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See all Premium member Presentation Transcript SEMISOLID DOSAGE FORMS BY: Prof.Prashant Aswar Government College of Pharmacy, Amravati-444604 : SEMISOLID DOSAGE FORMS BY: Prof.Prashant Aswar Government College of Pharmacy, Amravati-444604 SEMISOLID DOSAGE FORMS BY: Prof.Prashant Aswar Government College of Pharmacy, Amravati-444604 : SEMISOLID DOSAGE FORMS BY: Prof.Prashant Aswar Government College of Pharmacy, Amravati-444604 Pharmaceutical ointments and pastes : Pharmaceutical ointments and pastes Pharmaceutical ointments (termed unguents) are semisolid systems that are applied externally, primarily to the skin and also to mucous membranes, e.g. the rectum, the vagina/vulva, the eye. Typically, medicated ointments are used for the treatment of infection, inflammation and pruritus. However, non-medicated ointments are commonly used due to their emollient/lubricating properties. Pharmaceutical pastes are generally composed of ointment bases that contain a high concentration (frequently 50% w/w) of dispersed drug. The viscosity of pharmaceutical pastes is greater than that of pharmaceutical ointments. Advantages of pharmaceuticalointments, pastes, lotions, liniments, collodionsand gels : Advantages of pharmaceuticalointments, pastes, lotions, liniments, collodionsand gels Pharmaceutical ointments may be easily spread on skin, being retained at the site of application as an occlusive layer, thereby preventing moisture loss from the skin. This is particularly useful whenever restoration of the physical characteristics of the skin is required (e.g. due to inflammation). ■ Pharmaceutical ointments are associated with lubricating/emollient properties, properties that may be employed to reduce trauma of an affected site upon spreading. ■ In general, pharmaceutical ointments persist at the site of application, enabling the duration of drug release to be greater than for many other topical dosage forms. The increased viscosity of pharmaceutical pastes ensures that a thick film of the dosage form is applied to the site of action, which shows excellent persistence. This property is particularly useful if protection of an inflamed site is required, e.g. in eczema,psoriasis. ■ The hydrophobicity and retention of pharmaceutical ointments are useful attributes whenever applied to mucosa, e.g. inflamed hemorrhoids, eyelids, where fluid flow/ inflammation at these sites would normally serve to remove other formulations (e.g. oil in water creams) by dilution. It should be noted, however, that spreading of ointments on to moist surfaces may be difficult due to the hydrophobic properties of most ointments. Slide 5: Due to the high solids content, pharmaceutical pastes are often porous, allowing moisture loss from the applied site. Furthermore, pastes may act to absorb moisture and chemicals within the exudates. ■ The opaque nature of pastes (due to the high solids content) enables this formulation to be used as a sunblock. ■ The chemical stability of therapeutic agents that are prone to hydrolysis will be dramatically enhanced by formulation within pharmaceutical ointments and pastes. ■ Pharmaceutical gels may be formulated to provide excellent spreading properties and will provide a cooling effect due to solvent evaporation. Similarly solvent evaporation from liniments will provide a cooling effect. Disadvantages : Disadvantages ■ Pharmaceutical ointments are generally greasy and difficult to remove (and are therefore often cosmetically unacceptable). Similarly, liniments and lotions may also be cosmetically unacceptable to the patient and difficult to use. ■ Pharmaceutical pastes are generally applied as a thick layer at the required site and are therefore considered to be cosmetically unacceptable. ■ Staining of clothes is often associated with the use of pharmaceutical pastes and ointments. ■ The viscosity of pharmaceutical ointments, and in particular pastes, may be problematic in ensuring spreading of the dosage form over the affected site. Conversely, the low viscosity of liniments and lotions may result in application difficulties. Slide 7: ■ Pharmaceutical ointments may not be applied to exuding sites (however, this does not hold for pastes). Liniments may not be applied to broken skin. ■ Problems concerning drug release from pharmaceutical ointments may occur if the drug has limited solubility in the ointment base. ■ Pharmaceutical pastes are generally not applied to the hair due to difficulties associated with removal. ■ Therapeutic agents that are prone to hydrolysis should not be formulated into aqueous gels. Classification of Ointments : Classification of Ointments According to their therapeutic properties based on penetration According to their therapeutic uses. 1) According to their therapeutic properties based on penetration : 1) According to their therapeutic properties based on penetration Epidermic ointments- Act on epidermis & produce local effect. Used as protectives,antiseptic,local anti-infectives & parasiticides. Endodermic ointments- Act on deeper layers of citaneous tissues. Partially absorbed & act as a emollients, stimulants & local irritants. Diadermic ointments- Meant for deep penetration % release the medicaments that pass through the skin & produce systemic effects. 