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. [1] [2] [3] [4] They are formed from a mixture of gelator, solvent, active drug, and other excipients, and can be classified into organogels and hydrogels. [1] [5] [6] [7] Drug formulation and preparation methods depend on the properties of the gelators, solvents, drug and excipients used. [1] [2] [5] [3] [8]
A gel refers to the semi-
solid, 3-dimensional matrix formed from an interspersed system of colloidal particles or the permeation of a solvent into an entwined polymer chain network. [1] [2] [5] [3] [8] Pharmaceutical gels are formed by adding a gelator (gelling agent) to the solvent [5] [6] and active ingredient mixture.
Gelators used in gel formulation can be small molecules with low molecular weight or polymers (synthetic, semi-synthetic or natural). [5] [7] The solvent that is used as a dispersion medium can be aqueous, organic, inorganic, or a system of different solvents. [5]
Topical gels are used as a contact or transport medium for active drugs to act on [4] or through the skin. [9] The active drug molecules are entwined into the 3D mesh of the gel and delivered to the site of action.
Gels have certain special properties that put them apart from other dosage forms, in terms of swelling, syneresis, ageing, rigidity and rheology.
Gels can be classified through a variety of criteria such as their nature of the colloidal phase, nature of the solvent used and physical nature.
This is the most widely used classification of gels. They are classified into two main groups by the nature of the solvent: organogels and hydrogels.
Organogels are not as commonly used as mediums for drugs or vaccines when compared to other gel classes. [5] This is due to the untested or pharmaceutically unacceptable solvents and gelators commonly used in organogel synthesis. [5] Organogels that are used pharmaceutically include microemulsion-based gels and lecithin gels. [5]
Some manufacturers decide to use organogels as a medium for drug delivery due to its potentially emollient effect. Some organogels contain bases composed of oleaginous substances. [1] [6] These bases can help retain skin moisture through the formation of an occlusive layer on the area of application. [1] [6] This occlusive layer traps moisture, allowing hydration of the skin and providing an emollient effect. [1] [6] [10] This emollient effect is particularly helpful in formulation of topical gels for patients with dry and irritated skin. [1]
Hydrogels have a high water content, [7] with some hydrogels containing up to 90% water. [5] Active drugs and other substances dispersed as colloids or dissolved in water can be easily taken up by hydrogels. [5] Hydrogels are biocompatible. [5] [7] They also swell to a greater volume than organogels when in contact with water and other natural liquids. [8]
Hydrogels can be used as drug delivery vehicles, for transdermal application, ophthalmic drug delivery, [11] cancer treatment [12] or for wound dressing. [7] [13]
As a type of water based formulation, hydrogels are generally less greasy and are easier to be removed than oil-based formulations like organogels. [6] Examples of hydrogels include aluminum oxide gels, and bentonite magma. [1]
Drugs administered through topical application can act locally or systemically. [1] [6] However, the drug molecules must first be retained in and penetrate the surface layer of the skin. [6]
Absorption of the drug through the skin surface is a passive process of diffusion. [1] [9] Skin penetration of the drug can take place by passive diffusion directly through the epidermis (via transcellular or intercellular routes), or absorption through shunt routes (diffusion through hair follicles and sweat glands). [1] [6] [10] Initially, drug absorption may take place via the transfolliar route. After the drug reaches a steady state, transepidermal absorption may replace transfolliar absorption as the main pathway for absorption. [1]
Drug absorption through the skin varies depending on the concentration gradient between the surface of the skin and the body, [1] [14] with a higher rate of absorption resulting from a greater concentration gradient. [6] [14] The rate of drug absorption can be maintained at a constant level by ensuring that the drug concentration at the surface of the skin remains consistently and substantially greater than that in the body. [1]
The rate of penetration of the drug across the skin barrier depends on the physiological factors, physicochemical properties of the drug, and gel characteristics. [1] [6] Physiological factors include skin properties, [3] [1] [2] size of application area, frequency and force of application. [1] [6] Physicochemical properties of the drug include drug solubility, attraction to the skin and metabolism. [3] [1] [6] [10] Gel characteristics include stability, thermodynamic activity, and occlusive properties. [3] [1] [10]
Following penetration through the skin barrier, the drug may permeate through deeper skin tissues and reach the blood capillaries in the dermis. [6] [9] It may then proceed to enter the systemic circulation for systemic effect. [1] [6] [9]
Formulation of topical gels is determined by important factors such as appearance, odor, spreadability, extrudability, viscosity, pH, texture, microbial contamination potential and bioavailability. [1] The components of the vehicle should serve to make the skin surface more penetrable to the drug. [1]
Characteristics of the gel such as consistency and viscosity are affected by formulation design. [3] Consistency and viscosity affect the adhesion and retention property of the gel, and are important in ensuring the gel is retained at the site of application and effective delivery of the drug. [3]
The ingredients in topical gel formulation can be broadly categorized into four types: gelator, solvent, drug, and excipients.
