Transcript Topical Drug Delivery

Topical delivery dosage forms
1. Ointments
2. Definition and applications
3. Classification
4. Hydrocarbon bases
5. Absorption bases
6. Water-removable bases
7. Water-soluble bases
8. Selection of ointment bases
9. Preparation of ointments
10. Some requirements for ointments
11. Other dosage forms: cream, gel/jelly, paste
Ointments
• Ointments are semi-solid preparations intended for
external use. They are easily spread.
• Typically used as:
Emollients to make skin more pliable
Protective barriers
Vehicles in which to incorporate medication
Ointment bases
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Hydrocarbon
Absorption bases
Water-removable bases
Water-soluble bases
Hydrocarbon bases
1. Petrolatum, USP
Yellow petrolatum/petrolatum jelly
Vaseline (Chesebrough-Ponds/Unilever) (vahser-elaion)
Melts at 38-60oC
2. White petrolatum, USP
Decolored petrolatum,
White petroleum jelly/white vaseline
3. Yellow ointment, USP
Yellow wax (5%, w/w), petrolatum (95%)
4. White ointment, USP
White wax/white petrolatum
Mineral oil
• Liquid petrolatum
• Is a mixture of refined liquid saturated
hydrocarbons obtained from petroleum
• Levigating agent to incorporate lipiphilic
solids
• An excipient in topical formulations where
its emollient properties are exploited as an
ingredient in ointment bases.
Oleaginous bases
1. Synthetic esters:
glyceryl monostearate, isopropyl myristate,
isopropyl palmitate, butyl stearate, butyl
palmitate, and long-chain alcohol (cetyl alcohol,
stearyl alcohol, PEG)
2. Lanolin derivates:
Lanolin oil, hydrogenated lanolin
Comprehensive Pharmacy Review, 5th ed., by Shargel et al.
Hydrocarbon bases
• Oleaginous bases
• Emollient effect: hydrates skin due to sweat
accumulation
• Occlusive dressing
• Difficult to wash-off/remove
• Small amount of water can be incorporated into
it with difficulty and can be protective to water
labile drugs such as tetracycline and bacitracin.
• Is greasy and can stain clothing.
Occlusive and skin hydration
From S. Hoag, U Maryland
Absorption bases
• Those that permit the incorporation of aqueous
solution resulting in he formation of w/o
emulsions
--hydrophilic petrolatum, USP
Cholesterol 30 g, Stearyl alcohol 30 g
White wax 80 g, White petrolatum 860 g
--Aquaphor: A gentle healing ointment to help heal dry, cracked skin
(Petrolatum. Other Ingredients: Mineral Oil, Ceresin, Lanolin Alcohol,
Panthenol, Glycerin, Bisabolol)
• Those that are w/o emulsion
Hydrous lanolin: w/o emulsion containing 25% of water
lanolin USP: Anhydrous, contains < 0.25% of water, absorbs twice its weight
in water, also called wool wax, wool fat, or wool grease, a greasy yellow
substance from wool-bearing animals, acts as a skin ointment, waterproofing wax, and raw material (such as in shoe polish).
Properties of absorption bases
• Absorption bases (anhydrous)
Emollient
Occlusive
Absorbs water
Greasy
• W/O emulsion
Emollient
Occlusive
Contains water, absorbs additional water
Greasy
Water-removable bases
• Water-washable bases, O/W emulsion
• Hydrophilic ointment, USP
Methylparaben
Propylparaben
SDS
Propylene alcohol
Stearyl alcohol
White petrolatum
Water
0.25 g
0.15
10
120
250
250
370
• Vanishing cream: o/w emulsion contains la large % of water
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and humectant. An excess of stearic acid in the formula helps to
form a thin film when the water evaporates.
Dermovan: a hypoallergenic, greaseless emulsion
Unibase: non-greasy emulsion base has pH close to that of skin
Properties of water-removable bases
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Water-washable, easier to remove
Non/less greasy
Can be diluted with water
Non/less occlusive
Better cosmetic appearance
Better compliance
Water-soluble bases
• PEG ointment, NF
- PEG 3350 400 g, PEG 400 600 g
- Polyethylene glycol 200, 300, 400 (4-8oC), 600 (20- 25oC), 1000,
1450, 3350, 4000, 6000, 8000 and 20000
- Only a small amount of liquid (<5%) can be incorporated
- If 6-25% of liquid is to be incorporated, 50 g of the 400 g of PEG
3350 may be replaced with stearyl alcohol
• Examples
ZOVIRAX®, (acyclovir), GSK, Ointment 5%
BACTROBAN® SmithKline Beecham Mupirocin Topical
Antibiotic (Each g of ointment contains: mupirocin 20 mg (2%) in a
bland water-soluble ointment base consisting of PEG 400 and PEG
3 350 (PEG ointment, USP).
