Topical delivery dosage forms

1. Topical delivery dosage forms Ointments Definition and applications Classification Hydrocarbon bases Absorption bases Water-removable bases Water-soluble bases Selection of ointment bases Preparation of ointments Some requirements for ointments Other dosage forms: cream, gel/jelly, paste

2. 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

3. Ointment bases • Hydrocarbon • Absorption bases • Water-removable bases • Water-soluble bases

4. Hydrocarbon bases • Petrolatum, USP Yellow petrolatum/petrolatum jelly Vaseline (Chesebrough-Ponds/Unilever) (vahser-elaion) Melts at 38-60oC • White petrolatum, USP Decolored petrolatum, White petroleum jelly/white vaseline • Yellow ointment, USP Yellow wax (5%, w/w), petrolatum (95%) • White ointment, USP White wax/white petrolatum

5. 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.

6. 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.

7. 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.

8. Occlusive and skin hydration From S. Hoag, U Maryland

9. 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, water-proofing wax, and raw material (such as in shoe polish).

10. Properties of absorption bases • Absorption bases (anhydrous) Emollient Occlusive Absorbs water Greasy • W/O emulsion Emollient Occlusive Contains water, absorbs additional water Greasy

11. Water-removable bases • Water-washable bases, O/W emulsion • Hydrophilic ointment, USP Methylparaben 0.25 g Propylparaben 0.15 SDS 10 Propylene alcohol 120 Stearyl alcohol 250 White petrolatum 250 Water 370 • Vanishing cream: o/w emulsion contains la large % of water 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

12. Properties of water-removable bases • Water-washable, easier to remove • Non/less greasy • Can be diluted with water • Non/less occlusive • Better cosmetic appearance • Better compliance

13. 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).

14. 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.

15. Properties of water-soluble bases • 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.

18. 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

19. 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.

20. 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.

21. 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.

22. 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.

23. 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

24. Topical dosage form • Ointments • Creams • Pastes • Gels/jellies • Solution • Plasters • Aerosols • Powders

25. 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.

26. 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.

27. 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.

29. 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

30. 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. • Two-phase system: magma/milk of magnesia/magnesia magma, a gelatinous precipate of magnesium hydroxide

31. Pastes • Semisolid contains a larger proportion of solid materials than ointments. • Stiffer than ointment • Good protective barriers Opague, water impermeable, prevent dehydration • Good absorbent Lasser’s plain zinc paste Zinc oxide 25% Starch, 25% White petrolatum, 50% Anthralin in for psoriasis