Semisolid Dosage Forms and Transdermal Systems 2023 (PDF)

Semisolid Dosage Forms and Transdermal systems 1  Semisolid dosage forms used in the topical treatment of conditions and diseases of the skin include ointments, creams, gels, pastes, and plasters. Other dosage forms include solutions, powders, and transde...

Semisolid Dosage Forms and Transdermal systems 1  Semisolid dosage forms used in the topical treatment of conditions and diseases of the skin include ointments, creams, gels, pastes, and plasters. Other dosage forms include solutions, powders, and transdermal drug delivery systems. Oral therapy also may be used for skin conditions 2  Semisolid dosage forms may be applied to the skin, placed on the surface of the eye, or used nasally, vaginally, or rectally. Semisolid dosage forms are either ˗ Medicated: Used for the effects of the therapeutic agent they contain. ˗ Unmedicated: Used for their physical effects as protectants or lubricants. 3  Topical preparations (medicated) are used for both local and systemic effects. ˗ A topical dermatological product is designed to deliver drug into the skin in treating dermal disorders, with the skin as the target organ. ˗ A transdermal product is designed to deliver drugs through the skin (percutaneous absorption) to the general circulation for systemic effects, with the skin not being the target organ.  Systemic drug effects should always be considered when using topical preparations if the patient is pregnant or nursing. In treating skin diseases, the drug in a medicated application should penetrate and be retained in the skin for a while. 5  Drug penetration depends on: ˗ Physicochemical properties of the medicinal substance. ˗ Characteristics of the pharmaceutical vehicle. ˗ Conditions of the skin itself. Normal unbroken skin is collectively a laminate of barriers protecting against permeation by external agents (limiting both the rate and degree of drug penetration) and loss of water from body. 6  The skin is divided histologically into the ˗ Epidermis (Stratum corneum, the outer layer, and the living epidermis). ˗ Dermis. ˗ Subcutaneous layers Blood capillaries and nerve fibers rise from the subcutaneous fat into the dermis and up to the epidermis. 7  Sebaceous glands, sweat glands and hair follicles originating in the dermis and subcutaneous layers rise to the skin surface. The stratum corneum is the desquamating horny layer, a 10-15 μm thick layer of flat, partially desicated, dead epidermal cells. It is composed approximately of 40% protein (mainly keratin) and 40% water, with the balance being lipid, principally as triglycerides, free fatty acids, cholesterol and phospholipids. 8  On the surface is a film of emulsified material composed of a complex mixture of sebum, sweat, and desquamating epidermal cells. This film varies in composition, thickness, and continuity as a result of differences in the proportion of sebum and sweat produced and the extent of their removal through washing and sweat evaporation. It offers little resistance to drug penetration. 9  Hair follicles and gland ducts can provide entry for drug molecules, but because their relative surface area is minute compared to the total epidermis, they are minor factors in drug absorption. The stratum corneum, being keratinized, behaves as a semipermeable artificial membrane, and drug molecules can penetrate by passive diffusion. 10  The rate of the drug movement across the skin layer depends on: ˗ Concentration of the drug in the vehicle. ˗ Aqueous solubility of the drug. ˗ Oil-water partition coefficient between the stratum corneum and the drug’s vehicle. 11  Once through the stratum corneum, drug molecules may pass through the deeper epidermal tissue and into the dermis. If the drug reaches the vascularized dermal layer, it becomes available for absorption into the general circulation. 12 13  :Functions of skin Mechanical function: Containment of body fluids and tissues. Protection from harmful external environment (barrier function): microbial barrier, chemical barrier, radiation barrier, thermal barrier, electrical barrier. Reception of external stimuli (sensory organ): pain, pressure, thermal. 14  Regulation of body temperature and blood pressure Synthesis and metabolism Disposal of biochemical wastes (secretion) Inter- and Intra- species identification Many of these functions are classified as essential to survival 15  Drug blood levels achieved by transdermal delivery systems may be measured and equated against desired therapeutic levels. For topical non systemic dermatological, the therapeutically effective concentration in the skin is not known, so treatment is based on qualitative measures, with clinical efficacy often varying between patients and products. 