Role of Transdermal drug delivery System in the Treatment of Hypertension

Hypertension, or high blood pressure, is a persistent cardiovascular condition and a leading cause of global illness and death. Epidemiological studies show that hypertension is responsible for around 57% of stroke-related fatalities and 24% of deaths from coronary heart disease in India. The World Health Organization reports that over 1 billion people worldwide suffer from hypertension, leading to approximately 7.1 million deaths annually due to complications associated with uncontrolled blood pressure.
Managing hypertension typically requires long-term pharmacological treatment, including oral medications such as beta-blockers, calcium channel blockers, ACE inhibitors, and diuretics. However, oral drug delivery presents several challenges, including:
• First-pass metabolism in the liver, which decreases drug bioavailability.
• Frequent dosing, particularly for drugs with short half-lives.
• Fluctuating plasma drug levels, which can affect the efficacy of the treatment.
• Reduced patient adherence, especially among the elderly who may need to take multiple medications daily.
To overcome these limitations, Transdermal Drug Delivery Systems (TDDS) have emerged as an alternative. TDDS are adhesive patches applied to the skin that deliver medication steadily and at a controlled rate into the bloodstream. This method offers several benefits, such as:
• Avoiding gastrointestinal and hepatic first-pass metabolism.
• Extended therapeutic effects.
• Improved patient compliance due to less frequent dosing.
• Reduced side effects resulting from peak-trough fluctuations in drug levels.
Transdermal delivery is particularly advantageous for managing chronic conditions like hypertension. Clonidine was the first antihypertensive drug to be marketed as a transdermal patch (Catapres-TTS), setting the stage for further exploration of TDDS in cardiovascular treatments.
With the continued advancement of technologies like microneedle patches, biodegradable systems, and smart drug delivery platforms, TDDS are gaining increased attention. These innovations not only improve the efficiency of drug delivery but also offer the potential for responsive, programmable treatments that enhance patient outcomes. This review provides an in-depth analysis of TDDS in the context of antihypertensive therapy, addressing core principles, drug compatibility, formulation approaches, benefits, challenges, and future directions

3. Overview of Transdermal Drug Delivery Systems (TDDS)

3.1 Definition of TDDS

A Transdermal Drug Delivery System (TDDS) is a compact, self-contained dosage form designed for application to intact skin, enabling the controlled transport of a drug into the bloodstream. This method bypasses the gastrointestinal system and avoids first-pass hepatic metabolism, thereby enhancing the bioavailability of drugs that have poor oral absorption.

3.2 Historical Background and Clinical Applications

While the idea of transdermal drug delivery has existed for a long time, major progress was made in the 1980s, notably with the approval of clonidine transdermal patches (Catapres-TTS) for hypertension treatment. Since then, many medications, particularly those used for long-term therapy, have been reformulated for transdermal delivery. At present, transdermal systems are available for a variety of drugs, including nicotine, fentanyl, nitroglycerin, estradiol, and antihypertensive agents like clonidine, bisoprolol, and timolol maleate.

3.3 Benefits of TDDS

TDDS offer several advantages over traditional oral or injectable drug delivery methods:

• They bypass first-pass metabolism in the liver, improving drug bioavailability.
• They provide a steady and consistent release of medication, helping to maintain stable plasma drug levels.
• They require less frequent dosing, which enhances patient adherence to treatment plans.
• They offer a safer profile by minimizing peak drug levels and related side effects.
• They are non-invasive and can be easily discontinued if adverse reactions occur.

3.4 Limitations of TDDS

Despite their benefits, TDDS have certain limitations:

• They are only suitable for drugs with specific physicochemical properties, typically small molecules (under 500 Da) that are moderately lipophilic and potent in low doses.
• The stratum corneum, the skin's outermost layer, presents a major barrier to drug absorption.
• Local skin reactions, such as irritation or allergic reactions at the application site, may occur.
• Differences in skin permeability between individuals can affect drug absorption and treatment outcomes.
• The production cost of TDDS tends to be higher compared to oral formulations.

These challenges emphasize the need for careful drug selection, effective formulation design, and the use of enhancement techniques such as chemical permeation enhancers, microneedles, and iontophoresis to optimize transdermal drug delivery performance.

