Innovative nano approaches in cutaneous delivery of drugs

 

Naveenkumar R, Kavya HR, Sayani Bhattacharyya

Department of Pharmaceutics, Krupanidhi College of Pharmacy, No .12/1 Chikkabellandur,

Carmelaram Post, Varthur, Hobli. Bangalore 560035.

 

ABSTRACT:

Nanotechnology deals with exceptionally minute structures, size ranging from 0.1 to 100 nm. The field of nanomedicine and nanotechnology is currently undergoing explosive developments in various fields of science and other new areas. Properties related to the particle surface and quantum mechanics are the two main aspects that render the nanomedicine functionally different from other bulk formulations. Dermal diseases can be controlled by using the nano approaches which allows an enormous opportunity in designing the novel low dose and effective treatment systems. Therefore, they have received meticulous attention as topical drug delivery systems. The present review considers the anatomy of skin, skin diseases, novel nano-based formulation approaches with evaluation techniques and its applications in various aspects.

 

 

 

INTRODUCTION:

The present review is based on the potential use of nanoparticles over conventional therapy for dermal infections¹. The cutaneous drug delivery approach became a priority area in research and also for the development process in pharmaceutical companies as it shows the larger therapeutic window when compared to other conventional delivery of drugs². Penetrating the dermal barrier of the skin i.e., the stratum corneum is one of the majors challenges to deliver the large hydrophilic drugs cutaneously. Therefore, the delivery of the drug in a nanocarrier system can afford to penetrate the deeper tissues of the skin to provide a systemic action or a targeted action for therapeutic, diagnostic and prophylactic purposes³.

 

As per WHO, skin diseases are responsible for much disability, disfigurement, and distress. Skin diseases mostly prevail in rural communities in developing countries and low economic class. The serious fatal deaths in the hospital might be due to infections on the localized surface because of injuries, surgeries, abrasion and burn injuries^4,5.

 

Nanoparticles are target specific with high penetration power through the skin^6,7. Multi-drug loading efficiency is enhanced. It also provides a versatile platform for the delivery of drugs and nucleic acid⁸. It also shows the potential advantages of photothermal therapy and radiotherapy⁹. Therefore, as nanotechnology is advancing in its various aspects its products are also getting extremely authoritative¹⁰. Therefore, it can be successfully used for cutaneous delivery of drugs without any invasive procedures.

 

Physiology of skin:

The skin is a complex organ presenting a total area of approximately 2m² and known to be the largest organ exposed to the external environment in the human body. The properties of the skin vary from one part of the human body to the other part, also varies from one individual to another with respect to the color, thickness, texture and also the adnexal structures. Some of the vital roles of the skin include-

i.      Acts as a physical barrier from the external environment from pathogens, chemicals, thermal, mechanical and radiation damages.

ii.    Acts as a sensory detector and regulates interaction with the external environment

iii.  Acts as the thermoregulatory system¹¹.

iv.   Secrets hormones, cytokines, and growth factors and act as the endocrine and metabolic functioning system.

v.     Known as the excretory system, where the excretory products are released out through the skin pores and glands present on the layers of the skin^12,13

 

Human skin is comprised of three layers- stratified, cellular epithelium, dermis layer of connective tissue and hypodermis^14,15,16. The presence of ridges on the epidermis (rete ridges) is projected into the dermis through the dermal-epidermal junction. The undulating section of dermal-epidermal junction not only provides mechanical support but also acts as a partial barrier. Panniculus adiposus, a sheet of a fatty layer is present just below the dermis layer of the skin known as a subcutaneous layer which is separated by panniculus carnosus, a vestigial layer of striated muscle¹⁶.

 

The human skin is also susceptible to certain diseases as like other organs of the body, as listed in table-1

 

Table 1: Certain diseases of human skin

 

Selection of drugs for dermal delivery:

The human skin serves as a selective barrier for a huge number of drugs¹⁷. For effective penetration, through the skin, the drug should have specific physicochemical and biological properties¹⁸. The drug should not develop tolerance under the slow release profile from the dosage form. 

 

The physicochemical properties of an ideal drug for cutaneous drug delivery include:

·       The drugs with molecular weight less than approximately 1000 Daltons are often considered as ideal systems for dermal delivery.

·       The drug with high affinity for both lipophilic and hydrophilic phases is susceptible to cutaneous drug delivery. Extreme partitioning characteristics are not ideal for cutaneous drug delivery.

·       Drugs should have a low melting point.

·       Drugs should be potent in nature, with a short half-life and be non-irritating.

 

Therefore, molecules like insulin, human growth, hormone cyclosporine, do not fulfill these criteria. These categories of drugs are very challenging from the drug delivery point of view.

