Advancements In Transdermal Drug Delivery: A Comprehensive Review

Abstract

Many proteins and peptides that are not appropriate for oral delivery because of high firstpass metabolism have been developed as a result of advances in molecular biology. Despite its seeming simplicity, parenteral administration is not the best option for developing formulations that enable self-administration and long-term use in commercial settings. Transdermal distribution of these chemicals is gaining popularity; nevertheless, because the skin effectively blocks the reception of big molecular weight compounds, it is unlikely that therapeutic quantities could be reached through passive absorption. Utilizing a controlled approach, The Transdermal Drug Delivery System (TDDS) delivers medications via the skin at a predetermined and precisely controlled rates. This technique reduces the severity of the drug's effects and allows for continuous release, which helps to mitigate the side effects that are usually connected to oral delivery. The formulation of transdermal drugs is separate, self-contained dosages. They give the medication a regulated release through healthy skin. Within the delivery system, the skin or membrane controls the pace of distribution.

Keywords

Transdermal drug delivery system, Transdermal patch, TDDS, Skin anatomy & physiology, Transdermal therapy

Introduction

The transdermal drug delivery device (TDDS), often referred to as a patch, transmits a potent amount of medication to the patient's skin surface. Comprehensive examination of the skin's entire morphological, biophysical, and physicochemical properties is necessary to allow for the absorption of therapeutic compounds through the skin for systemic effects in the human body. Compared to oral formulations and injections, transdermal administration improves patient compliance and lessens problems associated with quick onset (1). A technique called a transdermal drug delivery system (TDDS) is intended to precisely and carefully distribute drugs via the skin. Enhanced patient adherence reduced adverse effects, increased bioavailability, prolonged therapeutic effects, and simpler treatment cessation are just a few benefits of this approach. Nonetheless, the oral administration approach has drawbacks, especially its limitation to tiny molecular weight compounds. As a result, transdermal drug technology specialists are investigating safe and efficient methods to administer high molecular weight medications in therapeutic dosages. Applying a medication's active components through the skin is part of the transdermal patches technique. The medicine enters the bloodstream more easily because of the skin's high absorption efficiency and the blood arteries that are found there. Every drug delivery system aims to distribute a therapeutically effective concentration of the medication within the shortest amount of time to the intended body site and maintain that concentration there for the duration of the dose(2).

Fleischer asserted in 1877 that the outermost layer of skin is totally impervious, but this extreme viewpoint was short-lived. By 1957, Monash had shown that absorption is hampered by a skin barrier. These preliminary investigations opened the door for more investigation, which finally showed that the outermost layer of epidermis (stratum corneum) is the main obstacle to medication absorption and that chemicals find it difficult to get through because of its properties. Drug levels are maintained for a prolonged length of time for effective action using transcutaneous drug delivery systems, which release medication via zero-order kinetics, first-order kinetics, or a combination of both (3).

 Definition

A healing adhesive strip, also known as a transdermal patch or skin patch, clings to the skin and transports an appropriate quantity of medication by using the skin into the bloodstream(4).

Fig 1: Transdermal Patch

TDD (Transdermal Drug Delivery) has received a great deal of interest since the introduction of the first transdermal patch, scopolamine, which is the process of delivering medication into the systemic bloodstream through unaffected skin. Drugs with low molecular masses that are particularly susceptible to first-pass hepatic metabolism or that are unable to endure the severe environment of the gastrointestinal tract must be delivered underneath the skin. A number of steps are involved in the release of the drug from the formulation that is applied to the skin and its subsequent absorption into the bloodstream: the drug is broken down within the formulation and released from it, it propagates travels through the lipid intercellular channel in the stratum corneum (SC), the skin's outermost layer, before entering the deeper dermal layers(4).

Types of Transdermal Patches:(5)

1. Single Layer Drug in Adhesive:

Hardwood provides the top sticky layer of this mechanism. In addition to binding the layers collectively and integrating the continuous system with the skin, this particular type of pool adhesive layer would facilitate the drug's release. They consist of a temporary liner that covers the adhesive layer and a support structure.

2. Multi-Layer Drug in Adhesive:

This patches, despite the appearance of a single-layer system, has two sticky layers that are contributing to drug delivery. There is another layer of adhesive in the horizontal multi-cloud system which is usually split by a membrane, but this is not always the case. This patch also includes a temporary liner layer, followed by a permanent support layer.                                

3. Reservoir:

The reservoir transdermal system includes an independent drug layer, whereas the single-layer and multi-layer drug-in-adhesive systems do not. It could include a coating layer that separates a suspension fluid or a pharmaceutical solution. This arrangement is reinforced by an additional layer. It follows that zero-order kinetics governs the release.

