A Review on Development of Transdermal Drug Delivery System

Abstract

A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. Often, this promotes healing to an injured area of the body. An advantage of a transdermal drug delivery route over other types of medication delivery such as oral, topical, intravenous, intramuscular, etc. is that the patch provides a controlled release of the medication into the patient, usually through either a porous membrane covering a reservoir of medication or through body heat melting thin layers of medication embedded in the adhesive. Transdermal drug delivery offers controlled release of the drug into the patient, it enables a steady blood level profile, resulting in reduced systemic side effects and, sometimes, improved efficacy over other dosage forms. The main objective of transdermal drug delivery system is to deliver drugs into systemic circulation through skin at predetermined rate with minimal inter and intrapatient variations

Keywords

Introduction

There is sufficient amphiphilic material in the lipid fraction, such as polar free fatty acids and cholesterol, to maintain a bilayer form. Viable epidermis is situated beneath the stratum corneum and varies in thickness from 0.06 mm on the eyelids to 0.8 mm on the palms. Going inwards, it consists of various layers as stratum lucidum, stratum granulosum, stratum spinosum and the stratum basal. In the basal layer, mitosis of the cells constantly renews the epidermis and this proliferation compensates the loss of dead horney cells from the skin surface. As the cells produced by the basal layer move outward, they alter morphologically and histochemically, undergoing keratinization to form the outermost layer of stratum corneum.

Adhesive Dispersion Type Systems (9)

Matrix Diffusion Controlled Systems

Micro-Reservoir Type or Micro-Sealed Dissolution Controlled Systems

Types of Transdermal Drug Delivery System (10)

a) Single layer drug in adhesive:

In this type the adhesive layer contains the drug. The adhesive layer not only serves to adhere the various layers together and also responsible for the releasing the drug to the skin. The adhesive layer is surrounded by a temporary liner and a backing.

 b) Multi -layer drug in adhesive:

This type is also similar to the single layer but it contains an immediate drug-releaselayer and other layer will be a controlled release along with the adhesive layer. The adhesive layer is responsible for the releasing of the drug. This patch also has a temporary liner-layer and a permanent backing.

c) Vapour patch:

The patch containing the adhesive layer not only serves to adhere the various surfaces together but also serves as to release the vapour. The vapour patches are new to the market, commonly used for releasing the essential oils in decongestion. Various other types of vapour patches are also available in the market which are used to improve the quality of sleep and reduces the cigarette smoking conditions.

d) Reservoir system:

In this system the drug reservoir is embedded between an impervious backing layer and a rate controlling membrane. The drug releases only through the rate controlling membrane, which can be micro porous or non-porous. In the drug reservoir compartment, the drug can be in the form of a solution, suspension, gel or dispersed in a solid polymer matrix. Hypoallergenic adhesive polymer can be applied as outer surface polymeric membrane which is compatible with drug

e) Matrix system:

i. Drug-in-adhesive system:

This type of patch is formulated by mixing the drug with adhesive polymer to form drug reservoir. It then followed by spreading on an impervious backing layer by solvent casting or melting method. The top of the reservoir is protected by an unmediated adhesive polymer layers. It may further be categorized into single-layer and multi-layer drug-in-adhesive. The system is considered to be compatible with a wide variety of drugs. Moreover the system is competent to deliver more than one drug in a single patch. It offers advantages in reduced size and thickness and improved conformability to the application site, helping drive patient preference.

ii. Matrix-dispersion system:

The drug is dispersed homogenously in a hydrophilic or lipophilic polymer matrix. It is then altered into a medicated disc with the definite shape and thickness. This drug containing polymer disk is fixed on to an occlusive base plate in a compartment fabricated from a drug impermeable backing layer. Instead of applying the adhesive on the face of the drug reservoir, it is spread along with the circumference to form a strip of adhesive rim.

f) Micro reservoir system:

The system consists of microscopic spheres of drug reservoirs which releases drug at a zero order rate for maintaining constant drug levels. Micro reservoir system is a combination of reservoir and matrix-dispersion system. The aqueous solution of water soluble polymer is mixed with drug to form a reservoir. It is then followed by dispersing the solution homogeneously using high shear mechanical force in a lipophilic polymer to form thousands of microscopic drug reservoirs. Cross linking agents are added to stabilize the thermodynamically unstable dispersion by in-situ cross-linking the polymer.

Primary components involved in transdermal drug delivery systems:

1. Drug Reservoir or Matrix:

• This holds the drug in the system, either as a reservoir (liquid or gel compartment) or within a matrix (a solid polymer structure).
• The drug is released at a controlled rate, allowing for consistent delivery over time.

2. Polymer Matrix or Carrier:

• A polymer matrix or adhesive layer contains the drug and controls its release rate.
• Common polymers include silicone, polyisobutylene, and acrylics.

3. Adhesive Layer:

• This attaches the patch to the skin and allows for close contact with the skin surface for effective drug transfer.
• Adhesives are typically hypoallergenic and must maintain adhesion over the duration of wear.

4. Rate-Control Membrane (Optional):

• This membrane, present in reservoir-type systems, regulates the rate at which the drug is released from the reservoir to the skin.
• Materials include ethylene-vinyl acetate or polyurethane.

5. Backing Layer:

• This is the outermost layer of the patch that provides structural support, protects the drug from environmental factors, and prevents leakage.
• It is usually impermeable and made from materials like polyester or polypropylene.

6. Release Liner:

• A disposable layer that protects the adhesive and drug before application.
• Made from materials like silicone-coated paper, it is peeled off before applying the patch.

7. Permeation Enhancers (Optional):

• Permeation enhancers increase the skin’s permeability to the drug by temporarily altering the skin’s barrier.
• Common enhancers include alcohols, fatty acids, and terpenes.

