Presentation on theme: "Topical delivery dosage forms"— Presentation transcript:
1Topical delivery dosage forms OintmentsDefinition and applicationsClassificationHydrocarbon basesAbsorption basesWater-removable basesWater-soluble basesSelection of ointment basesPreparation of ointmentsSome requirements for ointmentsOther dosage forms: cream, gel/jelly, paste
2OintmentsOintments are semi-solid preparations intended for external use. They are easily spread.Typically used as:Emollients to make skin more pliableProtective barriersVehicles in which to incorporate medicationBefore we talk about topical and transdermal drug delivery, we will introduce the ointment as a dosage form. Ointment itself alone can have some beneficial effects, such as being an emollients to make skin more pliable and to form a protective barrier. More importantly, we are interested in using ointment as a vehicle to carry medicinal chemicals.
3Ointment bases Hydrocarbon Absorption bases Water-removable bases Water-soluble basesUSP classified ointment as the following four different categories. Hydrocarbon, as its name indicates, is very lipophilic and oily. Therefore, it is very difficult to get water or other aqueous solutions inside it. Absorption bases are oily systems that are w/o emulsions or can become w/o emulsion upon the absorption of water or other aqueous solutions. Thus, it is possible to get some water into the systems. Water-removable or water washable bases are mainly o/w emulsions. This system is not messy and greasy. They are easy to apply and easily removable, and thus, preferred by costumers. Water soluble bases are prepared from water soluble polymers such as PEG. They are water removable and not greasy. However, this kind of systems do not have any occlusion activity.
4Hydrocarbon bases Petrolatum, USP Yellow petrolatum/petrolatum jelly Vaseline (Chesebrough-Ponds/Unilever) (vahser-elaion)Melts at 38-60oCWhite petrolatum, USPDecolored petrolatum,White petroleum jelly/white vaselineYellow ointment, USPYellow wax (5%, w/w), petrolatum (95%)White ointment, USPWhite wax/white petrolatumThe raw material for petroleum jelly was discovered in 1859 in Titusville, Pennsylvania where it was sticking to some of the first oil rigs in the U.S. The riggers hated the paraffin-like material because it caused the rigs to seize up, but they used it on cuts and burns because it hastened healing. Robert Chesebrough, a young chemist whose previous work, distilling kerosene from the oil of sperm whales, had been rendered obsolete by oil, went to Titusville to see what new materials might be created from the new fuel. Chesebrough took the unrefined black waxy crude back to his laboratory in Brooklyn to refine it and explore its medicinal possibilities.Chesebrough discovered that by distilling the lighter, thinner oil products from the crude, he could create a light-colored gel. Chesebrough patented the process of making petroleum jelly (U.S. Patent 127,568) in The process involved vacuum distillation of the crude material followed by filtration still residue through bone char.Before Chesebrough could try to sell it, he had to test it to see if it really worked on cuts and burns by using himself as the guinea pig. Having demonstrated the products efficacy on himself, Chesebrough was unable to sell any to drug stores until he travelled around New York State demonstrating his miracle vaseline. Before a rapt audience he'd burn his skin with acid or an open flame, then spread the clear jelly on his injuries, showing at the same time his past injuries, healed, he claimed, by his miracle product. To further create demand, he gave out free samples.Chesebrough opened his first factory in The term Vaseline was coined, according to some accounts, as a combination of the German word for water, Wasser (pronounced Vahser), and the Greek word for oil, elaion.Robert Chesebrough lived to the age of 96 and claimed to have eaten a spoonful of Vaseline everyday. He was such a believer in Vaseline that during a bout of pleurisy, he had his body completely covered with it from head to toe. He soon recovered.Eventually though, physicians have learned that Vaseline does not really have any medicinal effect or any effect on the blistering process. Vaseline’s effectiveness is due to the coating of cuts and burns which prevents germs from getting into the wound and because it keeps the burned skin moisturized. currying, stuffing, and oiling all kinds of leather. The finest grade of petroleum jelly is also adapted for use as a pomade for the hair. It is also used for treating chapped hands or lips, toenail fungus, and nosebleeds. Petroleum jelly may also be used as a lubricant when shaving with a razor.Yellow wax is purified wax obtained from the honeycomb of bee. Ointment was prepared by melting yellow wax on waterbath, adding petrolatum, and stir-cooling. It is a stiffening agent in ointment. it is straight chain esters. It helps of formation of w/o emulsion.
5Mineral oil Liquid petrolatum Is a mixture of refined liquid saturated hydrocarbons obtained from petroleumLevigating agent to incorporate lipiphilic solidsAn excipient in topical formulations where its emollient properties are exploited as an ingredient in ointment bases.
6Oleaginous bases 1. Synthetic esters: 2. Lanolin derivates: 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 lanolinSome books also include synthetic esters and lanolin into the oleaginous bases. One needs to be aware that this is not absolutely right. E.m. PEG is not oleaginous. It is water soluble. Lanoline and its derivates such as lanolin alcohols, and hydrous lanoline, they can be considered as a hydrocarbon base, but it is more like an absorption base because it can absorb quite a lot of water. Lanolin can absorb twice its weight of water. Mainly used for the formation of w/o emulsion.I will classify this as water soluble or removable.Comprehensive Pharmacy Review, 5th ed., by Shargel et al.