4. Matrix:

The Matrix system combines a semisolid matrix with a medicines solution or suspension. A thin layer of wood is encompassed by an additional coat of paste.

5. Vapor Patch:

These patches include a layer of adhesive which allows vapor escape in along with adhering layers collectively. This relatively new technology, vapor patches, can release essential oils for up to six hours. The essential oils released by these vapor patches are helpful in reducing congestion. To improve sleep, for example, some steam sheets are now made to act as steam regulators. (5)

Advantages & Disadvantages:  (6–9)

Ideal Properties of Drug for TDDS: (2)

 Flowchart 1: Ideal Properties of Drug for TDDS

Methods of Transdermal Drug Delivery System

In order to reach systemic effects, transdermal drug delivery systems (TDDS) migrate medications through the skin. TDDS use numerous strategies to enhance medication penetration even while the skin serves as a barrier. The main strategies used in transdermal medication delivery are as follows:

1. Passive Diffusion: 

• Mechanism:

Drugs travel through the skin from an area of higher concentration (in the formulation) to one of lower concentration (in the bloodstream). 

• Application:

Most conventional transdermal drug delivery systems (TDDSs) rely on this method, including patches that contain a drug reservoir or matrix. 

• Example: Transdermal patches for nicotine and fentanyl.

2. Iontophoresis:

• Mechanism:  

This technique uses electricity to help charged drug molecules move through the skin. The drug can either be charged on its own or mixed with ions that the electric current can push.

• Application:

It’s a great way to get drugs into the body that can’t easily pass through the 

Skin by themselves, like peptides or proteins.

• Example: Using lidocaine for numbing in a specific area

3. Electroporation:

• Mechanism: 

Electroporation can be explained in simple terms: applying short electrical impulses at a high skin voltage creates transient pores on skin’s lipid structure to allow the infusion of bigger drug molecules.

• Application: 

This includes macromolecules such as DNA, vaccines and peptides.

• Example: In appreciative science, electroporation has stimulated interests in gene delivery systems and some vaccines.

4. Sonophoresis (Ultrasound):

• Mechanism:

Ultrasound waves encourage the porousness of the skin by making minor bubbles that make strides sedate retention. This strategy quickly compromises the skin boundary.

• Application:

It is advantageous for bigger and hydrophilic medicate particles that ordinarily battle to pass through the skin obstruction proficiently.

• Use: Transdermal organization of anti-inflammatory medicines.

5. Microneedles:

• Mechanism: 

Microneedles are very small needles which create micro holes in the skin so as to permit the drug to traverse the epidermis and access deeper regions where it can be absorbed.

• Application: 

Microneedles are suitable not only vaccines, but also for peptides, insulin and some larger molecules too.

• Example: Microneedle patches for delivery of vaccine or insulin.

6. Chemical Penetration Enhancers:

• Mechanism: 

Chemical additives like ethanol, DMSO, or surfactants are incorporated into the formulation with the view of chemically compromising skin barrier properties for enhanced drug absorption.

• Application: 

Enhancers are commonly integrated into patches or gels with the aim of increasing the skin permeability of hydrophilic or large molecules.

• Example: Hydrocortisones or oestradiol via the transdermal route.

7. Hydrogels:

• Mechanism: 

Hydrogels are capable of retaining moisture and establishing a hydrated environment, which facilitates the absorption of drugs through the skin. They frequently incorporate penetration enhancers that optimize drug delivery.  

• Application: 

They are appropriate for controlled release formulations and can accommodate both small and large molecular compounds.  

• Example: Gel-based transdermal patches utilized for pain relief or hormone replacement therapy.

8. Vibration – Assisted Delivery:

?     Mechanism: 

Vibration is used to create mechanical disruption of the skin’s stratum corneum (the outermost layer), alleviate drug passage.

• Application: 

This method is search for improving the pitch of turgid drugs like peptide and vaccines.

• Example: Research applications for insulin delivery.

9. Thermal/Heat - Based Methods:

• Mechanism: 

Heat is put on to the skin, causing increased stemma flow and potentially heighten drug permeation by increasing tegument temperature and cut off the hide barrier.

• Application: 

Used to enhance the diffusion of lipophilic drugs that may otherwise induce difficultness crossing the skin.

• Example: Passion - base patches for annoyance relief.

10. Lipide - Ground Systems:

• Mechanism: 

Lipid - ground formulations, such as liposome, ectosomes, or transferosomes, are used to enhance the permeable Ness of the hide. This arrangement can carry both hydrophilic and lipotropic drugs through the skin.

