Topical drug delivery

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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. [1] [2] The formulation of topical drugs can be classified into corticosteroids, antibiotics, antiseptics, and anti-fungal. The mechanism of topical delivery includes the diffusion and metabolism of drugs in the skin. [1] 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 and potions were used on the skin. [3] [4] The delivery of topical drugs needs to pass through multiple skin layers and undergo pharmacokinetics, hence factor like dermal diseases minimize the bioavailability of the topical drugs. [5] 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. [4] [6] On the other hand, physical agents, like micro-needles is other approach for enhancement ofabsorption. [4] Besides using carriers, other factors such as pH, lipophilicity, and drug molecule size govern the effectiveness of topical formulation. [1]

Contents

History

Claudius Galenus Galenus of Pergamum.jpg
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. [3] Later on in 2000 BCE, the Chinese used topical remedies that wrap in bandages to treat skin diseases. [4] [3] The contact between these topical remedies and skin deliver its therapeutic 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. [3] More recently in the 1920s, some observations were made when applying topical skin, such as to determine its systemic effects. [4] In 1938, Zondek successfully managed urogenital infections after applying chloroxylenol on the skin by the use of disinfectant 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, 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. [4]

Skin absorption

Skin layers

Skin layers Labeled layers of the skin.jpg
Skin layers

The human body's largest organ is the skin layers, which protects against foreign particles. [7] [8] Human skin contains several layers, including the subcutaneous layer, the dermis, the epidermis, the stratum corneum, and the appendages. Each of these layers have an effect on the absorption of topical drug. [1] When the topical drug is applied to the skin, it must pass via the stratum corneum, which is the outermost skin layer. [8] Stratum corneum's function includes prevention of water loss in skin and inhibit the penetration of foreign molecules into the dermal layers. [8] Hence, it also prevents the hydrophilic molecules to get absorbed into the skin since it is made out of bilayered lipids. [9] With this barrier, stratum corneum 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 stratum corneum barrier via hair follicles. [5]

Diffusion

When drugs are applied to skin topically, the drug molecules will undergo passive diffusion. This process occurs down the concentration gradient when drug molecules move to one area to another region. Diffusion is described by a mathematical equation. [1] [4] The drug molecule (J), known as flux and it represents the entry of topical drug molecules across the skin membrane. 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 diffusion path length. [4] The (C) is the concentration of the diffusing substance across the skin layers and the (D) is the diffusion coefficient. The expression illustrates the transportation of topical drug molecules across the stratum corneum membrane through diffusion. [9]

Diffusion expression:

Mechanism

Upon application of the topical drug on the skin, it will diffuse to the outer layer of the skin, known as stratum corneum. 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 to bypass the stratum corneum barrier. [1] 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. [10] When the topical drug molecules transport via the paracellular route, it needs to travel across the stratum corneum, which is a highly fat region, but between the cells. [9] [1] 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 stratum corneum. Inside of the bilayered lipids in the stratum corneum is a water-soluble environment, and the drug molecules will diffuse through these bilayered lipids into deeper area of the skin. [1] [11] During the transportation of the topical drug molecules, it can bind to the keratin that exists as one of the skin components in the stratum corneum. [11]

Skin metabolism

The activities of skin metabolism are commonly occurring on the skin surface, appendages, the stratum corneum, and the viable epidermis. [1] [5] This process comprises phase one hydrolysis, reduction, and oxidation, 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, sulfation, and acetylation. It is found that phase two activities are lower than phase two in the skin. [12] One common example is thearylamine-type hair dye, after it is applied topically, it will undergo metabolism in the skin through enzyme N-acetyltransferase, thus resulting in a N-acetylated metabolite. [5] [3] These metabolic enzymes cause the loss of topical drug activities, thus reducing its bioavailability. They may eventually form atoxic compound that reaches to the systemic circulation and causes damage to the skin layers. [13] 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 enzymes saturation. [5]

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. [1] The first factor is the weight of the drug molecule. The smaller of the drug molecular weight or particle size, the higher rate of its diffusion and absorption into the skin. [1] [14] The second factor is the lipophilicity of the drug molecules, since the three pathways for absorption are quite lipophilic. The higher lipophilicity of it, the easier of the drug molecules to be absorbed when compared to the hydrophilic drug molecules. [14] 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. [14] These factors are vital to determine the permeability of topical drug delivery. [3] [1]

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. [15] [6] [16]