16  Differences in emollient and occlusive effects and ease of application and removal between products is a factor of the base used and product type. ˗ Oleaginous bases provide greater occlusion and emollient effects than do hydrophilic or water- washable bases. 17 ˗ Pastes offer even greater occlusion and are more effective than ointments at absorbing serous discharge. ˗ Creams, usually oil-in-water emulsions, spread more easily than ointments and are easier to remove. ˗ Water-soluble bases are non greasy and are easily removed. 18  Advantages and limitations Advantages of topical drug application to skin: ease of application; safe, convenient, and non-invasive nature of drug delivery; rapid termination of drug input (by removal of the application). Advantages of transdermal delivery: prolonged drug action and continuous administration of drugs at controlled rate, elimination of pulse entry, avoids hepatic first pass degradation, avoids GI irritation, and increases 19 patient compliance.  The main drawbacks of transdermal delivery is limited drug absorption, due to the inherent skin barrier function, and skin irritation. However, controlled delivery of drugs through skin continues to be of interest, with the further development of technologies, such as chemical penetration enhancement and physical penetration enhancement (iontophoresis, sonophoresis, electroporation, … etc). 20  Unless otherwise directed, before applying a dermatological product, the patient should: ˗ Thoroughly clean the affected area with soap and water and dry by patting with a soft cloth. ˗ In most instances, a thin layer of medication should be applied to the affected area and spread evenly using gentle pressure with the finger tips. Typically 1- 3 mg of ointment or cream is applied per cm2 of the skin. 21 ˗ Unless there is a specified need for an occlusive dressing to protect the area from excessive contact or contaminants, a bandage should not be used. ˗ After application, the hands should be thoroughly washed. 22  The pharmacist should be certain that the patient understands: ˗ Proper method of administration. ˗ Frequency and duration of use. ˗ Special warnings (such as those related to pregnancy or nursing). ˗ Therapeutic goals and the anticipated outcomes. ˗ Signs of adverse response. ˗ Allergic sensitivity reactions or treatment failure. ˗ Reasons to discontinue treatment and seek further professional guidance. 23  The patient should be advised that if symptoms persist or irritation develops, use of the product should be discontinued and a physician or pharmacist consulted. It is fairly common for patients to have an allergic response, such as a skin rash, to a topical product as a result of sensitivity to the medicinal or pharmaceutic ingredient. An alternative product that does not contain the suspected offending agent may be substituted to solve the problem. 24  Ointments Ointments are semisolid preparations intended for external application to the skin or mucous membranes. They may be medicated or unmedicated. Unmedicated are used for the physical effects they provide as protectants, emollients, or lubricants. Ointment bases may be used for their physical effects or as vehicles for medicated ointments 25 Ointment Bases: Ointment bases are classified by the USP into four general groups: ˗ Oleaginous bases. ˗ Absorption bases. ˗ Water-removable bases. ˗ Water-soluble bases. 26 Oleaginous (hydrocarbon) Bases: On application to the skin, they have an emollient effect, protect against the escape of moisture, are effective as occlusive dressings, can remain on the skin for long periods without drying out, and because their immiscibility with water are difficult to wash off. Water and aqueous preparations may be incorporated, but in small amounts and with some difficulty. Examples: Petrolatum, white petrolatum, white ointment , and yellow ointment. 27 Petrolatum, USP (yellow petroleum, petroleum jelly): It is an unctuous mass (greasy), varying in color from yellowish to light amber. It is a purified mixture of semisolid hydrocarbons obtained from petroleum. It melts at 38-60oC and may be used alone or with other agents as an ointment base. A commercial product is Vaseline. 28 White Petrolatum, USP (white petroleum jelly): It is a purified mixture of semisolid hydrocarbons obtained from petroleum that has been wholly or nearly decolorized. It is used for the same purposes as petrolatum, but because of its light color, it is considered more esthetically pleasing by some pharmacist and patients. A commercial product is white Vaseline. 29 Yellow (simple) Ointment, USP: It has the following formula for the preparation of 1000 g: Yellow wax 50 g Petrolatum 950 g Yellow wax is the purified wax obtained from the honeycomb of the bee Apis mellifera. 