INTRODUCTION:

Drug delivery through the skin is convenient route as compared to parenteral route due to steady state controlled the delivery of drug over the prolonged period of time and self-application is as well as possible. Said effects such as gastrointestinal disturbance and bowel ulcer related with oral drug delivery can be prevented by this route¹. Transdermal drug products have been established for a number of illnesses and defects, such as cardiovascular diseases, Parkinson's, Alzheimer, Anxiety, Depression and etc. Hence the major limitation is skin barrier which is effect on permeation of drug².

Drugs are able to penetrate the skin over the hair follicles, sweat ducts and directly through the stratum corneum. A transdermal patches are used to transport a particular amount of drug over the skin and systemic circulation. TDDS are presently accessible such as scopolamine (hyoscine) for motion illness, nitroglycerin andclonidine for cardiovascular sickness, fentanyl for treatment of chronic pain, nicotine use for smoking ending. Skin is a major organ of the human body with a range of 20 square feet and a multilayered biological membrane to perform various functions³. Transdermal pathway for conveyance of drug molecules is a fascinating alternative route because of more prominent patient comfort and well-being. This strategy allows various preferences over conventional dosage form like escape from first pass metabolism, plausible and delayed span of activity, lessening undesirable symptoms, usage of medications with short half-life, improving pharmacological action⁴.

STRUCTURE OF SKIN:

Skin is the major organ of the human body. It contain of largest surface area with through connection to the atmosphere. The human skin is consist of two layers, epidermis and dermis which is shown (Fig.1). Skin is not only protects the body from microbes, it also control and cover the muscles which indirectly maintains the temperature of body. Skin protects to us beside microbes, and furthermore gives the sensations about touch and temperature changes. The epidermis layer is the outer layer of the skin that comprises of keratinized, stratified squamous epithelium cells as five layers contingent upon its area in the body. From profound to shallow, these layers named as stratum basale, stratum spinosum, stratum granulosum, and stratum lucidum and stratum corneum⁵. The outermost layer, stratum corneum acts as a barrier which allows only lipophilic drug moieties of molecular weight less than 500 Da to cross the skin. Several techniques have designed to overcome this barrier and enhance the transdermal drug delivery of molecules with high molecular mass. Therefore, permeation enhancers have been used to alter the lipid content of stratum corneum and increase the permeability of drug molecules across the skin⁶. The dermis layer contain vascular, connective tissue, nerves, and hair follicles and sweat ducts. The epidermis layer is a vascular and called outermost layer of the skin. Stratum corneum, is the important barrier of skin especially to hydrophilic compounds, which is contains of keratin, dead epidermal cells named corneocytes fixed inside a fat rich matrix⁷.Skin also serves numerous critical abilities, including securing the body against injury, managing body temperature, balance the water and electrolyte level and contributes for vitamin D production. Topical or transdermal route of drug delivery has many advantages than other routes because of patient compliance, preventing the first pass metabolism, and few side effects.

Fig. 1: Diagram of Human Skin

But the major issue with these systems is transport of therapeutic moieties across the skin due to very small pore size of 20-40 nm which act as a barrier. Topical dermatologic dosage forms such as creams, lotions, and novel carrier based topical formulations can be applied for treatment of skin diseases⁸.

TRANSDERMAL DRUG DELIVERY SYSTEM:

TDDS is a topically applied drugs, contain separate dosage forms of patches, when administrated to the skin it deliver the active molecules, over the skin than the systemic circulation on controlled rate at an extended period of time to improve the therapeutic efficacy and decrease the adverse outcome of drug. Above the last two decades more than 35 transdermal patch have been approved in US. Ended the previous few decades, developed of controlled delivery system has slowly become significant in both pharmaceutical industry and pharmacological responses of drugs. Favorite satisfying effect and undesired adverse effect are related to the concentration of active ingredient at the place of action, therefore the human skin is maximum accessible surface area for delivery of active ingredient⁹.

ROUTES OF DRUG DELIVERY OVER THE SKIN:

When an active molecules of drug intact to the skin, it make links through the cellular debris, normal flora, sebum and other elements. Penetration of active molecules through the skin is possible by 3ways like sweat ducts, hair follicles and sebaceous glands¹⁰. The percutaneous absorption is a step-wise route of permeation of components into dissimilar layers of skin and penetration through the skin into total circulations can be classified into 3portions:

a. Penetration: Entry of an ingredient into a specific layer.

b. Permeation: Penetration of drug molecules from one layer to other layer.

c. Absorption: The being of an ingredient into systemic circulation¹¹.

