Transdermal Drug Delivery System: A Comprehensive Review

Abstract

This paper reviews the advantages, disadvantages, methodologies, evaluation, advancements and applications of transdermal drug delivery system (TDDS). which includes the concept of controlled release, permeation enhancers, Approaches for development of TDDS.

Keywords

Introduction

Fig.1 Structure of Human Skin Showing Epidermis, Dermis and Hypodermis.

According to estimates, every square centimeter of human skin has between 40 and There are 200 hair follicles and 70 to 250 sweat ducts. However, in reality these parts of the skin make up a pitiful 0.1% of the whole surface of the human skin.⁶ This trans-appendage At steady state, the percutaneous absorption route contributes very little to the overall kinetic profile of Permeation via the skin despite the fact that the foreign agents, especially the ones that dissolve in water, may be able to penetrate the skin via These parts of the skin at a pace that surpasses that of the whole region of the stratum corneum. Consequently, most of neutral chemicals transdermal Penetration may be viewed as a passive diffusion process via the interfollicular region's complete stratum corneum.⁷ Therefore, a basic multilayer model can be used to represent the different layers of skin tissue for the sake of the mechanistic investigation of transdermal medication infusion. When systemically active medications are administered topically, the substance will be absorbed, first going into the bloodstream and subsequently reaching the intended tissues.⁸

Fig.2 Membrane -Moderated Transdermal Drug Delivery Systems.

By altering the polymer composition, permeability coefficient, and the thickness of the adhesive and rate-limiting membrane. The rate at which medications are discharged from this kind of system can be customized. The main benefit of a membrane permeation regulated system is the drug's steady release rate. However, there is also a rare chance that dose dumping or the quick release of the full drug content could occur from an unintentional rupture of the rate-controlling membrane. Instances of this system include:

Fig.3 Adhesive Diffusion- Controlled Transdermal Drug Delivery Systems.

Fig.4 Matrix diffusion controlled Transdermal drug delivery system

4. Micro Reservoir Type or Micro Sealed Dissolution:²²

The medication delivery system in the form of a micro reservoir can be considered as a hybrid of the matrix diffusion and reservoir types. This method involves first suspending the drug solids in an aqueous solution of a water-soluble liquid polymer (like polyethylene glycol), and then using a high energy dispersion technique to disperse the medication equally suspension in lipophillic polymers, such as silicone elastomers, to create a number of distinct, impermeable microspheres of drug reservoirs. Cross-linking the polymer chains in-situ instantly stabilizes This unstable thermodynamic dispersion, resulting in a polymer disc with medication a fixed thickness and constant surface area.The medicated disc is then positioned in the center and encircled by a ring that is sticky to provide a transdermal treatment system Nitro-glycerine, for instance: launching a transdermal therapy device to treat angina pectoris once daily.

VIII. Evaluation of Transdermal Films:²³

1. In Vitro-Skin Permeation and Release Kinetics Studies:

In vitro studies play a major role in the design and creation of transdermal medication delivery systems. Prior to developing a transdermal treatment system, in vitro research can aid in examining the drug's mechanism skin penetration. The in vitro study's technique is comparatively simple to follow and typically gives the researcher more control over the experimental circumstances than in vivo. When choosing an in vitro system, the following elements need to be taken into account

1. The Rate Limiting Process: Drug solubilization or diffusion in the vehicle, drug partitioning and elimination by the receptor phase, drug diffusion via the test membrane, or drug solubilization or diffusion in the vehicle.
2. Both the permeate's perceived and intrinsic diffusivity.
3. The predominant diffusion pathway throughout the experiment, as well as the proportional amounts of drug binding and metabolism that take place in the membrane, delivery, and receptor phases.
4. The relative levels of drug binding and the predominant diffusion pathway throughout the trial.
5. The membrane's inherent barrier potential and potential impact of vehicle components on retardative qualities.

