Available online on 15.02.2023 at http://jddtonline.info

Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

Copyright  © 2023 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Open Access   Full Text Article                                                                                                                                                                      Review Article 

Transdermal Drug Delivery Systems  

Prakash Pasupuleti¹ , Kishore Bandarapalle¹ , Cherlopalli Sandhya*² , Gundam Neeraja² , Chilakala Afzal² , Chithrala Venkataramana ² , Golla VenkatSai² 

1. Department Of Pharmaceutics, Sri Padmavathi School of Pharmacy Tiruchanoor, Tirupathi, 517503, Andhra Pradesh, India.
2. Sri Padmavathi School Of Pharmacy, Tiruchanoor, Tirupathi, 517503, Andhra Pradesh, India.

Introduction

Transdermal Drug Delivery System are the systems that use skin as  a site for continuous drug delivery into systemic circulation are known as TDDS ¹.

• Drug is delivered by skin portal to systemic circulation.
• At predetermined rate.
• At Maintained clinically effective concertation. 
• At prolonged period of time.
• The bulk of small molecule medications are typically administered orally since oral administration and parenteral administration are the two most popular drug delivery methods . 
• The primary goal of a transdermal medication delivery system is to deliver pharmaceuticals into systemic circulation through the skin at a predefined rate with minimum inter- and intra-patient variation ².
• Pre-set dosages, mobility, and patient self-administration are benefits of the oral route. For these reasons, administering drugs orally is still the most practical method.
• However, due to fast stomach breakdown and size-restricted transport through the epithelium, the majority of therapeutic peptides or proteins are not administered orally ³. 
• Therefore, injections are the most common method of administering macromolecules. However, injections have some drawbacks, including the invasive nature of injections that cause pain and lower patient acceptance/compliance, in addition to the need for administration by a trained administrator. 

Advantages: 

• Prevent first-pass gastrointestinal and hepatic metabolism. 
• Make sure the control absorption remains constant.
• Lessens negative consequences.
• Limit exposure to harmful metabolites.
• Increased patient compliance because multiple dosage is no longer necessary.
• Increase the effectiveness of therapy.
• Simple to use and take away.
• Painless and minimally invasive
• Self-governance.
• Functions well for medications with brief biological half-lives and restricted treatment windows.
• Simple to stop dosing in the event of a bad reaction.
• Repeated sustain release ⁴. 

  Limitations: 

• Drugs requiring high blood levels cannot be administered through it.
• A medicine or its formulation may irritate and sensitise the skin.
• The skin's ability to act as a barrier varies from one site to another on the same individual, from person to person, and with age.
• Not feasible if the medicine is heavily metabolised in the skin and if the molecular size is too large to allow the molecules to diffuse through the skin. 
• Might lead to an allergic reaction.
• Consistency over time is challenging.

Types of Transdermal Patches [Figure 1]:

1. Single-Layer Drug-in-Adhesive ⁵:
2. The   Single-layer   Drug-in-Adhesive  system  is characterized  by   the  inclusion  of  the  drug   directly within  the  skin-contacting  adhesive. 
3. In   this transdermal  system  design,   the  adhesive  not   only serves to affix the system to the skin, but also serves as the formulation foundation, containing the drug and all the excipients under a single backing film.
4. The   rate of release of drug from this type of system is dependent on the diffusion across the skin^{4, 5}
5. The intrinsic rate of drug release from this type of drug delivery system is defined by The medication is housed in this system's sticky layer. 
6. The adhesive layer in this sort of patch not only helps to glue the numerous layers together and the overall system to the skin, but is also accountable for the drug's release. A temporary liner and a backing enclose the adhesive layer.

B. The Multi-Layer Drug-In Adhesive ⁶:

• Similar to the single-layer approach, the multi-layer drug-in adhesive patch likewise releases the drug via both sticky layers. For quick release of, one of the layers
• Drug and additional layer for controlled release of drug from reservoir. However, the multi-layer method differs in that it incorporates an additional layer of drug-in-adhesive, often separated by a membrane.
• Drug-in-Adhesive Multilayer (but not in all cases). A permanent backing and a brief liner layer are also present on this patch.

C. Reservoir:

• The reservoir transdermal system contains a distinct drug layer in contrast to the single-layer and multi-layer Drug-in-adhesive systems.
• The drug layer is a compartment of liquid that houses a medication solution or the sticky layer separating the suspension. The backing layer also supports this patch. The rate of release in this kind of system is zero order.  

 D. Matrix:

• A semisolid matrix that houses a drug solution or suspension is the drug layer of the Matrix system.
• The patch's layer of glue encircles and partially covers the drug layer. Likewise called a monolithic device. 