FACTORS ENFLUENCE THE PERMEABILITY OF DRUG ACROSS THE SKIN:

The factors which are affecting on the permeability of drug through the skin, are classified into following 3groups:

Fig. 4: Factors Effect on Drug Permeability

1. Puysicochemical properties of drug:

A- Partition Co-Efficient:

Hydrophilic and hydrophobic active ingredients are satisfactorily absorbed across the skin. Permeability of drug molecules dependent to the Partition co-efficient. Partition co-efficient of a drug moleculescan be changed by chemical adjustment, without disturbing the pharmacological action of the active ingredients¹².

B- pH Condition:

The pH mostly affect the rate of absorption of acidic and basic active molecules, while unionized form of active ingredient has well penetrating capability but transport of changeable drug, shows low permeability.

C- Drug Concentration:

Transdermal permeability of drug through the skin is dependent to the concentration of drug molecules.

2. Puysicochemical properties of delivery system:

A-The Similarity of Vehicle for the Active Molecules:

It can affect the release of the active molecule from the transporter. Solubility of drug molecule in the carrier defines the drug release rate. The release mechanism of active molecule depends on nature of drug, type of carrier, condition of skin and partition co-efficient of drug¹³.

B- Arrangement of Drug Delivery System:

Arrangement of drug delivery system effect both the release rate of active molecules and the penetrability of drug on the sub cutaneous by hydration.

C- Improvement of Drug Permeation:

The release of active ingredient from dosage form is less because it is related to the dead nature of the sub cutaneous. Penetration enhancers can be reason the physicochemical or physiological variations in SC layer and improve the penetration of active molecules across the skin. Numerous chemical materials are found to enhance the permeation properties of drug¹⁴.

3. Physiological and pathologycal condition of the skin

A- Age:

Skin of infant more permeable than skin of mature, therefore percutaneous absorption of transdermal steroids are rapidly in children than adults but permeation of water is same in adults and children.

B- Lipid Film:

Lipid film of skin surface formed by the help of excretion of sebaceous glands, cell lipids such as sebum and epidermal cell which compose of surfactant and provide a protecting film to avoid the elimination of natural moisturizingelement from the skin and help in keeping the barrier role of the sub cutaneous.

C- Hydration of Skin:

Hydration of sub cutaneous can improve transdermal penetrability. The rate of permeation study of salicylic acid across the skin through the dry and hydrate corneum exhibited that when the tissues hydrated, the penetration rate of hydrophilic esters more enhanced than other esters.

D- Temperature of Skin:

Increasing the temperature of skin outcome is an increasing the rate of skin permeation. Rising of skin temperature can also rise the vasodilation of blood vessels, when it contact with skin, hence the percutaneous absorption of skin increase.

E- Metabolism of Drug:

After overpass the sub cutaneous barrier, some of the active ingredients passed to the systemic circulation in active form while inactive or metabolic form, due to existence of metabolic enzymes existing in the layers of skin. Researchers are found more than 95% of absorbed testosterone was metabolized, therefore it present across the skin.

F- Species Differences:

Skin of Mammalian from diverse species show varied changes in anatomy in such features the thickness of sub cutaneous, amount of sweat glands and hair follicles per unit surface area.

G- Pathological Wound of Skin:

Damages of the skin can reason the trouble in the continuousness of sub cutaneous and leads to rise the skin permeability¹⁵.

Generation of transdermal drug delivery system:

Generally TDDS can be classified in 3 generations. The first include many of present patches by choice of targeted medicines that can over the skin at healing rates. The 2^nd generation created enhancements for minor molecules which are deliver by enhancing skin permeability and applying force for transdermal carrying. The 3^rdgeneration meant at allowing delivery of small and macromolecules molecule of drugs (proteins and DNA) and virus based and vaccines over targeted permeabilization of the sub cutaneous layer of the skin. The main aim of 3^rdgeneration of transdermal drug delivery system is, hardly disrupter the sub-cutaneous barrier to allow the large molecules of drug to pass in to systemic circulation, therefore more effective for transdermal delivery and protection of deeper tissues¹⁶.

The main contents of transdermal patch

Polymer Matrix:

The purpose of backbone of transdermal system is to control the release of active ingredients. The polymer which are used in formulation of patch should be non-reactive, stable, nontoxic with reasonable cost such as cellulose derivatives, zein, gelatin, shellac, waxes, gums, polybutadiene, hydrin rubber, polyisobutylene, silicon rubber, nitrile, acrylonitrile, polyvinylchloride, neoprene, polyethylene, Polyvinyl alcohol, polyacrylate, polyuria, polyamide, polymethylmethacrylate, polyvinylpyrrolidone.

