Topical Medication - Lecture Notes PDF

11. Topicals Dr Medha D Joshi Professor and Chair Department of Pharmaceutical Sciences Topical Preparations › Applied to the skin for protective or therapeutic functions – Topical: skin is the target organ › Intended for local effect › Surface activity – Transdermal: skin is NOT the...

11. Topicals Dr Medha D Joshi Professor and Chair Department of Pharmaceutical Sciences Topical Preparations › Applied to the skin for protective or therapeutic functions – Topical: skin is the target organ › Intended for local effect › Surface activity – Transdermal: skin is NOT the target organ › Systemic effect › Requires penetration into the epidermis and dermis Topical Preparations › In both cases, difficulty in: – Measuring correct dose › May require measuring device (metered pump, dosing syringe) – Maintaining contact with the skin Topical Preparations: Purposes › To achieve a local effect – E.g. – To protect injured areas from the environment – To moisturize the skin – To treat skin conditions Drug Penetration of the Skin Skin: barrier against chemical and physical attack › Largest organ of the body – Skin appendages › 1.5-4 mm in thickness and weighs › Hair follicles 3.kg in adults › Sebaceous glands › Serves as a barrier and plays roles in › Apocrine sweat glands role in temperature regulation and › Eccrine sweat glands excretion › Nails › Components: – Surface: sebum, sweat – Stratum corneum – Tissue layers: › Epidermis › Dermis (3-5 mm) › Subcutaneous layer  3 main layers 1. Epidermis 2. Dermis 3. Hypodermis: Subcutaneous fat OpenStax College, https://commons.wikimedia.org/wiki/File:501_Structure_of_the_skin.jpg Stratum corneum › Part of epidermis › Outermost dense layer › Mostly dead relatively dry cells › Rate-limiting barrier › Drug penetrates by passive diffusion › Rate of drug penetration across the stratum corneum is dependent on: – Drug concentration in the vehicle – Aqueous solubility – Partition coefficient of drug between the stratum corneum and the vehicle › Lipid component of stratum corneum is the factor responsible for low penetration of drug Three potential ports of entry for drug 1. Hair follicles 2. Sweat glands 3. Unbroken stratum corneum › The main route of penetration of drugs through the intact skin is through the stratum corneum Goals of the therapy as a function of site Systemic absorption of topical products › Unintentional systemic absorption – More likely if product is applied to broken or abraded skin or under occlusive barrier – May lead to adverse effects. Of particular concern in: › Pregnant women: drug may be transferred in the fetal blood supply › Nursing mothers: drug may be transferred in breast milk Functions of topical preparations › Protect injured areas from the environment and permit the skin to heal › Provide skin hydration or emollient effects › Convey medications to the skin for: – Local effect › The target is the surface of the skin › Systemic adverse effects are possible – Systemic effect (transdermal) Drug therapies to different skin layers › Surface: › Epidermis and dermis – Antibiotics – Anesthetics – Antiseptics – Anti-proliferatives (e.g. for psoriasis) – Protective films › Skin appendages › Stratum corneum – Acne: exfoliants, antibiotics – Moisturizers – Baldness: minoxidil – Keratolytics Desirable characteristics of topical dosage forms › The product should – Be free of grittiness – Be cosmetically elegant and aesthetically appealing to the patient – Not cause any skin irritation or sensitization › The viscosity of the formulation influences spreadability and retention on the skin surface Topical products › Advantages › Disadvantages – Localized effect – Messy – Easy to use – Unintended systemic effect Dosage form for topical route › Liquids › Solids – Solutions – Powders – Lotions – Sticks – Tinctures › Others – Collodians – Aerosols – shampoos – Foams › Semisolids – Dressings – Ointments – Tapes – Creams – Plasters – Pastes – Gels Useful definitions for this section Emollients › Agents that soothe and soften the skin – Fatty or oily agents – Increase tissue moisture content  make skin softer and more pliable – Work on stratum corneum › Examples: – Lanolin – Petrolatum – Cocoa butter – Sesame oil – Isopropyl myristate – Cetyl alcohol Humectants › Decrease the evaporation rate of water from the preparation – Hygroscopic – Used in O/W emulsion bases (creams) and lotions › Prevent the cream from drying out after application to the skin › Improve the consistency and rub-out qualities of the cream when it is applied to the skin › Prevent the formation of a crust when the cream is packaged in a jar Humectants › High concentrations, if used topically, may actually remove moisture from the skin, thereby dehydrating it › Examples: – Glycerin – Sorbitol solution – Propylene glycol – Polyethylene glycol (PEG) 300, PEG 400 Stiffening agents › Used to increase thickness or hardness of a preparation – Generally, waxes with high melting points (50-100°C) – Can raise the melting point of lower-melting point materials to an acceptable range for patient use – Excessive quantities will produce a stiff product that is difficult to spread – May be required in ointment, cream, paste, medication stick, and suppository formulations Stiffening agents › Examples: – Beeswax (white wax, yellow wax) – Paraffin – Cetyl esters wax – Fatty alcohols › Cetyl alcohol › Stearyl alcohol › Cetostearyl alcohol (50-70% stearyl, 20-35% cetyl, small quantities of other fatty alcohols) Fatty alcohols may increase the water-holding capacity of ointments Protectants › Substances that protect injured or exposed skin surfaces from harmful or annoying stimuli › Examples: – Zinc oxide – Calamine – Zinc stearate – Talc Rubefacients › Agents that cause reddening and warming of the skin – Act by increasing circulation in the area – Most rubefacient compounds can act as counter-irritants in higher doses › Example: – Camphor – Menthol – Methyl