7Hydrocarbon bases Oleaginous bases Emollient effect: hydrates skin due to sweat accumulationOcclusive dressingDifficult to wash-off/removeSmall 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.Is also called oleaginous bases because they are oily. It has emollient effect when applied on skin to make skin softer. When applied on skin, it can prevent to evaporation of water, it has occlusion effect. This is important because as we will discuss later that increase water container in the stratum corneum can enhance the diffusion of certain drugs through the sc layer.
8Occlusive and skin hydration From S. Hoag, U Maryland
9Absorption basesThose that permit the incorporation of aqueous solution resulting in he formation of w/o emulsions--hydrophilic petrolatum, USPCholesterol 30 g, Stearyl alcohol 30 gWhite 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 emulsionHydrous lanolin: w/o emulsion containing 25% of waterlanolin 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).Hydrophilic petrolatum prepared by melting SA with wax in a steam bath, adding the chol with stirring until dissolved, add petrolatum, allow cooling.Aquaphor is a variation of hydrophilic petrolatum and has the capacity to absorb up to 3 times of its weight in water.Lanolin alcohol is a crude mixture of steroidal and triterpene alcohols, including not less than 30% of chol and % of isocholesterol. The portion of water that can be added into petrolatum is increased 3-fold by the addition of 5% of lanoline alcohol. Ceresin is a white wax. Panthenol is the alcohol analog of pantothenic acid (Vitamin B3) and has equivalent biological activity. Bisabolol has a weak sweet floral aroma and is used in various fragrances. It has also been used for hundreds of years in cosmetics because of its perceived skin healing properties. Bisabolol is known to have anti-irritant, anti-inflammatory and anti-microbial properties. Glycerin is a humectant to promote the retention of moisture.
10Properties of absorption bases Absorption bases (anhydrous)EmollientOcclusiveAbsorbs waterGreasyW/O emulsionContains water, absorbs additional water
11Water-removable bases Water-washable bases, O/W emulsionHydrophilic ointment, USPMethylparaben gPropylparabenSDSPropylene alcoholStearyl alcoholWhite petrolatumWaterVanishing 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 emulsionUnibase: non-greasy emulsion base has pH close to that of skinSA and petrolatum are melted together at about 75oC. The other agents, dissolved in purified water, are added with stirring until the mixture congeals/solidify. SDS is the emulsifying agents, SA and petrolatum is the oil phase. Propylene alcohol is a humectant.
12Properties of water-removable bases Water-washable, easier to removeNon/less greasyCan be diluted with waterNon/less occlusiveBetter cosmetic appearanceBetter compliance
13Water-soluble bases PEG ointment, NF Examples - PEG g, PEG g- Polyethylene glycol 200, 300, 400 (4-8oC), 600 ( oC), 1000, , 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 may be replaced with stearyl alcoholExamplesZOVIRAX®, (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 (PEG ointment, USP).Mupirocin exerts a bactericidal action against sensitive organisms by inhibiting bacterial protein synthesis. It reversibly and specifically binds to bacterial isoleucyl transfer-RNA synthetase. tag_IndicationsIndications Indications And Clinical Uses: For the topical treatment of the following when caused by sensitive strains of staphylococcus and streptococcus species: impetigo, superficially infected dermatoses, lesions which are moist and weeping.
14Water-soluble bases Glyceryl monstearate polyhdric alcohol esters wildly used in cosmetic and ointment basesCellulose derivativesMethylcelluloseCelluloseHydroxyethyl celluloseCarbopol/carbomersynthetic high MW polymers of acrylic acid cross-linked with either allysucrose or allyl ethers of pentaerythritol.
15Properties of water-soluble bases Water soluble and washableNon-greasyNon/less occlusiveLipid freeSynthetic baseRelatively inertDoes not support mold growthLittle hydrolysis, stableMay dehydrate skin and hinder percutaneous absorption.
18Selection of the appropriate base Desired release rate of drug substanceDesirability for topical or percutaneous absorptionDesirability of occlusionStability of drug in ointmentEffect of drug on ointment baseDesire for easy removable
19Preparation 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.
20Incorporation 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 phaseGlycerin 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.
21Example Medication order Sulfur (3-6%, usually) Salicylic acid, 600 mg White petrolatum, 30 gThe 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.
22FusionUsed 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 phaseThe 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.
23Requirement 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
24Topical dosage form Ointments Creams Pastes Gels/jellies Solution PlastersAerosolsPowdersSolutions and others will be talked in details in OTC dermatology.
25CreamSemisolid 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.
26Cream 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 creamCurrently and most commonly, it is the o/w emulsion.
27Cold creamw/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 formulaWater, 34.6%, Borax, 1, methylparaben, 0.25Light mineral oil, 50%, synthetic beewax, 13, Glyceryl monostearate, 1, propylparaben, 0.15.consists principally of cetyl palmitate (ester of cetyl alcohol and palmitic acid), C15H31COO-C16H33.
29Creams as drug delivery systems Good patient acceptanceWater evaporation concentrates drug on skin surfaceMust avoid drug crystallizationCan add co-solvents such as propylene glycol
30Gels and jelliesJellies 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
31PastesSemisolid contains a larger proportion of solid materials than ointments.Stiffer than ointmentGood protective barriersOpague, water impermeable, prevent dehydrationGood absorbentLasser’s plain zinc pasteZinc oxide 25%Starch, 25%White petrolatum, 50%Anthralin in for psoriasis