Figure 1: Different types of Patches

Anatomy of the Skin: 

• The skin is the biggest organ in the human body, making up roughly 16% of the body's weight. A healthy adult man has skin that is 1.5 to 2 Sq m long and weighs 6 to 10 kg. The major layers of the skin are the subcutaneous layer, the underlying dermis, and the cellular epidermis ⁷.
• The epidermis' rete ridges extend downward to produce the dermis layer. In addition to serving as a partial barrier to the exchange of cells and big molecules, the dermal-epidermal interface mechanically supports the epidermis.                                               
• The subcutaneous layer, a fatty layer of panniculus adiposus tissues, lies beneath the dermis [Figure 2].  
• The two forms of human skin are glabrous and eccrine (i.e., non-hairy skin)

Figure 2: Structure of the Skin

Skin Layers Include:

  1. Epidermis:

• It is the skin's outermost layer and is characterized by the presence of Stratified Squamous Epithelial Tissues. principally keratinocytes that are diffusing through several stages of development.  The cells that make up the epidermis are called keratinocytes. Because it lacks blood vessels ⁸.
• The Epidermis depends on the dermis for nutrient absorption and waste removal via the basement membrane. 
• The epidermis has four layers overall [Figure 3], however there are five layers on the region of the body with thick skin.
• The foundation membrane (basal lamina) and hemi-desmosomes connect the stratum basale (stratum germinativum), the deepest layer, to the dermis. The cuboidal to columnar stem cells are mitotically active ⁹.
  1. Spike-like, irregular polyhedral cells make up the stratum spinosum (prickle cell layer).
  2. The stratum granulosum is composed of cornified cells with clumps of keratin filaments and diamond-shaped cells that contain keratohyalin granules
• Stratum lucidum, if present, is a thin, transparent layer made of eleidin (a byproduct of keratohyalin); it is often only visible in people with thick skin.

Figure 3: Structure of Epidermis

• The outermost layer, known as the stratum corneum, is composed of keratin and horny scales that were once live cells; dead cells, known as Squamous (Anucleate). This layer varies the greatest in thickness, being particularly thick in callused skin ¹⁰.
• The epidermis also comprises a variety of cells, the majority of which are keratinocytes, which make up roughly 95% of the epidermal cell population. 
• Melanocytes, Langerhans cells, and Merkel cells are some of the other cells.  Keratinocytes, which make up the majority of the epidermis and originate in the basal layer. 
• They produce keratin and help to form the epidermal water barrier.

2. Dermis:

• The dermis is a layer that lies underneath the epidermis [Figure 4] and is significantly thicker than the epidermal layer (1-5mm thick).  In order to maintain and support the epidermis, the dermis is essential ¹¹. 
• Collagen and elastin fibers make up the majority of the connective tissues in the dermis. It is home to a variety of specialized cells, including mast cells and fibroblasts, as well as organs and tissues, including blood arteries, lymphatics, sweat glands, and nerves. 

Figure 4: Structure of Dermis

• The connective tissues of the dermal layer are divided into two primary layers.
• Papillary layer: This thin layer, which is exposed to the outside, is made up of loose connective tissues.
• Reticular layer: This layer is less cellular, considerably thicker, and deeper, and it is made up of dense connective tissue and collagen fibre bundles.

3. The Hypodermis:

● The Panniculus layer or subcutaneous layer/fat are other names for Epidermis.

● The layer that lies underneath the dermis is what joins the skin to the muscles and bones' underlying connective tissue, or fascia [Figure 5].

Figure 5: Structure of Hypodermis

● A shock absorber, the hypodermis is made up of adipose tissues and well-vascularized, loose, areolar connective tissues that operate as an energy reserve, insulate the body to stop heat loss, and serve as a cushion to shield beneath structures from damage. 

● It is the primary location for fat storage in the body and is covered in blood vessels and nerves.

Functions of the Skin:

• Defense: The skin serves as the body's main physical defence against the outside world. Skin shields the body against microbes, poisons, dehydration, UV radiation, and mechanical harm ¹². 
• Sensation: for discomfort, heat, touch, and intense pressure.
• Mobility: enabling the body to move with ease.
• Endocrine activity: Vitamin D, which is crucial for calcium absorption and a healthy bone metabolism, is produced by the skin's biological reactions. 
• Exocrine activity: via urea, ammonia, and water release. Sebum, perspiration, pheromones, and other chemicals are secreted by the skin, which also performs crucial immunologic activities by secreting bioactive compounds like cytokines.
• Immunity: creation of defences against infections.
• Temperature Control: Skin contributes to thermal control by storing or releasing heat and aids in maintaining body temperature.  