salicylate Counter-irritants › Agents that cause irritation or mild inflammation when applied to the skin – Used to relieve more deep-seated pain or discomfort in muscles or joints › Examples: – Methyl salicylate – Camphor – Menthol – Capsicum Antioxidants › Sometimes required to delay the rate of rancidification of selected ointment bases › Example: – BHT – butylated hydroxytoluene – BHA – butylated hydroxyanisole Penetration enhancers › Improve solubility of a drug in the stratum corneum – Allow drug to diffuse through skin into bloodstream more readily – Useful in transdermal preparations › Examples: – Surfactants – Propylene glycol – Polyethylene glycol – Ethanol Physical Pharmacy of semisolids Rheology & Viscosity Rheology › The science of flow properties of matter with respect to viscosity – From the Greek: › Rheo = flow › Logos = science – Studied extensively with liquid and semi-solid dosage forms and cosmetics – Can affect: › Patient acceptability › Physical stability › Bioavailability Rheology › Important in: – Ointment preparation, application, and residence time – Mixing and flowing of materials – Packaging dosage forms and cosmetics into containers – Removing dosage forms and cosmetics from containers prior to use › Pouring from bottle › Extruding from tube › Passing through syringe needle Viscosity and fluidity › Viscosity: – The resistance offered when one part of the liquid flows past another – Viscosity (""): A measure of the resistance to flow (dv/dx) in response to an applied stress or force (F/A) › Higher viscosity  greater resistance › Example: honey versus maple syrup › Fluidity: – Reciprocal of viscosity – “Thinner” liquids are more fluid Rheology Applied force (F) 𝑨𝒓𝒆𝒂 (𝑨) ; shear stress; hand; spatula ( ) 𝒅𝒗 velocity 𝒅𝒙 𝒅𝒊𝒔𝒕𝒂𝒏𝒄𝒆 ; velocity gradient; shear rate; flow Top layer dv/dx Ointment x Bottom layer Ointment tile, skin/surface Viscosity ( ) increase in force  increase flow Material Viscosity at 20oC Water 1.00 cps Units poise= Ethanol 1.19 cps cps=centipoise Olive Oil 100 cps Glycerin 400 cps Castor Oil 1000 cps Material categories based on rheology › Based on if can be described by Newton’s law of flow 1. Newtonian systems - yes 2. Non-Newtonian systems - no A. Plastic B. Pseudo-plastic C. Dilatant – Terminology: › Shear rate: – How fast the liquid will flow when a stress is applied to it › Shear stress: – Force per unit area required to bring about flow Newtonian Systems Newtonian Systems › Materials for which flow begins immediately and viscosity remains constant regardless of the shear stress or force applied to the material 𝑭 𝒅𝒗 ›  𝑨 𝒅𝒙 › › › In this case y intercept is zero 𝑭 › Increase in increase in slope i.e  𝑨 › Higher viscosity liquids require greater shearing stress to produce a certain rate of shear Newtonian Systems Rate of Shear Viscosity Shearing stress Rate of Shear Rate of shear is directly Viscosity is independent proportional to the shear of shear rate stress Images adapted by Joshi 2020 Newtonian Systems › Examples of Newtonian materials: – True solutions – Pure liquid compounds › Acetone › Glycerin › Alcohol › Water › Olive oil – Viscosity of a Newtonian liquid decreases with temperature Non-Newtonian Systems Plastic Flow Non-Newtonian Flow: › Materials for which flow does not begin immediately and/or viscosity changes in response to the shear stress or force applied › Typically, “non-pure” materials e.g. most pharmaceutical mixtures › Plastic flow – 1) flow does not begin until a particular shear stress (yield stress) is achieved; 2) however, once flow begins, it behaves in a Newtonian fashion › common w/physical interactions between molecules/particles in semi-solids 𝑭 𝒅𝒗 ›  𝑨 𝒅𝒙 › In this case y intercept is NOT zero 𝑭 › Increase in increase in slope i.e  but Force applied but no flow 𝑨 Force applied but no flow after y intercept is met  Plastic Systems Rate of Shear Viscosity Shearing Stress Rate of Shear Images adapted by Joshi 2020 Plastic Systems › Plastic materials do not flow until a certain shearing stress (the yield value) is achieved › The curve: – Does not begin at the origin – Is nonlinear at low shear stress – Looks like a Newtonian curve after the yield value has been exceeded Plastic Systems › Examples: – Tomato Ketchup › Doesn’t pour until shaken › After shaking, contacts between adjacent particles are broken › Flow can then occur – Concentrated suspensions › If suspending fluid is very viscous › If particles are flocculated – Large and “fluffy” – Will be discussed in greater depth during suspensions lecture Non-Newtonian Systems Pseudo-plastic Flow Pseudoplastic flow › like Newtonian, flow begins immediately however, as the shear stress increases, viscosity decreases (i.e. shear-thinning) › common w/ polymers e.g. starch › In this case y intercept is zero 𝑭 › Increase in decrease in slope i.e  𝑨 Apply force Polymers untangle; Upon sitting polymers decrease in viscosity become entangled; increase in viscosity Pseudo-plastic Systems › Viscosity decreases with increasing shear rate – Shake bottle harder  › Liquid becomes less viscous › Pours from bottle more easily › The curve: – Begins at the origin › Flow begins as soon as shearing stress is applied – Is completely nonlinear › Cannot express viscosity by a single value  Pseudoplastic Systems Rate of Shear Viscosity Shearing Stress Rate of Shear Images adapted by Joshi 2020  Pseudo-plastic Systems › Examples: – Long-chain polymers in solution › Methylcellulose › Tragacanth – Paints At rest – Emulsions In shear field Images adapted by Nagel 2015 Non-Newtonian Systems Dilatant Flow  Dilatant flow › like Newtonian, flow begins immediately; however, as the shear stress increases, viscosity increases (i.e. shear-thickening) › not common, may occur with a high % of solid particles in semi- solids › Applied force causes increased interaction in mixtures › In this case y intercept is zero 𝑭 › Increase in increase in slope i.e  𝑨  Dilatant Systems Rate of Shear Viscosity