Topical drug delivery (TDD) is a route of drug administration that allows the topical formulation to be delivered across the skin upon application, hence producing a localized effect to treat skin disorders like

eczema Dermatitis is inflammation of the skin, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened. The area of skin involved c ...

. The formulation of topical drugs can be classified into

corticosteroids Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invol ...

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...

antiseptic An antiseptic (from Greek ἀντί ''anti'', "against" and σηπτικός ''sēptikos'', "putrefactive") is an antimicrobial substance or compound that is applied to living tissue/skin to reduce the possibility of infection, sepsis, or putre ...

s, and anti-fungal. The mechanism of topical delivery includes the

diffusion Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemical ...

and

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run ...

of drugs in the skin. Historically, topical route was the first route of medication used to deliver drugs in humans in ancient Egyptian and Babylonian in 3000 BCE. In these ancient cities, topical medications like

ointments A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes ...

and potions were used on the skin. The delivery of topical drugs needs to pass through multiple skin layers and undergo

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

, hence factor like dermal diseases minimize the

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

of the topical drugs.Goldsmith L.A., & Katz S.I., & Gilchrest B.A., & Paller A.S., & Leffell D.J., & Wolff K(Eds.), (2012). ''Fitzpatrick's Dermatology in General Medicine, 8e''. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=392§ionid=41138688 The wide use of topical drugs leads to the advancement in topical drug delivery. These advancements are used to enhance the delivery of topical medications to the skin by using chemical and physical agents. For chemical agents, carriers like liposomes and nanotechnologies are used to enhance the absorption of topical drugs. On the other hand, physical agents, like micro-needles is other approach for enhancement ofabsorption. Besides using carriers, other factors such as pH,

lipophilicity Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lip ...

, and drug molecule size govern the effectiveness of topical formulation. __TOC__

History

In ancient times, human skin was used as a layer for self-expression by painting cosmetic products on it. They used those products as a protection for their skin from the sun and dry environment. Later on in 2000 BCE, the Chinese used topical remedies that wrap in bandages to treat skin diseases. The contact between these topical remedies and skin deliver its

therapeutic effect Therapeutic effect refers to the response(s) after a treatment of any kind, the results of which are judged to be useful or favorable. This is true whether the result was expected, unexpected, or even an unintended consequence. An adverse effect ( ...

on the skin. The newer development of topical drugs occurred between 130 and 200 AD. This development was made by Claudius Galenus, a Greek physician. He first loaded the herb medication to Western medicine and formulated it as cream. More recently in the 1920s, some observations were made when applying topical skin, such as to determine its systemic effects. In 1938, Zondek successfully managed urogenital infections after applying chloroxylenol on the skin by the use of

disinfectant A disinfectant is a chemical substance or compound used to inactivate or destroy microorganisms on inert surfaces. Disinfection does not necessarily kill all microorganisms, especially resistant bacterial spores; it is less effective than s ...

in ointment form. After some years, observations were made from various experiments. These experiments led to the development of skin toxicology in the mid-1970s, including symptoms like irritation, skin inflammation, and skin photo-toxicity upon application of topical drugs. After the development of

toxicology Toxicology is a scientific discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnosing and treating e ...

, a mathematical model was also created for skin diffusion coefficient formulated by Michaels. This formulation suggests how they related to the aqueous solubility and partition coefficient in skin.

Skin absorption

Skin layers

The human body's largest organ is the skin layers, which protects against foreign particles. Human skin contains several layers, including the subcutaneous layer, the

dermis The dermis or corium is a layer of skin between the epidermis (with which it makes up the cutis) and subcutaneous tissues, that primarily consists of dense irregular connective tissue and cushions the body from stress and strain. It is divided ...

, the

epidermis The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water rel ...

, the

stratum corneum The stratum corneum (Latin for 'horny layer') is the outermost layer of the epidermis. The human stratum corneum comprises several levels of flattened corneocytes that are divided into two layers: the ''stratum disjunctum'' and ''stratum compa ...

, and the appendages. Each of these layers have an effect on the absorption of topical drug. When the topical drug is applied to the skin, it must pass via the

, which is the outermost skin layer.

Stratum corneum The stratum corneum (Latin for 'horny layer') is the outermost layer of the epidermis. The human stratum corneum comprises several levels of flattened corneocytes that are divided into two layers: the ''stratum disjunctum'' and ''stratum compa ...

's function includes prevention of water loss in skin and inhibit the penetration of foreign molecules into the dermal layers. Hence, it also prevents the

hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are n ...

molecules to get absorbed into the skin since it is made out of bilayered lipids. With this barrier,

affects the permeability of topical drugs. Another part of the skin is called the appendages, and it is known as the “shortcut” for topical drug delivery. The shortcut pathway allows the drug molecules to first pass the

barrier via

hair follicle The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction between ...

Diffusion

When drugs are applied to skin topically, the drug molecules will undergo passive

. This process occurs down the

concentration gradient Molecular diffusion, often simply called diffusion, is the thermal motion of all (liquid or gas) particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size (mass) ...

when drug molecules move to one area to another region.

