Transdermal Drug Delivery: Principles, Design and Evaluation – A Review

Abstract

A transdermal patch is a medicated adhesive patch that is applied to the skin to deliver a specific dose of a drug through the skin and into the bloodstream. This method allows the drug to act continuously and may help in healing or treating a particular condition. Compared to other routes of drug administration such as oral, topical, intravenous, or intramuscular delivery, transdermal drug delivery provides controlled and sustained release of medication over a prolonged period. The drug is released either through a porous membrane containing a drug reservoir or by body heat, which helps release the drug embedded within the adhesive layer. One major advantage of transdermal patches is the maintenance of consistent drug levels in the body. However, the main limitation of this system is that the skin acts as a strong protective barrier, allowing only drugs with small molecular size and suitable properties to pass through it. Despite this limitation, many pharmaceutical drugs are now successfully formulated as transdermal patches.

Keywords

transdermal drug delivery system, bioavability, Iontophoresis, Electroporation, ultrasound, microscopic projection

Introduction

1.6 Transdermal Patches

Transdermal systems deliver medication directly into systemic circulation through skin, offering an alternative to traditional delivery methods.

Working of transdermal patches

A skin patch controls the rate at which the liquid drug dispersed in the reservoir within the patch can pass though skin and into bloodstream by using a special membrane. When patch is applied over skin the occlusion traps the natural transepidermal moisture of the skin and increases water content of horny layer and causes swelling of the membrane, thus helps in compromising its barrier function.

1.7 Basic Components Involved In Transdermal System

(Sachan et al., 2013)

Polymer matrix: Polymers are the foundation of transdermal system.

Considerations to be done during polymer selection:

• Stable and non-reactive with the drug moiety.
• Easily available.
• The properties of polymer like molecular weight, glass transition temperature, melting point and chemical functionality etc. should not interfere in diffusion of drug through it and other components of system.
• Release of drug should be consistent throughout the life of system.

The polymers used in transdermal system are:

Natural Polymers: e.g. xanthum gum, natural rubber, cellulose derivatives, gelatin, zein, guar gum, shellac, waxes and chitosan etc.

Synthetic elastomers: e.g. silicon rubber, butyl rubber, polyisobutylene, polybutadiene, hydrin rubber, neoprene, acrylonitrile etc.

Synthetic Polymers: e.g. polyvinylpyrrolidone, polyamide, polyvinylchloride, polyethylene, polyvinyl alcohol, polypropylene, polyurea, polyacrylate, polymethylmethacrylate etc.

Release liners: The release liner is removed and discarded before the application of patch over the skin. The patch is covered by protective liner during its storage. It should be physically and chemically inert as it is in intimate contact with the transdermal system.

Backing laminate: Backing layer should follow below said properties.

• Must be flexible.
• Non irritant
• Compatible with transdermal system.
• Low water vapor transmission rate in order to promote skin hydration and thus increase skin permeability of drug.
• Good tensile strength.

Drug: Because of the limited permeability of the skin, drugs have to be delivered by passive diffusion through the skin and are limited by several important constraints:

• • Potent drugs (<20mg).
  • Non-ionic.
  • Non-irritant.
  • Molecular weight ≤ 500 Dalton., Adequate solubility in the vehicle.

2. REVIEW OF LITERATURE SURVEY :

Gannu et al (2007) prepared Nitrendipine matrix transdermal patches using HPMC E15, ERS100 and ERL100 as polymers by solvent evaporation method. All formulations carried 6 % v/w of carvone as penetration enhancer and 15%v/w of propylene glycol as plasticizer in dichloromethane and methanol as solvent system. The maximum drug release in 24 hrs for A series formulations was 89.29% (A4) and 86.17% for B series (B5), which are significantly (p < 0.01) different to the lowest values (57.58 for A1 and 50.64 for B1). Again formulations A4 (flux 23.51 µg/cm²/hr) and B5 (flux 22.98 µg/cm²/hr) showed maximum skin permeation in the respective series. The flux obtained with formulation A4 and B5 meets the required flux (19.10 µg/cm²/hr). The mechanical properties, tensile strength, elastic modulus (3.42 kg/mm² for A4 and 4.25 kg/mm for B5) reveal that the formulations were found to be strong but not brittle.

Mutalik et al (2009) studied the effects of chemical enhancer and sonophoresis on the transdermal permeation of Tizanidine hydrochloride (TIZ HCl) across mouse skin. Maximum enhancement was observed for TIZ formulated as a suspension in 50% v/v aqueous ethanol containing 5% v/v citral. Sonophoresis significantly (p < 0.05) increased the cumulative amount of TIZ permeated at 15 and 30 min (0.091 ± 0.011 and 0.220 ± 0.055 mg, respectively) from drug suspension in PB in comparison with passive diffusion, i.e., no sonophoresis (0.014 ± 0.002 and 0.025 ± 0.006 mg at 15 and 30 min, respectively).