Here, membrane hydration and the presence of penetration enhancers might be crucial. Examining the time course for the drug's penetration through a newly removed skin placed on a diffusion cell, like the Franz diffusion cell, allows for a more accurate analysis of the kinetics of skin penetration. Certain flaws in the Franz cell have been identified by Keshary and Chien, who have made modifications to bring the model closer to in vivo circumstances. Some diffusion cells are designed to hold the skin at a vertical position between donor and receptor chambers. The valia, Chien cell is a more contemporary example. It is better than similar older models because it prevents solvent loss from either phase and does not expose the donor and receptor phases to the same temperature. Additionally, the design gets around another drawback of the Franz cell, which is that its donor phase is sensitive to variations in the surrounding temperature. Lastly, it is possible to agitate the contents of the donor compartment, which qualifies the cell for transdermal medication delivery from suspensions and solutions. The literature has documented a variety of in vitro devices for assessing drug penetration characteristics through the skin. As seen below, they can be roughly divided into two groups.²⁴

Diffusion cell physical design:

• Horizontal Type
• Vertical Type
• Flow-Type Cell

Method of Sampling and Measurement:

• Continuing System
• Fluid Circulation System
• Non- Circulation System

• Intermittent System: Rotating Agitations Systems.

1. Membrane:²⁵

• It is recommended to utilize human skin only for the research of penetration kinetics.
• Other barriers may be utilized for investigations on the release of vehicles or devices.

• A molecule of known penetration kinetics should used prior to the test molecule, assess barrier function.
• The stratum corneum and Both healthy epidermis should be found in the skin sample.
• When appropriate, the metabolic viability of the epidermis can be evaluated.

2.Donor Compartment:²⁵

• Both flow-through and static are possible.
• Delivering the penetrant to the skin is made simple
• Controller for temperature (32 0C + 10C).
• Enough volume to keep the sink conditions endless
• Agitated without any discernible boundary layer forms.

3.Receptor Fluid:

• The function of the barrier shouldn't be compromised.
• The partitioning should be advantageous.
• When required, able to preserve epidermal vitality.
•  After being gathered, it must be contained.

Animal skins, such as hairless mice, guineas, rabbits, etc., are used in the majority of in vitro research. Despite these similarities, there is yet no animal skin that perfectly replicates the penetrating characteristics of human skin.

2. In- vitro Dissolution Studies:²⁵

1. Use the USP Apparatus 5 (Paddle-over-Disk) method and maintain the dissolution medium (e.g., PBS pH 7.4 ) at 32±0.5?.
2. Cut the patch to a specific area (e.g., 5 cm²) and fix the adhesive side onto the steel disk and place the disk at the bottom of the dissolution vessel containing the medium.
3. Set the paddle rotation speed to 50–100 rpm and withdraw a sample (e.g., 5 mL) at predefined time points (e.g., 0, 1, 2, 4, 8, 12, 24 hours).
4. Immediately replace the withdrawn volume with fresh, pre-warmed medium and filter the samples to prepare them for analysis.
5. Quantify the drug concentration using a validated method, such as HPLC or UV-Spectrophotometry.
6. Calculate the Cumulative Percent Drug Released over time to create the release profile.

3. In-vivo Assessment Of TDDS:^26,27

It is possible to perform an in-vivo evaluation of TDDS employing

1. Animal Models.
2.  Human Volunteers,
3. Bio-Physical Methods.

1. Animal Models:

In vivo animal there has been a preference for models and Resources are needed in order to carry out studies in humans. Some of the animals that have been used for in vivo testing are, rabbit, guinea pig, rat, mouse, hairless mouse, hairless rat, hair less dog, cat, dog, miniature pig, monkey, chimpanzee, rhesus monkey, horse, goat, squirrel, etc. To find out which animal models best anticipate how the technology under test will behave in people, a number of trials have been conducted.

2.  Human Volunteers:

 After the transdermal device is applied to human volunteers, pharmacokinetic and pharmacodynamic data must be gathered as the last step in the development process. In a fair amount of time, an in vivo evaluation involving human subjects should provide relevant information with the least amount of risk to the subjects. Percutaneous absorption is measured indirectly by measuring radioactivity in excreta after topical administration of the labeled medication in human models for in vivo study. Typically, radio-labelling uses 14C. The amount of radioactivity that is retained in the body or expelled through unmonitored channels must be understood by the investigator in order to determine absorption after topical delivery. This calls for the dose absorbed to be measured. However, this strategy has a number of drawbacks. Several There have been attempts to address these issues. Below is a description of these,

1. Reservoir Technique:

 Using this technique, the skin is exposed to the (radio-labeled) compound under investigation for a brief period of time. After that, tape stripping is used to remove the stratum corneum and the compound's content in the stratum corneum is analyzed. The amount of medicine that will permeate over an extended length of time can be predicted using this analysis.