Diffusion Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemical ...

is described by a mathematical equation. The drug molecule (J), known as

flux Flux describes any effect that appears to pass or travel (whether it actually moves or not) through a surface or substance. Flux is a concept in applied mathematics and vector calculus which has many applications to physics. For transport ...

and it represents the entry of topical drug molecules across the skin

membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. ...

. The skin membrane is the area (A) for the topical drug molecules to travel across. The skin membrane thickness is known as (h) in the expression, and it determines the

path length. The (C) is the concentration of the diffusing substance across the skin layers and the (D) is the

diffusion coefficient Diffusivity, mass diffusivity or diffusion coefficient is a proportionality constant between the molar flux due to molecular diffusion and the gradient in the concentration of the species (or the driving force for diffusion). Diffusivity is enc ...

. The expression illustrates the transportation of topical drug molecules across the

membrane through

. Diffusion expression:

J= ADC/h

Mechanism

Upon application of the topical drug on the skin, it will diffuse to the outer layer of the skin, known as

. There are three routes possible for the drugs to cross the skin. The first route is through the appendages. It is known as the "first cut" where the drug molecules will be partitioned into the

sweat gland Sweat glands, also known as sudoriferous or sudoriparous glands, , are small tubular structures of the skin that produce sweat. Sweat glands are a type of exocrine gland, which are glands that produce and secrete substances onto an epithelial ...

to bypass the

barrier. If the drug molecules is not transported via the "first cut", it is usually remains in the stratum corneum's bilayered lipids, where the drug molecules transport through either the transcellular route or paracellular route into the deeper area of the skin like subcutaneous layer. For the paracellular route, it means that the solutes transport via the junction between the cell. When the topical drug molecules transport via the paracellular route, it needs to travel across the

, which is a highly fat region, but between the cells. On the other hand, the topical drug molecules may travel through the transcellular route. This route allows molecules to be transported via the cell. Transcellular route transports the drug molecule into the bilayered lipid cells found in

. Inside of the bilayered lipids in the

is a water-soluble environment, and the drug molecules will diffuse through these bilayered lipids into deeper area of the skin. During the transportation of the topical drug molecules, it can bind to the

keratin Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. Alpha-keratin (α-keratin) is a type of keratin found in vertebrates. It is the key structural material making up Scale (anatomy), scales, hair, Nail ...

that exists as one of the skin components in the

Skin metabolism

The activities of skin

are commonly occurring on the skin surface, appendages, the

, and the viable epidermis. This process comprises phase one

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysi ...

, reduction, and

oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or ...

, also known as functionalization phase. If phase one is not sufficient enough to metabolize the drugs, phase two conjugation reaction occurs. This phase includes

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gl ...

sulfation Sulfation is the chemical reaction that entails the addition of SO3 group. In principle, many sulfations would involve reactions of sulfur trioxide (SO3). In practice, most sulfations are effected less directly. Regardless of the mechanism, the ...

, and

acetylation : In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply '' acetates''. Deacetylation is the oppos ...

. It is found that phase two activities are lower than phase two in the skin. One common example is thearylamine-type hair dye, after it is applied topically, it will undergo

in the skin through

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

N-acetyltransferase N-acetyltransferase (NAT) is an enzyme that catalyzes the transfer of acetyl groups from acetyl-CoA to arylamines, arylhydroxylamines and arylhydrazines. They have wide specificity for aromatic amines, particularly serotonin, and can also catalyz ...

, thus resulting in a N-acetylated

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...

. These metabolic

s cause the loss of topical drug activities, thus reducing its

. They may eventually form atoxic compound that reaches to the

systemic circulation The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, t ...

and causes damage to the skin layers. The longer the topical drug remains in the skin, the greater amount of it will be metabolized by the underlying enzymes. To reduce such an effect, the topical drug needs to remain on the skin for a shorter period of time. Also, certain amount of topical molecules needs to be applied to the skin and cause metabolic

s saturation.

Factors affect topical absorption

The amount of topical drug molecules being delivered to the skin is affected solely by the physicochemical properties of the topical drug. The first factor is the weight of the drug molecule. The smaller of the drug

molecular weight A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bio ...

or particle size, the higher rate of its

and absorption into the skin. The second factor is the

of the drug molecules, since the three pathways for absorption are quite lipophilic. The higher

of it, the easier of the drug molecules to be absorbed when compared to the

drug molecules. The third parameter is the pH level of the skin. The pH of the skin layers are basic, hence basic topical drugs will be absorbed better than acidic topical drugs. These factors are vital to determine the permeability of topical drug delivery.

Skin permeability enhancers

Colloidal System

Colloidal system is one of the techniques used for topical drug delivery into the skin and functions as skin permeability enhancers. They are known as carriers and can be classified into nanoparticles, liposomes, and nanoemugel.