Gelators serve as stabilizers and thickeners, thickening the gel solution while simultaneously maintaining the gel’s flexible nature. [8] When dispersed through the solvent as a colloid, gelators offer a stable internal structure to the gel. [8] Gelators are usually chosen based on their affinity for the solvent and the purpose of the gel. [5] The nature of the gelators used determines the rigidity of the gel. [8]
There are many types of gelators, of which carbomers are more frequently used due to their ability to thicken gels across a wide range of pH. [8]
Gelators can be classified by polymer types, namely natural, semi-synthetic and synthetic polymers. [8]
Natural gelators include tragacanth, [6] gelatin, collagen, [4] and guar gum; semi-synthemic gelators include methylcellulose and other cellulose derivatives; [5] [8] [6] while synthetic gelators include carbomers, [6] polyvinyl alcohol, polyethylene and its copolymers. [5]
Solvents are usually chosen based on the applications of the gel. [5] They can be hydrophilic, lipophilic, or organic. [5] Individual solvents can be used alone or as a mixture. [5]
Some examples of solvents include purified water, [3] glycerin, glycols, alcohols, sucrose, toluene, and mineral oils. [5] [10]
Topical delivery is often used for drugs that are easily degraded in the GI tract, or are highly susceptible to hepatic first pass effect. [1] [2] Even if the drug has to be administered for long periods of time or can induce adverse drug reactions in parts of the body other than the target location, it can still be formulated as a topical gel. [1] [9]
There are a number of physicochemical and biological properties that determine whether a drug is suitable for being delivered topically through a gel dosage form.
Physicochemical properties:
The drug must:
Biological properties:
Excipients are materials inert to the drug, which are added into dosage forms to improve the overall quality of the dosage form. [14] Some examples include antioxidants, sweetening agents, stabilizers, dispersing agents, penetration enhancers, buffers and preservatives. [5] [3]
Penetration enhancers are excipients that can increase skin permeability. [1] [6] Many classes of excipients can be used as penetration enhancers, such as glycerin, sulfoxides and related analogues, pyrrolidines, fatty acid and ethanol, surfactants etc. [1] [6]
Buffers can be added to control the pH of aqueous or hydroalcoholic based gels. [3] [9] Examples of buffers include phosphate and citrate. [3]
Preservatives are important for their antimicrobial action, [5] [3] and are especially important in formulation of hydrogels. [5] Examples of preservatives include parabens and phenolics. [3]
Antioxidants are used to prevent gel ingredients from being oxidised. [3] When choosing the antioxidant to be used, it is important to consider the nature of the solvent. [3] Since the solvent of most gels are aqueous in nature, water-soluble antioxidants are more commonly used. [3] Some common examples include sodium metabisulphite and sodium formaldehyde sulfoxylate. [6]
Sweetening agents are only used in gels that are designed to be used in the oral cavity such as dental gels. [3] Examples include sucrose, glycerol, sorbitol and liquid glucose. [3]
The process of gel formation involves finding a balance between the concentrations of the gelator and the solvent. [5] When adding a gelator to the solvent, the mixture remains in liquid state. [5] As the concentration of the gelator increases to a certain critical concentration (gelling point), gelation occurs through swelling to form the semi-solid gel. [5] Further increasing the concentration of the gelator beyond the gelling point will increase gel viscosity. [5]
The exact gelling point varies depending on the properties of the gelator and the solvent, such as structure uniformity, molecular weight of the polymer, and flexibility of the polymer chain. [5]
Generally, gels are prepared by firstly dissolving the soluble excipients in the solvent. [5] [3] The solution is then mixed using a mechanical stirrer. [3] After that, the gelator is added slowly to the stirred mixture in order to avoid aggregation. [3] Then, the mixture is continuously stirred until the polymer dissolves and a gel gradually forms. [3] The gel is allowed to settle for one to two days before the final consistency of the gel can be reached. [5]
The exact method of preparing gels depends on the properties of the formulation ingredients.