30  It is prepared by melting the yellow wax on a water bath, adding the petrolatum until the mixture is uniform, then cooling and stirring until congealed. It has slightly greater viscosity than plain petrolatum. 31 White Ointment, USP: This ointment differs from yellow ointment by substitution of white wax (bleached and purified yellow wax) and white petrolatum in the formula. 32 Absorption Bases: These are two types: ˗ Those that permit the incorporation of aqueous solutions resulting in the formation of water-in-oil emulsions (e.g., hydrophilic petrolatum). ˗ Those that are water-in-oil emulsions (emulsion bases) that permit the incorporation of additional quantities of aqueous solutions (e.g., lanolin). 33  These bases may be used as emollients, although they do not provide the degree of occlusion afforded by the oleaginous bases. Absorption bases are not easily removed from the skin with water washing, since the external phase of the emulsion is oleaginous. 34  Absorption bases are useful as pharmaceutical adjuncts to incorporate small volumes of aqueous solutions into hydrocarbon bases. This is accomplished by incorporating the aqueous solution into the absorption base and then incorporating this mixture into the hydrocarbon base. 35 Hydrophilic Petrolatum, USP: It has the following formula for the preparation of 1000 g: Cholesterol 30 g Stearyl alcohol 30 g White wax 80 g White petrolatum 860 g  It is prepared by melting the stearyl alcohol and white wax on a steam bath, adding the cholesterol with stirring until dissolved, adding the white petrolatum, and allowing the mixture to cool with stirring until congealed. A commercial product , Aquaphor, a variation of hydrophilic petrolatum, has the capacity to absorb up to three times its weight in water. 37 Lanolin, USP: It is obtained from the wool of sheep (Ovis aries). It is a purified waxlike substance that has been cleaned, deodorized, and decolorized. It contains not more than 0.25% water. Additional water may be incorporated into lanolin by mixing. Modified Lanolin, USP: It is lanolin that has been processed to reduce the contents of free lanolin alcohols and any detergent and pesticide residues. 39 Water-Removable Bases: They are oil-in-water emulsions resembling creams. Because the external phase of the emulsion is aqueous, they are easily washed from the skin and are often called water-washable bases. They may be diluted with water or aqueous solutions. They can absorb serous discharges. Hydrophilic ointment, USP is an example of this type of base. 40 Hydrophilic Ointment, USP: It has the following formula for the preparation of about 1000 g: Methyl paraben 0.25 Propyl paraben 0.15 Sodium lauryl sulfate 10.00 Propylene glycol 120.00 Stearyl alcohol 250.00 White petrolatum 250.00 Purified water 370.00 41  The stearyl alcohol and white petrolatum are melted together at about 75oC. The other agents, dissolved in the purified water, are added with stirring until the mixture congeals. Sodium lauryl sulfate is the emulsifying agent, with the stearyl alcohol and white petrolatum constituting the oleaginous phase of the emulsion and the other ingredients the aqueous phase. Methyl paraben and propyl paraben are antimicrobial 42 preservatives. Water-Soluble Bases: They do not contain oleaginous components. They are completely water soluble and often referred to as greasless. Because they soften greatly with the addition of water, large amounts of aqueous solutions are not effectively incorporated into these bases. They are mostly used for the incorporation of solid substances. Polyethylene Glycol Ointment, NF, is the prototype example of a water-soluble base. 43 Polyethylene Glycol Ointment, NF: Polyethylene glycol (PEG) is a polymer of ethylene oxide and water represented by the formula H(OCH2CH2)nOH in which n represents the average number of oxyethylene groups. The numeric designations associated with PEGs refer to the average molecular weight of the polymer. 44  PEGs having average molecular weight ˗ Below 600 are clear, colorless liquids. ˗ Between 600-1000 are semisolids. ˗ Above 1000 are wax like white materials. 45  The general formula for preparation of 1000 g of polyethylene glycol ointment is PEG 3350 400 g PEG 400 600 g Combining PEG 3350, a solid, with PEG 400, a liquid, results in a very pliable semisolid ointment. 46  If a firmer ointment is desired, the formula may be altered to contain up two equal parts of the two ingredients. When aqueous solutions are to be incorporated into the base, substitution of 50 g of PEG 3350 with an equal amount of stearyl alcohol is advantageous in rendering the final product firmer. 