2) According to their therapeutic uses. : Antibiotic ointments: Used to kill micro-organisms. Ex- bacitracin,Neomycin,Chlortetracylclines etc. Antifungal ointments- Inhibit or kill the fungi. Ex- Benzoic acid, salicylic acid,nystatin etc. Anti-inflammatory ointments: Relive inflammatory, allergic & pruritic conditions. Ex- Betamethasone valerate,Hydrocortisone & its acetates. iv) Anti-pruritic ointments: Relieve itching Ex.- Benzocaine & coal tar 2) According to their therapeutic uses. Slide 11: v) Astringent Ointments: Causes contraction of skin & decreases discharge. Ex- Calamine,ZnO,Acetic acid, Tannic acid vi) Anti eczematous Ointments: Prevent oozing & excretion from vesicles on the skin. Ex- Hydrocortisones,ichthamol,coal tar & salicylic acid & sulphar. vii) Keratolytic Ointments: Used to remove or soften the horny layer of the skin. Ex- Resorcinol, salicylic acid & sulphur viii) Counter-irritant Ointments: Applied locally to irritate skin, thus reducing or relieving another irritation or deep seated pain.Ex- Capsicum,methyl salicylate,iodine,oleoresin Slide 12: ix) Antidandruff ointments: Ex- Salicylic acid ,cetrimide. x) Ointment For Psoriasis treatment: Ex- coal tar,coticosteroid,dithranol b& salicylic acid mixed with suitable oint.base. xi) Parasiticide ointments: destroy or inhibit living infestation like ticks & lice. Ex- Benzyl benzoate,hexachloride,sulphur etc. xii) Protectant Ointments: Protect skin from moisture,air,sun rays or other subst. like soap & chemicals. Ex- Calamine,ZnO,silicones,titanium dioxide etc. Percutaneous absorption : Percutaneous absorption It refers to passage of medicinal substance through the skin. It also defined as penetration of substances from outside into the skin & through the skin into bloodstream. Factors influencing Percutaneous absorption Skin Struct.-Epidermis divided into five layers a) Stratum corneum (Horney layer)-Barrier & reservoir to Percutaneous absorption b) Stratum lucidum (Barrier zone)- Barrier to transfer of water across skin, damage resulted in increased permeability to variety of chemicals. c) Stratum granulosum (Granular layer)-Participate in keratinisation d) Stratum spinosum (Prickle cell layer) e) Stratum germinativum (Basal cell layer) Slide 14: ii) Diffusion- diffusion resistance is in s.cornum. iii) Drug solubility characteristics iv) Medicament concentration v) Skin Hydration- Hydration increases absorpton,salicylic acid promote absorption by irritation. vi) The Vehicle-Solubility of drug in vehicle,activity coefficient of drug & vehicle/skin partition coefficient of drug. vii) Skin condition-abnormal skin,excess keratinisation,old age viii) Penetration enhancers- DMSO,DMF,Azones etc solvates s.corneum & bring about configuration changes in skin protein struct. with resulting swelling & enhaces percutaneous absorption. ix) Miscellaneous Factrs- a) Site of application b) Time of cotact c) Amount of inunction employed d) Temp of skin-Ex-Aspirin,glucosteroids,Salicylic acid,carbinoxmine e) State of ionisation f) pH of applied preperation e) pH of Skin f) Molecular struct.& size,species variation etc. Slide 15: The formulation of ointments and pastes involves the dispersal or dissolution of the selected therapeutic agent into an ointment base and, therefore, in addition to the physical properties of the dispersed/dissolved drug, the physicochemical properties of the ointment base are fundamental to the clinical and non-clinical performance of this type of dosage form. The choice of ointment base is dependent on several factors, including: (1) the site of application; (2) the required rate of drug release; (3) the chemical stability of the drug; and (4) the effect of the therapeutic agent on formulation viscosity. The site of application : The site of application In certain clinical conditions the site to which the ointment will be applied may be dry, e.g. psoriasis, or moist. If the area is dry, ointments are often used to occlude the site, thereby retaining moisture. Indeed, this effect is considered to play an important role in the treatment of certain clinical conditions. Conversely, occlusive ointment bases are not applied to sites in which there is fluid exudate. The required rate of drug release Following application, the therapeutic agent must be released to exert its pharmacological effect, either locally or, after absorption, systemically. Drug release from the ointment base requires solubility (albeit partial) of the therapeutic agent within the formulation. This will allow diffusion of the therapeutic agent (a molecular process) through the ointment base until it reaches the biological substrate. Therefore the choice of the ointment base is partially dictated by the physicochemical properties (and in particular the solubility) of the therapeutic agent. Slide 17: The chemical stability of the drug If a therapeutic agent is prone to hydrolysis, incorporation into a water-based formulation, e.g. oil in water creams, may lead to drug degradation and hence a shortened shelf-life. This problem may be obviated by incorporating the drug into a hydrophobic ointment base. For example, the shelf-life of hydrocortisone is markedly greater in an ointment formulation than in an oil in water cream formulation. The effect of the therapeutic agent on formulation viscosity The effect of the physical incorporation of a therapeutic agent into an ointment base on the rheological properties of the formulated product will be dependent on the required drug concentration, the physical properties of the therapeutic agent (e.g. particle