4. Skin as a Barrier to Drug Delivery

The skin acts as the body’s foremost defense against environmental factors, and while it also provides a pathway for drug administration in transdermal systems, its complex structure—particularly the stratum corneum—poses a significant challenge for drug absorption.

4.1 Structure and Composition of the Skin

The skin is made up of three primary layers:

• Epidermis: The outermost layer, which includes the stratum corneum.
• Dermis: The middle layer, containing connective tissues, blood vessels, and nerve endings.
• Hypodermis (subcutaneous layer): The innermost layer, composed mainly of fat that provides cushioning and insulation.

The stratum corneum, which is around 10–20 µm thick, is the main obstacle to drug permeation. It has a "brick-and-mortar" composition, consisting of dead keratinized cells set in a lipid matrix, making it highly resistant to foreign substances.

4.2 Drug Permeation Pathways

For a drug to enter the bloodstream via the skin, it must traverse one or more of the following routes:

• Transcellular: Directly through the keratinocytes of the stratum corneum.
• Intercellular: Between the cells, passing through lipid-rich regions.
• Appendageal: Through structures like hair follicles and sweat glands.

The intercellular route is the most commonly utilized for drug delivery, although it presents a lengthy and complex path that limits drug diffusion.

4.3 Factors Affecting Skin Permeability

Several elements influence how well a drug can pass through the skin:

• Drug-related factors:
  • Molecular weight: Ideal under 500 Daltons.
  • Lipophilicity: A balance between water and fat solubility is key.
  • Ionization: Non-ionized drugs are more easily absorbed.
• Formulation factors:
  • Use of chemical agents (e.g., ethanol, oleic acid) to enhance penetration.
  • Incorporation of techniques like microneedles to aid delivery.
• Biological factors:
  • Skin hydration level.
  • Thickness of the skin at the application site.
  • Age and overall condition of the patient’s skin.

4.4 Overcoming the Skin Barrier

To enhance transdermal drug absorption, various techniques are employed:

• Chemical enhancers: These alter the lipid structure of the stratum corneum to improve permeability.
• Physical methods:
  • Microneedles
  • Iontophoresis (uses electric current)
  • Sonophoresis (uses ultrasound)
  • Electroporation (uses electrical pulses)

These methods are particularly helpful for delivering drugs that are large in size or water-soluble.

???? Table 1: Key Factors Influencing Transdermal Drug Delivery

5. Types of Transdermal Patches

Transdermal patches are engineered in different configurations to optimize drug release, enhance formulation stability, and improve user comfort. The selection of a specific patch design depends on several factors, including the drug’s chemical characteristics, the desired release profile, and the therapeutic goal.

Most commercially available transdermal systems can be categorized into the following types:

5.1 Drug-in-Adhesive System

In this commonly used design, the active drug is embedded directly within the adhesive layer that both secures the patch to the skin and facilitates drug delivery. Its straightforward construction and ease of manufacturing make it widely popular.

Advantages:

• Thin, pliable, and user-friendly
• Simplified production process
• Lower risk of sudden drug release ("dose dumping")

Example: Nicotine patches

5.2 Reservoir System

This patch consists of a liquid or gel drug reservoir sandwiched between an impermeable backing layer and a rate-controlling membrane. The drug is released through this membrane at a consistent rate over time.

Advantages:

• Precise and controlled drug delivery
• Ideal for potent drugs requiring prolonged administration

Disadvantages:

• If the membrane is compromised, there's a risk of uncontrolled drug release
• More complex and expensive to manufacture

Example: Catapres-TTS (Clonidine transdermal patch)

5.3 Matrix System

Here, the drug is evenly dispersed within a polymer matrix, and release occurs as the drug diffuses from the matrix into the skin. This design eliminates the need for a separate membrane to regulate release.

Advantages:

• Simplified formulation
• Flexible dosage customization
• Can provide a steady or zero-order release pattern

Disadvantages:

• Release rate may vary based on polymer composition

Example: Fentanyl matrix patches

5.4 Micro-Reservoir System

This system combines the characteristics of both reservoir and matrix types. It features microscopic drug reservoirs distributed within a polymer matrix, ensuring consistent and controlled drug diffusion.