Topical gels are commonly used as sustained release dosage forms. [5] [9] Usage of the sustained release dosage form reduces the administration of recurrent doses while maintaining serum dose levels at the therapeutic range (difference between toxic and therapeutic doses), hence improving patient compliance. [5]
Some topical gels are fast release gels, which are highly absorbent and can swell rapidly. [5] These fast release gels can be used to treat acute disorders.
Topical gels are also used as lubricants, or carriers for pharmaceutical agents. [5] They can be used as vehicles for different purposes, via different routes of administration, such as dental, dermatological [15] l, [16] [17] ophthalmic, [11] intranasal, vaginal, rectal and others. [5] [1] [2] [8]
Topical gels are commonly used in cosmetics, which include shampoos, dentifrices, skin and hair care formulations and fragrance products, [1] [2] and can be used to treat scalp inflammation. [2]
Topical gels can be used to deliver anti-inflammatory steroids to the scalp in treatment of scalp inflammations. [8]
Product | Manufacturer | Drug | Gelator | Use | Route |
---|---|---|---|---|---|
REGRANEX gel | Johnson & Johnson | Becaplermin | Sodium CMC | Treatment of diabetic neuropathic ulcers | Transdermal |
Topicort Gel | Taro | Desoximetasone | Carbomer 940 | Antipruritic | Transdermal |
Cleocin T Topical Gel | Pfizer | Clindamycin | Carbomer 934P | Treatment of acne vulgaris | Transdermal |
MetroGel Vaginal | Galderma | Metronidazole | Carbomer 934P | Treatment of bacterial vaginosis | Vaginal |
Condylox Gel | Watson | Podofilox | Hydroxypropyl cellulose | Treatment of anogenital warts | Rectal |
Examples of Commercially available topical gels. [6]
The texture of topical gels is less greasy as it contains a higher proportion of water compared with cream and ointment. [3] [1] [2] [8] These gels have an excellent spreading property and cooling effect due to solvent evaporation, and also has a higher retention time on the skin. [5] [3] [1] [2] [8] Topical gels are more stable than creams and ointments, and can adhere well to the site of application. [5] [2] They form an occlusive layer on the application site that can act as a form of protection. [5] They can be washed off easily and are nontoxic due to their unique composition and structure. [5] [2] [6] They have minimal side effects due to their localized effect. [1] Topical gels are convenient and easy to apply. [2] [6] The topical mode of action of topical gels is also non-invasive. [1] [6] These favorable factors of topical gels improve patient compliance and tolerability. [1] [2]
The formulation and manufacturing processes of topical gels are relatively simpler and more cost effective than other semisolid dosage forms. [5] [1] [8] The release profile of the gel can be modified by altering the properties of the gelator, allowing for continuous drug delivery. [1] Topical gels are also eco-friendly, biocompatible and biodegradable. [5] [8]
The drug can penetrate deeply into the skin [2] and be directly delivered to the target site, as the topical application allows it to avoid hepatic first pass metabolism. [1] [2] [8] [6] Difficulties in gastrointestinal absorption caused by pH, enzymatic activity and drug-food interactions can be minimized, while at the same time avoiding GI irritation. [1] [2] [6] The topical dosage form allows stable and continuous drug delivery to the site of application, [2] while having a faster drug release than ointments and creams. [1] All these can increase the drug’s bioavailability in the body. [2]
There may be flocculation in some gels, which may produce an unstable gel. [5] [8] The rheology of some gels are easily altered by environmental factors such as temperature and humidity, [5] resulting in stricter storage requirements. Syneresis of the gel may occur during storage, causing the gel to shrink unpredictably or even dry out. [5] [3] The gelators may precipitate and salt out, and some drugs may degrade in gel formulation due to the other ingredients present in the formulation. [5]
Some additives and gelators added into the formulation may cause irritation problems, [5] [8] such as skin irritation, dermatitis or allergic conditions. [2] The increased water content in gels increases the chances of microbial or fungal attack, [5] [8] which may contaminate the gel, making it unsuitable for use. Considering the direct route of administration, drugs must be very small in size to have an effective plasma concentration for action. The particle size and other properties of the drug may also affect its absorption through the skin barrier, [2] resulting in an unreliable effect.