size, shape) and the chemical composition and viscosity of the ointment base. Therefore, it is important that an ointment base is selected that will produce a product that may be readily applied to the required site. In light of the high drug content, this point is particularly important in the formulation of pastes. STRUCTURE, FUNCTION AND TOPICALTREATMENT OF HUMAN SKIN : STRUCTURE, FUNCTION AND TOPICALTREATMENT OF HUMAN SKIN The skin combines with the mucosal linings of the urogenital, digestive and respiratory tracts to protect the internal body structure from a hostile external environment of varying pollution, temperature, humidity and radiation. The skin safeguards the internal organs, limits the passage of chemicals into and out of the body, stabilizes blood pressure and temperature, and mediates the sensations of heat, cold, touch and pain. It expresses emotions (such as the pallor of fear, the redness of embarrassment and anger, and the sweating of anxiety). The integument identifies individuals through the characteristics particular to humans, e.g. colour, hair, odour and texture. Anatomy and physiology : Anatomy and physiology Slide 24: The human skin comprises three tissue layers: the stratified, avascular, cellular epidermis, the underlying dermis of connective tissue, and the subcutaneous fat .Hairy skin contains hair follicles and sebaceous glands; the glabrous skin of the soles and palms produces a thick epidermis with a compact stratum corneum, but there are no hair follicles or sebaceous glands. Slide 25: The epidermis The multilayered epidermis varies in thickness, ranging from about 0.8 mm on the palms and soles to 0.006 mm on the eyelids. The cells of the basal layer (stratum germinativum) divide and migrate upwards to produce the stratum corneum or horny layer. Humans survive in a non-aqueous environment because of the almost impermeable nature of this dead, dense layer, which is crucially important in controlling the percutaneous absorption of drugs arid other chemicals. The stratum corneum may be only 10 (Jim thick when dry but swells several fold in water. There are two main types of horny layer: the pads of the palms and soles, which are adapted for weight bearing and friction, and the remaining flexible, rather impermeable membranous layer. The basal cell layer also includes melanocytes, which produce and distribute melanin granules to the keratinocytes. Langerhans' cells (important in defence mechanisms operated by the immune system) are prominent in the epidermis. Slide 26: The dermis The dermis (or coriurri), at 3-5 mm thick, consists of a matrix of connective tissue woven from fibrous proteins (collagen, elastin and reticulin) that are embedded in an amorphous ground substance of mucopolysaccharide. Nerves, blood vessels and lymphatics traverse the matrix and skin appendages (eccrine sweat glands, apocrine glands, and pilosebaceous units) pierce it. The dermis needs an efficient blood supply to convey nutrients, remove waste products, regulate pressure and temperature, mobilize defence forces and contribute to skin colour. Branches from the arterial plexus deliver blood to sweat glands, hair follicles, subcutaneous fat and the dermis itself.This supply reaches to within 0.2 mm of the skin surface, so that it quickly absorbs and systematically dilutes most compounds passing the epidermis. The generous blood volume in the skin usually acts as a 'sink' for diffusing molecules reaching the capillaries, keeping penetrant concentrations in the dermis very low, maximizing epidermal concentration gradients, and thus promoting percutaneous absorption. Slide 27: The subcutaneous tissue The subcutaneous fat (subcutis, hypoderrri) provides a mechanical cushion and a thermal barrier; it synthesizes and stores readily available high-energy chemicals. The skin appendages The eccrine sweat glands (2-5 million) produce sweat (pH 4.0-6.8) and may also secrete drugs, proteins, antibodies and antigens. Their principal function is to aid heat control, but emotional stress can also provoke sweating (the clammy palm syndrome).The apocrine sweat glands develop at the pilosebaceous follicle to provide the characteristic adult distribution in the armpit (axilla), the breast areola and the perianal region. The milky or oily secretion may be coloured and contains proteins, lipids, lipoproteins and saccharides. Surface bacteria metabolize this odourless liquid to produce the characteristic body smell. Hair follicles develop over all skin except the red part of the lips, the palms and soles, and parts of the sex organs. One or more sebaceous glands, and in some body regions an apocrine gland, open into the follicle above the muscle that attaches the follicle to the dermoepidermal junction. Sebaceous glands are most numerous and largest on the face, the forehead, in the ear, on the midline of the back and on anogenital surfaces; the palms and soles usually lack them. These holocrine glands produce sebum from cell disintegration; its principal components are glycerides, free fatty acids, cholesterol,cholesterol esters, wax esters and squalene.Abnormal sebaceous activity may lead to seborrhoea (excess sebum), gland hyperplasia without clinical seborrhoea, obstruction of the pilosebaceous canal (acne and comedones - whiteheads or blackheads),and other types of dysfunction - the dyssebacias. Functions of the skin : Functions of the skin Mechanical function The