47 Selection of the Appropriate Base: This depends on the careful assessment of a number of factors, including: ˗ Desired release rate of the drug substance from the ointment base. ˗ Desirability of topical or percutaneous drug absorption. ˗ Desirability of occlusion of moisture from the skin. ˗ Stability of the drug in the ointment base. ˗ Effect, if any, of the drug on the consistency or 48 other features of the ointment base. ˗ Desire of an ointment base that is easily removed by washing with water. ˗ Characteristics of the surface to which it is applied. For example, an ointment is generally applied to dry, scaly skin; a cream is applied to weeping or oozing surfaces, and a lotion is applied to intertriginous areas or friction may occur, as between the thighs or under the armpit. The base that provides the best desired attributed 49 should be selected. Preparation of Ointments: Ointments are prepared, depending primarily on the nature of the ingredients, by two general methods: ˗ Incorporation ˗ Fusion 50 Incorporation The components are mixed until a uniform preparation is attained. On a small scale, the pharmacist may mix the components using a mortar and a pestle, or a spatula may be used to rub the ingredients together on an ointment slab (a large glass or porcelain plate or pill tile). 51 Incorporation of solids The ointment base is placed on one side of the working surface and the powdered components, previously reduced to fine powders and thoroughly blended in a mortar, on the other side. A small portion of the powder is mixed with a portion of the base until uniform. Geometric dilution is continued until all portions of the powder and base are combined and thoroughly and uniformly blended. 52  It is often desirable to reduce the particle size of a powder or crystalline material before incorporation in the ointment base so that the final product will not be gritty. This may be done by levigating, or mixing the solid material in a vehicle in which it is insoluble to make a smooth dispersion. 53  The levigating agent (mineral oil for base in which oils are the external phase or glycerin for bases in which water is the external phase) should be physically and chemically compatible with the drug and base. The levigating agent should be about equal in volume to the solid material to allow both reduction of particle size and dispersion of the substance in the vehicle. After levigation, the dispersion is incorporated in the ointment base. 54  Solids soluble in a common solvent that neither will not affect the stability of the drug nor the efficacy of the product may first be dissolved in the solvent (water or alcohol) and the solution added to the ointment base by spatulation or in a mortar and pestle. 55 Incorporation of a gummy material To incorporate a gummy material, such as camphor, pulverization by intervention can be used. The material is dissolved in a solvent and spread out on the pill tile. The solvent is allowed to evaporate, leaving a thin film of the material onto which the other ingredient or ingredients are spread. The material is then worked into the ingredients by trituration with a spatula. 56 Incorporation of liquids Liquid substances or solutions of drugs are added to an ointment only after due consideration of an ointment base’s capacity to accept the volume required. Only very small amounts of an aqueous solution may be incorporated in an oleaginous ointment, whereas hydrophilic ointment bases readily accept aqueous solutions. 57  When it is necessary to add an aqueous preparation to a hydrophobic base, the solution first may be incorporated into a minimum amount of a hydrophilic base and then that mixture added to the hydrophobic base. All bases, even if hydrophilic, have their limits to retain liquids, beyond which they become too soft or semiliquid. 58  Alcoholic solutions of small volume may be added easily to oleaginous vehicles or emulsion bases. Natural balsams, such as Peru balsam, are usually mixed with an equal portion of castor oil before incorporation into a base. Ointment or roller mills can be used to force coarsely formed ointments through stainless steel or ceramic rollers to produce ointments that are uniform in composition and smooth in texture. 59 Fusion By the fusion method, all or some of the components of an ointment are combined by being melted together and cooled with constant stirring until congealed. Components not melted are added to the congealing mixtures as it is being cooled and stirred. Heat liable substances and any volatile components are added last, when the temperature of the mixture is low enough not to cause decomposition or volatilization of the component. 60  Substances may be added to the congealing mixture as solutions or as insoluble powders levigated with a portion of the base. Once congealed, the ointment may be passed through an ointment mill or rubbed with a spatula or in a mortar to ensure a uniform texture. 