Semisolid Dosage Forms & Topical Drugs

Semisolid Dosage Forms

• Semisolid dosage forms include ointments, creams, and gels
• Intended for topical application to the skin, eyes, nose, vagina, or rectum
• Primarily deliver therapeutic agents for their effects
• Unmedicated versions offer physical protection or lubrication
• Used for local and systemic effects

Topical Drugs

• Designed to deliver drugs into the skin for treating skin disorders, with the skin as the target organ
• Transdermal products deliver drugs through the skin for systemic effects, the skin is not the target organ.
• Consists of the epidermis, the dermis, and subcutaneous fat
• Systemic drug absorption should be considered for pregnant or nursing mothers
• Ointments, creams, and gels are designed to deliver drugs systemically using penetration enhancers

Drug Movement Rate

• Drug concentration in the vehicle affects the movement rate
• Physicochemical properties (solubility, partition coefficient, pKa, molecular weight)
• Hydrophilic-lipophilic character and viscosity of the base or vehicle matters
• Skin conditions (broken, hydrated, etc.) also contribute

Ointments

• Semisolid preparations for external application to skin or mucous membranes
• Medicated or unmedicated
• Unmedicated ointments protect, emolliate, or lubricate
• Bases may be used for physical effects or as vehicles for medicated ointments

Ointment Base Groups

• Classified by the USP into four groups:
  • Oleaginous bases
  • Absorption bases
  • Water-removable bases
  • Water-soluble bases

Ideal Ointment Base Properties

• Stable and neutral
• Non-greasy, and non-degreasing
• Non-irritating and non-dehydrating
• Non-hygroscopic and water-removable
• Compatible with medications
• Free from objectionable odor and non-staining
• Suitable medium for water and lipid-soluble drugs
• Efficient on dry, oily, or moist skin
• Composed of readily available components with known chemical composition
• Easily compounded by the pharmacist
• Able to melt or soften at body temperature

Oleaginous Bases (Hydrocarbon Bases)

• Emollient effect
• Protect against moisture loss
• Effective as occlusive dressings
• Can remain on the skin for extended periods without drying
• Difficult to wash off due to water immiscibility
• Water and aqueous preparations can be incorporated, but only in small amounts and with difficulty
• Liquid petrolatum (mineral oil) may be used as the levigating agent when incorporating powdered substances

Examples of Oleaginous Bases

• Petrolatum ("Vaseline")
• White petrolatum ("White Vaseline")
• Yellow ointment
• White ointment

Petrolatum, USP

• Purified mixture of semisolid hydrocarbons from petroleum
• Yellow to light amber in color
• Also known as yellow petrolatum and petroleum jelly
• Vaseline is a commercial product

White Petrolatum, USP

• Purified mixture of semisolid hydrocarbons from petroleum but wholly or nearly decolorized
• Also known as white petroleum jelly
• White Vaseline is a commercial product

Yellow Ointment, USP ingredients for a 1,000g preparation

• 50g yellow wax
• 950g petrolatum
• Yellow wax is purified wax from the honeycomb of the bee

White Ointment, USP

• Differs from yellow ointment with white wax (bleached and purified) and white petrolatum

Ingredients for a 1,000g preparation

• 50g white wax
• 950g white petrolatum

Absorption Bases

• Permit the incorporation of solutions resulting in water/oil (w/o) emulsions (e.g., hydrophilic petrolatum)
• Permit the incorporation of additional quantities of aqueous solutions (e.g., lanolin)
• Used as emollients
• Not easily removed from the skin by water washing due to oleaginous external phase
• Do not offer the occlusion of oleaginous bases

Absorption Base Examples

• Hydrophilic petrolatum
• Lanolin
• Modified lanolin

Hydrophilic Petrolatum, USP ingredients for a 1,000g preparation

• 30g cholesterol
• 30g stearyl alcohol
• 80g white wax
• 860g white petrolatum
• Aquaphor and Aquabase are commercial products with the ability to absorb up to three times their weight in water
• Useful for incorporating water-soluble drugs like tobramycin sulfate into oleaginous ointments.

Lanolin, USP (Anhydrous Lanolin)

• Obtained from sheep wool
• Purified waxlike substance, cleaned, deodorized, and decolorized
• Contains no more than 0.25% water

Water-Removable Bases (Water-Washable)

• Oil-in-water emulsions (o/w) resembling creams
• External phase of the emulsion is aqueous making them easily washed from the skin
• Often called water-washable bases
• Can be diluted with water or aqueous solutions
• Can absorb serous discharges
• Hydrophilic Ointment, USP, is an example

Hydrophilic Ointment, USP ingredients for a 1,000g preparation

• 0.25g methylparaben
• 0.15g propylparaben
• 10g sodium lauryl sulfate
• 120g propylene glycol
• 250g stearyl alcohol
• 250g white petrolatum
• 370g purified water