dermis provides the mechanical properties of skin, with the epidermis playing a minor part. Skin is elastic, but once it has taken up its initial slack it extends further only with difficulty. With age, the skin wrinkles and becomes more rigid. The thin horny layer is quite strong and depends for its pliability on a correct balance of lipids, water-soluble hygroscopic substances (the natural moisturising factor - NMF) and particularly water. The tissue requires some 10-20% of moisture to act as a plasticizer and so maintain its suppleness. Slide 29: Protective function Microbiological barrier The stratum corneum provides a microbiological barrier and the sloughing of groups of corneocytes (squames), with their adhering microorganisms, aids the protective mechanism. However, microbes penetrate superficial cracks and damaged stratum corneum may allow access to the lower tissues, where infection may develop. The socalled acid mantle (produced by sebaceous and eccrine secretions, at pH 4.2-5.6) probably does not defend the skin against bacteria via its acidity, as was once thought. However, skin glands also secrete short-chain fatty acids that inhibit bacterial and fungal growth. Nitric oxide, produced from nitrates in sweat, may help to prevent infections from skin pathogens, just as acidified nitrite has an antimicrobial action in the oral and gastrointestinal tracts. Bacteria are unlikely to enter the tiny opening of the inner duct of the eccrine gland; the entrances to the apocrine gland and the hair follicle are much wider, and these appendages may become infected. Chemical barrier An important function of human skin is to bar the entry of unwanted molecules from outside while controlling the loss of water, electrolytes and other endogenous constituents. The horny layer is very impermeable to most chemicals and usually contributes the rate-limiting step in transdermal absorption. The intact skin is a very effective barricade because the diffusional resistance of the horny layer is large and the permeable appendageal shunt route provides only a small fractional area (about 0.1%). Slide 30: Radiation barrier For skin exposed to sunlight, ultraviolet light of 290-400 nm is the most damaging. Three main acute reactions follow irradiation:erythema, pigmentation and epidermal thickening. Ultraviolet light stimulates melanocytes to produce melanin, which partially protects the skin. In a severe photosensitive disease such as xeroderma pigmentosum, sunlight may induce changes even in patients whose intense racial pigmentation makes them less susceptible to sunburn. Chronic reactions to sunlight include skin 'ageing', premalignancy and malignancy. Sun-damaged skin may produce solar keratoses, progressing to a squamous cell carcinoma. Bowen's disease, malignant melanoma and basal cell carcinoma may evolve. Heat barrier and temperature regulation The stratum corneum is so thin over most body areas that it does not effectively protect the underlying living tissues from extremes of cold and heat; it is not an efficient heat insulator. The skin, however, is the organ primarily responsible for maintaining the body at 37 °C.To conserve heat, the peripheral circulation shuts down to minimize surface heat loss; shivering generates energy when chilling is severe. To lose heat, blood vessels dilate, eccrine sweat glands pour out their dilute saline secretion, water evaporates, and removal of the heat of vaporization cools the body. Electrical barrier In dry skin, resistance and impedance are much higher than in other biological tissues. Mechanical shock An acute violent blow bruises and blisters the skin; friction may blister or thicken the epidermis, producing callosities and corns. Accidental minor trauma to patients on corticosteroids may severely damage their skin, when the collagen is thinned by drug overuse. Rational approach to drug delivery toand via the skin : Rational approach to drug delivery toand via the skin There are three main ways to attack the problem of formulating a successful topical dosage form: 1. We can manipulate the barrier function of the skin: for example, topical antibiotics and antibacterials help a damaged barrier to ward off infection; sunscreen agents and the horny layer protect the viable tissues from ultraviolet radiation; and emollient preparations restore pliability to a desiccated horny layer. 2. We can direct drugs to the viable skin tissues without using oral, systemic or other routes of therapy. 3. The third approach uses skin delivery for systemic treatment. For example, transdermal therapeutic systems provide systemic therapy for conditions such as motion sickness, angina and pain. PROPERTIES THAT INFLUENCETRANSDERMAL DELIVERY : PROPERTIES THAT INFLUENCETRANSDERMAL DELIVERY When a preparation is applied to diseased skin the clinical result arises from a sequence of processes: 1. Release of the medicament from the vehicle; 2. Penetration through the skin barriers; 3. Activation of the pharmacological response. Effective therapy optimizes these steps as they are affected by three components, the drug, the vehicle and the skin. Biological factors : Biological factors Skin condition The intact, healthy skin is a tough barrier but many agents can damage it. Vesicants such as acids and alkalis injure barrier cells and thereby promote penetration, as do cuts, abrasions and dermatitis. In heavy industry, workers' skins may lose their reactivity