Basic Components of TDDS:

A. Polymer Matrix [Table 1]: 

● Polymer is a crucial and indispensable part of the transdermal drug delivery system. Rate-controlled medication delivery has been accomplished using a variety of polymeric material types ¹³.

● The physicochemical characteristics of the dig and polymer used in the device's construction determine the drug release mechanism.

● For a polymer to be employed in a transdermal system, it must meet the following requirements.

1. The polymer’s chemical functionality, glass transition temperature, and molecular weight must permit the diffusion and release of the particular medication.

2. The polymer should make it possible to include a significant quantity of dmg.

3. Neither physically nor chemically should the polymer and the medication interact.

4. The polymer should be pricey and simple to build into the required product.

5. In the presence of the medicine and any other excipients used in the formulation, at high humidity levels, or at body temperature, the polymer must be stable and must not disintegrate.

6. Non-toxic polymers and their breakdown products are required. 

Table 1: Polymer Matrix

2. Drug Substance: Choosing the right drug substance is crucial to the creation of a successful transdermal product ¹⁴. Important pharmacological characteristics that influence how well it diffuses through the apparatus and through the skin include:
3. Physical and chemical attributes
   1. The drug's molecular weight should be below 600 Daltons.
   2. The log P should fall between 1 and 7.
   3. The melting point must be below 200° C.
   4. The minimum number of hydrogen bonding groups is two.
   5. It must have an advantageous oil:water partition coefficient.
   6. Transdermal administration is not appropriate for medications that are strongly acidic or alkaline in solution.
   7. Solubility should be more than 1 mg/ml in both mineral oil and water.
   8. Less than 20 mg should be used as the daily systemic dosage.
   9. The medicine should have a brief half-life.
   10. The medication shouldn't irritate the skin 
   11. Drugs that break down in the GI tract or are inactivated by hepatic first pass effect are ideal for transdermal distribution.
   12. The drug shouldn't trigger an immunological reaction in the skin.

C. Penetration Enhancers: 

→They are regarded as an essential component of the majority of transdermal formulations and increase skin penetration. 

→They can alter the skin's resistance to penetration by reacting with the skin's surface or the applied substance.

The following qualities should be present in an ideal penetration enhancer ¹⁵: 

(I) Pharmacological inertness, affordability, and Cosmetically Acceptable 

(ii) Nontoxic

(iii) Nonirritating

(iii) Nonallergenic

(iv) Quick onset; predictable and appropriate duration of action for the medicine used , Chemical penetration enhancers' reversible impact on the stratum corneum's barrier properties. 

(v) Compatible with the delivery system both chemically and physically

(vi) Easily fitted into the delivery system

   1.Physical Enhancers

   2.chemical Enhancers

1. Physical Enhancers: 

When chemical enhancement's limitations were reached, physical enhancement technologies became popular. 

Methodologies:

               Ultrasound 

                Iontophoresis

     II. Structure Based Technique: Microneedles

     III. Velocity Based Technique: Jet-propulsion

1. Electrically Based Techniques:
2. Iontophoresis [Figure 6]:
3. It works by creating a repulsion between the charged electrode and the solute.
4. Current applied 0.5Ma/cm ²  

 Ex: Lidocaine, Vincristine

Figure 6: Iontophoresis

b). Electroporation [Figure 7]:

• Application procedure using high transdermal voltages generated by electrical pulses.
• Controllable by modifying the electrical pulse.

Figure 7: Electroporation

c) Ultrasound: 

• It produces physical air pressure above topical skin.
• Medication delivery with low frequency range [Figure 8]

Figure 8: Ultrasound 

II. Structure Based Technique:

a) Microneedles: 

• Microneedle [Figure 9] is micro size needles which are used in set of arrays.
• To boost skin permeability, they produce a silicon-based physical tunnel through the top epidermis.
• These Needles Easily Pierced in Epidermal Layer Of The Skin.

Figure 9:  Microneedles

III. Velocity Based Technique: 

1. Jet-Propulsion [Figure 10]:
2. It Splits the Drug into Skin
3. High velocity jet(100m/s) of compressed gas(Helium) (20-22)

Figure 10:  Jet Propulsion 

2. Chemical Enhancers:

Chemical Boosters Mechanism for Increasing Chemical Penetration There are three major methods through which penetration enhancers can function.

• The stratum corneum lipid's highly organised structure is disturbed. 
• Compatibility with intercellular proteins. 
• A more effective medication partition and enhancer and solvent into stratum corneum. 

