5cm from the glass plate and operated at a speed of 50rpm. 5ml of sample can withdraw at specific time interval for 24hrs and analysed by UV or HPLC. Perform the experiment in triplicate³³.

S. In vitro skin permeation studies:

By using diffusion cell in vitro skin permeation study is carried out. Here use of male wistar rat weighing 200-250gm. Take the abdominal skin of rat by removing the hairs from abdominal region by using electric clipper. Then dermal side of the skin is washed with distilled water to remove adhesive tissues then it is kept in dissolution media or phosphate buffer pH 7.4 for 1 hr. before starting the experiment and was placed on magnetic stirrer with small magnetic needle for uniform distribution of diffusant. The temperature of cell was maintained at 32±0.5°C using thermostatically controlled heater. Rat skin is placed between the compartment of diffusion cell with epidermis facing in upward into donar compartment. Specific amount of volume is withdrawn from receptor compartment at specific time interval and equal volume of fresh sample is added. Withdraw sample is filtered and analysed by UV or by using HPLC ³⁴.

T. Skin irritation test:

This study is performed on healthy rabbits (average weight 1.2 - 1.5kg). Remove the dorsal surface of rabbit by shaving and clean by using spirit³⁵. Formulation applied on skin surface and remove after 24hrs. Then skin is to be observed and classified in to 5 grades on the basis of severity of skin injury.

U. Stability studies:

Stability studies were done as per ICH guidelines where TDS samples are stored at 40±0.5°C and 75±5% RH for 6 months³⁵. The samples were withdrawn at 0, 30, 60, 90 and 180 days and analyzed suitably for the drug content.

6. CONCLUSION:

Transdermal drug delivery system is an novel drug delivery system which gives an assurity that the pharmacologically active substance give desired effect at target site with minimum side effects. Transdermal drug delivery system also overcome the problems associated with current drug delivery system, thus it has promising future.

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Received on 22.09.2021 Modified on 07.12.2021

Asian J. Pharm. Tech. 2022; 12(2):159-166.

DOI: 10.52711/2231-5713.2022.00027