61  Ointments containing beeswax, paraffin, stearyl alcohol, and high MW PEGs are prepared by fusion. The materials with the highest melting points are heated to the lowest required temperature to produce a melt. The additional materials are added with constant stirring during the cooling of the melt until the mixture is congealed. In this way, not all the components are subjected to the highest temperature. 62  Alternative methods entail melting the component with the lowest melting point first and adding the remaining components in the order of their melting points or simply melting all of the components together under slowly increasing temperature. By these methods, a lower temperature is usually sufficient to achieve fusion because of the solvent action exerted by the first melted components on the others. 63  In preparation of ointments having an emulsion base, the method of manufacture involves both melting and emulsification. The water-immiscible components such as oil and waxes are melted together in a steam bath to about 70-75oC. Meanwhile, an aqueous solution of the heat stable, water-soluble components is prepared and heated to the same temperature. 64  Then, the aqueous solution is slowly added, with mechanical stirring, to the melted oleaginous mixture. The temperature is maintained for 5-10 minutes and the mixture is lowly cooled and stirred until congealed. If the aqueous solution is not the same temperature as the oleaginous melt, some of the waxes will solidify on addition of the colder aqueous solution to the melted mixture. 65 Compendial Requirements for Ointments Ointments and other semisolid forms must meet USP tests for ˗ Microbial content. ˗ Minimum fill. ˗ Packaging. ˗ Storage. ˗ Labeling. Ophthalmic ointments must also meet tests for sterility and metal particles content. 66 Packaging Semisolid Preparations: Ointments and other semisolid preparations are packaged either in large-mouth ointment jars or in metal or plastic tubes. They must be stored in well closed containers to protect against contamination and in a cool place to protect against product separation in heat. 67  When required, light sensitive preparations are packaged in opaque or light resistant containers. Additional standards by the manufactures include examining the semisolid preparations for viscosity, and for in vitro drug release to ensure within-lot and lot-to-lot uniformity. In vitro drug release tests include diffusion cell studies to determine the drug’s release profile from the semisolid product. 68 Percutaneous absorption: Drug absorption through skin is mainly passive diffusion process. Drugs must first dissolve in the vehicle, then diffuse through the vehicle out to the surface of skin (released), and then penetrates through the different layers of skin (absorbed). 69  Drugs and nutrients also traverse biologic membranes using membrane transporters (specialized proteins) and to a lesser extent, cell surface receptors. This can be classified into energy dependent (active transport) or energy independent (passive transport). 70 Routes of percutaneous drug absorption: I. Transepidermal ˗ Intercellular for nonpolar drugs ˗ Intracellular (or transcellular) for polar drugs with small molecular weight II. Transappendageal through sweat ducts and the hair follicles which is significant only for large molecular weight polar compounds. 71.Stratum corneum and routes of penetration 72.Different routes of penetration.Any of these can be a rate limiting step in drug bioavailability through the skin 73  Drug diffusion: Passive diffusion I. Simple diffusion: Passive diffusion is described by Fick’s first law of diffusion, in which the flux (J) is the amount of drug that passes per unit time per unit area: In presence of a membrane which has thickness (h) and surface area (A); 74 or Under sink condition, where C1 >>> C2, and C2 is negligible, then: C1 = K Co, where Co is the concentration of the drug at the interface, then: 75  D, A, K, & h are constants related to the membrane permeability Membrane resistance (R) is the reciprocal of its permeability 76  If we plot Q against time (t), a straight line is obtained: Tlag is a function of membrane thickness and diffusivity (D) 77 II. Complex diffusion: A) Diffusion in series: describes the diffusion of drug through the different layers of skin, where each layer contributes a diffusional resistance (R). The total diffusional resistance (RT) of all the layers can be expressed as: RT = h1/D1K1 + h2/D2K2 + … + hn/DnKn n = number of layers 78  If one layer has greater resistance than the others (e.g., st. corneum), then the single high resistance phase determines the composite barrier properties, and the equation becomes as follows: RT = h1/D1K1 79 B) Diffusion in parallel: describes the diffusion of the drug through shunts and pores, such as hair follicles & sweat glands. The total diffusional flux (JT) is the sum of the individual fluxes through the separate routes: J T = f 1 J 1 + f 2 J 2 + … + fn J n n = number of pathways F = fractional surface area for each pathway 80  JT = Co (f1P1 + f2P2 + … + fnPn) P = thickness weighed permeability coefficients. If only one route allows diffusants to pass, then the flux is determined by the fractional area and the permeation rate through that route. 