Water-Soluble Bases (Greaseless)

• Lack oleaginous components and are completely water-washable
• Aqueous solutions cannot be effectively incorporated because they soften greatly with water

Water-Soluble Base Example

• Polyethylene Glycol Ointment NF

General Formula for 1,000g of PEG Ointment

• 400g PEG 335
• 600g PEG 4000

Ointment Base Selection

• The selection of an appropriate ointment base is on an assessment of factors, including drug release rate

Desirable ointment properties and characteristics include:

• Topical or systemic action
• Occlusion of moisture from the skin
• Drug stability in the ointment base
• Effect of drug on the consistency of the base
• Water wash ability of the base
• Surface characteristics for application
• Ointment is generally for dry, scaly skin
• Cream is for weeping or oozing surfaces

Ointment Preparation Methods

• Incorporation
• Fusion

Incorporation Method

• Components are mixed until uniform preparation is attained
• A pharmacist may mix components using mortar and pestle or rub them together on an ointment slab (glass or porcelain plate or pill tile)
• Hard rubber or silicone spatulas may be used when components react with metal

Preparing Ointments

• Thoroughly rub and work the components together until smooth and uniform
• Work with stainless steel spatula with a long, broad blade when incorporating solids
• Periodically removes ointment accumulation on the large spatula with a smaller one

Gummy Materials

• For incorporating gummy materials like camphor use pulverization by intervention
• Dissolve the material in a solvent, spread it on the pill tile, and let the solvent evaporate, leaving a thin film

Incorporation of Liquids

• Liquid substances or solutions of drugs are added after consideration of the ointment base's capacity to accept the volume required
• Small amounts of an aqueous solution are used for Oleaginous ointment
• Hydrophilic ointment bases readily accept aqueous solutions

Levigation in Ointment Preparation

• Reduces powder or crystalline material particle size before incorporation into the ointment base to avoid grittiness
• Done by levigating (mixing insoluble solid material in a vehicle for smooth dispersion, "wet grinding")
• The levigating agent (mineral oil or glycerin) should be physically and chemically compatible with the drug and base
• The levigating agent is used in an equal volume of the solid material
• A mortar and pestle are commonly used in levigation

Levigation Effects

• Reduces particle size
• Disperses the substance in the vehicle
• Affects neither the stability of the drug nor the efficacy of the product

Large-Scale Production

• Use ointment or roller mills can to force coarsely formed ointments
• Use stainless steel or ceramic rollers to produce uniformity/smoothness

Fusion Method

• Some or all ointment components are mixed, melted, and cooled with constant stirring until congealed
• Add heat-labile substances and volatile oils after cooling the mixture to prevent decomposition and volatilization

Fusion Method Cont.

• Substances may be added to the congealing mixture as:
  • Solutions
  • Insoluble powders levigated with a portion of the base
• Small scale: fusion may be done by using porcelain dish or glass beaker.
• Large Scale: carried out in large steam-jacketed kettles
• Pass through an ointment mill after congealing
  • "large scale"
• Rub with spatula
  • "small scale" to ensure uniform texture

Fusion Preparations Method

• Best for medicated ointments with beeswax, stearyl alcohol, or high molecular weight PEGs

Preparing a Melt

• Heat materials with the highest melting points to the lowest required temperature
• Then, add other substances, stirring constantly while cooling until the melt congeals
• This way, not all components are exposed to the highest temperature

Compendial Requirements for Ointments

• Ointments and other semisolid dosage forms must meet USP tests for:
  • Microbial content
  • Minimum fill
  • Packaging, storage, and labeling

Microbial Content

• Topical applications (except ophthalmic preparations) do not have to be sterile
• They must meet acceptable standards for microbial content
• Preparations with water tend to support microbial growth more than water-free ones
• Dermatological products should be free of Staphylococcus aureus and Pseudomonas aeruginosa bacteria
• Products for rectal, vaginal, and urethral application should be tested for yeasts and molds bacteria
• Products should contain preservatives

Common Antimicrobial Preservatives

• Methylparaben
• Propylparaben
• Phenols
• Benzoic acid
• Sorbic acid
• Quaternary ammonium salts
• Microbial limit tests are conducted for both raw materials and finished products
• USP states certain products should be routinely tested for microorganisms

Minimum Fill

• The USP's minimum fill test ensures the net weight or volume matches the labeled amount

Packaging, Storage, and Labeling

• Packaged in large-mouth ointment jars or metal/plastic tubes
• Topical dermatologic products are packaged in jars or tubes
• Ophthalmic, nasal, vaginal, and rectal semisolid products are packaged in tubes
• Jars and tubes should be compatible and stable with the intended product
• Ointment jars are made of clear or opaque glass or plastic
• Tubes are superior to jars and are lighter, cheaper, compatible with ingredients and protect from contamination
• Tubes are made of aluminum or plastic, sometimes with applicators