Sheth et al (2011) prepared and evaluated Propranolol hydrochloride transdermal patches using polymers like polyvinylpyrrolidone, Hydroxypropylmethycellulose (HPMC) and Ethyl cellulose (EC) in combination and propylene glycol as plasticizer. Optimized formulation containing ethyl cellulose was evaluated for permeation enhancement through rat skin using natural permeation enhancer Eugenol.

Vijayan et al (2011) developed transdermal patches of Repaglinide loaded solid lipid nanoparticles. Method of preparation for SLNs is hot homogenization method. Cephalin and lecithin were used as lipids and Tween 80 as stabilizer. SEM analysis showed spherical shaped particles with a size range between 85 – 120 nm and PDI in the range of 0.148 to 0.227. The zeta potential ranged between - 27.1 ± 2.5 to −36.1 ± 2.1 mV. The entrapment efficiency (EE %) and drug loading capacity (DL %) was 80.4 ± 4.2 % to 92.3 ± 7.2 % respectively. Freeze dried SLNs were incorporated in transdermal patches and ex-vivo & in vivo studies were performed. Cumulative amount of drug release (254.12± 0.42 µg/cm²) from SLNs was found to be high with formulation containing combination of two lipids. The blood glucose level in normal rats drastically reduced in orally administered drug upon 10 hrs and was reported as 54.08 ± 0.22 mg/ dl and 35.40 ±0.04 mg/dl for 48 hrs in the case of transdermal patches containing SLN. In STZ induced diabetes rats, the blood glucose level gradually reduced up to 98.48 mg/dl at t=10 hrs from 328.67 mg/dl. Transdermal patches containing SLN produced maximum drop of blood glucose at 92.74 mg/dl at 48 hrs.

Sarvaiya et al (2013) studied in vitro skin permeation of Lovastatin from Dodecyltri-methylammoniumbromide (DTAB) containing micellar composition. Lovastatin, a lipophilic drug can be delivered through skin effectively by Iontophoresis by using 0.5 mA/cm² pulsed DC current from cationic surfactant containing composition. Presence of electrolyte as counter ion negatively effects permeation of drug from micellar composition during Iontophoresis. Increase in flux was seen with increase in current density. Flux with passive diffusion was about 3.63±0.10 µg/cm²/h while on applying iontophoresis, flux was increased to11.06±0.7 µg/cm²/h with ER of 3.04. When current pattern changed from continuous to pulsed, there is increase in flux to about 19.47±1.81 µg/cm²/h with ER of 5.35.

Narender et al (2013) developed Nislodipine loaded solid lipid nanoparticulate (ND-SLNs) system composed of a glyceryl trimyristate (dynasan 114) as lipid matrix and polymeric non-ionic surfactants. A two-factor, five-level central composite design (CCD) was developed using Design of Expert (DOE) to study the effect of formulation variables on the drug delivery system. The ND-SLNs were prepared by hot homogenization followed by ultrasonication method, the amount oflipid (X1), amount of surfactant (X2) were taken as independent variables and size (Y1), PDI (Y2), entrapment efficiency (EE) (Y3) were selected as responses.

Statistically optimized formulation was having 100mg lipid and 75mg surfactant. The optimal formulation of Nisoldipine-loaded SLN had entrapment efficiency (EE) of 89.84±0.52%, particle size of 104.4±2.13 nm and polydispersity index (PDI) of 0.241±0.02 as responses. The morphology of nanoparticles was found to be nearly spherical in shape by scanning electron microscopy (SEM) observation. X-ray diffraction and differential scanning caloimetry analysis indicated that the drug incorporated into SLN was in an amorphous form but not in a crystalline state. Dialysis method was used for a period of 24hrs. HCl (0.1N) and pH 6.8 phosphate buffer were used as release media. No significant difference was observed in drug release in pH 6.8 phosphate buffer and 0.1NHCl at 24hrs in each formulation due to no pH dependent solubility of ND. The statistically optimized formulation was stable at refrigerated and room temperature for 3 months.

Chandrika et al (2014) designed and evaluated the transdermal patches containing Imidapril loaded solid lipid nanoparticles with an aim to improve the therapeutic efficacy pertaining to hyper-tension. The Imidapril loaded nanoparticles were prepared by homogenization followed by ultrasonication technique using the excipients such as lipid (dynasan 118), surfactant (polysorbate80) and emulsifier (soya lecithin).The patches were prepared by solvent casting technique using the polymers such as HPMC, Eudragit RS100.

