INTRODUCTION:

Richard Feynman, a Nobel laureate, once coined the phrase "There is plenty of room at the bottom" in 1959, which laid the foundation for the concept of nano scale structures and gave birth to the field of Nanotechnology. Nanotechnology deals with structures that are scaled down to one billionth of a meter, typically ranging from 10nm to 100nm. When materials are reduced to the nanoscale, various effects such as surface area, area to volume ratio, and other physical properties are significantly amplified. Consequently, nanosize has become a focal point of research in numerous technical and biomedical fields.¹

Nanoemulsions are transparent or translucent dispersions of oil and water that are thermodynamically stable. They are stabilized by a film of surfactant and cosurfactant molecules at the interface and have droplet sizes smaller than 100 nm.

Nanoemulsions, categorized as multiphase colloidal dispersions, are characterized by their stability and clarity. To achieve the nanoscale droplet size, high shear techniques such as microfluidics or ultrasonic approaches are commonly employed.¹

Many studies have been conducted to investigate the transdermal drug release from various delivery systems. Solid lipid nanoparticles, nanoemulsions, and polymeric nanosuspensions are among the formulations that have been explored. Among them, nanoemulsion has demonstrated efficient transdermal drug delivery capabilities.¹

1. Merits and Demerits of Nanoemulsion in Transdermal Patch:

a) Advantages of Nanoemulsion incorporated transdermal patch:²

· It gives site specific delivery of drugs.

· Nanoemulsion has capacity to dissolve large quantities of hydrophobics.

· Ability to protect drugs from degradation with long term stability which leads to making an ideal drug delivery system

· This may be used as substitute for the vesicles and liposomes.

· It is non-irritant and non-toxic.

· This are used to improves the bioavailability of drug.

· It provide greater absorption because have small-sized droplets having greater surface area.

· It is possible to formulate it in variety of formulations i.e., as creams, liquids, foams, and sprays.

· This is also used in taste masking.

· In cell culture technology it provides better uptake of oil-soluble supplements.

b) Disadvantages of Nanoemulsion incorporated transdermal patch:²

· It requires large concentration of surfactant and cosurfactant for stabilizing the nanodroplets.

· It generally shows a limited solubilizing capacity for high-melting substances.

· There is lacuna for understanding the interfacial chemistry which is involved in production of nanoemulsions.

2. Anatomy of skin:

The structure of human skin can be categorized into three main layers and represented in (Fig.1)^3,6

Figure 1. Structure of skin

a). Epidermis layer:

The outer surface of the body is covered by a stratified squamous epithelium that has the ability to continually regenerate itself. This epithelium consists of two main components, which are depicted in Figure 2. The first component is the living cells of the malpighian layer, also known as the viable epidermis. The second component is the dead cells of the stratum corneum, commonly referred to as the non-viable epidermis or the horny layer. The viable epidermis can be further divided into four distinct layers: the stratum lucidum, the stratum granulosum, the stratum spinosum, and the stratum basale.³The outermost layer of the skin, also known as the horny layer or stratum corneum, is typically around 10 mm thick when dry, but it expands to several times that thickness when fully hydrated. The stratum corneum serves as the primary barrier against drug penetration. In this context, the keratinized cells act as protein "bricks" embedded within a lipid "mortar." Beneath the stratum corneum lies the viable epidermis, which varies in thickness from 0.06 mm on the eyelids to 0.8 mm on the palms. The viable epidermis consists of several layers, including the stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale.³

Figure 2. Structure of epidermis

b). Dermis layer:

The layer of skin located just beneath the epidermis is known as the dermis. It is approximately 3 to 5 mm thick and consists of a connective tissue matrix that contains blood vessels, lymph vessels, and nerves. The cutaneous blood supply plays a crucial role in regulating body temperature. Additionally, it supplies nutrients and oxygen to the skin while eliminating toxins and waste products. When it comes to transdermal drug delivery, the dermis is often considered to be primarily composed of water in a gel-like state. As a result, it poses minimal barriers to the delivery of most polar drugs. However, when delivering highly lipophilic molecules, the dermal barrier may have a significant impact.³

c). Hypodermis:

The subcutaneous fat tissue is located beneath the dermis and epidermis layers of the skin. It acts as a supportive layer, providing structural support to the skin. It also serves as a storage area for fat. This layer plays several roles, including temperature regulation, providing nutritional support, and offering mechanical protection to underlying structures. The subcutaneous layer carries important blood vessels and nerves to the skin and may contain sensory pressure organs. In the context of transdermal drug delivery, the drug needs to penetrate through all three layers of the skin (epidermis, dermis, and subcutaneous tissue) in order to reach the systemic circulation.³