Liposome

Liposome Liposome.png
Liposome

Liposomes contain a bilayer of phospholipids in a sphere shape that may exist as one or more than one bilayer of phospholipids. With this structure, its function is to trap hydrophilic or lipophilic drug molecules within the spherical bilayers. [4] The hydrophilic drug molecule sticks to the hydrophilic head since it is polar and favours water. On the other hand, the lipophilic drug molecules will be entrapped in the phospholipid tails of the bilayer due to its lipophilic nature. [6] [4] With these mechanisms, liposomes will behave like carriers and carry the lipophilic or hydrophilic drug molecules into the stratum corneum and release them into deeper layers of the skin by interacting with the bilayers lipids found in stratum corneum. [15] The Use of liposome as carrier enhances the overall permeability of topical drug into the skin to reach the target site. [15] [17] For example, a drug like amphotericin B, is used to treat fungal infections. [18] The drug is loaded into liposome and this carrier enhances the penetration of amphotericin B into the skin, regardless of its molecular weight. [19]

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 matrix. The gels 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 or ointment, hence there is less incident in skin irritation. [16] Nanoemulgel increases the topical drug bioavailability 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 concentration gradient toward the skin, thus allowing for a rapid uptake of oil droplet into the stratum corneum. Also, the surfactant being incorporated into the nanoemulgel has the ability to penetrate through the bilayer lipid by interrupting the hydrogen bond between the lipid in the skin to further enhance its permeability. [16] In terms of treatment, the use of nanoemulgel is against cancer cells and useful in skin cancer. [16] Also, the formulation of nanoemulgel with methoxsalen is used to treat psoriasis. The carrier enhances both the penetration and accumulation of methoxsalen in the skin layers. [20]

Physical Agents

Micro-needles

Micro-needles Transdermal microneedles.png
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 stratum corneum. [6] [4] These tiny needles ensure that they will not contact the nerve endings or cutaneous blood vessels under the skin, hence they can be removed easily from the skin. [21] 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. [22] 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. [4] [23] It is found that micro-needles are safe and effective in enhancing skin permeability. [24]

Related Research Articles

<span class="mw-page-title-main">Phospholipid</span> Class of lipids

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. Marine phospholipids typically have omega-3 fatty acids EPA and DHA integrated as part of the phospholipid molecule. The phosphate group can be modified with simple organic molecules such as choline, ethanolamine or serine.

<span class="mw-page-title-main">Lipid bilayer</span> Membrane of two layers of lipid molecules

The lipid bilayer is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many viruses are made of a lipid bilayer, as are the nuclear membrane surrounding the cell nucleus, and membranes of the membrane-bound organelles in the cell. The lipid bilayer is the barrier that keeps ions, proteins and other molecules where they are needed and prevents them from diffusing into areas where they should not be. Lipid bilayers are ideally suited to this role, even though they are only a few nanometers in width, because they are impermeable to most water-soluble (hydrophilic) molecules. Bilayers are particularly impermeable to ions, which allows cells to regulate salt concentrations and pH by transporting ions across their membranes using proteins called ion pumps.

<span class="mw-page-title-main">Route of administration</span> Path by which a drug, fluid, poison, or other substance is taken into the body

In pharmacology and toxicology, a route of administration is the way by which a drug, fluid, poison, or other substance is taken into the body.

<span class="mw-page-title-main">Liposome</span> Composite structures made of phospholipids and may contain small amounts of other molecules

A liposome is a small artificial vesicle, spherical in shape, having at least one lipid bilayer. Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties, liposomes can be used as drug delivery vehicles for administration of pharmaceutical drugs and nutrients, such as lipid nanoparticles in mRNA vaccines, and DNA vaccines. Liposomes can be prepared by disrupting biological membranes.

<span class="mw-page-title-main">Topical medication</span> Medication applied to body surfaces

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 including creams, foams, gels, lotions, and ointments. Many topical medications are epicutaneous, meaning that they are applied directly to the skin. Topical medications may also be inhalational, such as asthma medications, or applied to the surface of tissues other than the skin, such as eye drops applied to the conjunctiva, or ear drops placed in the ear, or medications applied to the surface of a tooth. The word topical derives from Greek τοπικόςtopikos, "of a place".

<span class="mw-page-title-main">Cationic liposome</span>

Cationic liposomes are spherical structures that contain positively charged lipids. Cationic liposomes can vary in size between 40 nm and 500 nm, and they can either have one lipid bilayer (monolamellar) or multiple lipid bilayers (multilamellar). The positive charge of the phospholipids allows cationic liposomes to form complexes with negatively charged nucleic acids through ionic interactions. Upon interacting with nucleic acids, cationic liposomes form clusters of aggregated vesicles. These interactions allow cationic liposomes to condense and encapsulate various therapeutic and diagnostic agents in their aqueous compartment or in their lipid bilayer. These cationic liposome-nucleic acid complexes are also referred to as lipoplexes. Due to the overall positive charge of cationic liposomes, they interact with negatively charged cell membranes more readily than classic liposomes. This positive charge can also create some issues in vivo, such as binding to plasma proteins in the bloodstream, which leads to opsonization. These issues can be reduced by optimizing the physical and chemical properties of cationic liposomes through their lipid composition. Cationic liposomes are increasingly being researched for use as delivery vectors in gene therapy due to their capability to efficiently transfect cells. A common application for cationic liposomes is cancer drug delivery.