Storage and Labeling

• Semisolid preparations should be stored in well-closed containers
• Protect from contamination, separation from heat, a cool place
• Light-sensitive preparations are packaged in opaque or light-resistant containers
• USP requires labeling certain ointments and creams with the type of base used (water-soluble or water-insoluble)

Ophthalmic Ointments

• Sterile, unlike conventional ointments
• Ointment base qualities should include, non-irritating, permit medicinal substance diffusion that bathes the eye
• Ointment bases need to have softening point close to body temperature for comfort and drug release

Common Ophthalmic Ointment Base

• Mixtures of mineral oil and white petrolatum in medicated and non-medicated (lubricating) applications
• Medicinal agents are added as a solution or finely micronized powder
• Uniform, smooth ointment is achieved by fine milling

Residence Time and Drug Penetration

• General ocular drug penetration is limited by
  • Short surface residence time due to tearing
  • Small surface area of the cornea
  • The cornea's natural resistance to drug penetration Compared with ophthalmic solutions, gels and Ointments can provide more surface effects of the eye
• Ophthalmic ointments are cleared from the eye as slowly as 0.5% per minute
• Solutions can lose up to 16% of their volume per minute

Sterility and Preservation

• Ophthalmic ointments need to meet the USP Sterility tests and the test for metal particles
• Rendering an ophthalmic ointment sterile requires special aseptic techniques and processing
• Sterilize each ingredient before weighing and incorporating
  • Done to prevent terminal product sterilization ex: lack of steam penetration and owing to instability with dry heating
• Preservatives such as methyl/propylparaben combos, chlorobutanol, and benzalkonium chloride are added as needed
• Microscopic examination for metal particles must happen to a heat-melted ophthalmic ointment.

Pastes

• Semisolid preparations for skin application
• Higher proportion of solid material (e.g., 25%) than ointments which make them stiffer
• Can be prepared as ointments, mixing or heat to soften the base
• Levigating powder with a portion of the base instead of liquid makes these smooth
• Stiffer paste helps them remain in place after application and absorb serous secretions
• Not good for hairy areas because of stiffness and impenetrability
• A use is Zinc oxide paste contains 25% each of zinc oxide and starch and white petrolatum and
  • Absorb secretions better than zinc oxide ointment.

Creams

• Semisolid preparations with one or more medicinal dispersed in a water-in-oil (w/o) or oil-in-water (o/w) emulsion for external use
• Consistency and rheological properties depend on the emulsion type and solid in the internal phase
• Used topically, rectally, and vaginally
• Easier to spread and remove

Example of Creams

• Vanishing creams are oil in water emulsions (o/w) with high water, stearic acid, and oleaginous components Water evaporates, and leaves a thin layer of stearic acid and oleaginous components

Preparation of Creams

• Separate formula components : lipid and aqueous
• Lipid part: all water-insoluble components
• Aqueous part: water-soluble components
• Heat both to above the highest melting point
• Mix the phases, and stir until it congeals
• Preservative is often added if mixing immediately

Gels

• Semisolid systems of dispersed small or molecules in an aqueous liquid(jellies) by a gelling agent.

Gelling Agents

• Synthetic macromolecules like carbomer
• Cellulose derivatives such as CMC (Carboxymethylcellulose) or HPMC (hydroxypropyl methylcellulose)
• Natural gums like tragacanth
• Typically exhibit a usually translucent or transparent

Use of Gels

• Administered via skin, to mucous membrane of the eye, the nose, the vagina, and the rectum
• Gels thicken forming a thixotropic
• Must be shaken before liquefying and pouring for the mixture

Gel Preparation (Main Procedure)

• Disperse hydrophilic gelling agent in water with continuous stirring (at the correct temp)
• Drug is dissolved in solvent with the preservatives, and other additives
• Blend the two solutions

Gel Formulations

• Drug, solvents (alcohol and/or propylene glycol), antimicrobial preservatives (paraben/propy paraben), and stabilizers (edetate disodium).

Gelation Mechanism

• Junction zones are where adjacent polymer chains interact and fractions of them are involved
• Hydrophilic (physical) gels are linked by weaker intermolecular bonds such as hydrogen bonds

Gels in drug form:

1. Metronidazole (MetroGel Vaginal) has Carbomer 934P treats bacterial vaginosis
2. Clobetasol propionate (Temovate Gel) has Carbomer 934P, dermatologic, antipruritic
3. Cyanocobalamin (Nascobal) has Methylcellulose and is hematologic, nasal
4. Diclofenac sodium uses Voltaren Emulgel, transdermal

Emulgel

• Topical drug formulation is an emulsion and a gel, has a dual release
• Advantages allow hydrophobic drugs for choice these days
• Transparent, greaseless and can be removed with longer duration
• They contain diclofenac diethyl ammonium