Classification of Chemical Enhancers: 

1. Sulphoxides- DMSO, DMF. 
2. Azones- 1-dodecylazacycloheptan-2-one 
3. Pyrrolidones- N-methyl-2-pyro
4. Essential oils, terpenes, terpenoids, L-Menthol
5. Oxazolidinones- 4-decyloxazolidin-2-one 
6. Fatty  acids-   lauric  acid,  myristic   acid  and capric acid
7. Glycol-  diethylene   glycol  and  tetraethylene glycol 
8. Non Ionic  surfactant-   polyoxyethylene-2-oleyl ether, polyoxy ethylene-2-stearly ether.

Types of Permeation Enhancers ¹⁶:

1. Sulfoxides Dimethylsulfoxide (DMSO):
2. It is an efficient penetration enhancer that enhances permeation by lowering skin resistance to drug molecules or promoting drug partitioning from the dose form. 
3. It has been proposed that DMSO either denatures the intercellular structural proteins of the SC or enhances lipid fluidity by disrupting the ordered structure of the lipid chains. 
4. DMSO may also change the physical structure of the skin via elution of lipid, lipoprotein, and nucleoprotein components from the SC.

(b) Alcohols:  

(c) Polyols:  

 (d) Alkanes: 

 (e) Fatty acids: 

(f) Esters: Esters are moderately polar, hydrogen bonding chemicals that may improve penetration in a similar way as sulphoxides and formamides by permeating the SC and boosting lipid fluidity through disruption of liquid packing. 

D. Additional Excipients:

Adhesives: All transdermal devices must be adhered to the skin with a pressure sensitive adhesive that can be applied to the face or the rear of the device.

Both adhesive layers must meet the following requirements:

i. When in touch with the skin, it should not produce irritation, sensitization, or an imbalance in the natural skin flora.

ii. Should actively adhere to the skin.

iii. Be readily removed without leaving an unwashable residue.

The face adhesive system should also meet the following requirements:

• Should not interfere with medication penetration. 

• Should facilitate the administration of simple absorption enhancers.

 • Should not degrade adhesive characteristics as the drug enhancer and excipients penetrate into the adhesive. 

The three primary types of polymers evaluated for potential medical applications TDDS [Figure 11] Includes:

• Pressure sensitive adhesives of the polyisobutylene type
• Pressure sensitive acrylic adhesives
• Pressure sensitive silicone adhesives

Figure 11: Transdermal Drug Delivery System Device

Factors Affecting Permeation ^17-19:

Biological Factors:  

1.Skin conditions: 

• The intact skin functions as a barrier, but many substances, such as acids and alkalis, break through the barrier cells of the skin and open the intricate, thick structure of the horny layer.
• Lipid fraction is removed by solvents like methanol and chloroform, creating artificial shunts that make it easy for drug molecules to flow through.

2.Skin age:

3.Blood Flow:

4.Localized skin site:

Physical-chemical Factors: 

1.Skin moisture:

• The permeability of skin rises dramatically when it comes into touch with water.
• The most crucial aspect in promoting skin permeability is hydration. So humectant usage occurs during transdermal administration.

2.PH and temperature:

• With temperature change, drug permeability multiplies 10 times. As temperature drops, the diffusion coefficient lowers.  (29)
• Depending on the pH and pKa or pKb values, weak acids and bases separate. The drug concentration in skin is based on the percentage of unionised drug.
• Consequently, major parameters impacting medication penetration include temperature and pH.

3.Diffusion coefficient: 

• The drug's diffusion coefficient affects how well it penetrates the body.
• Keeping the temperature constant, theDrug diffusion coefficient is influenced by the characteristics of the drug, the diffusion medium, and their interactions.

4.Partition coefficient:

5.Size and form of molecules:

• The relationship between molecular weight and drug absorption is inverse. Larger molecules cannot penetrate as deeply as smaller ones. 
• Small molecules penetrate more quickly than ones of greater mass.

6.Molecular weight: 

7.Solubility and melting point:

8.Ionization: 

9.Drug concentration: 

Environmental Factors ²⁰: 

1.Sunlight:

• As a result of sunlight, blood vessel walls change colour.thinner, causing slight damage and bruising in sun-exposed places. 
• Moreover, pigmentation Freckles or solar lentigo are the most obvious pigment change brought on by the sun.

2.Cold Season: 

• Dry, itchy skin is a common effect of the cold season. As a reaction to the drying impacts of the weather, skin produces more oil.
• A decent moisturiser will aid in reducing the effects of dry skin. Additionally, consuming a lot of water may keep your skin moisturised and beautiful. 