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 diffuse through this system.
A hydrogel is a biphasic material, a mixture of porous, permeable solids and at least 10% by weight or volume of interstitial fluid composed completely or mainly by water. In hydrogels the porous permeable solid is a water insoluble three dimensional network of natural or synthetic polymers and a fluid, having absorbed a large amount of water or biological fluids. These properties underpin several applications, especially in the biomedical area. Many hydrogels are synthetic, but some are derived from nature. The term 'hydrogel' was coined in 1894.
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".
Excipient is a substance formulated alongside the active ingredient of a medication. Excipients serve various purposes, including long-term stabilization, bulking up solid formulations containing potent active ingredients in small amounts, or enhancing the therapeutic properties of the active ingredient in the final dosage form. They can facilitate drug absorption, reduce viscosity, or enhance solubility. Excipients can also aid in the manufacturing process by improving the handling of active substances, facilitating powder flowability, or preventing denaturation and aggregation during the expected shelf life. The selection of excipients depends on factors such as the route of administration, dosage form, and active ingredient.
Sodium polyacrylate (ACR, ASAP, or PAAS), also known as waterlock, is a sodium salt of polyacrylic acid with the chemical formula [−CH2−CH(CO2Na)−]n and has broad applications in consumer products. This super-absorbent polymer (SAP) has the ability to absorb 100 to 1000 times its mass in water. Sodium polyacrylate is an anionic polyelectrolyte with negatively charged carboxylic groups in the main chain. It is a polymer made up of chains of acrylate compounds. It contains sodium, which gives it the ability to absorb large amounts of water. When dissolved in water, it forms a thick and transparent solution due to the ionic interactions of the molecules. Sodium polyacrylate has many favorable mechanical properties. Some of these advantages include good mechanical stability, high heat resistance, and strong hydration. It has been used as an additive for food products including bread, juice, and ice cream.
Drug delivery refers to approaches, formulations, manufacturing techniques, storage systems, and technologies involved in transporting a pharmaceutical compound to its target site to achieve a desired therapeutic effect. Principles related to drug preparation, route of administration, site-specific targeting, metabolism, and toxicity are used to optimize efficacy and safety, and to improve patient convenience and compliance. Drug delivery is aimed at altering a drug's pharmacokinetics and specificity by formulating it with different excipients, drug carriers, and medical devices. There is additional emphasis on increasing the bioavailability and duration of action of a drug to improve therapeutic outcomes. Some research has also been focused on improving safety for the person administering the medication. For example, several types of microneedle patches have been developed for administering vaccines and other medications to reduce the risk of needlestick injury.
Amcinonide is a topical glucocorticoid used to treat itching, redness and swelling associated with several dermatologic conditions such as atopic dermatitis and allergic contact dermatitis. Amcinonide can also be classified as a multi-functional small molecule corticosteroid, which has been approved by the FDA and is currently marketed as an ointment, lotion, or cream. It acts as both a transcription factor for responses to glucocorticoids and modulator for other transcription factors while also regulating phospholipase A2 activity.