Mangesh et al (2016) developed and evaluated Solid lipid nanoparticle loaded Piroxicam transdermal patch. SLN dispersion was prepared using pre-emulsion probe sonication method using compritol ATO 188 as lipid. The prepared patches found to possess satisfactory physiochemical characteristics. Ex-vivo skin permeation studies showed a drug flux of 17.16 µg/cm²/h from pirox- SLN patch compared to 4.6 µg/cm²/h from plain Piroxicam patch attributing improved delivery of piroxicam from the transdermal patch. The increased AUC and C_max from in vivo study conclude that incorporation of drugs in SLN can improve transdermal bioavailability.

Suksaeree et al (2017) developed the Mefenamic acid matrix patches using ethyl cellulose as a polymer and diethyl phthalate as a plasticizer. PVP K90 was effective at 1:1.5 & 1:2 (drug: PVP) ratio in inhibiting the crystallization of the drug by solubilizing drug. This was evidenced by SEM analysis that the crystals of drug were absent in the matrix patch and showed homogeneous patches. The Mefenamic acid could release 44.12 ± 12.48%, 46.85 ±10.97%, 51.66 ±12.99%, 53.66 ±12.99% and 56.79 ± 17.98% from BM1, BM2, BM3, BM4, and BM5 formulas, respectively. When PVP K 90 was used as a crystallization inhibitor the drug release from the patches was increased. Drug release from all formulations followed Higuchi’s model with high R², i.e. drug release mechanism is determined by diffusion.

3. RATIONAL, NEED OF WORK

The rationale for developing a transdermal drug delivery system (TDDS) lies in overcoming the significant limitations of conventional oral and injectable routes, primarily by enhancing patient compliance, avoiding hepatic first-pass metabolism, and maintaining a constant drug concentration in the bloodstream. The need for work is driven by the inherent barrier function of the skin's stratum corneum, which restricts the passive diffusion of most drugs, requiring innovative delivery and rigorous evaluation methods to expand the range of applicable drugs. 

Rationale and Need for Development

• Bypassing First-Pass Metabolism: Drugs delivered orally are often extensively metabolized by the liver before reaching systemic circulation (first-pass metabolism), which reduces their bioavailability and efficacy. TDDS avoids the gastrointestinal tract and hepatic system entirely.
• Improved Patient Compliance: Patches are non-invasive, generally painless, and require less frequent dosing (lasting for hours, days, or even weeks), which greatly improves patient adherence, especially for long-term treatments or in cases of needle phobia.
• Steady Drug Levels: TDDS provides a controlled and prolonged release of the drug at a predetermined rate, avoiding the "peak and trough" plasma concentration profiles (and associated side effects or therapeutic failures) often seen with conventional dosing.
• Reduced Side Effects: By maintaining constant, lower concentrations in the bloodstream and avoiding the GI tract, TDDS minimizes gastrointestinal side effects and systemic toxicity.
• Treatment Termination: The application can be easily stopped if the patient experiences toxicity or adverse effects, simply by removing the patch.
• Alternative for Specific Patients: TDDS is suitable for patients who are unconscious, vomiting, or unable to take medication orally.

4. MECHANISM OF DRUG DELIVERY

Drug enters the body through different enhancement methods:

1. Iontophoresis

Uses small electric current to push drug through skin.

2. Electroporation

Short electrical pulses create temporary pores in skin.

3. Ultrasound (Sonophoresis)

Sound waves increase skin permeability.

4. Microneedles

Tiny needles create microscopic openings without pain.

5. TYPES OF TRANSDERMAL PATCHES

1. Single-layer Drug-in-Adhesive

Drug mixed directly in adhesive layer.

2. Multi-layer Drug-in-Adhesive

Contains multiple drug layers for controlled release.

3. Reservoir System

Drug stored in liquid reservoir; release controlled by membrane.

4. Matrix System

Drug dispersed in polymer matrix.

5. Vapour Patch

Releases vapours such as essential oils.

7. EVALUATION OF TRANSDERMAL PATCHES

1. Physicochemical Evaluation

• Thickness measurement
• Weight uniformity
• Drug content analysis
• Moisture content
• Folding endurance
• Tensile strength
• Adhesion tests

2. In-Vitro Studies

Laboratory tests measuring drug release using:

• Paddle over disc method
• Cylinder method
• Diffusion cells

3. In-Vivo Studies

Performed on:

• Animals (rats, rabbits, monkeys)
• Human volunteers during clinical trials
• Clinical trials check safety, effectiveness, and side effects.

7. CONCLUSION

Transdermal drug delivery systems provide a modern and effective method of administering drugs through the skin. They improve patient comfort, maintain stable drug levels, and reduce side effects compared to conventional dosage forms. Although limitations exist, advanced technologies are continuously improving their effectiveness. Transdermal patches represent an important development in controlled drug delivery systems.

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