81 Percutaneous Absorption Models The percutaneous absorption models fall into one of two categories, in vivo or in vitro. In vivo Studies In vivo skin penetration studies may be undertaken for one or more of the following purposes: 1. To verify and quantify the cutaneous bioavailability of a topically applied drug. 82 2. To verify and quantify the systemic bioavailability of a transdermal drug. 3. To establish bioequivalence of different topical formulations of the same drug substance. 4. To determine the incidence and degree of systemic toxilogical risk following topical application of a specific drug or a drug product. 5. To relate resultant blood levels of drug in human to systemic therapeutic effects. 83  In vivo studies are performed in ˗ Humans. ˗ Animal models (weanling pig, rhesus monkey, and hairless mouse or rat). Biological samples used in drug penetration and drug absorption studies include skin sections, venous blood from the application site, blood from the systemic circulation, and excreta (urine, feces, and expired air). 84 In vitro Studies Skin permeation may be tested in vitro using various skin tissues (human or animal whole skin, dermis or epidermis) in a diffusion cell. In vitro penetration studies using human skin are limited because of difficulties of procurement, storage, expense, and variation in permeation. 85  Excised animal skin may also vary in quality and permeation. Animal skins are much more permeable than human skin. One alternative that has been shown to be effective is shed snakeskin, which is not living, pure stratum corneum, hairless, and similar to human skin but slightly less permeable. Also the product Living Skin Equivalent (LSE) Test skin was developed as an alternative for dermal absorption studies. 86  The typical diffusion cell has two champers, one on each side of the test diffusion membrane. A temperature controlled solution of drug is placed in one chamber and a receptor solution in the other chamber. When skin is used as the test membrane it separates the two solutions. 87  Drug diffusion through the skin may be determined by periodic sampling and assay of the drug concentration in the receptor solution. The skin may also be analyzed for drug content to show permeation rates and/or retention in the skin. 88 Franz Diffusion Cell 89  Creams Pharmaceutical creams are semisolid preparations containing one or more medicinal agents dissolved or dispersed in either a water in-oil emulsion or an oil-in- water emulsion or in another type of water- washable base. 90  Vanishing creams are oil-in-water emulsions containing a large percentage of water and stearic acid or other oleaginous components. After application of the cream, the water evaporates, leaving behind a thin residue film of stearic acid or other oleaginous component 91  Creams find primary applications in topical skin products and in products used rectally and vaginally. Many patients and physicians prefer creams to ointments because they are easier to spread and remove. Pharmaceutical manufacturers frequently manufacture topical preparations of a drug in both cream and ointment bases to satisfy the preference of a patient and a physician. 92  Gels Gels are semisolid systems consisting of dispersions of small or large molecules in an aqueous liquid vehicle rendered jellylike by the addition of a gelling agent. Among the gelling agents used are synthetic macromolecules, such as carbomer 934; cellulose derivatives such as CMC or HPMC; and natural gums, such as tragacanth. 93 Gels 94  Carbomers are high-molecular weight water soluble polymers of acrylic acid cross linked with allyl ethers of sucrose and/or pentaerythritol. Their viscosity depends on their polymeric composition. They are used as gelling agents in concentrations of 0.5-2.0% in water. Gels are sometimes called jellies. 95  Gels are classified into: – Single-phase gels: Gels in which the macromolecules are uniformly distributed throughout a liquid with no apparent boundaries between the dispersed macromolecules and the liquid. – Two-phase system: Gel mass consisting of floccules of small distinct particles, often referred to as magma. Milk of magnesia (or magnesia magma), which consists of a gelatinous precipitate of magnesium hydroxide, is such a system. 