Topical drug delivery

Topical drug delivery(TDD) is aroute of drug administrationthat allows the topical formulation to be delivered across the skin upon application, hence producing a localized effect to treat skin disorders likeeczema.The formulation of topical drugs can be classified intocorticosteroids,antibiotics,antiseptics,andanti-fungal.The mechanism of topical delivery includes thediffusionandmetabolismof 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 likeointmentsandpotionswere used on the skin.The delivery of topical drugs needs to pass through multiple skin layers and undergopharmacokinetics,hence factor like dermal diseases minimize thebioavailabilityof the topical drugs.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 likeliposomesandnanotechnologiesare used to enhance the absorption of topical drugs.On the other hand, physical agents, likemicro-needlesis other approach for enhancement ofabsorption.Besides using carriers, other factors such aspH,lipophilicity,and drug molecule size govern the effectiveness of topical formulation.

History

Claudius Galenus

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 topicalremediesthat wrap in bandages to treat skin diseases.The contact between these topical remedies and skin deliver itstherapeutic effecton the skin. The newer development of topical drugs occurred between 130 and 200 AD. This development was made byClaudius 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 itssystemic effects.In 1938,Zondeksuccessfully managedurogenitalinfections after applyingchloroxylenolon the skin by the use ofdisinfectantin 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 oftoxicology,a mathematical model was also created for skin diffusion coefficient formulated by Michaels. This formulation suggests how they related to the aqueous solubility andpartition coefficientin skin.

Skin absorption

Skin layers

Skin layers

The human body's largest organ is the skin layers, which protects against foreign particles.Human skin contains several layers, including thesubcutaneous layer,thedermis,theepidermis,thestratum corneum,and theappendages.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 thestratum corneum,which is the outermost skin layer.Stratum corneum's function includes prevention of water loss in skin and inhibit the penetration of foreign molecules into the dermal layers.Hence, it also prevents thehydrophilicmolecules to get absorbed into the skin since it is made out of bilayered lipids.With this barrier,stratum corneumaffects the permeability of topical drugs. Another part of the skin is called theappendages,and it is known as the “shortcut” for topical drug delivery. The shortcut pathway allows the drug molecules to first pass thestratum corneumbarrier viahair follicles.

Diffusion

When drugs are applied to skin topically, the drug molecules will undergo passivediffusion.This process occurs down theconcentration gradientwhen drug molecules move to one area to another region.Diffusionis described by a mathematical equation.The drug molecule (J), known asfluxand it represents the entry of topical drug molecules across the skinmembrane.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 thediffusionpath length.The (C) is the concentration of the diffusing substance across the skin layers and the (D) is thediffusion coefficient.The expression illustrates the transportation of topical drug molecules across thestratum corneummembrane throughdiffusion.

Diffusion expression:

$J=ADC/h$

Mechanism

Upon application of the topical drug on the skin, it willdiffuseto the outer layer of the skin, known asstratum corneum.There are three routes possible for the drugs to cross the skin. The first route is through theappendages.It is known as the "first cut" where the drug molecules will bepartitionedinto thesweat glandto bypass thestratum corneumbarrier.If the drug molecules is not transported via the "first cut", it is usually remains in thestratum corneum'sbilayered lipids, where the drug molecules transport through either thetranscellularroute orparacellularroute into the deeper area of the skin like subcutaneous layer. For theparacellularroute, 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 thestratum corneum,which is a highly fat region, but between the cells.On the other hand, the topical drug molecules may travel through thetranscellularroute. This route allows molecules to be transported via the cell.Transcellularroute transports the drug molecule into the bilayered lipid cells found instratum corneum.Inside of the bilayered lipids in thestratum corneumis a water-soluble environment, and the drug molecules willdiffusethrough these bilayered lipids into deeper area of the skin.During the transportation of the topical drug molecules, it can bind to thekeratinthat exists as one of the skin components in thestratum corneum.

Skin metabolism

The activities of skinmetabolismare commonly occurring on the skin surface,appendages,thestratum corneum,and theviable epidermis.This process comprises phase onehydrolysis,reduction,andoxidation,also known as functionalization phase. If phase one is not sufficient enough to metabolize the drugs, phase twoconjugation reactionoccurs. This phase includesglucuronidation,sulfation,andacetylation.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 undergometabolismin the skin throughenzymeN-acetyltransferase,thus resulting in a N-acetylatedmetabolite.These metabolicenzymescause the loss of topical drug activities, thus reducing itsbioavailability.They may eventually form atoxic compound that reaches to thesystemic circulationand 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 metabolicenzymessaturation.

Factors affect topical absorption

The amount of topical drug molecules being delivered to the skin is affected solely by thephysicochemicalproperties of the topical drug.The first factor is the weight of the drug molecule. The smaller of the drugmolecular weightor particle size, the higher rate of itsdiffusionand absorption into the skin.The second factor is thelipophilicityof the drug molecules, since the three pathways for absorption are quitelipophilic.The higherlipophilicityof it, the easier of the drug molecules to be absorbed when compared to thehydrophilicdrug molecules.The third parameter is thepHlevel 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 systemis 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 intonanoparticles,liposomes,and nanoemugel.

Liposome

Liposome

Liposomescontain a bilayer ofphospholipidsin a sphere shape that may exist as one or more than one bilayer ofphospholipids.With this structure, its function is to traphydrophilicorlipophilicdrug molecules within the spherical bilayers.Thehydrophilicdrug molecule sticks to thehydrophilichead since it ispolarand favours water. On the other hand, thelipophilicdrug molecules will be entrapped in thephospholipidtails of the bilayer due to itslipophilicnature.With these mechanisms,liposomeswill behave like carriers and carry thelipophilicorhydrophilicdrug molecules into thestratum corneumand release them into deeper layers of the skin by interacting with the bilayers lipids found instratum corneum.The Use ofliposomeas carrier enhances the overall permeability of topical drug into the skin to reach the target site.For example, a drug likeamphotericin B,is used to treat fungal infections.The drug is loaded intoliposomeand this carrier enhances the penetration ofamphotericin Binto the skin, regardless of itsmolecular weight.

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 agelmatrix. Thegelsare 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 traditionalcreamorointment,hence there is less incident in skin irritation.Nanoemulgel increases the topical drugbioavailabilityby inserting thelipophilicdrug 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 highconcentration gradienttoward the skin, thus allowing for a rapid uptake of oil droplet into thestratum corneum.Also, thesurfactantbeing incorporated into the nanoemulgel has the ability to penetrate through the bilayer lipid by interrupting thehydrogen bondbetween 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 withmethoxsalenis used to treatpsoriasis.The carrier enhances both the penetration and accumulation ofmethoxsalenin the skin layers.

Physical Agents

Micro-needles

Micro-needles

Micro-needlebelongs 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 thestratum corneum.These tiny needles ensure that they will not contact the nerve endings orcutaneousblood 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 theviable 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 ofhydrogel.After poking its needle into the skin, it allows the skininterstitial fluiddiffuse into the micro-needles, thus it will swell todiffusethe drug molecules across the skin.It is found that micro-needles are safe and effective in enhancing skin permeability.