SEMISOLID DOSAGE FORMS Include drug delivery systems and dosage forms intended to be applied to the skin. Ointments Pastes Creams Gels
Preparations are applied to the skin for: • Physical effects • skin protection, lubricants, emollients, drying agents • Medical effects • Treatment of skin conditions (non-systemic topical effect) • as skin infections, itching, burns, diaper rash, insect stings and bites, corns, calluses, warts, dandruff, acne, psoriasis, and eczema. • Systemic effect
The Skin • The skin has a wide variety of functions: • Protect the organism from water loss and • mechanical, chemical, microbial, and physical • influences.
Structure of the Skin • The skin is the largest human organ and is composed of: • A film of emulsified material present upon the surface of the skin composed of a complex mixture of sebum, sweat • Blood capillaries and nerve fibers • Sweat glands • Hair follicles • Three functional layers: • Epidermis, • Dermis (true skin) • Hypodermis (Subcutaneous fat layer).
The epidermis is the outermost layer of the skin • 0.02 to 5 mm thickness • It has five layers, • Horny layer • (stratum corneum) • The uppermost layer • Composed of dead epidermal cells forms the permeability barrier • Barrier layer (stratum germinativum) • Beneath the hornylayer • Composed of living epidermal cells
The stratum corneum consists of: Horny skin cells (corneocytes) which are connected via protein-rich attachments of the cell membrane The corneocytes are embedded in a lipid matrix in “Brick and mortar” structure. The corneocytes of hydrated keratin comprise the bricks and the epidermal lipids fill the space between the dead cells like mortar
1 2 Routes of skin Penetration There are two diffusional routes to penetrate intact skin: The Transappendageal route: Include transport via: 1-Hair follicles and sebaceous glands 2-Sweat glands • These routes avoid penetration through the stratum corneum and therefore known as shunt routes.
Although these routes offer high permeability, they are of minor importance because of their relatively small area, 0.1% of the total skin area. 1 2 • The transappendageal route seems to be most important for ions and large polar molecules which hardly permeate through the stratum corneum.
The transepidermal route : Transepidermal transport means that molecules cross the intact horny layer
Two potential micro-routes are existing *The transcellular (intracellular) rout *The intercellular pathways The principal pathway taken by drugs is decided by its partition coefficient Hydrophilic drugs partition into the intracellular pathways, whereas lipophilic drugs traverse the stratum corneum via the intercellular route.
Factors Affecting Percutaneous Absorption Percutaneous absorption is the absorption of substances from outside the skin to positions beneath the skin, including entrance into the blood stream. • Factors concerning the nature of the drug • Factors concerning the nature of the vehicle • Factors concerning the condition of the skin
Factors concerning the nature of the drug • 1. Drug concentration Percutaneous absorption • Drug partition coefficient (greater attraction to the skin • than to the vehicle) Percutaneous absorption • Molecular weight below 800 • Percutaneous absorption • Particle Size • Percutaneous absorption • 5. Solubility in mineral oil and water • Percutaneous absorption
Factors concerning the nature of the vehicle 1. Spreadability of the vehicle Percutaneous absorption 2. Mixing with the sebum Percutaneous absorption 3. Hydration of the skin Percutaneous absorption Oleaginous vehicles act as moisture barriers through which the sweat from the skin cannot pass, thus increased hydration of the skin beneath the vehicle and increase Percutaneous absorption.