Shearing Stress Rate of Shear Images adapted by Langan 2015 Dilatant Systems › Reverse process of pseudo-plastic flow – Viscosity increases with increased shear rate – Stir or shake harder  › Liquid becomes more viscous › More difficult to stir › Can cause equipment overload and damage in manufacturing settings – Process is reversible Dilatant Systems › Examples: – Concentrated suspensions – Zinc oxide paste (50% solids) – Wet granulation masses (a tableting process) Summary › Flow Behavior/Rheology – Newtonian – Non-Newtonian › Plastic › Pseudoplastic Non-Newtonian › Dialatant Newtonian Plastic Pseudoplastic Dialatant Thixotropy Thixotropy › Materials that exhibit a particular flow behavior as shear stress is increased, but exhibit a different behavior once the shear stress is decreased › A phenomenon explaining that when at rest, the liquid has high viscosity, and when stress is applied, the material will have relatively higher flowability – Reversible gel-to-sol transformation › Examples: – Bentonite magma – Aluminum hydroxide gel – Paint – Ketchup – Time-dependent non-Newtonian behavior – Applicable to shear-thinning systems Thixotropy › Desirable property if liquid: – Should have a high consistency in the container – Pour or spread easily › Especially useful when making suspensions and emulsions – Viscous in container, so low sedimentation of suspended particles or liquid droplets – Shake, then pour  liquid flows more easily – Once movement of liquid stops, it can become viscous again Thixotropic Flow pseudoplastic Newtonian pseudoplastic Practice Problem Which of the following plots best represents pseudoplastic flow?.– LO 2 a. b. c. d. e F/A F/A F/A F/A F/A dv/dx dv/dx dv/dx dv/dx dv/dx Ointments and creams › Topical dosage forms includes solids, semisolids and liquids › Ointments are semisolid preparations intended for external application to the skin or mucus membranes; usually but not always, they contain a medicinal substance › Ointment bases are generally classified according to their interaction with water Classification of Ointment Bases Selection of bases › Ointments (and other semisolid preparations included in this section) typically contain medicinal substances › Must match ointment base to the drug being incorporated and the intended use of the product – May be used for their physical effects (protectant, emollient, lubricant) or simply as a vehicle Ideal ointment base › Should be: – Non-irritating – Easily removable – Non-staining – Stable – Non-pH-dependent – Compatible with a variety of drugs › Must permit diffusion of the drug › Ointment bases for ophthalmic use should have a softening point close to body temperature Types of ointment bases USP classification 1. Hydrocarbon (oleaginous) bases 2. Absorption bases a. Anhydrous b. W/O emulsions 3. Water-removable or emulsion bases 4. Water-soluble bases 1. Hydrocarbon /Oleaginous › Insoluble in water › Anhydrous › They will not absorb any water › Emollient effect › Protect against escape of moisture › Effective occlusive dressings; prolonged contact with skin › Can remain on skin for prolonged periods of time without drying out › Hydrophobic / greasy – Difficult to wash off (non-water washable) – Difficult to incorporate aqueous ingredients › When powdered substances are incorporated, mineral oil may be used as levigating agent Examples: 1. Hydrocarbon bases › Petrolatum USP – Yellow petrolatum, petroleum jelly, Vaseline® – Semisolid hydrocarbons obtained from petroleum – Color varies from yellowish to amber – Melts at 38°C to 60°C › White petrolatum USP – White Vaseline® – Purified and decolorized petrolatum Examples: 1. Hydrocarbon bases › Yellow ointment USP – Contains petrolatum and beeswax in the ratio of 95:5 › White ointment USP – Contains white petrolatum and bleached beeswax in the ratio of 95:5 2. Absorption bases › Two types: a) Anhydrous b) W/O emulsion › Ability to absorb water – Useful for incorporating small volumes of aqueous solutions into hydrocarbon bases › Emollient, greasy, not easily water washable › Less occlusive than oleaginous bases › Not easily removed with washing – Oil is the external phase 2a. Anhydrous Absorption Bases › Sometimes called emulsifiable bases – Oleaginous base + W/O emulsifier › Permit the incorporation of aqueous solutions – Form W/O emulsions – Do not initially contain water! – Are not emulsions, but can become emulsions on addition of water and agitation 2a. Anhydrous Absorption Bases › Examples: – Hydrophilic petrolatum USP › Composed of cholesterol, stearyl alcohol, white wax and white petrolatum – Aquaphor original ointment® › Refined variation of hydrophilic petrolatum › Has ability to absorb 3 times its weight of water – Anhydrous lanolin USP › Obtained from sheep wool › Problems: allergic reactions, rancidity 2b. W/O emulsion absorption bases › Are w/o semisolid emulsions › Oils is continuous phase, still occlusive but less compared to anhydrous and hydrocarbon › Already contain some water! – Permit the incorporation of additional quantities of aqueous solutions, but…. – Cannot incorporate as much additional water as the comparable anhydrous absorption base – E.g. Anhydrous lanolin can incorporate more aqueous solution than hydrous lanolin › Still greasy and still not water washable, but generally more pleasant than absorption bases 2b. W/O emulsion absorption bases › Examples: – Cold cream USP › Prepared with cetyl esters wax, white wax, mineral oil, sodium borate and purified water › About 75% oil (external phase) and 19% water (internal phase) – Hydrous lanolin › 25-30% water › Problems: allergic reactions, rancidity – Eucerin original healing rich creme® – Nivea creme® Comparing Absorption Bases ANHYDROUS LANOLIN HYDROUS LANOLIN 3. Water-removable bases › O/W emulsions – Water-washable, as water is the external phase – Can be diluted with water (to form lotion) – Has ability to absorb serous discharges › Creamy appearance › Non-greasy › Non-occlusive › Aqueous