Sonophoresis also known as phonophoresis, is a method that utilizes ultrasound to enhance the delivery of topical medications through the stratum corneum, to the epidermis and dermis. Sonophoresis allows for the enhancement of the permeability of the skin along with other modalities, such as iontophoresis, to deliver drugs with lesser side effects. Currently, sonophoresis is used widely in transdermal drug delivery, but has potential applications in other sectors of drug delivery, such as the delivery of drugs to the eye and brain.

Skin absorption is a route by which substances can enter the body through the skin. Along with inhalation, ingestion and injection, dermal absorption is a route of exposure for toxic substances and route of administration for medication. Absorption of substances through the skin depends on a number of factors, the most important of which are concentration, duration of contact, solubility of medication, and physical condition of the skin and part of the body exposed.

<span class="mw-page-title-main">Transdermal</span> Method of drug administration

Transdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution. Examples include transdermal patches used for medicine delivery. The drug is administered in the form of a patch or ointment that delivers the drug into the circulation for systemic effect.

Corneocytes are terminally differentiated keratinocytes and compose most of the stratum corneum, the outermost layer of the epidermis. They are regularly replaced through desquamation and renewal from lower epidermal layers and are essential for its function as a skin barrier.

<span class="mw-page-title-main">Niosome</span> Non-ionic surfactant-based vesicle

Niosomes are vesicles composed of non-ionic surfactants, incorporating cholesterol as an excipient. Niosomes are utilized for drug delivery to specific sites to achieve desired therapeutic effects. Structurally, niosomes are similar to liposomes as both consist of a lipid bilayer. However, niosomes are more stable than liposomes during formation processes and storage. Niosomes trap hydrophilic and lipophilic drugs, either in an aqueous compartment or in a vesicular membrane compartment composed of lipid material.

<span class="mw-page-title-main">Solid lipid nanoparticle</span> Novel drug delivery system

Lipid nanoparticles (LNPs) are nanoparticles composed of lipids. They are a novel pharmaceutical drug delivery system, and a novel pharmaceutical formulation. LNPs as a drug delivery vehicle were first approved in 2018 for the siRNA drug Onpattro. LNPs became more widely known in late 2020, as some COVID-19 vaccines that use RNA vaccine technology coat the fragile mRNA strands with PEGylated lipid nanoparticles as their delivery vehicle.

Buccal administration is a topical route of administration by which drugs held or applied in the buccal area diffuse through the oral mucosa and enter directly into the bloodstream. Buccal administration may provide better bioavailability of some drugs and a more rapid onset of action compared to oral administration because the medication does not pass through the digestive system and thereby avoids first pass metabolism. Drug forms for buccal administration include tablets and thin films.

Nanoparticles for drug delivery to the brain is a method for transporting drug molecules across the blood–brain barrier (BBB) using nanoparticles. These drugs cross the BBB and deliver pharmaceuticals to the brain for therapeutic treatment of neurological disorders. These disorders include Parkinson's disease, Alzheimer's disease, schizophrenia, depression, and brain tumors. Part of the difficulty in finding cures for these central nervous system (CNS) disorders is that there is yet no truly efficient delivery method for drugs to cross the BBB. Antibiotics, antineoplastic agents, and a variety of CNS-active drugs, especially neuropeptides, are a few examples of molecules that cannot pass the BBB alone. With the aid of nanoparticle delivery systems, however, studies have shown that some drugs can now cross the BBB, and even exhibit lower toxicity and decrease adverse effects throughout the body. Toxicity is an important concept for pharmacology because high toxicity levels in the body could be detrimental to the patient by affecting other organs and disrupting their function. Further, the BBB is not the only physiological barrier for drug delivery to the brain. Other biological factors influence how drugs are transported throughout the body and how they target specific locations for action. Some of these pathophysiological factors include blood flow alterations, edema and increased intracranial pressure, metabolic perturbations, and altered gene expression and protein synthesis. Though there exist many obstacles that make developing a robust delivery system difficult, nanoparticles provide a promising mechanism for drug transport to the CNS.

