Perspectives on Transdermal Drug Delivery System: A Review

Vani S^1,2_,Venkatesan N¹, Chandrasekar SB²_,Sreedhar C³, Anil T Pawar⁴

¹School of Pharmacy, Sri Balaji Vidyapeeth (Deemed to be University),

SBV Campus, Pillaiyarkuppam, Pondicherry - 607402, India

²Drugs Testing Laboratory, Drugs Control Department,

Government of Karnataka, Palace Road, Bangalore - 560001, Karnataka, India

³Karnataka College of Pharmacy, Hegde Nagar Main Road,

Thirumenahalli Post, Bangalore - 560064, Karnataka, India

⁴School of Health Sciences and Technology,

Dr. Vishwanath Karad MIT World Peace University, Pune - 411038, Maharashtra, India

*Corresponding Author E-mail: svani2078@gmail.com

ABSTRACT:

Drug delivery system (DDS) is a collective term used for techniques that carry drugs into or throughout the body for administration and distribution of drug substances to the target cells, specific tissues or desired organs, to exert optimal effects. Among various routes of DDS, the transdermal drug delivery system (TDDS) forms an attractive approach compared to other routes of administration in terms of easy application, non-invasive, avoiding first pass metabolism, for systemic / local effect, directly reaches blood stream, target drug delivery, controlled release of the drug, easy termination of drug action by removing the patch, suitable for geriatric, paediatric subjects, unconscious patients, enhanced subject compliance and decreased side effects and inter and intra-patient variability as well. In this review, we focused on physiology of skin, routes of percutaneous absorption and types of TDDS, design, development and formulation approaches, basic elements, pharmacokinetics, factors affecting drug penetration, characterization and its evaluation. Significant discussion of their specific advantages, benefits especially in pain management, clinical considerations, general guidelines for using TDDS, market demand etc. This article also provides valuable literature for suitability of most of the Non-steroidal anti-inflammatory drugs (NSAIDs) for transdermal administration mainly due to their pharmacological aspects. In recent years, the scope of TDDS has increased in national as well as foreign market. Hence there are increased research activities from many pharma companies and research institutes for potential drug candidates for TDDS. The promising response of transdermal patches has spurred further research and development in this area. The global transdermal patch pipeline is overflowing, pointing to a bright future for these patches in the coming years. Therefore, TDDS may be the best alternative to oral formulations for effective treatment of inflammatory conditions.

KEYWORDS: DDS, TDDS, Skin, Characterization, NSAIDs, pain.

INTRODUCTION:

Drug delivery systems (DDS):

DDS is a collective term used for techniques that carry drugs into or throughout the body for administration and distribution of drug substances to the target cells, specific tissues or desired organs, to exert optimal effects.

In other words, DDS is a device that administers therapeutically active substance or a drug substance into the systemic circulation with enhanced safety and efficacy by controlled release of drugs in the body at a predetermined rate, at a given time and at a specific place¹.

Table 1: Based on the route of administration different types of DDS²:

Sl. No.	Route of administration	Example
1	Gastrointestinal	Oral, sublingual, buccal, rectal
2	Parenteral	Sub-cutaneous, intramuscular, intravenous
3	Topical	Transdermal patches, instillations, irrigation or douching, throat paints
4	Inhalations	Aerosols, nebulisations, steam inhalations

Benefits of TDDS:

Among various routes of DDS, the TDDS forms an attractive approach compared to other routes of administration in terms of easy application, non-invasive, avoiding first pass metabolism, for systemic / local effect, directly reaches blood stream, target drug delivery, controlled release of the drug, easy termination of drug action by removing the patch, suitable for geriatric and paediatric subjects, suitable for unconscious patients, enhanced subject compliance and decreased side effects and inter and intra-patient variability as well⁵.

Market demands:

As such, transdermal patches are an established method of drug delivery which offers many advantages to patients, providers, and manufacturers. Developing a successful medical transdermal patch requires a lot of resources and expertise. However, the market is well regulated and the potential for new transdermal treatments is almost limitless⁶.

According to forecasts by healthcare experts and the latest market research, the global TDDS market by 2027 is expected to reach USD 9.6 billion. CAGR (Compound annual growth rate) of transdermal patch market is estimated to be 3.0%. Hence introduction of advanced drug delivery technologies are gaining importance. By 2028 the global TDDS market size will reach US$20 billion. The promising response of transdermal patches in the global market has spurred further research and development in this area. The global transdermal patch pipeline is overflowing, pointing to a bright future for these patches in the coming years⁷.