or 'harden' because of frequent contact with irritant chemicals. Many solvents open up the complex dense structure of the horny layer. Mixtures of non-polar and polar solvents, such as chloroform and methanol, remove the lipid fraction, forming artificial shunts through which molecules pass more easily. Disease commonly alters skin condition; fortunately, for biopharmaceutical purposes we need only an elementary understanding of the gross changes in deranged skin. We are interested mainly in visible damage. Is the skin inflamed, with loss of stratum corneum and altered keratinization? Slide 37: Skin age - It is often assumed that the skin of the young and the elderly is more permeable than adult tissue, but there is little evidence for any dramatic difference. Children are more susceptible to the toxic effects of drugs and chemicals, partly because of their greater surface area per unit body weight; thus potent topical steroids, boric acid and hexachlorophane have produced severe side-effects and death. Premature infants may be born with no stratum corneum. This can be turned to advantage by treating breathing difficulties with caffeine or pain with buprenorphine, via simple topical application instead of intravenous injection through tiny, delicate veins. Blood flow - Theoretically, changes in the peripheral circulation could affect transdermal absorption; an increased blood flow could reduce the amount of time a penetrant remains in the dermis, and also raise the concentration gradient across the skin. Usually the effect is not clinically important (although it can be shown experimentally). In clinically hyperaemic skin, any increase in absorption almost always arises because the disease damages the skin barrier. Potent rubefacients, such as nicotinic acid esters, would also only have a significant effect after damaging the skin. Potent vasoconstricting agents, such as topical steroids, could reduce their own clearance rate or that of another drug. Slide 38: Regional skin sites Variations in cutaneous permeability around the body depend on the thickness and nature of the stratum corneum and the density of skin appendages. Skin metabolism The skin metabolizes steroid hormones, chemical carcinogens and some drugs. Such metabolism may determine the therapeutic efficacy of topically applied compounds (particularly prodrugs) and the carcinogenic responses in the skin. It has been estimated that the skin can metabolize some 5% of candidate topical drugs. Species differences Mammalian skins differ widely in characteristics such as horny layer thickness, sweat gland and hair follicle densities, and pelt condition. The capillary blood supply and the sweating ability differ between humans and common laboratory animals. Such factors affect the routes of penetration and the resistance to permeation. Physicochemical factors : Physicochemical factors Skin hydration When water saturates the skin the tissue swells, softens and wrinkles and its permeability increases markedly. In fact, hydration of the stratum corneum is one of the most important factors in increasing the penetration rate of most substances that permeate skin. Hydration may result from water diffusing from underlying epidermal layers, or from perspiration that accumulates after the application of an occlusive vehicle or dressing. A dramatic example is the use of occlusive plastic films in topical steroid treatment, when the penetration of the steroid often increases tenfold. Occlusion decreases in the order: occlusive films = transdermal patches > lipophilic ointments > w/o cream > o/w cream. Powders, applied either as dusting powders or in lotions, provide a large surface area for evaporation and therefore dry the skin. Slide 40: Temperature and pH The penetration rate of material through human skin can change tenfold for a large temperature variation, as the diffusion coefficient decreases as the temperature falls. However, adequate clothing on most of the body would usually prevent wide fluctuations in temperature and penetration rates. Occlusive vehicles increase skin temperature by a few degrees, but any consequent increased permeability is small compared to the effect of hydration. According to the simple form of the pH-partition hypothesis, only unionized molecules pass readily across lipid membranes. Now weak acids and bases dissociate to different degrees, depending on the Ph and their pKa or pkb values. Thus, the proportion of unionized drug in the applied phase mainly determines the effective membrane gradient, and this fraction depends on pH. However, ionized molecules do penetrate the stratum corneum to a limited extent. Because they usually have a much greater aqueous solubility than the neutral species, in saturated or near-saturated solutions, they may make a significant contribution to the total flux Slide 41: Diffusion coefficient The diffusional speed of a molecule depends mainly on the state of matter of the medium. In gases and air, diffusion coefficients are large because the void space available to the molecules is great compared to their size, and the mean free path between molecular collisions is large. In liquids the free volume is much smaller, mean free paths are decreased and diffusion coefficients much reduced. In skin, the diffusivities drop progressively and reach their lowest values within the compacted stratum corneum matrix. For a constant temperature, the diffusion coefficient