<span class="mw-page-title-main">Ethosome</span>

Ethosomes are phospholipid nanovesicles used for dermal and transdermal delivery of molecules. Ethosomes were developed by Touitou et al.,1997, as additional novel lipid carriers composed of ethanol, phospholipids, and water. They are reported to improve the skin delivery of various drugs. Ethanol is an efficient permeation enhancer that is believed to act by affecting the intercellular region of the stratum corneum. Ethosomes are soft malleable vesicles composed mainly of phospholipids, ethanol, and water. These soft vesicles represent novel vesicles carriers for enhanced delivery through the skin. The size of the ethosomes vesicles can be modulated from tens of nanometers to microns.

<span class="mw-page-title-main">Topical cream formulation</span>

Topical cream formulation is an emulsion semisolid dosage form that is used for skin external application. Most of the topical cream formulations contain more than 20 per cent of water and volatiles and/or less than 50 per cent of hydrocarbons, waxes, or polyethylene glycols as the vehicle for external skin application. In a topical cream formulation, ingredients are dissolved or dispersed in either a water-in-oil (W/O) emulsion or an oil-in-water (O/W) emulsion. The topical cream formulation has a higher content of oily substance than gel, but a lower content of oily ingredient than ointment. Therefore, the viscosity of topical cream formulation lies between gel and ointment. The pharmacological effect of the topical cream formulation is confined to the skin surface or within the skin. Topical cream formulation penetrates through the skin by transcellular route, intercellular route, or trans-appendageal route. Topical cream formulation is used for a wide range of diseases and conditions, including atopic dermatitis (eczema), psoriasis, skin infection, acne, and wart. Excipients found in a topical cream formulation include thickeners, emulsifying agents, preservatives, antioxidants, and buffer agents. Steps required to manufacture a topical cream formulation include excipient dissolution, phase mixing, introduction of active substances, and homogenization of the product mixture.

Penetration enhancers are chemical compounds that can facilitate the penetration of active pharmaceutical ingredients (API) into or through the poorly permeable biological membranes. These compounds are used in some pharmaceutical formulations to enhance the penetration of APIs in transdermal drug delivery and transmucosal drug delivery. They typically penetrate into the biological membranes and reversibly decrease their barrier properties.

Topical gels are a topical drug delivery dosage form commonly used in cosmetics and treatments for skin diseases because of their advantages over cream and ointment. They are formed from a mixture of gelator, solvent, active drug, and other excipients, and can be classified into organogels and hydrogels. Drug formulation and preparation methods depend on the properties of the gelators, solvents, drug and excipients used.

<span class="mw-page-title-main">Intravesical drug delivery</span> Intravesical drug delivery, drug delivery to the bladder

Intravesical drug delivery is the delivery of medications directly into the bladder by urinary catheter. This method of drug delivery is used to directly target diseases of the bladder such as interstitial cystitis and bladder cancer, but currently faces obstacles such as low drug retention time due to washing out with urine and issues with the low permeability of the bladder wall itself. Due to the advantages of directly targeting the bladder, as well as the effectiveness of permeability enhancers, advances in intravesical drug carriers, and mucoadhesive, intravesical drug delivery is becoming more effective and of increased interest in the medical community.

<span class="mw-page-title-main">Invasomes</span> Transdermal drug delivery method

An invasome are a type of artificial vesicle nanocarrier that transport substances through the skin, the most superficial biological barrier. Vesicles are small particles surrounded by a lipid layer that can carry substances into and out of the cell. Artificial vesicles can be engineered to deliver drugs within the cell, with specific applications within transdermal drug delivery. However, the skin proves to be a barrier to effective penetration and delivery of drug therapies. Thus, invasomes are a new generation of vesicle with added structural components to assist with skin penetration.

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  23. ↑ Chang, Hao; Zheng, Mengjia; Yu, Xiaojun; Than, Aung; Seeni, Razina Z.; Kang, Rongjie; Tian, Jingqi; Khanh, Duong Phan; Liu, Linbo; Chen, Peng; Xu, Chenjie (2017-07-17). "A Swellable Microneedle Patch to Rapidly Extract Skin Interstitial Fluid for Timely Metabolic Analysis". Advanced Materials. 29 (37): 1702243. Bibcode:2017AdM....2902243C. doi:10.1002/adma.201702243. ISSN   0935-9648. PMID   28714117. S2CID   30791569.
  24. ↑ Liu, Ting-Ting; Chen, Kai; Wang, Qiao (2018-10-01). "Skin drug permeability and safety through a vibrating solid micro-needle system". Drug Delivery and Translational Research. 8 (5): 1025–1033. doi:10.1007/s13346-018-0544-2. ISSN   2190-3948. PMID   29858819. S2CID   46920352.
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