Semisolid Dosage Forms 312 PHT

Objectives - To introduce the student to the structure, functions and topical treatment of human skin - To deal with the principles of membrane diffusion, skin transport and properties affecting transdermal delivery - To identify dermatological vehicles and methods of preparation - To identify new trends in semisolid dosage form

SEMISOLID PREPRATIONS DEFINITION: Semisolid dosage forms are products of semisolid consistency and applied to skin or mucous membranes for therapeutic or protective action or cosmetic function.

IDEAL PROPERTIES OF SEMISOLID DOSAGE FORMS 1.PHYSICAL PROPERTIES: - a) Smooth texture b) Elegant in appearance c) Non dehydrating d) Non gritty e) Non greasy and non staining f) Non hygroscopic

IDEAL PROPERTIES OF SEMISOLID DOSAGE FORMS 2 IDEAL PROPERTIES OF SEMISOLID DOSAGE FORMS 2. PHYSIOLOGICAL PROPERTIES: - a) Non irritating b) Do not alter membrane / skin functioning c) Miscible with skin secretion d) Have low sensitization effect 3. APPLICATION PROPERTIES: - a) Easily applicable with efficient drug release b) High aqueous washability

TYPES OF CONVENTIONAL SEMISOLID DOSAGE FORMS 1 TYPES OF CONVENTIONAL SEMISOLID DOSAGE FORMS 1. OINTMENTS:- - They are soft hydrocarbon based semisolid preparations, e.g. pertrolatum. - Since they are mostly of greasy nature so they stain cloths, are generally poor solvent for most drugs, and usuallydecrease the drug delivery capabilities of the system.

TYPES OF CONVENTIONAL SEMISOLID DOSAGE FORMS 2 TYPES OF CONVENTIONAL SEMISOLID DOSAGE FORMS 2. CREAMS : - - They are viscous semisolid emulsion system with opaque appearance compared with the translucent ointments. Consistency and rheological characters depend on weather the cream is w/o or o/w. - Properly designed O/W creams are elegant drug delivery system, pleasing in both appearance and feel aftar pplication. - O/W creams are non greasy and are rinsable. They are good for most topical purposes

TYPES OF CONVENTIONAL SEMISOLID DOSAGE FORMS 3. PASTES:- - Pastes are basically ointments into which a high percentage of insoluble solid has been added. The extraordinary amount of particulate matter stiffens the system. - Pastes make particularly good protective barrier when placed on the skin chemicals before they ever reach the skin. - Like ointments, paste forms an unbroken relatively water – impermeable film. Unlike ointments, the film is opaque and therefore, an effective sun block accordingly.

TYPES OF CONVENTIONAL SEMISOLID DOSAGE FORMS 4. GELS (JELLIES) :- - Gels are semisolid coherent system in which a liquid phase is constrained within a polymeric matrix (consisting of natural or synthetic gum) having high degree of physical or chemical cross-linking. - Gels are aqueous colloidal suspensions of the hydrated forms of insoluble medicament. - Gels are transparent or translucent non-greasy semisolid gels. - They are used for medication or lubrication.

TYPES OF CONVENTIONAL SEMISOLID DOSAGE FORMS 5 TYPES OF CONVENTIONAL SEMISOLID DOSAGE FORMS 5. POULTICES:- It is soft, viscous, pasty preparation for external use. They are applied to skin while they are warm, after spreading on or between layers of cloth . Poultice must retain heat for a considerable time because they are intended to supply warmth to inflamed parts of body. - Poultices act by increasing blood flow, relaxing tense muscles, soothing inflamed tissues, or drawing toxins from an infected area. Thus, they can be used to relieve the pain and inflammation associated with abscesses; e.g. Kaolin poultice (B.P.C.)

TYPES OF CONVENTIONAL SEMISOLID DOSAGE FORMS 7 SEMISOLID FOAMS:- - Foams are system in which air or some other gas is emulsified in liquid phase to the point of stiffening. - E.g. shaving creams, whipped creams, aerosolized shaving creams.

- Conventional topical vehicles, such as ointments, creams or gels, predominantly exert their effect by releasing the drug onto the skin surface, and the drug molecules then diffuse through the skin layers. - The extent and duration of diffusion depends on the (1) physicochemical properties of the drug, (2) the type of base and (3) skin condition. - In general, the modification of drug absorption kinetics by these vehicles is the result of their ability to provide increased hydration by occlusion or some other mechanism.

Topical preparations - Preparations for dermal use - Preparations for transdermal use (percutaneous absorption)

Dermal and transdermal drug delivery - Semisolid dosage forms for dermatological drug therapy are intended to produce desired therapeutic action at specific sites in the epidermal tissue. - A drug’s ability to penetrate the skin’s epidermis, dermis, and subcutaneous fat layers will lead to transdermal (percutaneous) drug delivery giving rise to systemic action. - Therefore, the extent the drug can travel through the different skin layers determine the delivery system.