3.Air pollution:

Applications:

• Pain Management 
• Hormone Replacement Therapy
• Contraception
• Antiemetics
• Urinary Incontinence Treatment
• Cardiovascular System 
• Central Nervous System

Evaluation of Transdermal Patches:

A. Physicochemical evaluation

B. In vitro evaluation 

C. In vivo evaluation

A. Physicochemical Evaluation: 

 Transdermal patches were examined visually for:

Thickness

Folding stamina

• The folding durability of the created patches was measured manually. It is measured by the number of times the film is folded at the same location, either to break it or to generate visible fissures. This is necessary to test the sample's capacity to withstand folding.
• Brittleness is also indicated by this.
• Folding endurance of the film was measured repeatedly by folding a tiny strip of film at a specified location of 2 cm x 2 cm (4 cm2) for many times till a crack was noticed and subsequently broke. 

Weight Uniformity:

• Weight differences between the manufactured patches can result in differences in drug content and in-vitro behaviour, a research was conducted in which 5 patches were weighed in an electronic scale. All of the patches were chosen at random and should be of the same size (1 cm × 1 cm). 
• The following calculations were used to compute a patch's average weight and standard deviation.

Average patch weight = total patch weight/5

                (x-X)2/n-1 is the standard deviation.

Where,  x is the weight of the particular patch and X is the average weight.

              n denotes the number of patches.

Tensile Strength:

• The equipment, which was created in our lab, was used to measure tensile strength. Tensile strength was calculated using the average weight of three patches.
• On a glass plate, a tiny film strip (4 x 1 cm) was cut with a sharp blade. When inserted in the film holder, one end of the attached between adhesive tapes to provide support for the film.
• Another end of the film was sandwiched between the adhesive tapes with a tiny pin to maintain the strip straight while stretching.
• A tiny hole in the adhesive tape was formed near the pin, and a hook was inserted. A thread was hooked to the hook, which was then passed over the pulley with the little pan attached to it.
• The film was pulled using a pulley system to assess its tensile strength. Weights are gradually added to the pan in order to enhance the pulling power until the film breaks. 
• The elongation was calculated by recording the distance travelled by the pointer before the film broke on graph paper. Break force was defined as the weight required to break the film. 
• The following formula was used to compute tensile strength:

Tensile strength = Tensile load at break/a.b. (1+ L/L),

Where,

              a, b and L represent the width, thickness, and length of the strip, respectively

               L represents the elongation at break.

Break force is the amount of weight required to break 

IB-IO/IO x 100 = Elongation the film (kg)

Where ,  

IO denotes the original duration of the film.

IB = the length of film breaks

Probe Tack Test: 

Rolling Ball Test: 

B. IN VITRO Release Studies: 

• Transdermal patches can be examined in vitro in terms of Franz diffusion cell, which the cell is comprised of, according to in vitro release investigations the donor and receptor compartments.
• The receptor compartment has an effective surface area of 1–5 cm2 and a capacity of 5–12 ml. A magnetic bar continually stirs the diffusion buffer at 600 rpm. 
• A water jacket that envelops the receptor compartment is circulated with thermostated water to maintain the temperature in the majority of the solution.
• A proper technique is used to assess the drug content, and maintaining the state of the sink is crucial.

C. IN VIVO Release Studies: 

• Transdermal patches can be assessed in vivo for the most accurate representation of a drug's performance is found in in vivo tests. 
• The factors which cannot be accounted for in in vitro research can be thoroughly investigated in in vivo investigations.
• Animal models and human volunteers can be used to evaluate TDDS in vivo. (29)

Conclusion

Transdermal drug delivery system is employed in medication therapy for a less absorption, more uniform plasma levels, increased bioavailability, less adverse effects, effectiveness, and product quality. A patch is made up of a few basic components that play an important role in medication release via the skin. The future of TDDS would be centered on regulated therapeutic usage. There are many different varieties of transdermal patches, including matrix, reservoir, membrane matrix hybrid, micro reservoir type, and medication in adhesive type. These patches are made into transdermal patches utilizing the fundamental TDDS components.

Acknowledgement 

The corresponding author desires to explict utmost gratitude to the Management and Prof. Dr. D. Ranganayakulu, M. Pharm., Ph.D., Principal, Sri padmavathi school of pharmacy, Tiruchanoor, Andhra Pradesh, India for presenting all the necessary laboratory demands of the research and constant support.

Conflict of interest

The authors declare no conflict of interest, financial or otherwise.

Funding 

None.

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