Topical Preparations (PDF)

TOPICAL PREPARATIONS Prof Thiru Govender Discipline of Pharmaceutical Sciences Anatomy of the Skin Human skin → 3 tissue layers: 1. Epidermis Consists of 5 layers: stratum corneum, stratum lucidum, stratum granulosum, stratum, malphigi and stratum germinativ...

TOPICAL PREPARATIONS Prof Thiru Govender Discipline of Pharmaceutical Sciences Anatomy of the Skin Human skin → 3 tissue layers: 1. Epidermis Consists of 5 layers: stratum corneum, stratum lucidum, stratum granulosum, stratum, malphigi and stratum germinativum. Thickness: face = 0.1mm, hand-palm = 0.8-1mm, eyelids = 0.006mm Stratum corneum → keratin phospholipid complex of dead and relatively dry cells → barrier to penetration of H2O and foreign bodies. No blood vessels/lymphatics. pH of skin → 5-6. 2. Dermis Connective tissue matrix woven from fibrous proteins (collagen, elastin and reticulin). Nerves, blood vessels and lymphatic traverse the matrix. Skin appendages (e.g. eccrine, sweat glands, apocrine glands & pilosabaceous units) pierce it. Needs efficient blood supply to convey nutrients, remove waste, regulate pressure and temperature, mobilize defense forces. 3. Subcutaneous Tissue Layer of subcutaneous fat → provides mechanical cushion to external injury, is also a thermal barrier. Synthesizes and stores readily available high energy chemicals.  Absorption ž Condition of skin is important in terms of the degree of absorption. ž Absorption through skin → is a passive process → can takes place in 2 ways: 1. Transepidermal →– surface area of epidermis is 1000 times greater than any other route of absorption. Penetration is fairly rapid. 2. Transappendageal → refers to absorption through glands, hair follicles, etc. Drugs applied to the skin reach opening of sweat glands and hair follicles directly. Each hair follicle → has one/more connecting sebaceous glands →which empties secretion into follicular canal near surface of skin. Canals are lined with stratified squamous epithelium → readily penetrated by drugs.  Percutaneous Absorption Simplified diagram of skin structure and macroroutes of drug penetration: (1) via the sweat ducts; (2) across the continuous stratum corneum or (3) through the hair follicles with their associated sebaceous glands. Simplified diagram of stratum corneum and two microroutes of drug penetration.  Factors Affecting Absorption 1. Vehicle 7. pH of the Skin 2. Occlusion 8. Skin Location 3. Rubbing 9. Hydration state of the Skin 4. Contact Time 10. Temperature 5. Drug Release 11. Hyperaemia 6. Lipid layers of the Skin 12. Content of Drug  1. Vehicle ž Must easily cover skin surface. ž Must mix readily with sebum to bring the drug in contact with skin. ž Absorption → is better from animal and vegetable oils than from mineral oils. Mineral oils → can act as barriers. ž Vehicle that ↑ moisture content of skin →can ↑ absorption. ž Oily bases act as moisture barriers i.e. sweat cannot pass through and the skin remains occluded → enables hydration of skin. ž Vehicles with humectants keep the ointment moist but have a tendency to draw moisture from the skin when humidity is low.  2. Occlusion ž Hydration is affected by the presence/absence of a bandage and the type of bandage. ž Bandaging a non-occlusive application such as a water-miscible vehicle will ↑ the moisturizing affect →↑ absorption. 3. Rubbing ž Rubbing will ↑ absorption-Linked to blood flow. Longer the period of rubbing → greater is the absorption. 4. Contact Time ž ↑ contact time →can ↑ absorption. 5. Drug Release ž Rate of absorption is dependant on rate of drug release. ž Release rate is dependant on: — Partition co-efficient of drug between the base and skin. — Whether drug is dissolved or suspended in the base. — Size of drug molecule.  6. Lipid layers of the Skin ž Drug may be stored in the outer and deeper layers of the skin. ž Drugs can be bound to protein (keratin). ž Lipid layers may act as barriers. 7. pH of the Skin ž Secretions in and on the epidermis determine the pH of the skin (5-6) → pH has major influence on drug penetration and absorption. ž Stratum corneum allows for penetration of unionized drugs → pH of skin affects ionization and absorption. 8. Skin Location ž Thickness of skin influences absorption. Thicker skin → slower absorption. ž Slowest absorption → sole of foot. ž Fastest absorption → behind the ear. 9. Hydration State of the Skin ž Hydration affects the rate of penetration of substances. ž Hydration → is due to water diffusing from underlying epidermal layers or from perspiration that accumulates after occlusion of skin. ž Water-soluble substances responsible for water content of the skin e.g. — amino acids – 40%, — urea – 17%  10. Temperature ž Diffusion co-efficient depends on temperature- therefore ↑ temperature → increase rate of diffusion. ž Also causes vasodilation. 11. Hyperaemia ž ↑ blood flow →↑ removal of drug →↑ concentration gradient →↑ rate of absorption. 