3. Types of Transdermal Patch:

a) Single-layer drug-in-adhesive:

In this system, the adhesive layer plays a crucial role as it not only binds the different layers together and attaches the entire system to the skin but also functions as the drug release mechanism. The adhesive layer is enclosed by a temporary liner and a backing material.⁴

b) Multi-layer drug-in-adhesive:

The multi-layer drug-in-adhesive patch shares similarities with the single-layer system in that both utilize adhesive layers for drug release. However, the multi-layer system introduces an additional layer of drug-in-adhesive, typically separated by a membrane (although not always). This patch configuration also includes a temporary liner layer and a permanent backing material.⁴

c) Reservior:

In contrast to the Single-layer and Multi-layer Drug-in-adhesive systems, the reservoir transdermal system features a distinct drug layer. This drug layer is a liquid compartment that contains a solution or suspension of the drug, and it is separated from the skin by the adhesive layer. The patch is further supported by a backing layer. In this type of system, the release rate of the drug is maintained at a constant rate, following a zero-order release profile.⁴

d) Matrix:

In the Matrix system, there is a drug layer composed of a semisolid matrix that contains a drug solution or suspension. The adhesive layer in this patch partially surrounds the drug layer, overlaying it to provide adherence to the skin.⁴

e) Vapour patch:

In this particular type of patch, the adhesive layer has a dual function. It not only binds the different layers together but also facilitates the release of vapor. These vapor patches are a recent addition to the market and are designed to release essential oils for a duration of up to 6 hours. They are primarily used for decongestion purposes. Additionally, there are other vapor patches available, such as controlled-release vapor patches that aim to enhance sleep quality. Furthermore, there are vapor patches on the market that are specifically designed to reduce the number of cigarettes smoked per month.⁴

4. Penetration Enhancers – As a main component:^5,6

Penetration enhancers can be described as substances that facilitate the flux of a drug and enhance its interaction with the constituents of the skin. By doing so, they increase the permeation of the drug through the skin. These enhancers are commonly referred to as absorption or promoter enhancers because they promote the absorption of drugs or substances through the skin. Additionally, they enhance the skin's permeability, allowing for better penetration of the drug.

Ideal penetration enhancers should impart following properties:^5-6

· Must be stable chemically and non toxic

· Must be non irritant, inert as well as non allergic

· Should not impart pharmacological activity inside the body.

· Must be odorless, colorless and inexpensive.

· Should be accepted cosmetically.

· Rapid onset of action.

Chemical penetration enhancers have the ability to directly insert themselves between the hydrophobic lipid tails within the skin, leading to changes in the lipid layer. This alteration in the lipid layer subsequently results in an increase in the permeation of the drug. Chemical enhancers primarily act through three main mechanisms, which are:

a) Disruption of Lipid Packing:

The enhancers can disrupt the orderly arrangement of the lipid molecules within the skin, thereby increasing the fluidity of the lipid layer. This disruption allows for easier diffusion of the drug through the lipid matrix.

b) Solvent Effect:

Some chemical enhancers have solvent properties that can solubilize or dissolve the drug, enhancing its availability for diffusion through the skin. These solvents can also disrupt the intercellular lipids, further aiding drug permeation.

c) Protein Denaturation:

Certain chemical enhancers have the ability to denature proteins within the skin. This denaturation can lead to changes in the structural integrity of the skin's proteins, allowing for enhanced drug permeation.

Overall, chemical penetration enhancers work by modifying the lipid layer, solubilizing the drug, and altering protein structure, all of which contribute to an increased permeation of the drug through the skin.

The chemical enhancer act by altering one of these pathways. They cause conformational change in protein or solvent swelling during the pathway. The fluidity of the lipid portion is increased by fatty acid enhancers of the stratum corneum. While some absorbers act on polar as well as non-polar pathway for the penetration and increase the diffusion of drugs via skin proteins. This aspect of action depends on the type of enhancer employed.^5,6

5. Techniques of Preparation of Nanoemulsions:

The particle size range of nanoemulsions is very small; the high-pressure equipment can be used to manufacture them most effectively. The most commonly used methods of nanoemulsion processing are "high-pressure homogenization" and "microfluidization," which are used on a laboratory and industrial scale. Certain methods such as "Ultrasonification" and "In-situ emulsification" are also ideal for the preparation of nanoemulsion.⁷

a) High-pressure homogenization:

The production of nanoemulsions involves the use of high-pressure homogenization, a technique that enables the creation of extremely small particle sizes, reaching as low as 1 nm. This technique utilizes a high-pressure homogenizer or piston homogenizer. The process involves the dispersion of two liquids, an oily phase, and an aqueous phase, which are combined and then forced through a small inlet orifice under very high pressure (ranging from 500 to 5000 psi). The intense friction and hydraulic shear experienced by the fluid during this process lead to the formation of extremely fine emulsion particles. These particles have a fluid lipophilic (oil-loving) center, which is surrounded by a monomolecular layer of phospholipids that separates it from the surrounding aqueous phase. This arrangement allows for the formation of stable nanoemulsions. The high-pressure homogenization technique is highly efficient in achieving small particle sizes and ensuring emulsion stability. However, there are a couple of drawbacks associated with this method. Firstly, it requires significant energy consumption due to the high-pressure equipment involved. Additionally, the emulsion temperature tends to increase during the processing due to the energy input. These factors should be considered during the preparation of nanoemulsions using high-pressure homogenization.⁷

Advantages:⁷

§ Small batch-to-batch variation and simple scale-up

§ Narrow product delivery nanoparticulate.

§ The product's value is flexible

§ Effective use of thermolabile materials.

b) Microfluidization:

Microfluidization is a mixing technique that utilizes a microfluidizer system. This system involves the use of a high-pressure positive displacement pump, typically operating at pressures ranging from 500 to 20,000 psi. The fluid to be processed is driven through a contact chamber, which contains microchannels, small channels designed to facilitate mixing. The liquid flows through these microchannels and enters the impingement area, where intense forces result in the formation of very small submicron scale particles. Initially, a coarse emulsion is produced by combining the aqueous phase and oily phase solutions and processing them together in an inline homogenizer. This coarse emulsion is then passed through a microfluidizer for further processing into a stable nanoemulsion. The coarse emulsion undergoes multiple cycles of being passed through the interaction chamber of the micro fluidizer until it reaches the desired particle size. This repetitive processing helps to break down larger droplets and achieve a more uniform and fine emulsion. To ensure the uniformity of the nanoemulsion, the bulk emulsion is circulated through a filter under a nitrogen atmosphere. This filtration step helps remove any remaining large droplets that could potentially impact the stability and uniformity of the final nanoemulsion product. In summary, microfluidization using a microfluidizer system involves high-pressure pumping of fluids through microchannels, resulting in the production of submicron particles. It is an effective method for creating stable nanoemulsions from coarse emulsions, and additional filtration steps can further enhance the uniformity of the final product.⁷

c) Ultrasonication:

The preparation of nanoemulsions has been extensively studied in various research papers, with the objective of minimizing droplet size using ultrasonic sound frequencies. One approach involves utilizing a constant sonotrode amplitude that exceeds the ambient value at system pressures. It is known that increasing the external pressure can raise the cavitation threshold within an ultrasonic field, thereby reducing bubble formation.However, it is worth noting that increasing external pressure can also lead to an increase in the pressure required for bubble collapse during cavitation. This means that when cavitation occurs, the collapse of the bubbles becomes more forceful and intense compared to atmospheric pressure conditions. Cavitation, which is the primary mechanism for power dissipation in low-frequency ultrasonic systems, is directly influenced by changes in power density resulting from these variations in pressure. To ensure optimal conditions during the process, a water jacket is often employed in the equipment to control the temperature. This helps maintain the desired temperature range for effective nanoemulsion preparation.⁷

d) Phase inversion method:

Fine dispersion is obtained by chemical energy as a result of phase transitions produced by the emulsification pathway. The phase transition is generated by varying the composition of the emulsion and holding the temperature constant, or vice versa. Shinoda et al first performed the phase inversion temperature. It was concluded that the increase in temperature results in chemical changes of polyoxyethelene surfactants by degrading the polymer chain with the temperature.⁷

e) Spontaneous emulsification:

This includes three main steps: i. Preparation of homogenous organic solution consisting of oil and lipophilic surfactant in liquid miscible solvent and hydrophilic surfactant. ii. The organic phase was injected under magnetic stirring in the aqueous phase, forming the emulsion of o / w. iii. The water-miscible solvent was extracted by evaporation under reduced pressure.⁷

f) Solvent Evaporation Technique:

This technique involves the preparation of a pharmaceutical solution with its emulsification into another non-solvent medicinal substance. Evaporation of the solution contributes to precipitation of the material. Through creating high shear forces with a high speed stirrer, it is possible to control the growth of crystals and the aggregation of particles.⁷

6. Characterization of Nanoemulsion:

a) Zeta potential:

Zeta potential is measured by an instrument called Zeta PALS. It is used in nanoemulsion to calculate the load on the droplet surface. Do not only emulsifiers serve as a mechanical barrier, but also by generating surface charges. Zeta potential among approaching oil droplets can produce repulsive electrical forces, and this hinders coalescence. The more negative the zeta potential, the higher the net droplet charge and the more stable the emulsion. A high degree of physical stability is usually demonstrated by zeta potential values below-30 mV. Malvern Zetasizer is based on the dispersion of dynamic light and measures the potential of Zeta.^8,9

b) Polydispersity:

The ratio of standard deviation to mean droplet size is polydispersity, thereby implying the uniformity of droplet size within the formulation. The higher the polydispersity in the formulation the lower the uniformity of the droplet size. Malvern Zetasizer is based on dynamic light dispersion and polydispersity measurements.^8,9

c) Particle size analysis:

Dynamic light scattering (DLS) method is generally used to measure particle size and its distribution in the case of nanoemulsion.^8,9

d) Percent Drug Loading:

Pre-weighted nanoemulsion is extracted by dissolving into an appropriate solvent of 25ml, extract is extracted from spectrophotometric / H.P.LC analysis. Against the standard drug solution. By reverse phase HPLC method, the drug content is determined using various columns of appropriate porosity.^8,9

e) Transmission Electron Microscopy (TEM):

Nanoemulsion morphology and structure can be analyzed using electron microscopy (TEM) transmission.^8,9

f) In-vitro drug release:

Nanoemulsion-containing drug studies in vitro release may be investigated using semipermeable membrane used in a dissolution apparatus. Instead of the basket, a glass cylindrical tube (2.5 cm in diameter and 6 cm in length) should be attached and covered tightly with the semi-permeable membrane. Drug-loaded nanoemulsion is placed on the semipermeable membrane surface in the cylindrical tube. The cylindrical tube should dip into a 100 ml buffer that keeps the pH to allow sink conditions to be established and permanent solubilization to be maintained. The analysis of release can be conducted for 24 hours at 32̊ C. The stirring shaft will spin at a rate of 100 rpm. At fixed time intervals (1, 2, 4, 6, 8, 12, 20, 24 hrs.) onemilliliter aliquots of the release medium are collected and diluted, processed for examination and replaced by the same volume of the buffer solution in order to maintain a steady size. UV spectrometer 30 can be used to measure the absorption of the collected samples.^6,8,9

7. Regulatory Issues:

The primary role of regulatory authorities is to ensure the safety and efficacy of medicines, including those delivered through transdermal drug delivery. Several factors need to be considered in this context, including the drug itself, the excipients used, and the device involved. The regulatory authorities must ensure that the active ingredient is delivered through the skin at an appropriate rate and does not have any adverse effects on the skin. It is surprising to discover that many chemical compounds have some level of skin toxicity, irritancy, or allergenicity. The presence of solvents in the delivery system, used to solubilize the medicine or enhance its penetration through the skin, can exacerbate these issues. Therefore, it is crucial to choose enhancers that are toxicologically safe and do not irreversibly alter the barrier function of the skin. Furthermore, solvents present in the polymers or adhesives of transdermal patches can potentially leach components, such as plasticizers, which raises safety concerns. Thorough testing is necessary to ensure the safety of these issues. For active delivery systems, it is important to ensure that the devices are capable of delivering the drug consistently to skin sites that may vary in terms of permeability characteristics. Stability is another important aspect to consider. Transdermal patches often contain high drug loads to minimize their surface area. This means that the active ingredient is often close to saturation, and precautions must be taken to prevent crystallization during storage, as it could affect the medication's effectiveness. In the case of iontophoresis, where drug flux is proportional to the current applied, tests must demonstrate that a constant current is provided across a range of conditions and after device storage. Overall, regulatory authorities play a crucial role in evaluating and ensuring the safety, efficacy, and stability of transdermal drug delivery systems, considering various factors such as drug characteristics, excipients, and device functionality.Top of Form⁸^{, 9}

8. Recent Advancement:

Jaganmohan Somagon and colleagues have developed a novel drug delivery system called Nanomiemgel for topical application. This system combines both nanoemulsion and nanomicelle components. The aim of their study was to explore the advantages of utilizing this combination as a carrier system for the topical application of Aceclofenac and Capsaicin.¹⁰