Liposome

Liposomes contain a bilayer of

phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...

s in a sphere shape that may exist as one or more than one bilayer of phospholipids. With this structure, its function is to trap

or lipophilic drug molecules within the spherical bilayers. The

drug molecule sticks to the

head since it is

polar Polar may refer to: Geography Polar may refer to: * Geographical pole, either of two fixed points on the surface of a rotating body or planet, at 90 degrees from the equator, based on the axis around which a body rotates *Polar climate, the cli ...

and favours water. On the other hand, the lipophilic drug molecules will be entrapped in the

tails of the bilayer due to its lipophilic nature. With these mechanisms, liposomes will behave like carriers and carry the lipophilic or

drug molecules into the

and release them into deeper layers of the skin by interacting with the bilayers lipids found in

. The Use of liposome as carrier enhances the overall permeability of topical drug into the skin to reach the target site. For example, a drug like

amphotericin B Amphotericin B is an antifungal medication used for serious fungal infections and leishmaniasis. The fungal infections it is used to treat include mucormycosis, aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, and cryptococcosis ...

, is used to treat fungal infections. The drug is loaded into liposome and this carrier enhances the penetration of

into the skin, regardless of its

Nanoemulgel

Nanoemulgel is another type of enhancer for delivery of topical drugs into the skin. The formulation process for nanoemulgel is produced by incorporating the nanoemulsion into a

gel A gel is a semi-solid that can have properties ranging from soft and weak to hard and tough. Gels are defined as a substantially dilute cross-linked system, which exhibits no flow when in the steady-state, although the liquid phase may still di ...

matrix. The

s are made out of aqueous bases and it allows for a more rapid release of drugs through dissolution. The use of nanoemulgel enhances patient compliance because the use of gel is less greasy than traditional

cream Cream is a dairy product composed of the higher-fat layer skimmed from the top of milk before homogenization. In un-homogenized milk, the fat, which is less dense, eventually rises to the top. In the industrial production of cream, this process ...

ointment A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes ...

, hence there is less incident in skin irritation. Nanoemulgel increases the topical drug

by inserting the lipophilic drug molecules into the oil droplet of the nanoemulgel and it will travel through the skin layers. With its high dissolution rate, the nanoemulgel produces a high

toward the skin, thus allowing for a rapid uptake of oil droplet into the

. Also, the

surfactant Surfactants are chemical compounds that decrease the surface tension between two liquids, between a gas and a liquid, or interfacial tension between a liquid and a solid. Surfactants may act as detergents, wetting agents, emulsion#Emulsifiers , ...

being incorporated into the nanoemulgel has the ability to penetrate through the bilayer lipid by interrupting the

hydrogen bond In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a l ...

between the lipid in the skin to further enhance its permeability. In terms of treatment, the use of nanoemulgel is against cancer cells and useful in skin cancer. Also, the formulation of nanoemulgel with

methoxsalen Methoxsalen, sold under the brand name Oxsoralen among others, is a medication used to treat psoriasis, eczema, vitiligo, and some cutaneous lymphomas in conjunction with exposing the skin to ultraviolet (UVA) light from lamps or sunlight. Met ...

is used to treat

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to comple ...

. The carrier enhances both the penetration and accumulation of

in the skin layers.

Physical Agents

Micro-needles

Micro-needle belongs to the physical enhancer to improve absorption of topical drug molecules into the skin. It is known as ‘poke and patch’ because it uses tiny needles and stick into the skin across the

. These tiny needles ensure that they will not contact the nerve endings or

cutaneous Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different d ...

blood vessels under the skin, hence they can be removed easily from the skin. There are several types of micro-needle, the first one is solid micro-needles. The solid micro-needles are used to project into the skin. Once the needles are removed after insertion, the topical drugs are applied to skin. This enhances the ability of drugs to diffuse across the viable epidermis. The second type is the dissolvable micro-needle. These types of needles are composed of materials that allow them to dissolve after poking into the skin, hence no need to remove the needles after injection. The third type of micro-needle is the swell-able micro-needles, which consist of

hydrogel A hydrogel is a crosslinked hydrophilic polymer that does not dissolve in water. They are highly absorbent yet maintain well defined structures. These properties underpin several applications, especially in the biomedical area. Many hydrogels ar ...

. After poking its needle into the skin, it allows the skin interstitial fluid diffuse into the micro-needles, thus it will swell to diffuse the drug molecules across the skin. It is found that micro-needles are safe and effective in enhancing skin permeability.{{Cite journal , last1=Liu , first1=Ting-Ting , last2=Chen , first2=Kai , last3=Wang , first3=Qiao , date=2018-10-01 , title=Skin drug permeability and safety through a vibrating solid micro-needle system , url=https://doi.org/10.1007/s13346-018-0544-2 , journal=Drug Delivery and Translational Research , language=en , volume=8 , issue=5 , pages=1025–1033 , doi=10.1007/s13346-018-0544-2 , pmid=29858819 , s2cid=46920352 , issn=2190-3948

References

Routes of administration Drug delivery devices