phase contains preservatives › AKA creams 3. Water-removable bases › Upon application water evaporates and application shrinks to a thin film › Under optimal conditions, the drug concentrates without crystallizing out › Thin film can be continuous but not oleaginous so it will be less occlusive than oily ointments › Less protective and less emollient than oily ointments › Emolliency can be enhanced by moisturizers › Most acceptable by patients 3. Water-removable bases › Examples: – Hydrophilic ointment USP – Vanishing cream – Velvachol® – Unibase® – Dermabase® – Lubriderm® 4. Water-soluble bases › Do not contain oleaginous compounds › Usually anhydrous – Addition of water softens them greatly › Cannot effectively add large amounts › Completely water-washable › Non-greasy › Non-occlusive › No emollient properties › Can be irritating › Mostly used for incorporation of solids › Example: – Polyethylene Glycol Ointment NF Summary of some key ointment base characteristics Hydrocarbon Absorption W/O Emulsion O/W Emulsion Water- Gels soluble Greasy Feeling (less pt compliance) +++ +++ ++ + - - Emollient / Protective / +++ +++ ++ + - - Lubricating Difficult to Wash Off +++ +++ ++ + - - (less pt compliance) Absorbs Water + + (too much - +++ (near zero ++ + will dissolve max) base) Occlusive +++ + ++ + -- - Selection of an Appropriate Ointment Base Criteria for selecting an ointment base › Desired rate of drug release from the base – Drug dissolves in base  slower release – Drug is suspended in base  faster release › Site of drug action (local versus systemic) – Does the base enhance absorption through the skin? › Short- and long-term stability of the drug in the base › Influence of the drug on the consistency and other properties of the base. › Patient factors (dry versus wet skin) › Is moisture occlusion desired? › Is ability to remove with water desired? Classification based on skin penetration Base Type Skin Penetration Example Base Epidermic None or very little Oleaginous Endodermic Into the dermis Absorption Diadermic Into and through the Water-removable, skin water-soluble  Penetration Enhancers Chemical classification Examples › Improve the solubility Alcohols Ethanol, Propanol, Octanol of the drug in the Fatty alcohols Myristyl alcohol, cetyl alcohol, stearyl alcohol stratum corneum Fatty acids Myristic acid, stearic acid, oleic acid – Drug diffuses through skin into bloodstream Fatty acid esters Isopropyl myristate, isopropyl palmitate more easily Sugar alcohols Propylene glycol, polyethylene glycol, glycerol Anionic surfactants Sodium lauryl sulfate Cationic surfactants Benzalkonium chloride, cetylpyridinium chloride Amphoteric surfactants Lecithins Nonionic surfactants Spans®, Tweens®, poloxymers, Miglyol® Adapted from Allen LV Jr. Compounding Dermatological Products. Int J Pharm Compounding. 2:260-264, 1998. Practice Question Which of the following classes of bases would be expected to have the most emollient and occlusive nature? LO 3 – a. Hydrocarbon bases – b. Absorption base – c. O/W Emulsion base – d. Water-soluble bases – e. Gel bases Preparation of Ointment Bases Preparation › Two methods – Fusion – Incorporation Fusion › Heat and mix all ingredients while stirring › Melt material with highest melting point first › Components not melted are added to the congealing mixture as it is being cooled and stirred: – As a solution, or – As an insoluble powder levigated with a portion of the base Fusion › Method is primarily used to prepare the ointment base itself › Cannot use this method with ingredients that are: – Heat sensitive – Volatile Fusion › Equipment – Small scale: Porcelain dish or glass beaker – Ointments may be further manipulated after congealing to ensure uniform texture, by: › triturating in a mortar and pestle › rubbing with a spatula on an ointment tile › running through an ointment mill Incorporation › Components are mixed by various means until a uniform mixture has been obtained – Mortar and pestle – Ointment tile and spatula – Ointment pad – Kitchen mixer – Plastic bag › This method should not be used when reactive components are used Incorporation – Industrially, and in large scale compounding: › All three products thoroughly homogenize ingredients – Ointment mill most effective in dramatically reducing particle size / may be required if highly concentrated topical of 10% or more to reduce grittiness – Unguator® works quickly, reduces cross-contamination and limits exposure to harmful chemicals › Ointment mill › Unguator® › Homogenizer Ointment mill Unguator® Homogenizer  http://pharmlabs.unc.edu/labs/emulsions/images/homog.jpg http://exaktusa.com/wp-content/uploads/process.png http://www.concepfarma.com/images/unguator_manual.jpg http://www.labotal.co.il/Upload/catalogImages/KI_PT1200E.jpg  Incorporation - Equipment › Mortar and pestle – Easy to clean – May be used for particle size reduction in addition to mixing Evan-Amos https://commons.wikimedia.org/wiki/File:White-Mortar-and-Pestle.jpg Incorporation - Equipment › Ointment tile and spatula – Easy to clean – May be used for particle size reduction in addition to mixing › Ointment pad – Made of parchment paper – May absorb moisture and tear unless work quickly – Disposable  easy cleanup  Incorporation - Equipment › Kitchen mixer – Useful for large-scale batches – Frequently used in pharmacies that do lots of compounding Aaron Headly, https://commons.wikimedia.org/wiki/File:Purple_KitchenAid_M ixer_in_motion.jpg Incorporation - Equipment › Zip-top bag – Disposable  easy cleanup – Cut hole in corner of bag to pipe product directly into jar or tube Incorporation – Two Methods › Levigation › Dissolution Levigation › Levigating agent: – Used to reduce particle size and to incorporate solids easily – Usually a viscous liquid; works as a lubricating agent – Usually not more than 5% of the total product weight Levigation › Do you need a levigating agent? › Not used if: 1. The solid being incorporated has a very