of a drug in a topical vehicle or in skin depends on the properties of the drug and the diffusion medium and on the interaction between them. Slide 42: Drug concentration It was seen previously that the flux of solute is proportional to the concentration gradient across the entire barrier phase. Thus, drug permeation usually follows Pick's law. One requirement for maximal flux in a thermodynamically stable situation is that the donor solution should be saturated. A formulator can optimize the solubility of a drug such as a corticosteroid by controlling the solvent composition of the vehicle. Then a saturated solution may be obtained at a selected concentration of the drug by experimenting with a series of solvents or,more usually, by blending two liquids to form a miscible binary mixture with suitable solvent properties. Slide 43: Partition coefficient The partition coefficient is important in establishing the flux of a drug through the stratum corneum. When the membrane provides the sole or major source of diffusional resistance, then the magnitude of the partition coefficient is very important: this can differ by a factor of 108, drug to drug or (for one penetrant) vehicle to vehicle. The stratum corneum-to-vehicle partition coefficient is then crucially important in establishing a high initial concentration of diffusant in the first layer of the membrane. Slide 44: Ideal molecular properties for drug penetration • A low molecular mass, preferably less than 600 Da, when the diffusion coefficient will tend to be high; • An adequate solubility in oil and water, so that the concentration gradient in the membrane can be high; • A balanced partition coefficient; • A low melting point; this correlates with good ideal solubility. Types of base for ointments and pastes : Types of base for ointments and pastes There are four types of base that are used to formulate pharmaceutical ointments and pastes: (1) hydrocarbon; (2)absorption; (3) water-miscible/removable; and (4) water-soluble. Slide 46: Hydrocarbon bases Hydrocarbon bases are non-aqueous formulations, based on various paraffins, that have the following properties: ■ emollient, thereby restricting water loss from the site of application due to the formation of an occlusive film ■ excellent retention on the skin ■ predominantly hydrophobic, and therefore difficult to remove from the skin by washing and difficult to apply to (spread over) wet surfaces (e.g. mucous membranes, wet skin) ■ only a low concentration ( 5%) of water may be incorporated into hydrocarbon bases (with careful mixing) ■ chemically inert. Hydrocarbon bases frequently contain the following components: (1) hard paraffin; (2) white/yellow soft paraffin; (3) liquid paraffin (mineral oil); and (4) microcrystalline wax. Slide 47: Hard paraffin This is a mixture of solid saturated hydrocarbons that are derived from petroleum or shale oil. Hard paraffin is a colourless or white wax-like material that is physically composed of a mixture of microcrystals. The melting temperature of hard paraffin is between 47 and 65C and, when solid, it is used to enhance the rheological properties of ointment bases. White/yellow soft paraffin This is a purified mixture of semisolid hydrocarbons (containing branched, linear and cyclic chains) that are derived from petroleum. White/yellow soft paraffin consists of microcrystals embedded in a gel composed of liquid and amorphous hydrocarbons that are themselves dispersed in a gel phase containing liquid and amorphous hydrocarbons. The melting range of the soft paraffins is between 38 and 60C. White soft paraffin and yellow soft paraffin (the former being a bleached form of yellow soft paraffin) may be used as an ointment base without the need for additional components, although it may be combined with liquid paraffin Slide 48: Liquid paraffin (mineral oil) This is a mixture of saturated aliphatic (C14–C18) and cyclic hydrocarbons that have been refined from petroleum. It is usually formulated with white/yellow soft paraffin to achieve the required viscosity for application to the required site. Formulations containing liquid paraffin require the incorporation of an antioxidant due to the ability of this material to undergo oxidation. Microcrystalline wax This is a solid mixture of saturated alkanes (both linear and branched) with a defined range of carbon chain lengths (C41–C57).This excipient is used to enhance the viscosity of ointments (and creams). One of the advantages of microcrystalline wax is the greater physical stability provided to formulations containing liquid paraffin (reduced bleeding of the liquid component). Slide 49: Absorption bases Unlike hydrocarbon bases, absorption bases may be formulated to contain significant amounts of an aqueous phase. These may be either non-aqueous formulations to which an aqueous phase may be added to produce a water in oil emulsion (termed nonemulsified bases) or water in oil emulsions that can facilitate the incorporation of an aqueous phase (without phase inversion or cracking). Although absorption bases can accommodate a larger volume of aqueous phase than hydrophobic bases, they are still difficult to remove from the site of application by washing. This is due to the predominantly hydrophobic properties of this formulation class. Slide 50: Non-emulsified bases These are hydrophobic formulations to which water may be added. Following application, a film is formed