The researchers found that the absorption of the combined system, Nanomiemgel, was superior to that of either individual drug delivery system. This enhanced absorption can be attributed to the utilization of multiple absorption pathways available for each specific drug. By combining the nanomicelle and nanoemulsion, the maximum possible paths of absorption were utilized, resulting in improved drug delivery efficiency.¹⁰

This study highlights the beneficial effects of the nanomicelle-nanoemulsion combination in enhancing the topical delivery of Aceclofenac and Capsaicin, showcasing the potential of Nanomiemgel as a novel carrier system for these drugs.¹⁰

CONCLUSION:

Nanoemulsions are highly desirable systems for use in various industries such as cosmetics, pharmaceuticals, foods, and pharmaceuticals for several reasons. Firstly, they require a minimal amount of surfactant, which is advantageous from a formulation perspective. Additionally, nanoemulsions exhibit high stability, preventing the coalescence of droplets over time. This stability contributes to their prolonged shelf life and improved product quality. Furthermore, nanoemulsions possess lower toxicity and irritant characteristics, making them safe for use in consumer products and medical applications.

The colloidal dispersions of solid nanoscale particulates, enabled by the permeability characteristics of nanoemulsions, have garnered significant attention. This has opened up new possibilities for drug delivery and other applications where enhanced skin permeability is desired.

Moreover, advancements in high-throughput production techniques have expanded the potential for widespread commercial use of nanoemulsions in consumer products and medical applications. This suggests that nanoemulsions may become as prevalent as polymer solutions and solid particulate dispersions in the future.

Overall, nanoemulsions offer a promising platform with numerous advantages, and their future prospects indicate extensive utilization in various industries.

REFERENCES:

1. Reza, K. H. Nanoemulsion as a novel transdermal drug delivery system. International Journal of Pharmaceutical Sciences and Research. 2011; 2(8): 1938.

2. Halnor, V. V., Pande, V. V., Borawake, D. D., and Nagare, H. S. Nanoemulsion: A novel platform for drug delivery system. J Mat Sci Nanotechol. 2018; 6(1): 104.

3. Ch. Nagadev, M. Durga Srinivasa Rao, P. Venkatesh, D. Hepcykalarani, R. Prema. A Review on Transdermal Drug Delivery Systems. Asian J. Res. Pharm. Sci. 2020; 10(2):109-114.

4. Nikhil Patel, Chetan Patel, Savan Vachhani, ST Prajapati, CN Patel. Recent Advances in Transdermal Drug Delivery System. Research J. Pharma. Dosage Forms and Tech. 2010; 2(2):113-119.

5. Rakesh K Sindhu, Mansi Chitkara, Gagandeep Kaur, Preeti Jaiswal, Ashutosh Kalra, Inderbir Singh, Pornsak Sriamornsak. Skin Penetration Enhancer’s in Transdermal Drug Delivery Systems. Research J. Pharm. and Tech. 2017; 10(6): 1809-1815.

6. Chien, YW, Novel drug delivery systems, Drugs and the Pharmaceutical Sciences, Vol.50, Marcel Dekker, New York, NY;1992;797

7. Rahul P. Jadhav, Vikranti W. Koli, Amruta B. Kamble, Dr. Mangesh A. Bhutkar. A Review on Nanoemulsion. Asian J. Res. Pharm. Sci. 2020; 10(2):103-108.

8. Mithun Bhowmick, Tamizharasi Sengodan, Sivakumar Thangavel. Challenges Facing Transdermal Drug Delivery Systems: A Conceptual Approach. Research J. Science and Tech. 2012; 4(5): 213-219.

9. Samadhan K. Deore, Rajendra K Surawase, Avish Maru. Formulation and Evaluation of O/W Nanoemulsion of Ketoconazole. Res. J. Pharma. Dosage Forms and Tech.2019; 11(4):269-274.

10. Somagoni, J., Boakye, C. H. A., Godugu, C., Patel, A. R., Mendonca Faria, H. A., Zucolotto, V., and Singh, M. Nanomiemgel - A Novel Drug Delivery System for Topical Application - In Vitro and In Vivo Evaluation. PLoS ONE. 2014; 9(12): e115952. doi:10.1371/journal.pone.0115952

Received on 05.11.2022 Modified on 16.04.2023

Asian J. Res. Pharm. Sci. 2023; 13(4):303-308.

DOI: 10.52711/2231-5659.2023.00051