fine particle size 2. The quantity of solid to incorporate is small 3. The ointment base is soft 4. The final product is to be a stiff ointment or paste › Levigating agent may soften product Levigation › What levigating agent do you select? › Should be: – Non-sensitizing – Non-allergenic (use lanolin with caution) – Non-volatile › Volatile solvent will evaporate while levigating and leave crystals of drug behind – Use the minimum amount necessary – Document the agent and the amount used Levigation › If a liquid is already in the formula, check if it can used – Is your solid soluble and stable in it? › If so, use it, and incorporation by dissolution instead – If your solid is not soluble in it, would it be an appropriate levigating agent? Levigation › Levigating agents are chosen so that they are compatible with the base – W/O emulsion base: › Do not use Tween 80 › Forms O/W emulsion › May cause phase inversion if added to W/O emulsion – Mineral oil bases (petrolatum, etc.) › Do not use castor oil › Incompatible with base Levigation › Assuming no incompatibilities, chose levigating agent chemically similar to ointment base – Petrolatum  use mineral oil – O/W base  glycerin, PEG, propylene glycol – See chart on next slide for further details on selection  Levigating Agents Ointment Bases Mineral oil Oleaginous bases Absorption or Emulsifiable Bases W/O Emulsion Bases PEG 400 O/W Emulsion Bases Glycerin Water-soluble Bases Propylene glycol Special levigating agents for certain drugs Agent Drug Tween 80 Coal Tar Castor Oil Peruvian Balsam Glycerin, fixed oils, or Aquaphor® Ichthammol Dissolution › Soluble solids may be dissolved in a compatible solvent and then added to the base › Useful method when difficult to grind solids are to be included in the ointment base – Urea – Camphor – Testosterone esters Dissolution › What solvents do you use? – Water-miscible solvents › Water › Alcohol › Isopropyl alcohol › Glycerin › Propylene glycol › PEG 300 or 400 – Lipophilic solvents › Mineral oil › Fixed oils (castor, cottonseed, olive and corn) Dissolution › How do you select? – Use references for solubility information – If a liquid ingredient is already in the formula, check if it can be used – Use a minimum amount of solvent › Measure the amount of solvent to be used › Subtract that amount from the total amount of the ointment base that is to be used › You must document the amount and type of solvent – Check compatibility of the solvent with ointment base and other ingredients Dissolution Solvents that can be incorporated › Hydrocarbon bases › W/O emulsion bases – Oil – Oil – Limited amounts of – Moderate amounts of water alcohol – Depends on emulsifier used › Anhydrous ointment › O/W emulsion bases bases – Limited amounts of oil – Oil – Small amounts of water – Large amounts of water – Depends on the emulsifier – Limited amounts of used alcohol Dissolution Solvents that can be incorporated › What if you need to incorporate an aqueous solution into a hydrophobic base? – Not a problem if an absorption base › Anhydrous can incorporate fairly large amounts › W/O emulsion bases can incorporate at least some additional water – Hydrocarbon base? › Ideally, switch to a W/O emulsion base or an absorption base › Can incorporate the aqueous solution in a minimum amount of a hydrophilic base, then mix the hydrophilic base with the hydrophobic base General guidelines for incorporating active ingredients Suggested Bases and Method › Water soluble ingredients – Dissolve the ingredients in water – Incorporate the solution into water-miscible base: › Absorption bases (anhydrous or W/O emulsion) › O/W emulsion › Water soluble base Suggested Bases and Method › Alcohol soluble ingredients – Dissolve the ingredients in alcohol – Incorporate the solution into water-miscible base: › Absorption base › Water miscible base (O/W or W/O emulsion) – High amounts of alcohol may break down the emulsion bases › Water soluble base Suggested Bases and Method › Hydroalcoholic solutions – Incorporate the solution into water-miscible base: › Absorption base › Water miscible base (O/W or W/O emulsion) – High amounts of alcohol may break down the emulsion bases › Water soluble base – Or, use one of the above bases as a levigating agent and incorporate into a hydrocarbon base Suggested Bases and Method › Ingredients that are soluble in other water-miscible solvents – Dissolve in appropriate solvent › Isopropyl alcohol › Propylene glycol › Glycerin › PEG 300 or 400 – Incorporate solution into water-miscible base Suggested Bases and Method › Ingredients that are soluble in lipophilic solvents – Dissolve in or levigate with appropriate agent › Mineral oil › Castor oil – Does not incorporate well into petrolatum / mineral oil bases › Cottonseed oil › Olive oil › Corn oil See previous table for specific examples – Incorporate into oil-miscible base Suggested Bases and Method › Eutectic mixtures – Triturate ingredients to form eutectic mixture – Incorporate into appropriate base – Levigating agent may be required to facilitate incorporation Note: › If aqueous / alcoholic solutions are to be added to a base that will not absorb water, then: 1. Change the base (either whole or part) › Remember that the prescriber’s permission is required for any base change 2. Add small amounts of emulsifier to a hydrocarbon base 3. Add stearyl alcohol or cetyl alcohol to water-soluble PEG bases to improve water or alcohol absorption Preservation of Ointments Preservation of ointments › Ophthalmic ointments must pass USP sterility test › Other ointments must meet acceptable standards for microbial content › Preparations which are prone to microbial growth must be preserved with antimicrobial preservatives: – Parabens – Phenols – Benzoic acid – Sorbic acid – Quaternary ammonium salts (benzalkonium chloride) Preservation of ointments › Must control the presence of microorganisms with high capacity to infect the skin – Ability of skin to resist bacteria