Ease of administration, self-administered, non-invasive, pain-less application

Reduced dose frequency, termination of drug action by removing the patch

Controlled delivery, prolonged/ sustained delivery of drug

Bypasses first pass metabolism: enhanced bioavailability, constant plasma

Suitable for non-responsive patients, unconscious or comatose patients

Preprogrammed delivery of drug, less chances of under or over dosing

Drugs having short half-life and gastro Intestinal irritation/ side effects like nausea and vomiting

Multi day therapy just with a single application, enhanced patient compliance

Fig. 1:Main features of TDDS^8,9

They ensure controlled absorption and more uniform plasma drug concentrations. Bioavailability is improved by avoiding ﬁrst-pass hepatic metabolism and enzymatic or pH-associated deactivation. Delivery of the drug is via a simple and pain-less application. There is increased ﬂexibility in terminating drug administration by patch removal. Patient compliance is improved as patches are simple, non-invasive, and convenient.

Physiology of skin^{10,11,12,13,14}:

Fig. 2: Structure of the skin

Average adult body surface area: males-18,000 cm 2 and females- 16,000 cm 2

Receives one third of circulating blood

Three layers: epidermis, dermis, subcutaneous

Epidermal layer: stratum corneum, stratum granulosum, stratum spinosum, stratum basale

Extracellular lipid membranes are heavily keratinized and composed of free fatty acids, cholesterol and ceramides

Having 200–250 sweat glands and10–70 hair follicles per square centimeter of skin surface

Barrier effect of stratum corneum is due to hard, flattened stack of dead cells comprising of proteins (79-90%) and also lipids (5-15%) with10-20 μm thick, enabling waterproof protection and imparting impermeability

Usually thickness of the skin membrane varies from 0.5 mm (in eyelids) to 4 mm (in palms and soles of the feet)

The stratum corneum along with its barrier properties regulates the natural water evaporation from the surface of the skin at the rate of 5-30 g/m2 h, at pH and temperature of 5.0-5.4 and 31-33°C respectively

After application of transdermal patch to the intended site, continuous penetration of active medicament takes place for the required time and also can be terminated easily by washing with soap

Thus maintains a steady plasma drug concentration in the body for a prolonged period of time without the need of frequent dosing over time

Fig. 3: Functions of the skin

Cutaneous routes of TDDS:

They come in different sizes and contain multiple ingredients. When applied to intact skin, it overcomes various skin barriers and releases medicament into systemic circulation. A transdermal patch containing medicament when applied on to the skin, usually releases the drug for an extended period of time which diffuses into bloodstream for a prolonged period¹⁵.

Routes of drug passage via skin: Hair follicle, Sebaceous glands and Sweat ducts.

Two major pathways of drug penetration across skin:

1) Trans cellular (passing through corneocytes and lipid lamellae)

2) Intercellular (permeation along tortuous pathways along lipid lamellae)

Applications of TDDS^{16,17,18,19,20,21,22}:

Table 2: Different types of pain and examples

Sl No	Type	Example
1	Acute pain	NSAIDs, opioids
2	Chronic pain	Fentanyl, buprenorphine
3	Local pain	Capsaicin, lidocaine
4	Malignancy (Acute pain)	Fentanyl patches- fentalis, tilofyl, durogesic D
5	Malignancy (Chronic pain)	Buprenorphine patches- transtecw patch, buttransw patch
6	Local anaesthetic action	Lidocaine patch- versatis (5%)
7	Enhancing drug action	Scopolamine patch- TTS-S

Types of transdermal patches^23,24:

Table 3: Different types of transdermal patches with examples

Sl No	Type	Nature	Example
1	Self-adhesive single layer	Reservoir of drug dispersion	Methylphenidate (daytrana)
2	Self-adhesive multi-layer	Drug reservoir layer along with an adhesive layer	Smoking cessation drugs and hormones
3	Vapor patches	Single layer of adhesive, Drug polymer system with vapor release properties	Essential oils as antidepressants and tranquilizers (nicoderm CQ, alt-tacura)
4	Membrane modulated reservoir patch	Drug reservoir with an impermeable metal-plastic laminate backing and a porous polymeric membrane	Nitroglycerin (transderm-nitro) scopolamine (transderm-scop) clonidine (catapres)
5	Matrix: drug-in-adhesive	Drug distributed over the adhesive polymer	Estradiol (climara)
6	Matrix: dispersion	Drug reservoir is evenly dispersed in a hydrophilic or lipophilic polymer matrix	Nitroglycerin (nitro-dur, minitran)
7	Micro reservoir patch	Combination of matrix dispersion and drug reservoir	Nicotine (nicoderm)
8	Miscellaneous patches	Matrix delivery systems	Tapes, gels, sprays

Pharmacokinetics of TDDS²⁵:

TDDS requires the active ingredient to be present in required concentrations inside the patch. The energy required to discharge active ingredient from the concentration gradient that exists among the saturated active ingredient solution within the system and the reduced concentration in the membrane. Active ingredient penetrates by diffusion, due to its increased concentration in the patch than compared to plasma. The penetration of active ingredient continues maintaining its steady state of plasma concentration. The permeation rate through the skin is given by the following formula.