Permeation Enhancers:

Permeation enhancers are increase the permeability of skin and improve the therapeutic levels of the medicines. Permeation enhancers are broadly classified in to 3 types such as lipophilic solvent, surfactants and co-solvents like DMSO.

Backing Laminates:

These materials should be with high flexibility and low modulus for example vinyl and polyethylene.

Release Liner:

This liner defends the product through the storage condition. Another excipients also used in transdermal formulation such as plasticizers and solvents¹⁷.

Fig. 8: Multi-layer Drug-in-Adhesive

Table 1: Ideal Specification of Transdermal Drug Delivery System

S. No.	Specification	Limitation
1	Shelf life	Should be up to 2.5 years
2	Patch size	Should be less than 40 cm²
3	Dose frequency	Once a daily - once a week
4	Appearance	Should be clear or white color
5	Packaging properties	Should be easily removable of release liner
6	Skin reaction	Should be non-irritating
7	Release Properties	Should have consistent pharmacokinetic and pharmacodynamics profiles over time
8	Packaging properties	Should be easily removable of release liner

Table 2: Ideal Specification of Drug for Transdermal Drug Delivery System

S. No.	Parameters	Specification
1	Dose	Should be low
2	Half-life in hours	Should be 10 or less
3	Molecular weight	Should be less than 500
4	Skin permeability coefficient	Should be less than 0.5 x10-3cm/hr
5	Partition coefficient	Log P ( octanol-water) between –1 and 3
6	pH of saturated aqueous solubility	5-9
7	Oral bioavailability	Should be low
8	Dose deliverable	<10mg/day

CATEGORIES OF TRANSDERMAL PATCHE:

1. Single-Layer Drug in Adhesive:

The adhesive film of above system includes the active ingredient. The adhesive layer of this form of transdermal patch it not helps only adhere layer but serves the different layers together, with the whole system to the skin, therefore it is liable to release the active ingredient. The adhesive film is enclosed by an impermanent liner and backing.

2. Multi-Layer Drug in Adhesive:

This system is similar to the single film, in both system the adhesive films are similarly liable to release the active ingredients. One layer has responsible for repaid release of the active ingredients while another layer control the release of active molecules from the reservoir system. This system is diverse but that helps other layers of active molecules in adhesive, which is frequently parted with a membrane. This system (patch), also has an impermanent liner layer and a stable backing.

Fig. 9: Design of Adhesive Type of Transdermal Patch

3. Reservoir System:

This system is not like single and multi-layer system but the reservoir of TDDS has a separated active molecules layer. The active molecules layer is a watery compartment having drug as a suspension or solution and disconnected with adhesive film. This type of patch is supported with backing layer. The release rate of this system is zero order¹⁸.

4. Matrix system:

In this system the active content layer is a semisolid matrix, which having solution or suspension of drug. The adhesive cover of this system surroundings the medicine layer partly overlaying it. This system is known as a monolithic device.

5. Vapour Patch:

In this system the adhesive layer isn't only helps to adhere the several layers together but it release the vapour. These systems are novel and they able to release the essential oils up to 6 hours and mainly applied in the case of decongestion. Another vapour systems are also accessible which are used to increase the quality of sleeps and decrease the amount of cigarettes which are accessible as a one smokes per month¹⁹.

EVALUATION OF TRANSDERMAL PATCH:

1. Thickness of Film:

The thickness of therapeutic patch is measure in diverse parts by using a specified micrometer, the mean thickness is measure to confirm the thickness of the manufactured film. The thickness of transdermal patch is measured by moving microscope dial gauge, screw of gauge or micrometer at difference parts of the patch²⁰.

2. Weight Uniformity:

The formulated films are dried (60°c) for 4 hours. For this purpose a quantified part of patches are cut down in various portion and consider in automatic balance. The mean weight and standard deviation values of formulation measured from the different weights²¹.

3. Folding Strength:

A part of exact area of patch be cute and continually folded at the similar side until breaks. Patch might be folded at number of times without breaking therefore provides the significancestrength²².

4. Percentage Humidity Content:

The manufactured patches are individually weighed and saved in desiccators which having calcium chloride and kept for 24 hours at room temperature. After 24 hours patch are reweighed calculated the percentage humidity from the below formula²³.

initian weight – Final weight

% Moisture content = –––––––––––––––––––––––x 100

Final weight

5. Content Uniformity Assessment:

For this purpose 10 patches are carefully chosen and content of selected patches are calculated for separate films. If 9 patches out of 10 have content among 85% to 115% and one patch content isn't less than 75% and more than 125% of the indicated value, transdermal formulation content uniformity is passed. While three films have contented in the series of 75% to 125%, hence extra 20 films are examined for active ingredient content. When 20 films have content from 85% to 115%, now patch pass the uniformitytest²⁴.