Enhancement of transdermal delivery by equipment (active delivery)

External stimuli, such as electrical, mechanical, or physical stimuli, are known to enhance skin permeability of drugs and biomolecules, as compared to the delivery of drugs by topical application on the skin (11) TDDS supplemented by appropriate equipment is termed as active transdermal delivery, which is known to deliver drugs quickly and reliably into the skin. In addition, this mode of enhanced TDDS can accelerate the therapeutic efficacy of delivered drug (12-14)

1.Iontophoresis

Iontophoresis promotes the movement of ions across the membrane under the influence of a small externally applied potential difference (less than 0.5 mA/cm2), which has been proven to enhance skin penetration and increase release rate of several drugs with poor absorption/permeation profiles. This technique has been utilized in the in vivo transport of ionic or nonionic drugs by the application of an electrochemical potential gradient [15]. The efficacy of iontophoresis depends on the polarity, valency, and mobility of the drug molecule, the nature of the applied electrical cycle, and the formulation containing the drug. In particular, the dependence on current makes drug absorption through iontophoresis less dependent on biological parameters, unlike most other drug delivery systems (Fig. 2A, B) [16]. This modality could additionally include electronic means of reminding patients to change dosages, if desired, to increase patient compliance [17, 18].

2. Sonophoresis

The desired range of ultrasound frequencies generated by an ultrasound device can improve transdermal drug delivery [19,20]. Low-frequency ultrasound is more effective, because it facilitates drug movement by creating an aqueous path in the perturbed bilayer through cavitation (Fig. 2C) [21]. The drug under consideration is mixed with a specific coupler, such as a gel or a cream, which transmits ultrasonic waves to the skin and disturbs the skin layers, thereby creating an aqueous path through which the drug can be injected. Drugs typically pass through passages created by the application of ultrasonic waves with energy values between 20 kHz and 16 MHz. Ultrasound also increases the local temperature of the skin area and creates a thermal effect, which further promotes drug penetration.

3.Electroporation

This method uses the application of high voltage electric pulses ranging from 5 to 500 V for short exposure times (~ms) to the skin, which leads to the formation of small pores in the SC that improve permeability and aid drug diffusion [22, 23]. For safe and painless drug administration, electric pulses are introduced using closely positioned electrodes. This is a very safe and painless procedure involving permeabilization of the skin and has been used to demonstrate the successful delivery of not only low MW drugs, such as doxorubicin, mannitol but also high MW ones such as antiangiogenic peptides, oligonucleotides, and the negatively charged anticoagulant heparin. However, this method has the disadvantages of small delivery loads, massive cellular perturbation sometimes including cell death, heating induced drug damage, and denaturation of protein and other biomacromolecular therapeutics only low MW drugs, such as doxorubicin, mannitol but also high MW ones such as antiangiogenic peptides, oligonucleotides, and the negatively charged anticoagulant heparin. However, this method has the disadvantages of small delivery loads, massive cellular perturbation sometimes including cell death, heatinginduced drug damage, and denaturation of protein and other biomacromolecular therapeutics.

4. Photomechanical waves

Photodynamic waves transmitted to the skin can penetrate the SC, allowing the drug to pass through the transiently created channel [24-26]. The incident wave produces limited ablation, which is achieved by low radiation exposure of approximately 5–7 J/cm2 to increase the depth to 50–400 μm for successful transmission. This limited ablation showed a longer increase and duration as compared to that in other direct ablation techniques, which made it necessary to control properties of the photodynamic waves to ensure delivery of the product to the intended depth in the skin. The wave generated by a single laser pulse also showed increased skin permeability within minutes, allowing macromolecules to diffuse into the skin. Dextran macromolecules of 40 kDa weight and 20 nm latex particles could be delivered by a single photodynamic laser pulse of a 23-ns duration.

1. Microneedle

The microneedle drug delivery system is a novel drug delivery system, in which drugs are delivered to the circulatory system through a needle [27]. This represents one of the most popular methods for transdermal drugdelivery and is an active area of current research. This involves a system in which micron-sized needles piercethe superficial layer of the skin, resulting in drug diffusion across the epidermal layer. Because these microneedlesare short and thin, these deliver drugs directly to the blood capillary area for active absorption, whichhelps in avoiding pain [28]. Scientists have attempted to use multiple techniques for appropriate optimizationand geometric measurements required for effective insertion of microneedles into human skin, which also represents the broad objective of research on microneedles. The fabrication of microneedle system has been widelyinvestigated with considering the objective, drug type and dose, and targets for use [29]. Up to now, the microneedle can be fabricated with laser-mediated techniques and photolithography. The laser-mediated fabricationtechniques are used for manufacturing metal or polymer microneedle. The 3D structure of a microneedle is generated through cutting or ablating on a flat metal/polymer surface using a laser [30,31]. Photolithography isknown as the method of elaborately fabricating microneedle and has the advantage of being able to manufactureneedles of various shapes using various materials. This method is mainly used to manufacture dissolving/hydrogel microneedles or silicon microneedles via making an inverse mold based on the microneedle structurethrough etching of photoresist [32]. In addition, 3D printing [33], Microstereolithography [34], and Twophotonpolymerization [35] are also investigated for preparing various microneedlesystem. The prepared microneedles could be of several types, such as solid microneedles that simply make a physical path through which drugs can be absorbed, drug-coated microneedles which facilitate delivery of drugs coated on the surfaces of the needles as the latter enter the skin, dissolving microneedles made of drug formulations that dissolve in the body, naturally delivered melting needles which involve drug storage in hollow needles followed by administration (such as a specific injection type), and microneedle patches combined with diverse patch types

 [36-40].

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