96  Gels may thicken on standing, forming a thixotrope, and must be shaken before use to liquefy the gel and enable pouring. In addition to the gelling agent and water, gels may be formulated to contain a drug substance, solvents, such as alcohol and/or PG; antimicrobial preservatives, such as methylparaben and propylparaben or chlorhexidine gluconate; and stabilizers, such as edetate disodium. 97  Medicated gels may be prepared for administration by various routes, including the skin, the eye, the nose, the vagina, and the rectum. 98  Transdermal Preparations Recent years have seen an increase in the number of topical ointments, creams, and gels designed to deliver the drug systemically. It is considered ideal for the drug to migrate through the skin to the underlying blood supply without buildup in the dermal layers. 99  This in contrast to the topical dosage forms, in which drug residence in the skin, the target tissue, is desired. This is often accomplished by the addition of penetration enhancers to the topical vehicle. Penetration enhancers include dimethyl sulfoxide (DMSO). Ethanol, PG, Glycerin, PEG, urea, dimethyl acetamide, SLS, the poloxamers, Spans, Tweens, lecithin, terpnes, and many others. 100  Evidence of percutaneous drug absorption may be found through: – Measurable blood levels of the drug. – Detectable excretion of the drug and/or its metabolites in the urine. – Clinical response of the patient to the therapy. 101  A tansdermal preparation commonly used is pluronic lecithin organogel (PLO gel). It consists of a pluronic (poloxamer) F127 gel (usually 20 or 30% concentration) mixed at a ratio of approximately 1:5 with a mixture if equal parts of isopropyl palmitate and lecithin. This gel vehicle aids in rapid penetration of many active drugs through the skin. TDDSs facilitate the passage of therapeutic quantities of drug substances through the skin and into the general 102 circulation for their systemic effects.  Miscellaneous Semisolid Preparations: Pastes, Plasters, and Glycerogelatins Pastes They are semisolid preparations intended for application to the skin. They generally contain a larger proportion of solid material (such as 25%) than ointments and therefore are stiffer. 103  Pastes can be prepared in the same manner as ointments, by direct mixing or by the use of heat to soften the base prior to incorporating the solids, which have been comminuted and sieved. 104  However, when a levigating agent is to be used to render the powdered components smooth, a portion of the base is often used rather than a liquid, which would soften the paste. Because of the stiffness of pastes, they remain in place after application and are effectively employed to absorb serous secretions. Because of their stiffness and impenetrability, pastes are not suited for application to hairy parts of the 105 body.  Among the few pastes in use today is zinc oxide paste, which is prepared by mixing 25% each of zinc oxide and starch with white petrolatum. The product is very firm and is better able to protect the skin and absorb secretions than is zinc oxide ointment. 106 Plasters Plasters are solid or semisolid adhesive masses spread on a backing of paper, fabric, moleskin, or plastic. The adhesive material is a rubber base or a synthetic resin. Plasters are applied to the skin to provide prolonged contact at the site. Plasters are classified into: – Unmedicated plasters: They provide protection or mechanical support at the site of application. 107 ˗ Medicated plasters: They provide effects at the site of application. They may be cut to size to conform to the surface to be covered. Among few plasters in use today is salicylic acid plaster used on the toes for the removal of the corns. The horny layers of skin are removed by the keratolytic action of salicylic acid. The concentration of salicylic acid used in commercial corn plasters ranges from 10-40%. 108 Glycerogelatins They are plastic masses containing gelatin (15%),glycerin (40%), water (35%), and an added medicinal substance (10%) such as zinc oxide. They are prepared by first softening the gelatin in water for about 10 minutes, heating on a steam bath until gelatin is dissolved, adding the medicinal substance mixed with glycerin, and allowing the mixture to cool with stirring until congealed. 109  They are applied to the skin for the long term. They are melted before application, cooled, to slightly above the body temperature, and applied to the affected area with a fine brush. Following the application, the glycerogelatin hardens, is usually covered with a bandage, and allowed to remain in place for weeks. The most recent official glycerogelatin was zinc gelatin, used in the treatment of varicose ulcers. It was also known as zinc gelatin boot because of its ability to form a pressure bandage. 