INTRODUCTION:

From the past three decades there are huge changes and developments in formulation technology. Innovations in systems of drug delivery are not only associated with the development of novel drug delivery forms but also with the development of new formulations using existing drugs for the treatment. These innovations in delivery of drug have many benefits like better patient compliance, maintenance of steady state concentration of drug for longer duration, reducing dosing frequency, targeting of drug to specific site and low side effects and this transdermal route of drug delivery has more benefits and convenience than oral route.¹

One of the most general route for delivery of drug is through oral cavity having many pros and some cons like drug degradation in GI Tract due to enzymes and pH and Hepatic first pass metabolism and to reduce these associated problems novel drug delivery systems were developed.²

Table No. 1: Drug administered using TDDS

Sr. No	Name of drug	References
1	Nifedipine	6,7
2	Nitroglycerin	8,9
3	Captopril	10
4	Chlorpheniramine	11
5	Propranolol	12,13,14
6	aspirin	15
7	Norethindrone	16
8	Hydrocortisone	17
9	Acyclovir	18
10	Fentanyl	19
11	Theophylline	20
12	Nicotine	21,22
13	Testosterone	23
14	Clonidine	24,25
15	Lidocaine	26
16	Scopolamine	27
17	Estrogen	28
18	Norelgestromin	29
19	Estradiol	30,31
20	Triptolide	32
21	Rivastugmine	33
22	Terbinafine	34
23	Primaquine	35
24	Rotigotine	36
25	Methylphenidate	37
26	Seligiline	38

TDDS is also known as “Skin Patch”, which is a dosage form designed for delivery of effective quantity of drug through the skin of patient.³ It provides both controlled and continuous administration drug by means of membrane which terminates the pulsed entry of drug in systemic circulation due to which side effects are observed.⁴

This technology for delivery of drug through skin was developed in 1970s & first was authorized in 1979 by FDA having scopolamine as an active ingredient for the treatment of motion sickness.⁵now a day’s many drugs are now present there in the form of transdermal patches and the details of drugs are given in table No.1

ADVANTAGES OF TDDS:

1. Constant and stable administration of drug for prolonged duration.

2. Therapeutic Problems associated with irregular dosing can be reduced which results in less side effects.

3. This route of administration is option for those patients having problem with oral dosage forms.

4. Problems like GI Irritation, low absorption, Food-drug and Drug-drug interaction can be avoided.

5. Avoids Hepatic first pass metabolism.

6. Reduction in degradation of drug.

7. Reduction in fluctuation of circulating drugs.

8. More uniform drug effect.

9. Ease of self-administration and non-invasive.

10. Inconvenience of parenteral administration can be avoided.

11. By simply removing the patch drug therapy can be discontinued.

12. Improved patient compliance.

13. Drug delivery is unaffected by Vomiting and diarrhea.³⁹

DISADVANTAGES OF TDDS:

1. Due to permeability of skin, entry of drug is limited and only potent drugs can be administered by TDDS.

2. Problems are caused due to Ionic drugs.

3. There are Chances of skin irritation, dermatitis or hypersensitivity and requires discontinuation or removal of patch.

4. Long term adherence is difficult and also sometimes long term adherence creates discomfort to the patient.

5. Administration of dose more than 10 mg is difficult.

6. Those drug having size more than 500 daltons are not suitable for TDDS.

7. It is hard to achieve high plasma concentration.

8. Drugs having low partition coefficient are not able to reach systemic circulation.⁴⁰

BARRIERS TO TRANSDERMAL DRUG DELIVERY :

It is clear and there are number of evidences that show main hurdle for Transdermal drug delivery is skin and its is an impermeable protective barrier, but studies and investigations since last three decades proved that skin is also used as a route of administration. Skin is an easily reachable and most important organ of the body.

Figure No.1: The Structure of skin⁴¹

SKIN:

External protective covering of human body is skin which protects underlying muscles, bones & internal organs from environment and drug substances.

EPIDERMIS:

It is the Outermost hard and thin surface of the skin as shown in Figure No. 1. Mainly the cells present in epidermis are Keratinocytes, these cells forms cells in inner layer of epidermis know as basal layer. These are brick wall like structure and they are composed of dead cell which is the outermost part of epidermis and this layer acts as barrier, many drugs are not able to penetrate stratum corneum but the lipophilic drugs can easily penetrate as compared to hydrophilic.

DERMIS:

It is a lower layer of epidermis as shown in figure No. 1, which is a thick and fibrous layer of elastic tissue containing blood vessels, hair follicles and nerve endings. This layer transmits drug from patch to hypodermis.