12. Content of Drug ž ↑ concentration of drug → ↑ absorption. Types of Topical Preparations May contain: i. Active ingredient ii. No active → applied to act as a barrier § Preparation containing an active: — Those acting on the surface of the skin. — Those producing a therapeutic response only when they reach the water containing tissues e.g. antihistamines and cortico-steroids. Topical preparations divided into 3 broad categories ž 1. Topical Powder Preparations ž 2. Topical Liquid Preparations A. Solutions for external use B. Suspensions for external use C. Liquid Emulsions for External use ž 3. Topical Semi-Solid Preparations A. Semi-Solid emulsions for external use - Creams B. Ointments, Pastes and Gels 1. Topical Powder Preparations ž Used to absorb moisture from skin → keep skin dry → contain: starch, bacteriostatics or bacteriocides, and or antiseptics. ž Dusting powders → for applications to body surfaces but not to open wounds unless sterilized e.g. treatment of athletes foot.  2. Topical Liquid Preparations A. Solutions for external use Liniments → solutions formulated with alcoholic or oily vehicle → intended for rubbing into unbroken skin. Active applied for counter- irritant effect, analgesic effect or warming effect. Must contain a preservative.  Lotions → intended to be applied to unbroken skin without friction. Vehicle may be alcoholic/acetone if intended to evaporate rapidly from skin. Paints → applied to skin with a brush. Solvent → H2O or organic (if rapid evaporation required). B. Suspensions for external use Lotions containing suspended solids → when they evaporate → it leaves a light deposit of medicament on skin. The evaporation causes a cooling effect → which can be ↑ by addition of alcohol. Thickening agent is added which forms a strong, non-sticky film → holds medicament in contact with skin and gives protection. May require a preservative when applied to broken skin. C. Liquid Emulsions for External use Emulsions formulated as liniments and lotions → must contain a preservative. 3. Topical Semi-Solid Preparations A. Semi-Solid emulsions for external use Creams → viscous semi-solid o/w – aqueous creams w/o – oily creams Microbial contamination → must be minimized. Therefore, choose suitable preservative. Preparation must be under strict hygiene or aseptic conditions → therefore prepare with freshly boiled and cooled purified water. B. Ointments, Pastes and Gels Ointments → has emollient effect, for protection of lesions and for topical medication. Pastes → contain large amounts of finely powdered solids (up to 50%). Are emollients but porous and absorb exudates. Usually used for chronic infections. Gels → water-soluble bases from natural gums e.g. alginates. May be used as dermatologicals or to lubricate catheters and examination gloves.  Gel Paste Ointment Cream Preservation of Topical Preparations ž Plastic containers may absorb preservative →leads to a ↓ in their concentration → this can ↓ effectiveness. ž Preservatives may sting or irritate mucous tissue of the eye and nasal passages e.g. parabens are more irritating to nasal passages than quarternary ammonium compounds (QAC’s). ž Interaction of preservative with active or excipients, storage temp → can ↓ concentration of preservative → makes them ineffective. ž Preservative efficacy depend on concentration of free preservative in the aqueous phase. ž Preservative solubilised with surfactants may be bound within micelles and be activated. ž Minimum inhibitory concentration (MIC) of preservatives must be established for preparations via microbiological testing. ž Product must be tested for its ability to withstand accidental or deliberate microbial contamination → preservative challenge test. ž Good manufacturing practice employed in manufacture → to ↓ contamination. ž Aseptic technique → important for certain creams, ophthalmics and certain ointments. ž Oil/water partition co-efficient of preservative is important.  Ointments ž Greasy, semi-solid preps, often anhydrous and containing dissolved or dispersed medicaments. ž Medicament may be dissolved, suspended or emulsified into the base. Ideal ointment base: — Non-irritant — Smooth — Odourless — Physically and chemically stable — Compatible with a wide range of medicaments — Must not retard the healing process Rheology ž Ointments are visco-elastic material which soften and spread easily when a shearing stress is applied. ž Flow properties depend on nature and quantities of constituents → waxes confer structure and rigidity, fats/oils confer flexibility as well as a matrix in which the constituents may be carried. Classification of Ointment Bases ž Four main groups, according to USP and Pharmaceutical Codex: 1. Hydrocarbon Bases 2. Absorption Bases 3. Water-miscible Bases 4. Water-soluble Bases 1. Hydrocarbon Bases ž These bases: — Are immiscible with H2O — Are not absorbed by skin — Are almost inert — Absorb very little H2O from the formulation or from skin exudates — Inhibit H2O loss from skin — By improving hydration may encourage absorption ž Constituents of hydrocarbon bases include: — Soft Paraffin, Hard Paraffin & Liquid Paraffin. — Paraffin Substitutes & Paraffin Ointment BP A. Soft