• Application: 

These systems are particularly useful for delivering drug like steroids, fungicide, or local anaesthetics.

• Example: Liposomal gel for local anaesthetic delivery.

11. Nanoparticle - Base Delivery:

• Mechanism: 

Nanoparticles might enhance solubility of drug and penetration into the skin, and examples include solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs).

• Application: 

Frequently used to enhance targeted distribution or for drugs that have properties that make them poorly soluble in water.

• Example: Nanoparticle - based formulations for delivering anti - aging compounds or corticosteroids. (10)

Applications of Transdermal Patches:

The Nicotine patch, which releases nicotine in controlled dosages to aid in tobacco smoking cessation, is the best-selling transcutaneous patch in the United States.(19)

1. In addition to post-menopausal osteoporosis, estrogen patches are occasionally administered to address menopausal symptoms. Another hormonal delivery transdermal patchup is the contraceptive darn, which is sold under the names Ortho Evra and Evra.
2. .Nitro-glycerine patches may be used instead of sublingual pills to treat angina pectoris.
3. The anti - hypertensive drug Clonidine is available in transdermic patch for.
4.  Selegiline, an MAOI, became the first antidepressant to be delivered transdermally.
5. A transdermal delivery agent for attention deficit hyperactivity disorder.(20)

Mechanism of Action of Transdermal Patches:(22)

Flowchart 2: Mechanism of Action

Physiological Properties of Transdermal Patches

The active substances in transdermal patches are meant to be released gradually via the intact skin, resulting in a systemic absorption rate that is both sustained and suitably steady. Often, the skin's ability to absorb substances serves as the principal barrier to systemic absorption of active compounds. As an alternative, the active components can be dissolved or incorporated into a (semi-solid) reservoir where a membrane controls the diffusion and release of the active ingredients from the patch, thereby limiting absorption. Furthermore, the transdermal patch can be created by combining the two drug delivery techniques to control how the medicine is delivered to the skin's surface.

Performance testing can be employed to evaluate the degree to which product design and formulation can influence the ability to penetrate the active ingredients through the skin.

1. Dissolution
2. The release of drugs with the use of a synthetic membrane and
3. Skin permeability testing 

It offers benefits as well as drawbacks of its own. The simultaneous findings of disintegration and penetration via the skin can shed light on how the skin and the patch alter absorption.

In order to ensure that transdermal patches can be utilized properly and without harm, the active substance or ingredients must enter the skin sufficiently, remain in place for the period of the patch's usage, and not irritate or create sensitivity. The active ingredient's side effects must not be exacerbated or adversely affected by the excipients. The effects of skin enhancers on the skin barrier should be transient. It is imperative that the solvents employed do not interact with the patch system's components. The active component in transdermal patches is usually more than that which is administered to the patient while using them. While reducing the patch's surface area, the extra amount is necessary to provide a therapeutically effective delivery rate over time. The active ingredient's concentration might get nearer to its saturation point, which increases the risk of crystallization during storage and may negatively impact the product's efficacy and quality. Furthermore, the residual active ingredient in the patch after usage may pose a danger to patient, public, and environmental safety. Additionally, discarded transdermal patches, especially those that contain narcotic drugs, may be abused. Transdermal patches can release the same total amount of medication over a specified time period, despite variations in surface area and drug content. Reducing the leftover active ingredients is therefore beneficial. (23)

CONCLUSION

For patients who have trouble swallowing or remembering their medications, transdermal drug delivery systems are useful development in medication administration. Compared to more invasive and conventional oral drug delivery approaches, topical administration of therapeutic agents supplies the quantity of alternatives. It offers numerous noteworthy benefits, such as declined hepatic first-pass metabolism, expanded therapeutic efficacy, and consistent plasma drug levels. Because TDDS can deliver both hydrophobic and hydrophilic active substances as effective medications, it shows great potential. Recent advancements in innovation have made the transdermal route a more popular way to administer medications because it can deliver medications to the desired location without compromising the integrity of the skin barrier. This page provides crucial information on the creation and assessment of TDDS.

ACKNOWLEDGEMENT

The organization and individuals whose participation and guidance have significantly improved the caliber and comprehensiveness of this research deserve my sincere gratitude.

I would like to begin by appreciating Mr. Pradeep Ghogare, my primary advisor, for his steadfast support wisdom, and persistent encouragement during the research process time. His skills and experience were helpful in making this project a success.  I am eternally grateful to the SMBT College of Pharmacy for providing the facilities and resources, which facilitated the successful completion of the research.

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