HYPODERMIS:

Hypodermis lies below dermis as shown in figure No. 1; it is thick fatty coat which insulates body from heat and cold climatic conditions, protects skin from outer environment and also serves as a storage house of energy.^55-57

BLOOD VESSELS:

Dermis gets a wealthy blood supply with superficial artery plexus and subcutaneous venous networks shown in figure No. 1. It acts as a barrier when there is poor blood flow.⁴²

FACTORS AFFECTING DELIVERY OF DRUG BY TRANSDERMAL ROUTE:

Biological Factors:

· Condition of skin

· Age of skin

· Flow of blood

· Metabolism of skin

· Difference in species

· Skin sites (regional)

PHYSIOLOGICAL FACTORS:

· Hydration of skin

· pH and temperature

· Coefficient of diffusion

· Concentration of drug

· Coefficient of partition

· Shape and Molecular size.⁴³

ELEMENTS OF TRANSDERMAL DRUG DELIVERY SYSTEM:

1. Polymer matrix

Polymer is an important factor which controls the release of drug and before using it in transdermal patch following criteria’s should be satisfied.

· Chemical functionality and Molecular weight of polymer should be such that drug gets out of it properly.

· It should be stable.

· It should be non-toxic in nature.

· It should be easily fabricated.

· It should be cost effective.

· Degradation product must be non-toxic.

Examples of polymers used:

Gelatin (Natural), Shellac (Natural), Cellulose derivative (Natural), Slilicone rubber (Synthetic elastomer), Polysiloxanes (Synthetic elastomer), Poly Vinyl chloride (Synthetic), Polyurea (Synthetic).^44,45

2. Drug:

A drug candidate for TDDS should have following properties:

Physicochemical Properties:

· Drug should have molecular weight <500 daltons.

· Drug molecule should have affinity for both lipophilic as well as hydrophilic phases.

· Melting point of drug should be low.

Biological properties:

· Nature of drug should be potent.

· Half life of drug should be short.

· It should not produce any kind of irritation or allergic response.

· Those drugs that are degraded in GI tract or get affected by hepatic first pass metabolism are suitable candidates for transdermal drug delivery.

· Tolerance to the drug should not be developed under near zero order release profile of Transdermal drug delivery.

· Drugs that requires long term administration or drugs that produces side effects to non-targeted tissue sites can be give by TDDS.^46,66

4. Permeation enhancers:

Permeation enhancers are used to promote the permeability of the stratum corneum by altering lipid layer and proteins and can be classified as:

· Solvents:

Involves swallowing of protein and lipid layer which results in increased permeability. Example: Methanol, ethanol, dimethyl sulfoxide etc.

· Surfactants:

Used to enhance polar pathways. Example: Non-ionic: Pluronic F68, Pluronic F127, Anionic: Sodium lauryl sulphate, Dioctyl sulphosuccinate.^47,63,68

5. Adhesives (Pressure sensitive):

These are the Materials which are which are non-reactive in nature and easily forms a bond with substrate when pressed and no residue is left after removal, These adhesives are used to maintain contact between skin surface and patch.

These pressure sensitive adhesives should remain in stable form while using in formulation with drugs, penetration enhancers and all other excipients of the dosage form and should not sensitize the skin, leave any unwashable residue and should adhere to skin firmly.

Example: Polyacrylate, polysiloxane, etc.⁴⁸

6. Backing membrane:

It is a flexible and impermeable membrane which protects the product from the outer environment, while selecting the materials of membrane, chemical resistance and compatibility of material should be taken into consideration and backing membrane should have properties like good transmission of oxygen, highly flexible, high moisture vapour transmission rate etc.

Example: Occlusive base plates, Adhesive foam pads and Metallic plastic laminates.⁴⁹

Liner:

It protects the product during its storage and it is removed before use, the drug solution is in direct contact with liner that’s why it is considered as primary packaging material and liner is made up of Teflon or silicone coat and a supportive layer that may be occlusive or non-occlusive.⁵⁰

Types of TDDS:

Drug-in-adhesive (Single layered):

In this system drug is incorporated within adhesive layer which is responsible for drug release and serves as a base that adheres to the system as well as to the skin. Liner and backing membranes are there which surrounds the layer and rate of release of drug depends on dissemination of drug across the skin.⁵¹

Drug-in-adhesive (Multi-layered):

In this type there are two layers of drug solution (Controlled and immediate release layer) with adhesive layer which is there for release of the drug and it includes a permanent backing layer and temporary liner.^52,69

Drug-in-adhesive (Reservoir):

In this type reservoir of drug is sandwiched between rate controlling membrane and backing layer. Drug present in reservoir is in solution form or in suspension gel form or dispersed in solid bio-compatible polymer matrix and this is then discharged through porous rate controlling membrane.^53,70

Drug-in-adhesive (Matrix):

In this type semisolid matrix containing solution of drug or gel suspension is incorporated which is in contact with rate controlling release liner and laminate and concentric configuration is formed around the semisolid matrix.^54,71

Classification of TDDS:

Classification of TDDS based on their technical Sophistication⁵⁵ is given in Figure No. 2.