6. Moisture Uptake:

After measured weigh, patches are placed in desiccators for 24 hours at room temperature. Then subjected to 84% respective humidity and using potassium chloride saturated solution in desiccators till a constant weight is reached. % humidity uptake is considered from the below formula²⁵.

Final weight – Initial weight

% Moisture Uptake = –––––––––––––––––––––––x 100

Initial weight

7. Drug Content:

A specific part of film is dissolved in an appropriate solvent in specified volume, then the prepared solution is filtrated and examine the active ingredinet contain with the appropriate technique, such as HPLC or UV²⁶.

8. Shear Adhesion Assessment:

This assessment carry out for the measuring of cohesive rigidity polymer. It influence by molecular weight, grade of cross connecting and arrangement of polymer, form and quantity of tackifier used. An adhesive covered tape is made of stainless steel plate, than a quantified weight is pendent from the selected tape. Shear adhesion rigidity is specified by calculating the time which is takings to pull the tape of plate. The extensive time yield for removal, bigger is the shear rigidity²⁷.

9. In vitro Drug Release:

According to USP (paddle over disc, apparatus V) this technique is applicable for valuation of drug release from the manufactured patch. Dry patches of identified thickness are cut with specific form, weighed and kept through a glass plate by an adhesive. Than filled glass plate with 500 ml of dissolution medium (PBS, pH 7.4) and maintain the temperature of device to 32± 0.5°C. The distance of paddle should be fixed at 2.5cm upper of glass plate and set the speed to 50 rpm, 5 ml of sample withdrawn at suitable time interval up to 24 hours, therefore, investigated the sample by HPLC or UV spectrophotometer. The experiment can be carry out by below apparatus²⁸.

Fig. 12: Diffusion Cell for In -Vitro Experiments

Table 3: Marketed Formulation of Transdermal Drug Delivery System

Drug	Type of Transdermal Patch	Application
Fentanyl	Reservoir	Analgesics
Estradiol	Matrix	Hormone Replacement Therapies
Testosterone	Membrane	Hypogonadism in males
Clonidine	Membrane	Hypertension
Scopolamine	Drug in adhesive	Motion Sickness
Nicotine	Drug in adhesive	Smoking Cessation
Flubiprofen	Drug in adhesive	Anti-inflammatory
Ketaprofen	Drug in adhesive	Anti-inflammatory
Selegiline	Matrix	Anti-depressant
Nitroglycerine	Drug in adhesive	Angina Pectoris
Lidocaine	Drug in adhesive	Anesthetic
Diclofenac	Drug in adhesive	Anti-Inflammatory
Estrogen	Matrix	Postmenstrual syndrome
Oxybutynin	Matrix	Overactive bladder

Application of transdermal drug delivery system:

The first drug which is formulated as a transdermal delivery is Selegiline (API), it act as a monoamine oxidase inhibitors (MAOI), therefore it used as antidepressant²⁹.Nicotine transdermal patch, releases the nicotine in controlled amounts to aid with ending of (tobacco) smoking. Nitroglycerine transdermal patches are likewise sometimes recommended for the management of angina. Clonidine patch is used as antihypertensive and ketoprofen patch contents non-steroidal anti-inflamatory drug which is used in the treatment of inflammation³⁰.

CONCLOSION:

Transdermal drug delivery has been applied as a safe and efficient delivery system since 1981. More development has been done in the area of TDDS. Due to more merits of this system, the researchers shown more interests. In recent years the application of biophysical methods has helped for understanding the nature and structure of stratum corneum barrier and techniques in which chemical ingredients act with barrier. Transdermal drug delivery system proposals inducingchances for low bioavailability of several oral medicines. Recently marketed formulation of 1^stgeneration (transdermal patches), 2^ndgeneration (chemical enhancers)and 3^rd generation (physical enhancer's such as ultrasound, thermal ablation, microneedles, delivery of macromolecules and vaccines) are available. This article deliver inestimable information about the transdermal drug delivery systems, application and assessment procedures.

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Received on 07.04.2019 Modified on 21.05.2019

Research J. Pharm. and Tech 2019; 12(9):4550-4558.

DOI: 10.5958/0974-360X.2019.00783.2