that offers occlusion (and hence emollient properties); however, the extent of occlusion is less than for hydrocarbon bases. The spreading properties of these formulations are more favorable than for hydrocarbon bases. Typically non-emulsified bases are commonly composed of: (1)one or more paraffins and (2) a sterol-based emulsifying agent. Examples of the types of emulsifying agents used in absorption bases include: (1) lanolin (wool fat); (2) lanolin alcohols (wool alcohols); and (3) beeswax (white or yellow). Slide 51: Lanolin (wool fat) Lanolin is a wax-like material that is derived from sheep’s wool. It is available in two forms, termed lanolin (wool fat) and hydrous lanolin (wool alcohols). Lanolin is typically mixed with vegetable oils or paraffins to produce an ointment base that can absorb approximately twice its own weight of water to produce water in oil emulsions. The usual concentrations of lanolin used in ointments (e.g. Simple Ointment BP) range from 5 to 10% w/w. Lanolin alcohols (wool alcohols) As detailed in Chapter 3, wool alcohol is a crude mixture of sterols and triterpene alcohols and contains at least 30% cholesterol and 10–13% isocholesterol. This is added to mixtures of paraffins (hard, so white/yellow soft or liquid) to produce the required consistency. The inclusion of wool alcohols (5% w/w) results in a 300% increase in the concentration of water that may be incorporated into paraffin bases. Beeswax (white or yellow) Beeswax is a wax that consists of esters of aliphatic alcohols (C24–C36 even numbers) and linear aliphatic fatty acids (up to C36, even numbers) that is combined with paraffins to produce non-emulsified bases. White beeswax is the bleached form of yellow beeswax. Slide 52: Water in oil emulsions Ointment bases in this category can accommodate a greater concentration of water but yet can still provide similar performance to that provided by non-emulsified bases with respect to, e.g. occlusion, spreading properties. A common excipient that is employed in the formulation of this type of ointment base is hydrous lanolin, which is a mixture of lanolin and circa 25–30% water. It is incorporated into paraffins and oils to produce a base that can incorporate the subsequent addition of an aqueous phase. The water content of bases that have been formulated using hydrous lanolin is significant, e.g. Oily Cream BP is a water in oil emulsion ointment base that is composed of wool alcohols (50% w/w) and water (50% w/w). Slide 53: Water-miscible/removable bases These are water-miscible bases that are used to form oil in water emulsions for topical applications. The use of these bases offers a number of advantages, including: ■ They are able to accommodate large volumes of water, e.g. aqueous solutions of drug, excess moisture at the site of application, e.g. exudate from abrasions and wounds. ■ They are not occlusive. ■ They may be easily washed from the skin and from clothing. Furthermore, they may be readily applied to (and removed from) hair. ■ They are aesthetically pleasing. Slide 54: The British Pharmacopoeia describes three water-miscible/ removable bases: 1. emulsifying ointment 2. cetrimide emulsifying ointment 3. cetomacrogol emulsifying ointment. Each of these contains: liquid paraffin 20% w/w white soft paraffin 50% w/w anionic, cationic or non-ionic emulsifying wax 30% w/w. As may be observed, an important component of this ointment base is emulsifying wax, of which there are three types: (1) anionic; (2) non-ionic; and (3) cationic. The important properties of these waxes are as follows: Anionic emulsifying wax ■ This is a waxy solid that, when incorporated into a paraffin base, may be used to produce an oil in water emulsion, e.g. Aqueous Cream BP (which contains 10% w/w anionic emulsifying wax). ■ Anionic emulsifying wax is composed of: cetostearyl alcohol 90 g sodium lauryl sulphate 10 g purified water 4 ml. Slide 55: Non-ionic emulsifying wax ■ This is also referred to as Cetomacrogol Emulsifying Wax BP and is composed of: cetostearyl alcohol 800 g cetomacrogol 1000 (macrogol cetostearyl ether 22) 200 g. Cationic emulsifying wax ■ This is also referred to as Cetrimide Emulsifying Wax BP. ■ Cationic Emulsifying Wax BP is composed of: cetostearyl alcohol 900 g cetrimide 100 g. Slide 56: Water-soluble bases The reader will have observed that the three previous ointment bases are predominantly hydrophobic, are hydrophobic with added surface-active agents or are water-miscible, containing both water soluble and insoluble components. In contrast, water-soluble bases are composed entirely of water-soluble ingredients. The advantages of the use of these bases include: ■ They are non-greasy and may be easily removed by washing. ■ They are miscible with exudates from inflamed sites. ■ They are generally compatible with the vast majority of therapeutic agents. Water-soluble bases are predominantly prepared using mixtures of different molecular weights of polyethylene glycol to produce the required ointment consistency. Lower average molecular weights of this polymer (200, 400 and 600 g/mol) are liquids. As the average molecular weight increases, the consistency of this polymer changes from a liquid to a waxy solid ( 1000 g/mol). Slide 57: Blends of 60% w/w polyethylene glycol 400 (a liquid) and 40% w/w polyethylene glycol 4000 (a solid) have been used as a water soluble ointment base. If required, the consistency may be increased