Why Transdermal drug delivery? - Avoiding hepatic first pass effect - Continuous drug delivery - Fewer side effect - Therapy can be terminated at any time - Improved patient compliances Disadvantages: - cosmetically non-appealing - may display erratic (irregular) absorption

The fraction of the drug that penetrate the skin via any route depends on: – The physicochemical nature of the drug, specially its size, solubility and partition coefficient – The site and condition of the skin – The formulation – How vehicle component temporarily change the properties of the stratum corneum

Skin Permeability - Basic principle of diffusion through membranes Fick’s Law of Diffusion DAK/ h) (C 1-C2)) = dQ /dt dQ/dt - rate of diffusion D - diffusion coefficient A - surface area of membrane K - partition coefficient h - membrane thickness C1 - C2 = concentration difference for solute Generally, C1>>C2

Where P - permeability constant Skin Permeability Since D, K, and h are constant for a given drug/membrane; and given that C1>>C2: dQ / dt = PC1 Where P - permeability constant

Ideal molecular properties for drug Penetration - A low molecular weight (generally less than 500 Daltons) - An adequate solubility in oil and water - A balanced partition coefficient - A low melting point - Potent drug (maximum 50 mg/day)

Factors Affecting Transdermal Delivery - Physiological factors - Physicochemical factors

PHYSIOLOGICAL FACTORS 1. Skin condition – Intact skin is a barrier – Damaged skin more permeable – Diseased skin usually more permeable 2. Skin age - babies and children – greater area/weight than adult- absorb more drug e.g. steroids - premature infants- no stratum corneum - e.g. the use of topical caffeine for breathing difficulties

PHYSIOLOGICAL FACTORS 3. Skin hydration - important as it usually promotes permeation principle factor - Rank order (decreasing): - occlusive film - ointment - cream 4. Regional skin site - wide variation, e.g. face to foot

PHYSICOCHEMICAL FACTORS 1. Temperature and pH - diffusion depends on temperature(direct relationship). - nonionic molecules is more permeable than ionic - Stratum corneum, pH = 4.5 – 6 - How pH affect drug penetration??? ?

PHYSICOCHEMICAL FACTORS 2. Drug concentration obeys Fick’s law dQ/dt = KDC/h 3. Partition coefficient - also obeys Fick’s law - moderate value (Why????) 4. Diffusion coefficient 5. Molecular size - absorption should be inversely proportion to size (M.Wt.)

Topical dosage forms - Ointments - Creams - Pastes - Gels/jellies - Solution - Plasters - Aerosols - Powders

Ointments An ointment is a viscous semisolid preparation used topically on a variety of body surfaces. These include the skin and the mucus membranes of the eye (an eye ointment), vagina, anus, and nose. An ointment may or may not be medicated. Typically used as: Emollients to make skin more pliable Protective barriers Vehicles in which to incorporate medication

Ointment 1.2. Ointment Bases - Semisolid bases do not only act as the carriers of the medicaments, but they also control the extent of absorption of medicaments incorporated therin. - An ointment base should be compatible with skin, stable, smooth, non-irritating, non-sensitizing, inert, capable of absorbing water or other liquid preparations, and of releasing the incorporated medicament, readily. - A base for ophthalmic semisolids must be non-irritating to the eye, and It should also be sterilizable conveniently.

Appropriate Selection of Ointment Base: Selection of ointment base depends on the following: 1. Desired release rate of the drug substance from the ointment base. 2. Rate and extent of topical or percutaneous drug absorption. 3. Desirability of occlusion of moisture from skin. 4. Stability of the drug in the ointment base. 5. Effect of drug on the consistency of base. 6. Easy removal of base on washing. 7. Characteristic of the surface to which it is applied

Ointment Bases - Ointment bases may be classified in several ways but the following classification based on composition is generally used which are as follow, A) Oleaginous (hydrocarbon) base. B) Absorption base. C) Emulsion base. D) Water soluble base.

Ointment bases A) Oleaginous (hydrocarbon) bases: - This is a purified mix of liquid, semi-solid or- solid hydrocarbons from petroleum - Most of the early ointment bases used to be exclusively oleaginous in nature but nowadays the materials obtained from plant, animal, as well as synthetic origin are employed as oleaginous ointment bases. - Combinations of these materials can produce a wide range of melting points and viscosities

Ointment bases A) Oleaginous (hydrocarbon) bases: - These bases are: - Immiscible with water (they are difficult to wash off) - Not absorbed by the skin, remain on the skin for prolonged period of time without “drying out” - Absorb very little water from formulation or from skin exudates. - Inhibit water loss from the skin by forming a water proof film (OCCLUSIVE DRESSING). - Improving hydration, may encourage penetration of the medication through skin. Examples: Vaseline, hard paraffin, liquid paraffin, white ointment Uses: protectants, emollient, and vehicle for solid drugs

Ointment bases B) Absorption (Emulsifiable) Bases: - Absorption bases (also called emulsifiable bases) are mostly W/O type emulsions and have capacity to absorb considerable quantities of water or aqueous solution without marked changes in consistency.