 

Dermal pathway for drug penetration:

There are two pathways for the drug to penetrate through the skin. They are

·       Transepidermal pathway (diffusion across skin layers)

·       Appendageal pathway (diffusion via follicles of hair or sweat ducts)

 

Transepidermal pathway:

In the trans epidermal pathway, the permeant crosses the intracellular and/or extracellular spaces through the various layers of skin. While passing the permeant crosses a series of separating and interspersing hydrophilic and lipophilic domains, through the process of diffusion and partition^18,19. In the extracellular matrix, permeant maneuvers through the convoluted path, without passing through cells. Hydrophilic small molecules favor the transcellular route over the intercellular route and vice versa in the case of lipophilic molecules.

 

Appendageal pathway:

The appendageal pathway or shunt pathway is bound to permeation via follicles of hair (trans follicular route) or sweat ducts²⁰. The skin penetration pathway is depicted in fig-1.

 

Fig-1: Skin penetration pathway

 

Diffusion of nanoparticles through the skin:

Passive diffusion: the drugs which are lipophilic in nature pass across a lipid membrane, through the process of passive diffusion. The drug embedded in the nano-lipid carriers also helps to penetrate a hydrophilic drug in the same manner through passive diffusion. The charge on the surface of the nanoparticles influences the diffusion process. A 3 to 5 fold increase in penetration is observed in the uptake of nanoparticles across lipid bilayer containing cholesterol²⁰.

 

Factors affecting nano delivery systems through the skin:

1.     Particle size distribution and zeta potential:

Particle size and shape often influences the pharmacokinetics of the drug. The drug release, stability and apical uptake of the nanoparticle systems are greatly dependent on its size and shape^21,22. The critical process parameters such as homogenization speed, temperature, viscosity, and the phase volume ratio of the organic and the aqueous phase affect the yield and size distribution of each system^22,23.

 

2.     Surface properties:

The presence of negatively charged sulphated proteoglycans on the cellular surfaces -influences cellular motility migration and proliferation²². Surface charge is the main functioning property of nanoparticles for its attachment to the cell membrane. The surface charge can influence the tissue binding of the direct nanoparticles to the cellular components both in vivo and in vitro.

 

3.     Hindrance through stratum corneum:

The five layers of stratum corneum and their unique structure with a series of layers of dead cells and flattened corneocytes create a lipid envelope and provide a hindrance for penetration of the drug in the deeper layer. The layers of the skin comprise highly dynamic tissues that combine with the dead cells to form a water repellant layer that also provides protection against particles²².Individual compounds show different permeability characteristics, dependent on their own particular properties of solubility and diffusion. The skin is also composed of hair follicles (0.2% of the skin surface) and the sweat ducts (0.4% of the skin surface) which allow faster penetration of some of the aqueous and organic solutions ^23,24.Therefore, this route can be used in medicine for the release of nanoparticle bound drugs or vaccines, which are subsequently delivered into the systemic circulation²⁵.

 

Dermatopharmacokinetics:

Dermatopharmacokinetics describe the assessment of skin kinetics of external formulations to determine the drug bioavailability on application. As no correlations can be established between the availability of the drug in skin and drug blood levels dermatopharmacokinetics involves the estimation of the drug in the outermost layer of the skin with time to correlate the amount of drug absorbed²⁶. The methodologies generally used to assess the dermatokinetcs of topical formulations are tape stripping and microdialysis^27,28. Parameters used to estimate the bioavailability through dermal absorptions are the maximum quantity of drug molecules in the stratum corneum (Cmax), time to reach maximum concentration (Tmax). The bioequivalence of the cutaneous applications is estimated by assessing Area under the curve (AUC) in terms of drug level in stratum corneum versus time²⁹. These approach works better for local topical formulations which are intended to give action on stratum corneum, in case of targeted delivery via skin with the use of nanoformulations the similar method can be used with few more considerations like (1) size of the nanoformulation to penetrate the rate-limiting barrier of stratum corneum (2) improvement of diffusivity of the drug in nanocarriers and (3) the surface charge of the nanomaterials^30,31.

 

Novel nano approaches for cutaneous drug delivery:

Nano approaches to deliver the drug cutaneously use different carrier systems in the form of niosomes, solid lipid nanoparticles, polymeric nanoparticles, carbon nanotubes, etc. The proposed carrier systems favor the transportation of drugs through the skin with a controlled release and optimum drug retention³².

 

Niosomes:

Niosomes consists of nonionic surfactant vesicles and cholesterol, which are used in improving the solubility and stability of the pharmaceutical compounds. These also help in providing the targeted and controlled release of the drug from the natural carrier system by changing the characteristics and properties of the natural drugs inside the body after the administration of the dosage form. It can protect natural drugs from degradation and increases drug efficiency through ligand binding³³. Niosomes can be mainly used in cancer chemotherapy, vaccine and antigen delivery, carrier for hemoglobin, etc.