often already compromised in patients being treated for skin conditions – Examples: › Pseudomonas aeruginosa › Staphylococcus aureus Preservation of ointments › Some preparations encourage microbial growth, while others discourage it – Parabens and benzoic acid are highly lipophilic › May partition into oil phase of ointment › Higher concentration of preservative may be needed Preservation of ointments › Preparations which contain water support microbial growth to a greater extent than those without water – BUD guidelines: › Non-preserved aqueous: 14 days refrigerated › Preserved aqueous: 35 days room temp or refrigerated › “Low water activity”(nonaqueous): 90 days room temp or refrigerated › “Solids” (tablets, capsules, powders, granules): 180 days room temp or refrigerated Stability Chemical Stability › PEG bases may – 1) facilitate drug oxidation and – 2) react with dispensing containers made using polystyrene Microbial Stability › Those bases containing a significant amount of water have a greater risk of microbial growth › And, this is especially a concern since these products are commonly applied to “compromised” skin › Preservatives (e.g. benzyl alcohol) may be used to prevent excessive microbial growth Physical Stability 1. Drying: – Bases containing water may dry out through evaporation – Humectants (e.g. glycerin and sorbitol) may be used to prevent water loss – Humectants are typically hygroscopic 2. Bleeding: – Separation of liquid and semi-solid ingredients – Most common with emulsion bases – consist of very dissimilar components Performance Performance › In most cases, drug should either be retained within (topical delivery) or pass through (transdermal delivery) the site of application › 1 2 – Where, – Km = permeability constant – S = surface area of dosage form – C1 = conc. in ointment product – C2 = conc. in skin – (C1 – C2) = concentration gradient › increasing residence time (t) will increase amount absorbed Performance › Increase dC/dt by: – Increase in S: decrease particle size / increase application area – Increase in C1: may add more drug to the product – Increase Km › D = diffusion coefficient ›  = membrane thickness › k = partition coefficient – Increase D: lower MW drug / increased temperature › may occur due to occlusion › also bandages / plastic wraps – Decrease depends upon application site & skin condition ( ) – Increase K: by occlusion ( ) Packaging Packaging › Ointment Jars 1) Ointments are packed toward the bottom and along the sides to avoid trapping air 2) The jar should be appropriately sized so that it appears full 3) No ointment should be on the outside of the jar or on the inside of the lid › Ointment Tubes 1) Provide greater administration convenience / cleanliness 2) While offering greater protection from external conditions / contamination 3) But are more difficult to fill Classification of Dermatologicals Classification of dermatologicals › Semisolids › Gels › Liquids › Solids › Aerosols Topical Semisolids Ointments › Semisolid preparations intended for external application to skin or mucous membranes › Typically used as: – Emollients to make the skin more pliable – Protective barriers to prevent harmful substances from coming in contact with the skin – Vehicles in which medications are incorporated › Should soften, but not necessarily melt, at body temperature, and spread easily › Should not be gritty Ointments › Prepared from hydrocarbon or anhydrous absorption bases – Preferred for dry, scaly lesions – Less drying than creams Creams › O/W or W/O emulsion bases › Creams are opaque; ointments are translucent › Creams are generally more fluid than ointments and pastes Creams › Pharmaceutical manufacturers frequently make topical preparations of a drug in both ointment and cream – Patients tend to favor creams over ointments › Easier to spread › Less greasy › Easier to remove – W/O creams: cold creams, emollients – O/W creams: vanishing cream, shaving creams, foundation creams Creams › Term is often applied to soft, cosmetically acceptable types of preparations – Used as emollients or for medicated application to skin – Have drying effect on moist, weeping lesions › Fluids are miscible with their aqueous phase and are absorbed by the cream – Useful on chafed areas, where the occlusive effects of ointments may cause folliculitis and maceration by trapping moisture against the skin Pastes › Semisolid preparations containing greater than 20% solids › Base is usually petrolatum › E.g. of powders zinc oxide, talc, starch, bentonite, aluminum oxide, titanium oxide › In comparison to ointments, pastes are – Stiffer – More difficult to remove from the skin – Remain in place for a longer time – Less greasy › High solid content means proportionally lower amount of oleaginous ingredients than ointment Pastes › Presence of high powder component changes the ointment base – Usually less greasy – Less occlusive – Absorptive – Generally, more protective – Can be more stiff and this more difficult to apply › Without water they are fairly stable Pastes › Bases used: – Fatty bases › Most common › Petrolatum is frequently used – Aqueous bases › Relatively uncommon › Single-phase aqueous gels such as carboxymethylcellulose sodium › Polyethylene glycol Pastes › Are reasonably absorptive – Suited for application on and around moist lesions › Heavy consistency imparts a degree of protection – A thick layer of material can protect the tissue from mechanical, chemical or light damage – In some instances, pastes may obviate the need for bandages › Diaper rash products are often pastes – Protects skin – Absorbs moisture Pastes › Not suitable for application to hairy parts of the body – Stiff – Impenetrable › Examples: – Diaper rash products – Zinc Oxide Paste (Lassar’s Paste) › 25% zinc oxide › 25% starch › 50% white petrolatum Paste Preparation › Same methodology as ointment preparation – If levigation is needed, a portion of the base is often used rather than a liquid › Adding a liquid levigating agent such as mineral oil would dilute and soften the paste › Melting a portion of the ointment base instead would allow the paste to remain thick, as the base will resolidify on standing – Fusion › Easiest method of preparing pastes › The product must be stirred thoroughly during the cooling process to prevent settling Plasters › Solid or semisolid adhesive masses spread upon a backing material of paper, fabric, moleskin, or plastic – Adhesive is rubber or synthetic resin – Provide prolonged contact at site of application Plasters › Medicated plasters – Provide effects at the site › Non-medicated plasters of action – Provide protection or – May be cut to size to mechanical support at the conform to the surface site of application being covered – Adhesive tape was formerly – Example: known as “adhesive plaster” › Salicylic acid plaster for corn removal Glycerogelatins › Plastic masses containing: – Gelatin (15%) – Glycerin (40%) – Water (35%) – Medicinal substance (10%), often zinc oxide › Intended for long-term application to the skin › Melted before application – Cooled to slightly above body temperature – Applied with a brush Glycerogelatins › After the glycerogelatin hardens: – Covered with bandage – Remains in place for a period of weeks › Example: – Zinc Gelatin › Was used in treatment of varicose ulcers › Known as the “zinc gelatin boot” due to its ability to form a pressure bandage › Now, the Unna Boot more commonly contains zinc oxide paste instead Gels › Semisolid systems in which liquid phase is constrained within interlocked, polymeric matrix of a natural or synthetic gum › Semisolid systems consisting of dispersions made up of: – Large organic molecules interpenetrated by a liquid: single-phase gels › Clear – preferred by patients (clarity and “sparkle”) › Examples: any number of pharmaceutical and cosmetic preparations – Small, inorganic particles suspended in a liquid: two-phase gels › Turbid › Example: calamine lotion (a suspension), thickened with bentonite magma (a gel)  Other gel classifications Hydrogels Organogels › Gels in which the ingredients are › Ingredients are generally lipophilic soluble or dispersible in water – Hydrocarbons: petrolatum – Organic hydrogels: pectin, tragacanth – Animal, vegetable fat: lard, cocoa – Natural and synthetic polymers: butter methylcellulose, pluronic, Na-CMC – Hydrophilic organogels contain PEG – Inorganic hydrogels: bentonite ointment, which is water-washable magma Gels › Colloidal dispersions › Should maintain viscosity and character over a wide range of temperatures › Most are: – Water-washable – Water soluble – Water absorbing – Greaseless Gel Formulation Considerations › Natural gums gel on cooling › Inorganic salts compete with water in gel and cause gelation at lower concentrations › Alcohol lowers the dielectric constant of the media and may cause separation, precipitation, or gelation › Appropriate preservatives are needed in aqueous gels Commonly used polymers in topical gels › Poloxamer (Pluronic) › Carbomers (Carbopol) › Methylcellulose – E.g. methylcellulose 400, 1500, or 4000 – Number specifications are for viscosity (in cps) of a 2% (w/v) solution at 25°C › Polyethylene glycol (PEG) – E.g. PEG 400, 1500, 3350 – Number specification designates the average molecular weight of the polymer Poloxamer Gels (Pluronic) › Polyoxyethylene-polyoxypropylene copolymer – Letter specification denotes physical appearance (L-Liquid, P-Paste and F-Flake) – Number designation relates to molecular mass of propylene oxide and percentage of ethylene oxide Poloxamer Gels (Pluronic) › Widely used as a vehicle in extemporaneous compounding – Exhibits thermoreversible properties › Liquid when refrigerated › Solid when at body temperature › Why might this be advantageous? – Inclusion of lecithin and isopropyl palmitate (LIPS) enhances drug absorption from poloxymer gel Carbomer gels (Carbopol) › Synthetic water-soluble acrylic acid polymers › Anionic in nature – Due to –COOH groups › Aqueous solution has a pH between 2.8-3.2 › Different varieties of carbomer are available – 910 NF, 934P NF, etc. – Number specification designates the “grade” of Carbopol – Have variation in rheology, viscosity, clarity, electrolyte tolerance Carbomer gels › Why use carbomers? – Produce hydrogels with the greatest viscosity / unit concentration › 0.2% produces a good gel in water › A slightly higher concentration of carbomer is required if alcohol / water systems are being used – Carbopol gels have high viscosity on standing › When applied to skin, they collapse and are very easy to spread Why do carbomers gels? › Carbomer in water (before pH adjustment) – Molecule is hydrated – pH is low (about 3) › Viscosity is low › After addition of base – The –COOH group becomes ionized and acquires a negative charge – Molecule becomes uncoiled – Increases viscosity of gel (polymer is taking up more space; molecules tangle with neighboring molecules) Topical administration of gels › Advantages – High degree of clarity – Ease of application and removal – Often provide faster drug release when compared to ointments and creams – Non-comedogenic Topical and other non-oral administration of gels › Examples: – Products used to treat acne vulgaris › Retin-A® (tretinoin) › Desquam-X® (benzoyl peroxide) › Cleocin T® (clindamycin) – Regranex® (becaplermin): treatment of diabetic ulcers – NaCl gel: for electrocardiogram – Purell® and other hand sanitizers – Topical anti-itch products › Benadryl Clear® and generics – Uroject®: lubricant for catheters Topical Liquids Liquids › Solutions and tinctures › Suspensions › Emulsions – Lotions › Liniments › Collodions Liquids › Wider selection of vehicles than those used for oral delivery › Why? Possible vehicles › Examples: – Propylene glycol – Polyethylene glycol – Isopropyl alcohol – Anhydrous ethanol – Acetone – Isopropyl palmitate Liquid Dermatological Preparations Lotions › Fluid suspensions or emulsions (usually O/W) for external application › Continuous phase is aqueous › Are less viscous than creams or ointments – Often used for application to the scalp – Many medicated shampoos are lotions › Advantage: can spread thinly – May economically cover a large area of skin › Are designed to be applied to the skin without friction › Water washable, non greasy, easy to apply Lotions › Have a lubricating effect and are thus often applied to intertriginous areas – Areas where the skin rubs together, such as between fingers or thighs or under the arms › May contain: – Alcohol › Evaporates quickly, imparts a cooling effect (e.g. in salicylic acid lotion) – Humectants › Help to retain moisture on the skin after product is applied Lotion › Examples – Calamine lotion – Clotrimazole lotion – Selenium sulfide lotion – Cetaphil lotion Liniments › Alcoholic or oleaginous solutions or emulsions intended to be rubbed on the skin with friction – May be liquid or semisolid › Require external use only label › Should be stored in tight containers – Many contain alcohol and/or volatile oils › May require shake well label – If an emulsion, or if contains insoluble ingredients Liniments › Are applied primarily to provide temporary relief from pain › Not applied to skin areas that are broken or bruised – Excessive irritation might result › Examples: – Absorbine Jr. (now referred to as Liquid) – Tiger Liniment – Various massage oils Alcoholic or hydroalcoholic liniments › Penetrate the skin more readily than oil-containing liniments › Potentially useful effects: – Rubefacient – Counter-irritant – Mild astringent Oleaginous Liniments › Are employed primarily when massage is desired › Are less irritating to the skin › May be used as emollients and protective coatings › Contain: – Fixed oils: › Almond, peanut, sesame, jojoba or cottonseed – Volatile oils › Oil of wintergreen, turpentine – Combination of fixed and volatile Collodions › Liquid preparations composed of: –Pyroxylin (4% w/v), a cotton derivative dissolved in a solvent mixture of alcohol:ether (1:3) –Active ingredient (optional) Collodions – Pyroxylin (soluble gun cotton) › Made by the action of a mixture of nitric and sulfuric acids on cotton › Consists mostly of cellulose tetranitrate – Extremely flammable and volatile – Early motion picture film also contained cellulose nitrate (now use the much safer acetate) › “External use only” label › Dispensed in tightly closed glass container › Applied to the skin with a brush or glass applicator Collodions › Form occlusive protective film on the surface of the skin following evaporation of the solvent › Collodion holds edges of incised wounds together › Inflexible, so uncomfortable on the skin – FYI: Also used in theatrical makeup; shrinks as solvent evaporates, causing skin to wrinkle (used to simulate old age or scars) Collodions Disadvantages: Extremely flammable and volatile Uncomfortable because of inflexible nature Can be extemporaneously compounded, but safety of the compounding pharmacist is a concern Ether was used in the past as a general anesthetic! Collodions › Flexible collodion – Often used over bandages or stitched incisions to make them waterproof and to protect them from external stress – Contains: › 2% camphor – Makes product waterproof › 3% castor oil – Makes product flexible – More comfortable to use, esp. on fingers and toes Collodions › Salicylic acid collodion –10% salicylic acid in flexible collodion –Keratolytic effect; application directly on corn or wart Topical Solids Solid preparations › Types: – Dusting powders – Aerosol powders – Sticks (border between solid and semisolid) › Convenient means of application › Less messy – Avoid use of fingertips › More expensive packaging (aerosols) › Can be difficult to apply to small areas Dusting powders / aerosol powders › Examples: – Anti-infectives: › Athlete’s foot powders – Dusting powder and spray versions › Betadine® (povidone-iodine) spray Sticks › Convenient, portable dosage forms which allow topical medication to be applied directly to the affected areas of the body › Used for cosmetic and medicinal purposes › Easily compounded – Melt base – Incorporate drug – Pour in tube – Allow to solidify Sticks › Should – Spread easily – Be uniform, stable, and free from mottling › Should not: – Be excessively greasy – Sweat, crumble or crack Sticks › Types: 1. Soft opaque sticks › May contain petrolatum, cocoa butter, and PEG bases › Most medication sticks are this type 2. Soft clear sticks › Usually contain sodium stearate and propylene glycol › Water or alcohol are added 3. Hard sticks › Crystalline powders fused together by heat OR held together with a binder such as cocoa butter or petrolatum › Example: stypic pencils Sticks › Examples – Lipsticks / lip balm – Local anesthetics – Muscle pain relievers – Sunscreens – Oncology drugs – Antivirals – Antibiotics MixtureUSA, Flickr, 2/12/2015 Practical consideration on topical drug usage › Amount of topical medication needed – For a single (thinly applied) application – Fingertip Unit (FTU)= amount dispensed from a typical tube, reaching from the finger tip to the first crease of the index finger – Rule of hand= amount of product needed to apply a thin film to the area of both sides of the hand (one hand area) Practical consideration on topical drug usage › General advice › The area to be treated should be cleaned and patted dry – Depending on the condition, it may be best to apply the product after bathing or soaking the area in water › Clean the hands › Apply the product – Creams and ointments: apply thin film with gentle rubbing – Lotions: apply as drops and massage lightly until the drops disappear – Gels: rub in gently and completely › Clean hands after application Practical consideration on topical drug usage › Be careful when applying to › Thin SC areas (e.g. face, back of hands) › Intertriginous areas (e.g. between buttocks or fingers, under breasts, axilla) › Large areas › Children