Topical Semi-Solid Dosage Forms I - Shih

Topical drug products

Are applied to the skin or eyes mainly for local action. Do not result in significant drug concentrations in the blood and tissues. Cause fewer systemic adverse reaction. Different from transdermal which crosses the skin to get systemic effects.

Examples of topicals

Antiseptics, antifungals, eye drops, anti-inflammatory agents

Semisolid dosage forms

One or more active ingredients dissolved or dispersed uniformly in a suitable base and any excipients used.

Types of semisolid dosage forms

Ointments, creams, gels, lotions, topical oils, pastes

Ointments

Semisolid dosage forms for external applications to the skin or mucous membranes. May be medicated or non-medicated (protectants, lubricants). Generally opaque or translucent, heavy, oleaginous and insulating. Typically semisolid emulsions or suspensions. Contain either 50% hydrocarbons or PEF as the base and <20% water/volatiles

Ointment bases

May be used for physical effects or as vehicles as medicated ointments

1. Oleaginous (hydrocarbon) base

2. Absorption base (anhydrous absorption and water-in-oil bases)

3. Oil in water (water-removable base)

4. Water-soluble base

Oleaginous bases

Hydrocarbons, fat and oils

Insoluble in water

anhydrous

not water-washable

Do not absorb water

emollient

occlusive

greasy

Examples of oleaginous bases

white petrolatum

white ointment

vaseline

Advantages of oleaginous bases

not expensive

generally not reactive/irritating

good emollience, protectiveness, and conclusiveness

not water washable so stays on skin longer

Disadvantages of oleaginous bases

Patient discomfort - greasy

Not easily removed by washing

Cannot absorb water and liquid

Difficult to incorporate aqueous ingredients

Aqueous skin secretions do not readily dissipate

Petrolatum

Purified mixture of semisolid hydrocarbons obtained from petroleum

yellow or light amber in color

also known as yellow petrolatum and petroleum jelly

White petrolatum

Purified mixture of semisolid hydrocarbons from petroleum that has been decolorized. More aesthetically pleasing

Yellow ointment

50g yellow wax + 950 g petrolatum

Slightly greater viscosity than plain petrolatum

White ointment

Same as yellow ointment but substitution of white wax and white petrolatum in the formula

Anhydrous Absorption bases

Anhydrous absorption

hydrocarbon base w/o emulsifier

Insoluble in water

Emollient occlusive and greasy

Examples of anhydrous absorption bases

Lanolin

Aquaphor

Hydrophilic petrolatum

Water in oil emulsion absorption base

Hydrocarbon base with <45% water w/o an emulsifier

Insoluble in water

emollient greasy

Examples: Eucerin, nivea

Advantages of absorption bases

ability to absorb water and liquid

maintain emollience, protectiveness, and conclusiveness

do not wash off easily

Disadvantages of absorption bases

Patient discomfort

not easily removed

compatibility issues between drugs and emulsifiers

water causes hydrolysis of drugs

water can promote microbial growth

Water-removal bases

Hydrocarbon base + water o/w emulsifier

Insoluble in water but still water washable

contain water and can absorb water

not occlusive

non greasy

Ex: hydrophilic ointment, vanishing cream

Advantages of water-removeable bases

Non greasy

Easily water washable

Allow dissipation of skin secretions

absorb some water and liquid

can absorb limited amount of oil

Disadvantages of water removable base

Less emollient, protective or occlusive

compatibility issues between drugs and emulsifiers

may have similar drug compatibility and stability problem associated with water, preservatives requires

May dry out over time

Water soluble bases

Water soluble

water washable

may contain water

can absorb water

not occlusive or greasy

no oleaginous components

PEG ointment, cellulose, glyceryl monostearate

Advantages of water soluble bases

Water soluble

very easily

water washable

non-greasy

no residue

Disadvantages of water soluble bases

Can only absorb limited water or liquids before becoming lotion or dissolving the base

can be irritating to injured skin or mucous membranes

have little to no occlusive or emollient properties

may have similar drug compatibility and stability problems

requires preservatives

Considerations when choosing an appropriate base

Desire drug release rate

desired percutaneous and topical drug absorption

desirability of occlusion of moisture from the skin

Drug stability in ointment base

drug interactions with base

washability

characteristics of the surface on which the ointment is to be applied

Incorporation method

Components are mixed until uniform preparation is attained.

Room temperature blending

Levigation

Mix solid material in vehicle to make smooth dispersion then use mortar and pestle

Levigation

Process of moistening a powdered chemical before mixing it into a cream or ointment. Done to reduce the size of solid material before incorporation into ointment base.

Where is incorporation method used

Small scale laboratory - mortar and pestle, rubbing ingredients together on ointment slab. Also can use an unguator which is an electronic mortar and pestle

Fusion method

All or some of the components of an ointment are combined by being melted together and cooled with constant stirring until congealed.

High temperature blending, small scale in porcelain dish or glass beaker, large scale in steam jacketed kettles, once congealed the ointment may be passed through an ointment mill or rubbed with a spatula or in mortar to ensure uniform texture

Examples of fusion method

White ointment - melt wax, add petrolatum, heat, cool with stirring

Water soluble ointment - melt PEGs add together, cool with stirring

Consideration while preparing ointments

Microbial content: not sterile, need preservatives, ophthalmic must be sterile

Minimum fill: ensure proper contents compared with label amount

Packaging/storing: in wide mouth jars, light sensitive

Rheological (flow) behavior: viscosity

Water activity: pH

In vitro performance: release and permeation

Rheology

Study of flow of liquids and deformation of solid properties of matter.

Addresses the viscosity characteristics of the dosage form

Applies directly to mixing, manufacturing, packaging, and use of a formulation

Affects patient acceptability and biological availability

Studies shear force

Viscosity (n)

The resistance offered by liquid or fluid to flow

Higher means poorer flow

Shear force

Force to produce a velocity gradient between two parallel planes of a block of material.

Action: apply force to the top plate

Result: velocity gradient between two adjacent plates

Velocity equation

Shear stress/Shear rate

Shear stress

F/A

Shear rate

V/X

Newtonian flow

Characterized by constant viscosity regardless of the shear rates applied. Viscosity is a constant for a fluid at a given temperature and pressure. Increase in shear forces does not change viscosity of the liquid.

Non-Newtonian fluids

Characterized by change in viscosity characteristics with increasing shear rates. Flow includes plastic, pseudoplastic, and dilatant flow

Plastic flow

Behaves as solids under static conditions. A certain amount of force must be applied to the fluid before any flow is induced. Toothpaste, mayonnaise

Pseudoplastic fluids

Decreasing viscosity with increasing shear rate. Viscosity is not a constant value. Stirring decreases viscosity. The greater the force he greater the flow.

Paint, ketchup, ophthalmic ointments

Dilatant fluids

Increasing viscosity with increasing shear rate

n is not a constant value

Relatively rare in pharmaceuticals

oobleck

Thixotropy

Some gels become fluid upon agitation but resume their solid or semisolid state after remaining undisturbed for a period of time

Takes time to recover from applied stress

Has applications in density

Rheometers

Works for all types of fluids

Measures viscosity, thixotropy, shear stress, and shear strain

Wide rages of shear rate can be achieved