Water-soluble bases
• Glyceryl monstearate
polyhdric alcohol esters
wildly used in cosmetic and ointment bases
• Cellulose derivatives
Methylcellulose
Cellulose
Hydroxyethyl cellulose
• Carbopol/carbomer
synthetic high MW polymers of acrylic acid cross-linked with either
allysucrose or allyl ethers of pentaerythritol.
Properties of water-soluble bases
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Water soluble and washable
Non-greasy
Non/less occlusive
Lipid free
Synthetic base
Relatively inert
Does not support mold growth
Little hydrolysis, stable
May dehydrate skin and hinder percutaneous absorption.
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
Preparation of ointments
• Incorporation: components are mixed until a uniform preparation
is attained.
-- Incorporation of solid:
-- Incorporation of liquid:
• Fusion: All or some components are combined by being melted
together and cooled with constant stirring until congealed.
-- High melting temperature bases such as beewax, paraffin, stearyl
alcohol, and high Mw PEG.
• Ointments having emulsion bases usually
involve melting and emulsification steps.
Incorporation
• A spatula with a long, broad blade should be used
• Insoluble substances should be powdered finely in a
mortar and mixed with an equal amount of base until a
smooth mixture is obtained. The rest of the base is
added in increment.
• Levigation of powders into small portion of base is
facilitated by the use of levigating agents.
• Levigating agents:
Mineral oil for oily bases or bases where oil are the external phase
Glycerin for bases where water is the external phase.
Levigating agent should be equal in volume to the solid material.
• When liquid is added into an ointment, care must be taken to
consider the capacity of the ointment in accepting the liquid. When it
is necessary to add an aqueous preparation to a hydrophobic base,
the solution should be added into minimal amount of the hydrophilic
base first. The mixture should be then added into the hydrophobic
base.
Example
• Medication order
Sulfur (3-6%, usually)
Salicylic acid, 600 mg
White petrolatum, 30 g
The particle sizes of sulfur and salicylic acid are
reduced separately in a mortar and then blended
together. The powder mixture is then levigated
with the base using geometric dilution.
Fusion
• Used when the base contains solids that have higher
melting points. Also for solid medications that are readily
soluble in melted bases.
• The oil phase should be melted separately, starting with
materials having the highest melting point.
• The ingredients in the water phase are combined and
heated separately to temperature equal to above that of
the oil phase
• The two phases are them combined. If a w/o system is
desired, the hot aqueous phase is incorporated into the
hot oil phase with agitation.
• Volatile materials are added after the melted mixture
cools to desired temperature.
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.
• Minimum fill:
• Packaging, storage, labeling: (label should
include the type of base used)
• Additional standards: viscosity, in vitro release
Topical dosage form
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Ointments
Creams
Pastes
Gels/jellies
Solution
Plasters
Aerosols
Powders
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.
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
• Typically of low viscosity, two phase
system (w/o or o/w)
• 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.
Cold cream
• w/o emulsion frequently using a borax-beewax
combination as the emulsifying agent and mineral oil or
vegetable oil as the oily phase. A protective film remains
on the skin following the evaporation of the water. The
slow evaporation of water gives the skin a cooling effect.
• To prepare, melt white wax, spermaceti, and almond oil
together, adding host aqueous solution of sodium borate,
and stir until the mixture is cool.
• A formula
Water, 34.6%, Borax, 1, methylparaben, 0.25
Light mineral oil, 50%, synthetic beewax, 13, Glyceryl
monostearate, 1, propylparaben, 0.15.
Creams as drug delivery systems
• Good patient acceptance
• Water evaporation
concentrates drug on skin
surface
• Must avoid drug
crystallization
• Can add co-solvents such
as propylene glycol
Gels and jellies
• Jellies are water soluble bases prepared from natural
gums such as tragcanth, pectin, alginates, boroglycerin,
or from synthetic derivatives of natural substances such
as methylcellulose and NaCMC.
• Gels: semisolids consisting of dispersions of small or
large molecules in an aqueous liquid vehicle rendered
jelly-like through the addition of a gelling agent.
• Single-phase gel:
• Carbomers: high Mw water soluble polymers of acrylic acid cross-linked
with allyl ethers of sucrose or pentaerythritol.
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Two-phase system: magma/milk of magnesia/magnesia
magma, a gelatinous precipate of magnesium hydroxide
Pastes
• Semisolid contains a larger proportion of
solid materials than ointments.
• Stiffer than ointment
• Good protective barriers
Opague, water impermeable, prevent
dehydration
Lasser’s plain zinc paste
Zinc oxide 25%
• Good absorbent
Starch, 25%
White petrolatum, 50%
Anthralin in for psoriasis