Factors concerning the condition of the skin Transdermal absorption follow Fick’s First Law of Diffusion Js = Km D Cs E Js = Flux of solute through the skin Km = Distribution coefficient of drug between vehicle and stratum corneum Cs = Concentration difference of solute across the membrane D = Membrane Diffusion coefficient for drug in stratum corneum E = Thickness of stratum corneum
1. The thickness stratum corneum Percutaneous absorption 2. Multiple application dosing Percutaneous absorption than single Application 3. Time of contact with the skin Percutaneous absorption 4. Broken skin permit (remove of the stratum corneum) Percutaneous absorption
Percutaneous Absorption Enhancers • Mechanisms of action by which Materials enhance absorption through stratum corneum is either by • Enhancing drug release from the formulation to the skin • Reduction of the resistance of the stratum corneum by altering it physicochemical properties
This can be achieved by the following mechanisms: • Alteration of the hydration of the stratum corneum using occlusive formulations • Carrier mechanisms in the transport of ionisable drugs • Enhance absorption by directly influencing the stratum corneum (CHEMICALLY or PHYSICALLY)
Chemicals used to enhance absorption by directly influencing the stratum corneum • Chemicals interact with the keratin structure in the stratum • corneum and open the tight protein structure, this leads • increase the diffusion coefficient D for substances which use • the transcellular route: • Surfactants, Dimethylsulfoxide (DMSO) and Urea • Solvents extract lipids and making the stratum corneum more • permeable: Dimethylsulfoxide (DMSO) and Ethanol
Chemical enhancers which intercalate into the structured • lipids of the horny layer and disrupt the packing. Thus • make the regular structure more fluid and increases the • diffusion coefficient of drugs: • Azone, Oleic acid, and isopropyl myristate • Solvents increase solubility and improve partitioning: • Alcohol, acetone, polyethylene and propylene glycol
Ointments • Ointments are semisolid preparations intended for external application. • Ointments may be medicated or non-medicated • Non-medicated ointment bases used for their emollient, lubricating effect or as vehicles in the preparation of medicated ointments
Ointment Bases • Ointment bases are classified into 4 groups: • Hydrocarbon bases (Oleaginous Base) • Absorption bases • Water-removable bases • Water soluble bases
Hydrocarbon bases (oleaginous bases) • Water-free • Difficult to wash off • Aqueous preparations are difficult to be • incorporated into them • Used as occlusive dressings for their emollient effect • (helps the skin retain moisture) • It can treat diaper rash (protect skin from • urine) and dry skin (retain moisture) • Stable, don’t dry upon aging
Petrolatum (Soft Paraffin) Yellow Petrolatum (Vaseline) • Mixture of semisolid hydrocarbons obtained from petroleum. • Melts at temperatures between 38° and 60°C • Form an ointment-like gel with Polyethylene (PLASTIBASE) which is compatible with most medicaments. White Petrolatum (White Vaseline) • Decolorized petrolatum • More esthetically acceptable to patients than petrolatum.
Yellow Ointment (Simple Ointment) • Contains 5% of yellow wax and 95 % of petrolatum. • Yellow Wax, is the purified wax obtained from the honey White Ointment (Simple Ointment) • Contains 5% of White wax and 95 % of White petrolatum
Absorption Bases • An absorption base is an oleaginous base that permit the • incorporation of aqueous solutions, and can be used as • emollients • Like the oleaginous bases, • Absorption bases are not water washable • They can incorporate 50% of their volume water, • where aqueous solution first incorporated into the • absorption base, then added into the oleaginous base
There are two types of absorption bases: 1) Contains a w/o emulsifying agent: When water is taken up into the base, it will form a w/o emulsion (e.g. Hydrophilic Petrolatum and Anhydrous Lanolin) 2) Water-in-oil emulsions (emulsion bases) that permit the incorporation of small, additional quantities of aqueous solutions (e.g. Lanolin and Cold cream)
Hydrophilic Petrolatum (Aquaphor) Hydrophilic Petrolatum is composed of 3% cholesterol, 3% stearyl alcohol, 8% white wax, and 86% white petrolatum. It has the ability to absorb water (upto 3 times its weight), with formation of water-in-oil emulsion W/O
Anhydrous Lanolin (Wool Fat) It is insoluble in water, but mixes without separation with water twice its weight of water with the formation of a waterin-oil emulsion Lanolin (Hydrous Wool Fat) • Obtained from the wool of sheep • It is a water-in-oil emulsion W/O that contains between 25 and 30% water Additional water may be incorporated into lanolin by mixing
Water-Removable Bases oil-in-water emulsions • Oil in Water emulsions • Have the general formula: 30 % Emulsifying wax 50 % White soft Paraffin 20 % Liquid Paraffin • Water washable • They can be diluted with water or with aqueous solutions. “water-loving “ • They have the ability to absorb serous discharges in dermatologic conditions
Hydrophilic Ointment Have the general formula: Methyl and propyl parabens are used as preservatives
Water-Soluble Bases (greaseless bases) • Unlike water-removable bases, • which contain both water-soluble and water-insoluble • components, water-soluble bases contain only watersoluble • components with the absence of any oleaginous materials • Like water-removable bases, • They are water washable • Because they soften greatly with the addition of water, aqueous solutions are not preferred to be incorporated into these bases. They are better used for the incorporation of nonaqueous or solid substances
Polyethylene Glycol Ointments Polyethylene glycols are polymers of ethylene oxide and water represented by the formula HOCH2(CH2OCH2)nCH2OH The chain length varied to achieve polymers with different physical form (liquid, semisolid, or solid).