D m / d t = D Co P / h

Where, D= diffusion co-efficient, Co= drug concentration in the patch which is constant, P= partition coefﬁcient exist between solution and skin, h= skin thickness. The penetration of drug across skin via transdermal patch is enhanced with the following properties of drug: If molecular weight is 500 Da, afﬁnity for both hydrophilic and lipophilic phases, having low melting point which affects the ease of drug release, if it is non-ionic, potent which is effective at low dose and having short half-life.

Design of TDDS²⁶:

The basic design of TDDS includes drugs either dissolved or dispersed in inert polymeric solution to provide a support and platform for the drug delivery from the patch. Based on the nature of polymeric system and drug release properties from the patch, there are two basic designs of the patch, namely monolithic patch or matrix system and membrane patch or reservoir system.

Development technology for TDDS²⁷:

There are several techniques for the development of a successful transdermal patch for the controlled release of drug across skin. The three basic approaches in TDDS development are:

Permeation-controlled TDDS - polymer membrane:

Here drug is sandwiched between a rate-controlling polymer membrane impermeable and a metal-plastic laminate. The rate-limiting polymer membrane can be either micro porous or nonporous in nature which regulates the release of drug molecule. Drug penetration can be increased by using ethylene-vinyl acetate copolymers. Silicone adhesives are drug-compatible, hypoallergenic and pressure-sensitive adhesives in nature, providing intimate contact between the device and the skin. Examples: Duragesic system, transderm nitro system, catapres transderm therapeutic system (TTS), transderm scope system, estraderm system.

Diffusion controlled TDDS - matrix:

Here drug-loaded polymeric reservoirs are prepared by uniformly dispersing the active medicament in lipophilic or hydrophilic polymer matrix. This polymer disc having the drug reservoir is attached to a closed baseplate in a compartment which is made up of an impermeable plastic liner. An adhesive polymeric solution is applied around a perimeter of the patch to get a thin layer of adhesive surrounding medicated disc. Examples: Nitro major system (NMS), Nitro transdermal system (NTS).

Gradient-controlled TDDS - reservoir:

It is a hybrid of matrix and reservoir systems wherein drug loading levels are modified and multi-layer adhesive systems are made, thereby altering the drug release profile. Here drug reservoir is generally prepared first by uniformly dispersing a water-miscible drug suspension in lipophilic polymer, then subjected to mechanical shear force in order to get plenty of non-leaching microscopic drug reservoirs. A thermodynamically unstable dispersion is obtained. It is immediately stabilized by in situ crosslinking of the polymer chains to get drug loaded discs with constant thickness and constant surface area. Example: Nitrodisc system.

Elements of a TDDS^{28,29,30,31,32,33}:

Matrix of polymer/reservoir of drug, drug candidate, penetration enhancers, pressure sensitive adhesive (PSA), backing laminates, rate controlling membrane, release liner, solvents and plasticizers.

Table 4: Types of polymers

Types	Examples
Natural polymers	Natural rubber, gums, gelatin, waxes, cellulose derivatives, shellac, chitosan, zein etc.
Synthetic elastomers	Hydrin rubber, silicone rubber, butyl rubber, polyisobutylene, polybutadiene, neoprene, acrylonitrile etc.
Synthetic polymers	Polyethylene, polyvinylchloride, polyvinylpyrrolidone, polyvinyl alcohol, polymethylmethacrylate, polyurea, polyamides, polyacrylate, polypropylene etc.

Penetration enhancers:

The uppermost layer of skin, stratum corneum is the obstacle for drug penetration. Thus penetration enhancers (or permeation enhancers) are used to weaken the barrier properties of the stratum corneum efficiently and reversibly thereby allowing drugs to penetrate into the systemic circulation. They should be inert. They enhance the permeability by various mechanisms such as, loosening the lipids molecules in the stratum corneum, moisturizing stratum corneum or by increasing the fluidity of intercellular lipid molecules in the stratum corneum. By all these mechanisms the permeability of the skin increases allowing drugs to penetrate into deeper skin tissues. Example: Alcohols, fatty alcohols, fatty acids, surfactants, terpenes, glycols, urea, sulfoxides, pyrrolidones and bile salts.

Pressure sensitive adhesive (PSA):

PSA is viscoelastic chemical that adheres to skin under low pressure. They are tacky and offer strong holding power to adhere to the skin with a slight finger press and can be removed easily from skin surfaces without leaving any residue. Their adhesive properties are important for transdermal devices as they provide full and intimate contact with the skin surface and patch which is required for effective delivery of drug. The interatomic and intramolecular attractive forces build up PSA in the skin to achieve required level of contact. Example: Natural rubber, elastomers, acrylics, silicone-based adhesives and thermoplastic polyisobutylene (PIB).