CHARACTERIZATION:

Physical evaluation:

Drug content uniformity:

Take specified number of patches, dissolve them in appropriate solvent, filter the solution by using membrane filter and finally analyze the sample by using HPLC or UV Spectrophotometer.

pH Determination:

Take specified no. of patches, Keep it in contact with distilled water, drain off excess water & check the pH of solution by using pH meter.

Folding Endurance:

Cut the patches in specific size by means of sharp blade and fold that patch at same place till it is broken. Folding endurance is the number of times the patch is folded at sample place without breaking.

Patch Thickness:

By means of Micrometer screw gauge one can easily determine the thickness of the batch.

Weight of patch:

Take specified number of patches from the prepared batch and weigh them individually on digital balance and calculate the standard deviation.

Moisture content:

Cut the prepared patches into strips of specific size, weigh them individually and place in desiccator filled with activated silica and temperature should be maintained at 30ºC, after 12 hours remove the films are reweigh them.

Percentage moisture content= Reduction in weight/ initial weight X 100

Water absorption study:

Cut the prepared patches into strips of specific size, weigh them individually and place in desiccator silica and temperature should be maintained at 40ºC after 24 hours remove the patches and expose them to 75% relative humidity (Constant Saturated solution of NaCl) at room temperature and weigh the patches till constant weight is obtained.

Capacity of water absorption= Rise in weight/ Initial weight X 100

Drug Carrier interaction:

Chromatographic methods like TLC or HPLC is used for determining the drug-carrier interactions.

Tack properties:

Tack property means ability of a polymer to adhere to the substrate when little contact pressure applied and it is dependent on polymeric composition and molecular weight of Polymer.

Tensile Strength:

Place the films between corked liner plates, one end of film is kept fixed by means of iron screen while other end is tied on freely movable thread over a pulley and gradually weights are increased in pan hanging on the end of thread. Elongation of film and weight required to break the film is noted simultaneously.⁵⁷

Tensile strength= Breaking force/ Film’s width X Film’s Thickness (1+ Film’s Length/1)

In-Vitro Drug Release studies:

Commonly used method for determination of in-vitro drug release is by using Franz diffusion cell which is made up of 2 compartments i.e. donor and receptor compartment (Volume 5-12ml & effective surface area 1-5cm²) and there is a thermostated jacket for maintaining temperature surrounding the receptor compartment and the diffusion buffer is continuously stirred at 600rpms by means of magnetic bar and the specified amount of solution is withdraw from receptor compartment at selected time intervals and the samples are analyzed by suitable method for drug release. ^58,62

In-vitro Drug permeation studies:

Franz diffusion cell is most commonly used apparatus for In-vitro drug permeation studies, in this method Thick abdominal skin of wistar rats weighing 200-250 gm is used which acts as semi-permeable membrane (Allow the skin to equilibrate with medium for 1 hour before use), Take a magnetic stirrer having small magnetic needle for uniform distribution of diffusant, Maintain the temperature of cell at 32ºC ± 5ºC by means of thermostat, Mount the isolate rat skin between donor and receptor compartments of franz diffusion cell with epidermis in upper direction, withdraw specified amount of sample from receptor compartment and add same amount of fresh one, filter the samples and analyze them by using UV Spectrophotometer or HPLC.^59,64,65

Skin irritation test:

In this test Formulated patches are applied on the dorsal surface of shaved skin of healthy rabbits and the skin is observed after 24 hours for any allergic/hypersensitivity reactions.⁶⁰

Stability studies:

Stability study protocols are performed according to the ICH Guidelines. For the stability studies prepared patched are stored at specified conditions (temperature 40ºC ± 0.5ºC and Relative humidity 75±5%) for 6 months and the drug content of the sample is analyzed at the intervals of 0, 30, 60, 90 and 180 days.

It is performed according to ICH guidelines. The formulated patches are stored at 40ºC±0.5ºC and 75± 5% relative humidity for 6 months. The samples were analyzed for drug content at intervals of 0, 30, 60, 90 and 180 days.⁶¹

CONCLUSION:

This article is an attempt to compile valuable information related to all aspects of TDDS and it will serve as a valuable source of information for all the researchers and scientist that are involved in research on TDDS and for exploring new insights into it.

ACKNOWLEDGEMENT:

The authors are thankful to the Management and Dean of Madhyanchal professional university, Bhopal for providing necessary support and facilities.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 29.12.2020 Modified on 17.04.2021

Research J. Pharm.and Tech 2022; 15(3):1371-1377.

DOI: 10.52711/0974-360X.2022.00229