Preparation of polyethylene glycol ointment base: Combine polyethylene glycol 3350 (solid) 40 % and polyethylene glycol 400 (liquid) 60 % If an aqueous solution is to be incorporated into the base, substitution some of polyethylene glycol 3350 with an equal amount of stearyl alcohol would be advantageous to render the final product more firm.
Selection of the Appropriate Base The selection of the base of an ointment depends on many factors: Patient Factors The condition of the patient's skin, e.g. oozing or dry The rule in dermatology that if a patient's skin is dry-wet it, If it is wet-dry it if a patient's skin is dry, occlusive ointment base that retain moisture is preferable
Physicochemical Factors 1 The desired release rate of the drug from the ointment base The desired enhancement of the percutaneous absorption of the drug The desired occlusion of moisture from the skin by the base The stability of the drug in the ointment base, for a drug that hydrolyzes rapidly as antibiotics, a hydrocarbon base would provide the greatest stability The influence of the drug on the consistency of the ointment base 2 3 4 5
The influence of the drug on the consistency of the ointment base The desired washability of the base as for application to hairy regions, a Polyethylene Glycol base is preferred For ophthalmic ointments, non-irritant bases are desired. Absorption O/W emulsion bases and water soluble bases are irritants due to the effect of the surfactants in the base It is preferred to use yellow paraffin but not white due to the irritation effect of the bleaching agents 6 7 8
Incorporation method Fusion method. Preparation of Ointments depending on the nature of the ingredients ointments are prepared by two methods:
Incorporation method • A- INCORPORATION OF SOLIDS: • Using the geometric dilution method • The powdered components reduced to fine powders to • prevent grittiness • Fine powdered drugs are blended • Then powder are levigated with agent that is compatible • with the base, e.g., mineral oil or glycerin • The amount of levigating agent equal to the material to be • levigated
Solid materials soluble in a solvent that is compatible • with the product may first be dissolved • e.g., dissolve salicylic acid crystals in alcohol • Mix with a portion of the base until the product is smooth • and uniform • Another portion of the base is added to the • mixture • The process being repeated until all of the ointment base has been incorporated
Ointment roller mills resulting in a products • that are smooth and uniform in composition • and texture
INCORPORATION OF LIQUIDS • For aqueous solutions: • Water-absorbable or hydrophilic ointment bases are suitable • In oleaginous ointment base, a portion of the base must be replaced with a hydrophilic base, • Incorporates the solution in it, and mixes the product with the original base
For Alcoholic solutions • Oleaginous vehicles or emulsion bases are suitable • Other liquid materials as natural balsams • (Peru balsam) • It is difficult to be incorporated into ointment bases • Mix balsam with an equal portion of castor oil before • incorporating it into the base • This procedure reduces the surface tension of the balsam • and aid in distribution of the balsam through the vehicle
Fusion method Ointment bases containing components as: beeswax, paraffin, stearyl alcohol, and high molecular weight polyethylene glycols, which do not mix well by incorporation, are prepared by fusion
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 mixture during cooling and stirring Heat-labile and volatile substances are added when the temperature of the mixture is low enough
Many substances are added to the congealing mixture in solution, others are added as insoluble powders levigated with a portion of the base Once congealed, the ointment may be passed through an ointment mill to ensure a uniform texture
If the item having the highest melting point is melted first and the other components are added to this hot liquid, all the components will be subjected to this high temperature, irrespective of their own individual melting points