Advantages:

• Offers the benefits of matrix and reservoir designs
• Enhanced control over drug delivery and improved stability

Disadvantages:

• More complicated to formulate and produce

Example: Some cosmetic patches and experimental drug delivery systems

???? Summary Table: Comparison of Transdermal Patch Types

6. Antihypertensive Drugs for TDDS

The success of transdermal drug delivery is highly dependent on the physicochemical properties of the drug candidate. For an antihypertensive drug to be effectively delivered transdermally, it must exhibit:

• Molecular weight < 500 Da
• Moderate lipophilicity (Log P between 1 and 3)
• High potency at low doses
• Adequate skin permeability
• Non-irritating and non-sensitizing properties

A variety of antihypertensive agents have been assessed for transdermal application. Some have received regulatory approval, while others are in different stages of experimental or clinical research.

6.1 Summary of Common Antihypertensive Drugs in TDDS

6.2 Highlights from Selected Drug Studies

Clonidine (Catapres-TTS®)

• First FDA-approved transdermal antihypertensive patch.
• Delivers medication over a 7-day period.
• Significantly enhances compliance, especially in elderly patients.

Carvedilol

• Oral bioavailability is low (~30%) due to first-pass metabolism.
• Transdermal matrix patches with Eudragit and PVP exhibit zero-order drug release and improved systemic availability (~71% in preclinical trials)

Metoprolol Tartrate

• Characterized by a short half-life (2–3 hours) and significant hepatic metabolism.
• Eudragit RL100 and PVA-based patches demonstrated sustained drug release (up to 95% over 48 hours) and minimal skin irritation.

Atenolol

• Limited by poor skin permeability due to its hydrophilicity.
• CAP: PVP patches combined with penetration enhancers (e.g., isopropyl myristate) showed improved permeation following Higuchi kinetics.

Nicardipine Hydrochloride

• Rapidly cleared from systemic circulation after oral administration.
• Transdermal formulations using propylene glycol and oleic acid exhibited enhanced skin permeation and prolonged pharmacologic effect.

6.3 Experimental and Future Prospects

• Beta-blockers and calcium channel blockers remain the primary classes investigated for TDDS applications.
• Microneedle-based systems are being explored for emergency antihypertensives like sodium nitroprusside (SNP), potentially enabling rapid blood pressure control in acute care.
• New-generation antihypertensive agents such as valsartan, lisinopril, and amlodipine are under preclinical evaluation for transdermal delivery in the form of sustained-release patches or hybrid systems.

7. Formulation Techniques and Evaluation

The efficacy of a Transdermal Drug Delivery System (TDDS) is determined not only by the drug’s physicochemical compatibility with transdermal administration but also by the choice of polymers, formulation techniques, and comprehensive evaluation. An optimized patch design ensures consistent drug release, mechanical integrity, and skin compatibility, thereby enhancing patient adherence and therapeutic outcomes.

7.1 Formulation Techniques

a) Solvent Casting Method

This widely used method involves dissolving or dispersing the drug in a polymeric solution containing plasticizers and permeation enhancers. The mixture is cast onto a flat surface and allowed to dry, forming a uniform film.

Example:

• Carvedilol patches prepared using HPMC and Eudragit RL100 via solvent casting exhibited strong mechanical properties and sustained drug release.

b) Matrix-Type Formulation

Here, the drug is uniformly distributed within a polymer matrix, allowing controlled diffusion upon application to the skin.
Example:

• Metoprolol tartrate patches formulated with Eudragit RL100:PVA matrices released 95% of the drug over 48 hours, following Higuchi kinetics.

c) Reservoir-Type Formulation

The drug is enclosed in a gel or liquid reservoir positioned between an impermeable backing layer and a rate-controlling membrane.

Example:

• Nicardipine HCl patches formulated with ethylene vinyl acetate (EVA) membranes enhanced drug flux through the skin.