Backing laminate:

The backing material is chemically stable and inert to other excipients in the formulation system. Also, it is necessary to prevent the additive from being washed away. It should be flexible and allows moisture and oxygen transfer. Example: Ethylene vinylacetate (EVA), silicone oil and polyisobutylene.

Rate controlling membrane:

It is an inert membrane that controls the drug release in a limited manner. The diffusion of the active ingredient though this inert membrane is controlled either by varying its composition or by altering the thickness.

Characterization and Evaluation of Transdermal Patches^36,37,38,39:

Table 6: Various evaluation methods with explanation

Sl No	Evaluation studies	Method
1	Compatibility study	Interaction of drug, polymer and other excipients are analyzed by Infrared radiation, Nuclear magnetic resonance or Digital scanning colorimetry
2	Thickness	By using digital micrometer gauge, multiple readings are taken at 3-5 points on the patch to find the average thickness
3	Uniformity of weight	Standard deviation and mean weight of 10 patches should be determined
4	Folding tenacity	Patch is evenly cut and folded over again at same place till it breaks, which determines firmness
5	Water content	Positioned in desiccator for 24 hours along with molten calcium chloride
6	Water uptake	Positioned in desiccator for 24 hours with RH 84% along with saturated potassium chloride solution
7	Water vapour permeability	By using hot air over and weighing patch before and after drying for 24 hours, the amount of water vapour permeated through patch is calculated
8	Content uniformity	Patch is cut into suitable size, dissolved in suitable solvent, sonicated for 24 hours, filtered and drug content is estimated with suitable analytical method
9	Flatness	Measure the length of patch after cutting into 3 longitudinal strips (right, left and middle) and initial and final length is determined
10	Stability studies	Prepared patches should be kept at 40 ± 0.5°C and RH 75 ± 5%. Drug content is determined for the sampling intervals at 0, 30, 60 and 90 days
11	Adhesive strength	Probe tack, peel tack and adhesion test using a substrate and adhesive
12	Tensile strength	Using tensiometer. The force required to break the patch is found
13	In vitro drug release	Using reciprocating disc, modified cylinder or paddle over disc apparatus or franz diffusion cell

DISCUSSION:

Based on the reviews obtained, this article provides valuable literature on various routes of drug administration with main emphasis on TDDS, its benefits, main features, structural components, various types, formulation and evaluation aspects, factors affecting the action of transdermal patches and its applications especially in the management of pain⁴⁰.

With the development of TDDS, there is enhanced bioavailability by enzymatic or pH-associated deactivation and avoiding ﬁrst-pass hepatic metabolism. With simple, non-invasive and convenient mode of application thereby enhanced patient compliance and releases the drug in a predefined controlled rate into the systemic circulation. Thus transdermal drug delivery (TDD) technology is growing swiftly in and as a preparation tool that can enhance drug penetration through skin. Most of the non-steroidal anti-inflammatory drugs (NSAIDs) are suitable for transdermal administration mainly due to their pharmacological aspects⁴¹.

We conclude that new studies on TDD technologies with a considerable number of subjects will enhance the knowledge about its safety and efficiency, allowing its use for pain regulation even in the paediatric population as well. In recent years, the scope of TDDS is increased in national as well as foreign market. Hence there are increased research activities from many pharma companies and research institutes for potential drug candidates for TDDS. The global TDDS market is predicted to perceive excessive growth rates as skin is well-thought-out to be safest port for drug administration for controlled release of drug into systemic circulation⁴².

In addition, approaches in TDDSs could act as a driving force for the development of other categories of drugs used for treating diseases of central nervous system, cardiovascular system, neuromuscular diseases, genetic diseases, diabetes, other infections and supporting patient for self-administration of medicaments for chronic illness. Thus transdermal patches have potential as a future sophisticated TDD strategy.

ACKNOWLEDGEMENTS:

The authors acknowledge the guidance and support received from Sri Balaji Vidyapeeth (Deemed to be University), Pondicherry, India. The authors also acknowledge the support received from B.T. Khanapure, The Drugs Controller of Karnataka and Mohan. S, Principal Scientific Officer of Drugs Testing Laboratories of the Drugs Control Department of Government of Karnataka, India.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 28.07.2023 Modified on 21.11.2023

Research J. Pharm. and Tech. 2024; 17(3):1425-1431.

DOI: 10.52711/0974-360X.2024.00226

Rate-regulating membranes	Nature
EVA	Biocompatible, readily available, and permeable to many drugs
Silicone rubber	Silicone is a rubber-like material, which is a polymer containing carbon, oxygen and hydrogen. Biocompatible, readily available and permeable to many steroids.
Polyurethane (PUs)	The combination of polyols and polyesters results in polyester urethanes. They are rubbery, permeable, biodegradable and resistant to hydrolysis.