Paraffin – purified mix of semi-solids hydrocarbons from petroleum or heavy lubricating oils → 2 varieties – yellow & white. Melting range → 38-56°C. Yellow form → less likely to elicit an adverse skin reaction. B. Hard Paraffin – mixture of solid hydrocarbons obtained from petroleum and shale oil. Colourless, odourless, translucent, wax-like substance → slightly greasy. Solidified between 50-57°C. Used to stiffen ointment bases. C. Liquid Paraffin – mixture of liquid hydrocarbons obtained from petroleum. Transparent, colourless, almost odourless, oily. Liable to oxidation → include antioxidant. Used to soften ointment bases and to ↓ the viscosity of creams. D. Paraffin Substitutes – produced by dissolving polyethylene in liquid paraffin with the aid of heat and cooling the resulting solution rapidly to form a gel → consistency varies little over temp range -15°C to 60°C. compatible with most medicaments. readily applied to skin. E. Paraffin Ointment BP – official ointment base.  2. Absorption Bases A. Non emulsified → absorb H2O and aqueous solution to produce w/o emulsions. Consists of a sterol-type emulgent with one or more paraffins. Constituents include: i. Wool fat: wax → can absorb ± 50% of its weight of H2O. Patients may become sensitized. To sticky to be used on its own. ii. Wool alcohols: emulsifying fraction of wool fat. iii. Beeswax & Cholesterol: beeswax consists mainly of myrical palmitate with small amounts of cholesterol. Has good water-absorbing properties. B. Water-in oil Emulsions Greater water-absorbing properties. Advantages: less occlusive than hydrocarbon bases, easier to spread, good emollient, assists oil soluble medicaments in penetrating the skin.  3. Water-miscible Bases Easy to wash from skin. Can emulsify a large quantity of H2O but is immiscible with an excess. Contains paraffins and an o/w emulgent. General formula: Emulsifying wax (30%) White soft paraffin (50%) Liquid paraffin (20%) Advantages: miscibility with exudates, good contact with skin, high cosmetic acceptability, easy removal from hair. May promote absorption of certain drugs.  4. Water-soluble Bases Developed from macrogols → mixtures of polycondensation products of ethylene oxide & H2O. Completely H2O soluble. Advantages: non-toxic and non-irritant to the skin unless it is badly inflamed, non occlusive, miscible with exudates, non-staining and easily removed by washing. Disadvantage: very limited capacity to take up H2O without physical change. Solidifying points range from 40-60°C depending on molecular weight. 5% solutions → pH range 4 – 7.5 ↓ activity of a no. of preservatives Reacts with plastics  Expected effects of common vehicles on skin hydration and skin permeability – in approximate order of decreasing hydration Effect on skin Vehicle Examples/constituents Effect on skin hydration permeability Occlusive Plastic film, unperforated Prevents water loss; full Marked increase dressing waterproof plaster hydration Paraffins, oils, fats, waxes, Prevents water loss; may Lipophilic fatty acids, alcohols, esters, Marked increase produce full hydration silicones. Absorption Anhydrous lipid material Prevents water loss; Marked increase base plus water/oil emulsifiers marked hydration Emulsifying Anhydrous lipid material Prevents water loss; Marked increase base plus oil/water emulsifiers marked hydration Water/oil Retards water loss; raised Oily creams Increase emulsion hydration Oil/water May donate water; slight Aqueous creams Slight increase? emulsion hydration increase Can decrease or act Water-soluble bases, May withdraw water; Humectant as penetration glycerol, glycols decrease hydration enhancer Aid water evaporation; Clays, organics, inorganics, Little effect on Powder decreased excess ‘shake’ lotions stratum corneum hydration Other Excipients of Ointment Bases 1. Vegetable Oils: arachis, castor, coconut and olive oils. — Used as emollients. — Disadvantages of natural substances i.e. variation in composition and susceptibility to oxidation. 2. Synthetic esters of fatty acids: e.g. isopropyl myristate, palmitate-stearate. — More consistent in composition than vegetable oils and more resistant to oxidation. — May be used as a substitute for vegetable oils. 3. Higher fatty alcohols: e.g. cetostearyl alcohol — Good emollient properties. — Non-greasy. — Do not rancidify. — Facilitates the incorporation of H2O. 4. Silicones: e.g. dimethicones, dimethyl polysilicones. — Used in barrier ointments to protect skin against water-soluble irritants. 5. Propylene glycol: used to disperse very small quantities of actives through a relatively large quantity of ointment base. Other Excipients 1. Antioxidants: e.g. BHA and BHT Chelating agents e.g. EDTA Must be compatible with ointment base, active and other excipients. 