by lowering the ratio of polyethylene glycol 400 to polyethylene glycol 4000 in the ointment base. Blending the two polyethylene glycol fractions is performed by heating the mixture followed by cooling of the homogeneous liquid at a controlled rate. The main disadvantage associated with water-soluble bases is their inability to incorporate large volumes of aqueous solutions as these will soften and, if the concentration of water is large enough ( 5% w/w), dissolve the ointment base. Therefore the use of these bases is usually reserved for the incorporation of solid therapeutic agents. However, these bases may incorporate up to 25% of an aqueous solution if a portion of the lower-molecular-weight polyethylene glycol is replaced with stearyl alcohol. This will enhance the mechanical properties of the ointment. Miscellaneous excipients used in theformulation of ointments and pastes : Miscellaneous excipients used in theformulation of ointments and pastes In these the therapeutic agent may be directly incorporated as a solid component or, in the case of the absorption and water-miscible bases, the addition may be in the form of a solution. This solution may be aqueous, alcoholic (e.g. propylene glycol, glycerol) or hydroalcoholic and must not adversely affect the physical stability and/or appearance of the formulated product. Other excipients may be included in ointments and pastes, including: (1) additional/alternative solvents; (2) preservatives; and (3) antioxidants. Slide 59: Additional/alternative solvents These are hydrophobic liquid components that may be added to ointment bases (predominantly hydrophobic or absorption bases). Examples of these include: (1) liquid silicone; (2) vegetable oils;and (3) organic esters. Liquid silicone (polydimethylsiloxane) This may be used in barrier ointments due to the water-repellent properties of this component. Vegetable oils Vegetable oils may be used either to replace mineral oils or, alternatively, may be added to hydrophobic or absorption bases to increase the emollient properties of the formulated product. Examples of oils that are used for this purpose are coconut oil and arachis oil. Organic esters These may be used partly to replace a mineral oil to enhance the spreadability and to enhance drug dissolution within the ointment base. One of the most commonly used examples is isopropyl myristate. Slide 60: Preservatives Topically applied ointments and pastes are not sterile products; however, they are manufactured under clean conditions to minimise the microbial bioburden within the formulated product.Ointments/pastes that do not contain water do not usually require the addition of a preservative (due to the low water activity in the formulation). However if the product contains water, then a preservative will be required. Preservatives that may be used in formulations designed for external use include: ■ phenolics: phenol (0.2–0.5%), chlorocresol (0.075–0.12%) ■ benzoic acid and salts (0.1–0.3%) ■ methylparabens (methyl parahydroxy benzoic acid) (0.02–0.3%) ■ propylparabens (methyl parahydroxy benzoic acid) (0.02–0.3%) (and their mixtures) ■ benzyl alcohol ( 3.0%) ■ phenoxyethanol (0.5–1.0%) ■ bronopol (0.01–0.1%, usually 0.02%) In the preservation of ointments, the same physicochemical and microbiological principles exist and therefore partitioning of the preservative from the aqueous to the non-aqueous phase may occur. Under these circumstances it is important to ensure that the required concentration ( ≥ minimum inhibitory concentration) of the antimicrobial species is present within the aqueous phase. Slide 61: Antioxidants The use of antioxidants has been described in previous chapters. In pharmaceutical ointments antioxidants are employed to prevent or reduce oxidation of either the non-aqueous components of the ointment base (e.g. mineral/vegetable oils) and/or the therapeutic agent. The types of preservatives used for this purpose include: ■ lipophilic antioxidants (to be dissolved within the non-aqueous vehicle), e.g. butylated hydroxyanisole (0.005–0.02%), butylated hydroxytoluene (0.007–0.1%),propyl gallate ( 1%) ■ hydrophilic antioxidants (to be dissolved in the aqueous phase), e.g. sodium metabisulphate (0.01–0.1%), sodium sulphite (0.1%). Manufacture of ointments and pastes : Manufacture of ointments and pastes The manufacture of ointments and pastes is similar to that described for emulsions and creams. The most straightforward example involves the dispersal of the powdered therapeutic agent into the preheated hydrocarbon base using a mechanical mixer. Heat is required to lower the viscosity of the base, thereby facilitating the mixing of the solid drug. If the therapeutic agent is incorporated into the ointment base as a separate liquid phase, the hydrophobic components and hydrophilic components are separately dissolved in the lipophilic and hydrophilic liquid phases, respectively (again with the aid of heating and mechanical mixing). In general (following dissolution of the various components), the two phases are maintained at circa 70°C and then mixed together (with stirring). The mixing of the two phases may be performed by: ■ mixing the two phases simultaneously ■ adding the aqueous phase to the non-aqueous phase. Following complete mixing, the temperature of the formulation is gradually reduced to room temperature. Slide 63: THANKS! You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.