Ointment bases Absorption bases are: - less occlusive than the hydrocarbon bases. - Incorporation of aqueous solution is possible. - easier to spread. - good emollients - They hydrate the stratum corneum. - Not easily removed from the skin with water washing (external phase is oleaginous) - Uses: protectants, emollient, and vehicle for aqueous solutions and solid drugs

Ointment bases (cont.) Absorption base (cont.) - Lanolin, anhydrous lanolin, wool fat, wool wax (obtained from wool of sheep) - This is a type of wax- like that can absorb about 50% of its weight of water and is used in ointments in which the proportion of aqueous fluid is too large for incorporation into a hydrocarbon base. - Wool fat is a major constituent of Simple Ointment BP - Other examples: hydrous lanolin, bees wax and cholesterol (they are added to some ointment bases to increase their water-absorbing power)

Ointment bases (cont.) (C) Emulsion Bases: - They are either w/o or o/w - Hydrophilic Ointment USP - Cold cream: W/O emulsions, emollient, cleansing, not water washable, non occlusive, shiny appearance, not need glycerin. - Vanishing cream: O/W emulsion contains large % of water and humectant. An excess of stearic acid in the formula helps to form a thin film when the water evaporates.

Ointment bases (cont.) Properties of Emulsion bases: - Water-washable, easier to remove - Non/less greasy - Can be diluted with water Non/less occlusive - Better cosmetic appearance - Better compliance; Patients prefer cream to an ointment because the cream spreads more readily, - less greasy, evaporating water soothes the inflamed tissue. Uses: Cleansing creams, emollients and vehicle for solid and liquid drugs.

D) Water Soluble Bases: - - Water soluble and water washable “greaseless”, - Because they soften with the addition of water, large amounts of aqueous solutions are not effectively incorporated into these bases. Uses: drug vehicle

D) Water Soluble Bases (cont D) Water Soluble Bases (cont.): - The water-soluble bases have the advantages of being: - Water soluble and washable - Non-greasy, non-staining - Non/less occlusive - Lipid free - Relatively inert - Does not support mold growth - Little hydrolysis, stable -Disadvantages: May dehydrate skin and hinder percutaneous absorption.

- Polyethylene glycol (so called macrogols or carbowax) are mixtures of poly-condensation products of ethylene oxide and water and they are described by their average molecular weights (viscous liquids to waxy solids). - Different grades of cabowaxes are available which are designated by a number roughly representing their average molecular weights e.g.- PEG 200, PEG 400, PEG1000, PEG1540, and PEG 6000

A general rule is that: - For wet lesions the patient should use an aqueous dressing, - For dry skin a lipophilic base is best.

Selection of the appropriate base - Desired release rate of drug substance - Desirability for topical or percutaneous absorption - Desirability of occlusion - Stability of drug in ointment - Effect of drug on ointment base - Desire for easy removable

METHODS OF OINTMENT PREPARATION 1 BY TRITURATION:- In this finely subdivided insoluble medicaments are evenly distributed by grinding with a small amount of the base followed by dilution with gradually increasing amounts of the base. 2 BY FUSION:- When soft fats or waxes are to be incorporated with hard fats or waxes then of this to be melted to get homogenous mixture with stirring. - ingredients are melted together in descending order of their melting points. 3 BY OINTMENT MILLS:- It is used for large scale production where triple roller mill is utilized which is faster than others.

Requirement for ointments - Microbial content: do not need to be sterile, but must meet the FDA requirement of the test for absence of bacteria such as S. areus and P. aeruginosa for dermatological products. - Packaging, storage, labeling: (label should include the type of base used) - Additional standards: viscosity, in vitro release

CREAM - Semisolid preparations containing one or more medicinal agents dissolved in either an o/w or w/o emulsion or in another type of water-washable base. - Typically of low viscosity, two phase system (w/o or o/w), compared to ointment. - Appears “creamy white” due to the scattering of light. - Traditionally, it is the w/o cold cream Currently and most commonly, it is the o/w- emulsion.

Creams as drug delivery systems - Good patient acceptance - Water evaporation concentrates drug on skin surface Examples; Vanishing cream: o/w with high % of water and stearic acid. Cold cream: (an emulsion for softening and cleansing the skin): w/o, white wax, spermaceti, almond oil, sodium borate.

CREAM Important in creams -Ideal properties of emulsifier includes, a) Must reduce surface tension for proper emulsification. b) Prevents coalescence. c)Effective at low concentration

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