110 Factors Affecting Percutaneous Absorption Among the factors playing a part in percutaneous absorption are ˗ Physical and chemical properties of the drug, including its molecular weight, solubility, partition coefficient and dissociation constant (pKa). ˗ Nature of the carrier vehicle. ˗ Condition of the skin. 111 Research findings: Drug concentration: Generally, Flux increases with the increase in the concentration of the drug in the TDDS. Area of application: The larger the area of application (the larger the TDDS), the more drug is absorbed. Physicochemical attraction to the skin: The drug should have a greater physicochemical attraction to the skin than to the vehicle so that the drug will leave the vehicle in favor of the skin. 112  Solubility of the drug: Some solubility of the drug in both lipid and water is essential for effective percutaneous absorption; the aqueous solubility of the drug determines the concentration presented to the absorption site, and the partition coefficient influences the rate of transport across the absorption site. Form of the drug: Drugs generally penetrate the skin better in their un-ionized form. 113  Polar/Non polar characteristic of the drug: Nonpolar drugs tend to cross the cell barrier through the lipid- rich regions (transcellular route), whereas, the polar drugs favor transport between the cells (intercellular route). Molecular weights: Drugs with molecular weights of 100-800 and adequate lipid and aqueous solubility can permeate the skin. The ideal MW of a drug for transdermal drug delivery is believed to be 400 or 114 less.  Hydration of the skin: It generally favors percutaneous absorption. The TDDS acts as an occlusive moisture barrier through which sweat cannot pass, increasing skin hydration. Site of application: Percutaneous drug absorption appears to be greater when the TDDS is applied to a site with a thin horny layer than with a thick one. 115  Duration of application: Generally, the longer the medicated application is permitted to remain in contact with the skin, the greater the total drug absorption. Skin condition: These general statements apply to the skin in the normal state. Skin that is abraded or cut permits drugs to gain direct access to the subcutaneous tissues and the capillary network, defeating the function of the TDDS. 116  Sterile Products: Features and Use of Ophthalmic Ointments and Gels Among the dosage forms used in topical treatment of conditions and diseases of the eye are – Ointments and gels. – Other forms include solutions, suspensions, and inserts. Systemic therapy also may be undertaken, as the use of diuretics in the adjunctive treatment of glaucoma. 117  The ointment base selected for an ophthalmic ointment – Must be nonirritating to the eye. – Must permit the diffusion of the medicinal substance throughout the secretions bathing the eye. – Must have a softening point close to body temperature, both for comfort and for drug release 118  Most often, mixtures of white petrolatum and liquid petrolatum (mineral oil) are used as the base in medicated and unmedicated (lubricating) ointments. Sometimes, a water miscible agent such as lanolin is added. A gel base of PEG and mineral oil is also used; this form permits water and water-insoluble drugs to be retained within the base. 119  Medicinal agents are added to an ointment base either as a solution or as a finely micronized powder. The ointment is made uniform and smooth by fine milling. Ophthalmic ointments must meet the USP sterility tests and the test for metal particle in ophthalmic ointments. Rendering an ophthalmic ointment sterile requires special technique and processing. 120  Terminal sterilization of a finished ointment may be problematic. – Steam sterilization or ethylene oxide methods are ineffective because neither is capable of penetrating the ointment base. – Although dry heat sterilization can penetrate the ointment base, the high heat required may poise a threat to the stability of the drug substance and introduces the possibility of separating the ointment base from the other components. 121 ˗ Rather, strict methods of aseptic processing are employed as each drug and nondrug component is rendered sterile and then aseptically weighed and incorporated in a final product that meets the sterility requirement. The USP directs that ophthalmic ointments must be packaged in collapsible ointment tubes. These tubes have elongated narrow tip to facilitate application of a narrow band of ointment to the eye. 122  When an antimicrobial preservative is needed, among those used are ˗ Methylparaben (0.05%) and propylparaben (0.01%) combinations ˗ Phenylmercuric acetate (0.008%) ˗ Chlorobutanol (0.5%) ˗ Benzylkonium chloride (0.008%). 123