SEMISOLID DOSAGE FORMS

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

Routes of skin Penetration There are two diffusional routes to penetrate intact skin: The Transappendageal route: 1 2 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. The transappendageal route seems to be most important for ions and large polar molecules which hardly permeate through the stratum corneum. 1 2

The transepidermal route : Transepidermal transport means that molecules cross the intact horny layer

*The intercellular pathways 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

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 5. Solubility in mineral oil and water Factors concerning the nature of the drug

Factors concerning the nature of the vehicle 1. Spreadability of the vehicle Percutaneous absorption 2. Mixing with the sebum 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 4. Broken skin permit (remove of the stratum corneum)

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

Alteration of the hydration of the stratum 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: emulsifying agent 1 % 1 % Sodium Lauryl Sulfate emulsifying agent 25 % Stearyl Alcohol   oleaginous phase White Petrolatum   aqueous phase 12 % Propylene Glycol aqueous phase 37 % Purified Water 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).

AVERAGE MOLECULAR WEIGHT Clear viscous colorless liquid MOISTURE CONTENT MAX. HYDROXYL VALUE MELTING POINT AVERAGE MOLECULAR WEIGHT PH APPEARANCE AT 25° C PEG 1.0% 500-550 <65°C 190-210 4.0-7.0 Clear viscous colorless liquid PEG-200 340-394 <15°C 290-310 PEG-300 264-300 4-8°C 390-410 PEG-400 176-200 15-17°C 590-610 PEG-600 105-120 37-38°C 950-1050 White waxy solid PEG-1000 70-90 44-45°C 1450-1550 PEG-1500 50-70 45-46°C 1950-2050 White flakes PEG-2000 30-36 53-56 °C 3800-4200 PEG-4000 16-20 55-63 °C 5500-6500 PEG-6000

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.

ABSORPTION OINTMENT BASES Drug Incorporation Potential WATER-SOLUBLE OINTMENT BASES WATER-REMOVABLE ABSORPTION OINTMENT BASES OLEAINOUS G   Polyethylene Glycols (PEGs) Oleaginous base + Water (> 45%) + O/W surfac. (HLB >9) Oleaginous bases + w/o surfactant Oleaginous compounds Composition anhydrous, hydrous hydrous anhydrous Anhydrous Water Content hydrophilic Hydrophobic Affinity for Water moderate to easy easy difficult Spreadability washable non-washable Washability stable unstable oils poor; hydrocarbons better Stability Solid Aqueous solutions Non-aqueous solutions Aqueous solutions (small amounts) Solids Oils Oils (oil soluble drugs) Drug Incorporation Potential

ABSORPTION OINTMENT BASES WATER-SOLUBLE OINTMENT BASES WATER-REMOVABLE ABSORPTION OINTMENT BASES OLEAGINOUS Continue  good fair to good poor but > oleaginous Drug Release no yes Occlusiveness Drug vehicles Emollients Vehicles for solid, liquid, or non-hydrolyzable drugs Protectants Vehicles for aqueous solutions, solids, and non hydrolyzable drugs Vehicles for hydrolysable drugs Uses PEG Ointment Hydrophilic Ointment Hydrophilic Petrolatum (Aquaphor®), Anhydrous Lanolin Yellow White Ointment Examples

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

6 7 8 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

Preparation of Ointments depending on the nature of the ingredients ointments are prepared by two methods: Incorporation method Fusion method.

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

Ointment bases containing components as: 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

By melting the component having the lowest melting point first and adding the components of higher melting points in order of their individual melting points a lower temperature is usually sufficient to achieve fusion *This is due to the solvent action exerted by the first melted component on the other components

In the preparation of ointments having an emulsion type: Melting process and emulsification process are used The water­ immiscible components such as oil and waxes are melted together in a steam bath to about 70 to 75°C Aqueous solution of all of the heat-stable, water-soluble components is prepared in the amount of water in the formula and heated to the same temperature as the oleaginous components The aqueous solution is slowly added to the melted oleaginous mixture, with constant stirring

The temperature is maintained for 5 to 10 minutes to prevent crystallization of waxes. Then the mixture is slowly cooled with the stirring until congealing

Preservation of Ointments Semisolid preparations as ointments especially those utilizing bases which contain water require the addition of antimicrobial preservatives to inhibit the contamination Using preservatives as p­hydroxybenzoates, phenols, benzoic acid, sorbic acid, quaternary ammonium salts Ultra filtration of the vehicle and using aseptic manufacturing processes

Packaging and Storage of Ointments Semisolid preparations must be protected through proper packaging and storage from the destructive influences of air, light, moisture, and heat, and the possible chemical interactions between the preparation and the container

The jars Ointments are usually packaged either in jars or in tubes May be made of Plastic or glass, uncolored, colored green, amber, or blue, or opaque and porcelain-white. The jars Opaque and colored-glass containers are useful for ointments containing drugs that are light sensitive Jars for ointments may vary in size from as little as 1/2 oz to 1lb or more

The jars Ointment jars are filled by forcing the ointment down and along the sides of the jar to avoid the entrapment of air Ointments prepared by fusion may be poured directly into the ointment jars for congealing within the jar Most ointments must be stored at temperatures below 30°C to avoid the softening and liquefying of the base, to prevent settling of insoluble medicaments to the bottom of the containers to prevent separation of emulsion bases into two phases The jars

Tubes The collapsible tubes are made of tin or plastic Some tubes co-packaged with special tips when the ointment is to be used for rectal, ophthalmic, vaginal or nasal application Tubes of ointments for topical use are of 5 g to 30 g size Tubes of ointments for ophthalmic use are most commonly packaged in small, tin or plastic collapsible tubes holding about 3.5 g of ointment

Tubes are filled by pressure fillers from the open back end which is then closed and sealed Ointments in tubes are less exposed to air and contaminants and are more stable than ointments packaged in jars 1 3 2