2.  Mass Balance Technique:

This technique entails covering the application site with an occlusive chamber and replacing it with a new one after a predetermined amount of time. During these periods, the site is also washed. In addition to using radio-labeling techniques, the patients' faces, urine, chambers, and washings are analyzed. Using surface wash measurements to anticipate percutaneous absorption and achieving mass balance between the administered dose and excretion levels are two advantages of this technique.

3. Bio- Physical Methods:

The literature has described models based on linear kinetics, the solution of Fick's second law of diffusion for the device, stratum corneum, and viable epidermis, as well as the steady-state mass balance equation. There is need for improvement despite the fact that numerous methods for evaluating transdermal systems in vivo have been proposed. The skin's barrier function as we age, skin metabolism, penetration enhancers' in-vivo operation, etc. are some of the unsolved problems.

IX. Applications of Transdermal Patches:²⁸

The nicotine patch, which helps people quit smoking tobacco by releasing nicotine in controlled dosages, is the most popular transdermal patch in the US.

1. Fentanyl (marketed as Duragesic) and buprenorphine (marketed as BuTrans) are two opioid drugs that are commonly applied as patches to treat extreme pain 24/7.
2.  Postmenopausal osteoporosis and menopausal symptoms can occasionally be treated with estrogen patches. The contraceptive patch (marketed as Ortho Evra or Evra) is another type of transdermal patch used to distribute hormones.
3. In place of sublingual pills, nitro-glycerine patches are occasionally prescribed to treat angina.
4. Clonidine, an antihypertensive medication, comes as transdermal patches.
5. The first transdermal antidepressant administration system was the transdermal version of the MAOI selegiline.
6. An attention deficit hyperactivity disorder (ADHD) transdermal administration system.

X. Transdermal Market Product:²⁹

For the foreseeable future, the transdermal product industry is anticipated to maintain its notable increasing trend. Around the world, a growing quantity of TDD goods are still providing patients with genuine therapeutic benefits. Approximately 16 active Compounds are permitted for use in TDD products worldwide, and over 35 TDD products are now authorized for sale in the US.

Table II

Examples Of Currently Marketed Transdermal Patches

XI. Advance Developments In TDDS:³⁰

Adhesives and excipients are the subject of two formulation research topics. Drugs in adhesive technology have become the preferred approach for passive transdermal distribution. The primary objective of adhesive research is to tailor the adhesive to improve skin adhesion over time, improve drug stability and solubility, reduce lag time, and expedite delivery. Since there isn't a single adhesive that works for all medicine and formulation chemistries, the transdermal formulator can optimize the effectiveness of the transdermal patch by customizing the adhesive chemistry. Over the past ten to fifteen years, research has been successful in developing transdermal technologies that use mechanical energy to increase the drug flux over the skin by either altering the stratum corneum, the skin barrier, or increasing the energy of the drug molecules. Thermal energy, electroporation (which uses short high voltage electrical pulses to create temporary aqueous pores in the skin), sonophoresis (which uses low frequency ultrasonic energy to disrupt the stratum corneum), and iontophoresis (which uses low voltage electrical current to drive charged drugs through the skin) are some of these so-called "active" transdermal technologies. (which increases the energy of drug molecules and increases skin permeability by using heat). Magnetophoresis, or magnetic energy, has also been researched to enhance drug flux across the skin.

CONCLUSION:

For the research scientist working on TDDS, the TDDS review papers offer useful information about transdermal drug delivery systems and the specifics of its evaluation procedure. The a fore mentioned demonstrates the immense potential concerning TDDS, which might be used to create promising deliverable pharmaceuticals with both hydrophobic and hydrophilic active substances. More knowledge of the various biological interaction processes and polymers is needed to optimize this drug delivery technology. TDDS is a viable, real-world use case for the next drug delivery technology.

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