Dosage forms are pharmaceutical drug products in the form in which they are marketed for use, with a specific mixture of active ingredients and inactive components (excipients), in a particular configuration, and apportioned into a particular dose. For example, two products may both be amoxicillin, but one is in 500 mg capsules and another is in 250 mg chewable tablets. The term unit dose can also sometimes encompass non-reusable packaging as well, although the FDA distinguishes that by unit-dose "packaging" or "dispensing". Depending on the context, multi(ple) unit dose can refer to distinct drug products packaged together, or to a single drug product containing multiple drugs and/or doses. The term dosage form can also sometimes refer only to the pharmaceutical formulation of a drug product's constituent drug substance(s) and any blends involved, without considering matters beyond that. Because of the somewhat vague boundaries and unclear overlap of these terms and certain variants and qualifiers within the pharmaceutical industry, caution is often advisable when conversing with someone who may be unfamiliar with another person's use of the term.
Pharmaceutical formulation, in pharmaceutics, is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product. The word formulation is often used in a way that includes dosage form.
Modified-release dosage is a mechanism that delivers a drug with a delay after its administration or for a prolonged period of time or to a specific target in the body.
Thiolated polymers – designated thiomers – are functional polymers used in biotechnology product development with the intention to prolong mucosal drug residence time and to enhance absorption of drugs. The name thiomer was coined by Andreas Bernkop-Schnürch in 2000. Thiomers have thiol bearing side chains. Sulfhydryl ligands of low molecular mass are covalently bound to a polymeric backbone consisting of mainly biodegradable polymers, such as chitosan, hyaluronic acid, cellulose derivatives, pullulan, starch, gelatin, polyacrylates, cyclodextrins, or silicones.
Thin-film drug delivery uses a dissolving film or oral drug strip to administer drugs via absorption in the mouth and/or via the small intestines (enterically). A film is prepared using hydrophilic polymers that rapidly dissolves on the tongue or buccal cavity, delivering the drug to the systemic circulation via dissolution when contact with liquid is made.
Mucoadhesion describes the attractive forces between a biological material and mucus or mucous membrane. Mucous membranes adhere to epithelial surfaces such as the gastrointestinal tract (GI-tract), the vagina, the lung, the eye, etc. They are generally hydrophilic as they contain many hydrogen macromolecules due to the large amount of water within its composition. However, mucin also contains glycoproteins that enable the formation of a gel-like substance. Understanding the hydrophilic bonding and adhesion mechanisms of mucus to biological material is of utmost importance in order to produce the most efficient applications. For example, in drug delivery systems, the mucus layer must be penetrated in order to effectively transport micro- or nanosized drug particles into the body. Bioadhesion is the mechanism by which two biological materials are held together by interfacial forces. The mucoadhesive properties of polymers can be evaluated via rheological synergism studies with freshly isolated mucus, tensile studies and mucosal residence time studies. Results obtained with these in vitro methods show a high correlation with results obtained in humans.
In polymer chemistry, an organogel is a class of gel composed of an organic liquid phase within a three-dimensional, cross-linked network. Organogel networks can form in two ways. The first is classic gel network formation via polymerization. This mechanism converts a precursor solution of monomers with various reactive sites into polymeric chains that grow into a single covalently-linked network. At a critical concentration, the polymeric network becomes large enough so that on the macroscopic scale, the solution starts to exhibit gel-like physical properties: an extensive continuous solid network, no steady-state flow, and solid-like rheological properties. However, organogels that are "low molecular weight gelators" can also be designed to form gels via self-assembly. Secondary forces, such as van der Waals or hydrogen bonding, cause monomers to cluster into a non-covalently bonded network that retains organic solvent, and as the network grows, it exhibits gel-like physical properties. Both gelation mechanisms lead to gels characterized as organogels.
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.
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.
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. 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. 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. 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. 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, and drug molecule size govern the effectiveness of topical formulation.
Vitaliy Khutoryanskiy FRSC is a British and Kazakhstani scientist, a Professor of Formulation Science and a Royal Society Industry Fellow at the University of Reading. His research focuses on polymers, biomaterials, nanomaterials, drug delivery, and pharmaceutical sciences. Khutoryanskiy has published over 200 original research articles, book chapters, and reviews. His publications have attracted > 11000 citations and his current h-index is 52. He received several prestigious awards in recognition for his research in polymers, colloids and drug delivery as well as for contributions to research peer-review and mentoring of early career researchers. He holds several honorary professorship titles from different universities.
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.
An invasome is 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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