 

Nanoemulsions:

Nanoemulsions are isotropic nanosized dispersed systems with two immiscible liquids resulting in O/W or W/O type emulsions. It can be used to entrap both hydrophobic and hydrophilic drugs. They are nonirritant and also nontoxic^34,35. They are specially used for topical and Transdermal applications for cosmetic, drug and gene delivery. They have shown their mart applications on photodynamic therapy of skin. They are found to be beneficial for dermal products in terms of hydration of skin, hair and nail care products.

 

Lipid-based nanoparticles:

A lipid-based nanoparticle is preferred over polymeric nanoparticles. The advantage includes drug delivery of lipid particles show the ability to protect the drug from chemical decomposition, can modulate the release of drug and forms an adhesive lipid film providing the possible occlusive effect. The emerging development of nanotechnology in the recent decade has enlightened the use of lipid nanoparticle for dermal applications and mostly they are marketed as cosmetics in the treatment of fungal infections, psoriasis and Transdermal delivery of medicinal agents³⁶.

 

Solid nanoparticles:

These are the solid colloidal particles of size ranging from 1 to 1000nm. These are the macromolecular particles which can be therapeutically used as the carriers for various drugs. The active therapeutic ingredient is dissolved, entrapped or encapsulated. The main theory of solid nanoparticles is enhanced permeability and retention properties^35,36. Some of the solid nanoparticles which are used in topical drug delivery are Quantum dots, zinc oxide-based nanosystems, silver nanosystems.

 

Polymeric nanoparticles:

Polymeric nanoparticles are the systems that are prepared from polymers which are biocompatible and biodegradable. The size of biodegradable polymers ranges between 10-100nm. Polymeric nanoparticles can be prepared by either dissolving, entrapping, encapsulating the drug with the polymeric matrix to form a polymeric nanoparticle. The polymeric nanoparticles can modify the functionality of drugs, sustain the release of drug from the formulation and also adhesivity or the permeability of the drug can be increased with the use of a polymeric matrix. Stratum corneum is known to be the main skin layer responsible for the permeation and distribution of the drug throughout the skin layers. The nanoparticles act as good reservoirs for the lipophilic drugs thus helping the drug for its action³⁷.

 

Table 2: Marketed products of Nano formulations

 

Carbon nanotubes and fullerenes:

Carbon nanotubes are the carbon nanosystems that are stable. Carbon nanotubes possess the potential antioxidant property and cytoprotective ability. Carbon nanotubes are particularly small systems having the mean diameters (<100 nm). Fullerenes are 1-nm scale in size. A fullerene is a particle composed exclusively with carbon atoms, in the form of a hollow sphere, ellipsoid, tube, and many other shapes. The therapeutic opportunities of the carbon nanotubes and fullerenes are due to their small size, shape and hollow interior. Many of the cosmetic products such as sunscreens, moisturizers, makeup products with long-lasting properties propose the use of carbon nanotubes as their basic principle system.

 

The various marketed nano deliveries through cutaneous route are listed in table-2

 

CONCLUSION:

Nanotechnology and nanosystems are a promising development in the ground of pharmaceutics. Even the drug with larger molecular size can be incorporated into a nanoparticle. The decrease in particle size will enhance the absorption and bioavailability with the increased surface area. Multidrug resistance which is observed in conventional delivery can be overcome with the use of nanoparticles. With conventional therapy, normal tissues are damaged but with the use of nanoparticles only infected cells will be targeted without any further damage to the nearby tissues. In the case of conventional therapy, the drug may be degraded or may be metabolized from the enzymes present in the liver via the first-pass metabolism but nanoparticles release the drug at a particular site. Biological drugs can also be encapsulated within the nanoparticles and degradation of the drug prior to its release at a specific site is minimized. The route of administration may be parenteral or oral⁴⁸. The stability of the nanoformulation is enhanced, the cost of the treatment is reduced, toxicity levels can be minimized and shelf-life of the proprietary drugs can be extended⁴⁹.

 

ACKNOWLEDGMENT:

Authors thanks to the management and Principal Dr. Amit Kumar Das of Krupanidhi College of Pharmacy, Bangalore, Karnataka, India to provide us the support and encouragement to complete the review work.

 

AUTHOR CONTRIBUTIONS:

All the authors were equally involved in gathering information and framing the manuscript.

 

CONFLICT OF INTEREST:

The author confirms that this article content has no conflict of interest.

 

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Received on 05.02.2020           Modified on 31.03.2020

Accepted on 07.05.2020         © RJPT All right reserved