7.2 Polymers Used in TDDS

7.3 Plasticizers and Permeation Enhancers

• Plasticizers improve patch flexibility and reduce brittleness:
  Common examples include propylene glycol, PEG-400, glycerin, and dibutyl phthalate.
• Permeation Enhancers disrupt the stratum corneum’s lipid matrix to increase drug penetration:
  Common agents: oleic acid, isopropyl myristate, menthol, and limonene.

7.4 Evaluation Parameters

A. Physicochemical Characterization

• Thickness: Measured using a micrometer screw gauge.
• Weight uniformity: Ensures batch-to-batch consistency.
• Folding endurance: Reflects mechanical strength and flexibility.
• Tensile strength: Evaluates patch durability under stress.
• Surface pH: Ensures skin compatibility (ideally close to skin pH).
• Moisture content & Water Vapor Transmission Rate (WVTR): Indicate stability and breathability.

B. Drug Content Uniformity

Determines even distribution of drug across the patch. Typically analyzed using UV-Visible spectrophotometry or High-Performance Liquid Chromatography (HPLC).

C. In Vitro Drug Release Studies

• Conducted using Franz diffusion cells with artificial membranes or animal skin.
• Data analyzed using kinetic models:
  • Zero-order kinetics: Constant drug release (ideal).
  • First-order kinetics: Rate depends on drug concentration.
  • Higuchi model: Describes diffusion-controlled release.

Example:

• Carvedilol patches demonstrated zero-order release kinetics, suitable for maintaining stable plasma drug concentrations.

D. Skin Irritation Studies

• Performed on animal models (e.g., rat abdominal skin) to assess dermal safety.
• Ensures the patch is non-irritating, non-sensitizing, and safe for prolonged use.

8. Recent Advances in Transdermal Drug Delivery Systems

Although traditional transdermal patches have demonstrated success with drugs such as clonidine and fentanyl, challenges like limited drug candidates, dose constraints, and variable skin permeability have prompted significant innovation in the field. Recent technological advances aim to improve delivery efficiency, targeted release, and patient-centric design, thus broadening the therapeutic scope of TDDS.

8.1 Smart Patches

Smart patches integrate biosensors with drug delivery platforms to monitor physiological markers (e.g., glucose, pH, temperature) and regulate drug release dynamically. These systems often incorporate microneedles and stimuli-responsive polymers for precision delivery.

Example:

• A smart insulin patch equipped with 121 microneedles loaded with insulin and glucose-sensing enzymes. Upon detecting hyperglycemia, insulin is automatically released via a hypoxia-sensitive polymer, mimicking natural insulin response.

Benefits:

• Painless and minimally invasive
• Responsive to real-time physiological changes
• Reduces risk of overdose or underdose
• Enhances patient compliance

8.2 Microneedle-Based Patches

Microneedles bypass the stratum corneum, enabling enhanced transdermal penetration without pain. These systems are categorized by structure and function:

Example:

• Sodium nitroprusside (SNP), a potent antihypertensive agent, was effectively delivered using dissolving microneedles, achieving rapid blood pressure reduction in preclinical models.

8.3 Dissolving/Biodegradable Patches

These patches dissolve upon contact with skin, releasing the drug without leaving residues. Ideal for single-use therapies such as vaccines, antibiotics, or pediatric medications.

Example:

• Gentamicin-loaded dissolving microneedle patches showed efficacy against Klebsiella pneumoniae infections in mice.

Advantages:

• No removal required
• Reduced biohazardous waste
• Enhanced biocompatibility and safety

8.4 3D-Printed and High-Loading Patches

3D printing technology enables the fabrication of customized patch geometries, allowing precise drug loading and tailored release profiles. These patches can be designed for complex conditions requiring high-dose or multi-drug regimens.

Example:

• Curcumin-loaded 3D-printed patches embedded with phase-change materials (PCMs) release the drug upon heat stimulation, offering thermally-triggered delivery.

8.5 Dual-Function Smart Patches

These patches offer simultaneous monitoring and therapy, especially beneficial for chronic wound care and diabetic ulcers.

Examples:

• pH-sensitive patches for monitoring wound infection status.
• Hydrogel-based patches that both promote healing and deliver antibiotics or analgesics.

Applications:

• Diabetic foot ulcers
• Bedsores in immobile patients
• Post-surgical wound management

Summary of Recent Innovations