2. Preservatives: may not be required in anhydrous ointments. Most commonly used- parabens, organic, mercurial and QACs. Compounding of Ointments & Pastes Basic method of preparation of ointments: Weighing, measuring liquids, size reduction and size separation and mixing. Two techniques of mixing: ž Mixing by Fusion ž Mixing by Trituration  1. Mixing by Fusion ž Ingredients melted together and stirred to ensure homogeneity. ž Generally carried out in an evaporating basin over a water bath-glazed porcelain or stainless steel basins are preferred. a) Preparation of ointment Base by Fusion - Constituents of the base should be placed in the basin and allowed to melt together. - To decrease the melting time - high melting point ingredients are grated into the basin and melted while the other ingredients are being massed. - After melting, ingredients should be stirred gently until cool. - Localized cooling may result in separation of hard lumps of high melting pt. ingredients. - Foreign particles visible on melting may be removed by decantation or by passage through a warm strainer. - If the product is granular after cooling → may be remelted with minimum heat and stirred until cold. - E.g. wool alcohol BP b) Preparation of Medicated Ointments and Pastes by Fusion - Solids that are completely/partially soluble in the base should be added in fine powder and the mixture stirred until cool. - Liquids and semi-solids should be added just as the base is thickening (approx. 40°C). - When a solid is soluble in a liquid ingredient, it may be more convenient to add it in solution. - Insoluble solids (zinc) should be passed through a 180µm sieve and added in small amounts with stirring to the melted base. - If product contains liquid paraffin or a fixed oil, a small amount can be used to levigate the powder before adding to the base to produce a smoother product. 2. Mixing by Trituration ž Applicable when the medicament is a solid which is insoluble in the base or a liquid present in small amounts. ž Solids should be finely powdered and passed through a sieve of appropriate size. ž A 250µm sieve is suitable unless the formula specifies a fine powder (180µm) or a very fine powder (125µm). ž Trituration can be carried out with an ointment tile and spatula or using a mortar and pestle.  1. Dissolution Similar to the tablet dissolution test. Sample of known strength is placed in a container which has a cellulose acetate phthalate (CAP) membrane of known surface area, which separates the product from the sampling medium (H2O at 37°C). Stirring paddle used to break up the boundary layers → to maintain concentration gradient. Samples removed at set intervals and assayed for drug concentration. Rate of release calculated and expressed i.t.o. surface area.  2. Physico-chemical Properties i. Stability Emulsion type bases → evaluated by centrifugation. Semi-solid preps → determined by storage for long period of time at normal temp. Bases prepared from oils, fats and waxes of mineral/synthetic origin → stable. Fats and oils of vegetable origin → can lead to oxidation → manifests as rancidity → detected by smell or yellowing/browning. ii. Rheological Properties Ideally prep should be plastic in nature with a moderate yield value i.e. high viscosity at low shearing stresses→ remains localized, low viscosity when shearing stress is applied. Thixotropic properties are advantageous. Phase separation can be monitored with a viscometer. iii. Particulate Matter Major hazard especially if preparation is applied to broken skin/membranes e.g. opthalmics. USP particulate test for opthalmics (refer to USP). iv. Microbial Contamination Do not have to be sterile (excluding opthalmics). Preserve efficacy must be evaluated by means of a challenge test.  3. Cosmetic Criteria i. Feel of the preparation ii. Non-greasy & smooth (non-gritty) Ointments and pastes by nature are greasy and visible on the skin. Synthetic bases (PEG’s) – less greasy. Waxy material (cetyl alcohol) – result in less tacky films. Efficient particles size reduction → ↓ gritty feel – particles < 20µm. Penetration Enhancers Substances which temporarily diminish the impermeability of the skin. Used to enhance the penetration rate of drugs and possibly even treat patients systemically through the dermal route → must be non-toxic.  Ideal Penetration Enhancer i. Pharmacologically inert. ii. Non-toxic, non-irritant and non-allergenic. iii. Action should be immediate and the effect should be suitable and predictable. iv. Upon removal of the material, the skin should immediately & fully recover its normal barrier properties. v. Should not cause loss of body fluids, electrolytes or other endogenous materials. vi. Compatible with all drugs and excipients. vii. Good solvent for drugs. viii. Cosmetically acceptable. ix. The chemical should formulate into all varieties of topical preparations. x. Odourless, tasteless, colourless and inexpensive.  Most effective penetration enhancers are aprotic solvents e.g. dimethyl sulphoxide (DMSO) dimethylformamide (DMF) and dimethylacetamide (DMA). Accelerate penetration of many compounds e.g. barbiturate, steroids, griseofluvin, phenylbutazone, local anaesthetics, antibiotics. Pyrrolidones can be used. Surfactants. Combination of oleic acid or oleyl alcohol with propylene glycol. H2O → best penetration enhancer - safety and effectiveness.