Ointments: Preparation & Evaluation of Drug Release
Upon completion of this exercise, you should be able to:
- Classify an ointment base formulation as 1 of 5 types.
- Describe the physical properties of ointment bases and determine the purposes for which they are best suited.
- Extemporaneously prepare each type of ointment base and incorporate a solid drug into it.
- Relate the composition and type of ointment base to the release of a drug contained therein.
Ointments are used topically for several purposes, e.g., as protectants, antiseptics, emollients, antipruritics, kerotolytics, and astringents. The vehicle or base of an ointment is of prime importance if the finished product is expected to function as any one of the above categories. In the case of a protective ointment, it serves to protect the skin against moisture, air, sun rays and other external factors. It is necessary that the ointment neither penetrates the human skin barriers nor facilitates the absorption of substances through this barrier. An antiseptic ointment is used to destroy or inhibit the growth of bacteria. Frequently bacterial infections are deeply seated; a base which has the capacity to either penetrate or dissolve and release the medication effectively is therefore desired. Ointments used for their emollient effect should be easy to apply, be non-greasy and effectively penetrate the skin.
Dermatological Formulations: Ointments and Pastes
Dermatological formulations are among the most frequently compounded products because of their wide range of potential uses. These include solutions (i.e., collodions, liniments, aqueous and oleaginous solutions), suspensions and gels, emulsions, lotions, and creams. Lotions can be either suspensions or emulsions but are fluid liquids that are typically used for their lubricating effect. Creams are emulsions and are typically opaque, thick liquids or soft solids used for their emollient properties. Creams also have the added feature that they tend to “vanish” or disappear with rubbing. Distinctions between lotions and creams are open to individual interpretation.
Other dermatological formulations that are not commonly compounded include aerosols, dusting powders, and devices such as transdermal patches, tapes, and gauzes. These formulations are typically manufactured.
This chapter will deal with two other dermatological formulations, ointments and pastes. Pastes have more solid material in them than ointments. These two formulations are also termed “semisolids” because they appear to be solid but still have fluid properties.
Local and Systemic Effects of Dermatological Formulations
Regardless of the formulation, all dermatological formulations are applied to the skin.
The skin is the largest and heaviest organ in the body and accounts for about 17% of a person’s weight. Its major function is to protect the underlying organ systems from trauma, temperature, humidity, harmful penetrations, moisture, radiation, and microorganisms. It is composed of three layers of stratified tissue: epidermis, dermis, and subcutaneous tissue. The thickness of the skin is 3 – 5 millimeters. The thickness of the skin varies with the different parts of the body. The thickest parts of the skin are the palms and soles and the thinnest parts are the eyelids and genitals. Within the structure of the skin are several skin appendages: hair follicles, sebaceous glands, sweat glands, and nails.
In normal skin, the epidermal cells are continually replenished by the formation of initially viable cells from the basal germinative layer. As the new cells develop, they displace the outer epidermal cells. The outer layer is called the stratum corneum and these cells are sloughed off to the environment. As the cells migrate to become the stratum corneum, they become flattened, lose their nuclei, and the organized cell contents becomes replaced with keratin fibrils. The turnover time from germination to sloughing is about 21 days.
It is the stratum corneum that is the barrier to drug penetration through the skin. The stratum corneum is approximately 10 microns thick. It can swell to approximately three times its original thickness and absorb about five times its weight in water. When the stratum corneum hydrates, it becomes more permeable. Therefore, occlusive dressings are often used to hydrate the stratum corneum and increase the penetration of certain drugs. Dermatoses such as eczema and psoriasis can also hydrate the stratum corneum and increase the absorption of some drugs.
Dermatological formulations produce a local drug effect either on or in the skin. Besides the specific therapeutic action of incorporated active drugs, the formulations also serve as protectants, lubricants, emollients, or drying agents. Examples of treatments using dermatological formulations include minor skin infections, itching, burns, diaper rash, insect stings and bites, athlete’s foot, corns, calluses, warts, dandruff, acne, psoriasis, and eczema.
Some dermatological formulations are intended to systemically deliver a drug. Percutaneous (through the skin) absorption is the result of three competing processes:
- the potential of the drug to cross the stratum corneum
- the potential of the drug to leave the formulation
- the influence of the formulation on the stratum corneum.
Although the percutaneous absorption of drugs is a complex process, several generalizations are possible:
- More drug is absorbed when the formulation is applied to a larger surface area.
- Formulations or dressings that increase the hydration of the skin generally enhance percutaneous absorption.
- The greater the amount of rubbing in or inunction of the formulation, the greater the absorption.
- The longer the formulation remains in contract with the skin, the greater will be the absorption.
Percutaneous administration affords an ease of administration not found in other routes, and patient compliance is generally good with dermatological formulations. There is also the possibility of continuous drug administration exemplified by the transdermal patches. In addition, dermatological formulations can be easily removed if necessary.
The major disadvantage of this route of administration is that the amount of drug that can be absorbed will be limited to about 2 mg/day. This may become a significant limitation if the route is being considered for systemic therapy. However, several chemicals have been found that promote the percutaneous absorption of drugs. These “penetration enhancers” improve the solubility of the active drug in the stratum corneum and facilite the diffusion of the drug through this barrier into the systemic circulation. Below is a list of penetration enhancers used in dermatological formulations. (reference 1) Other commonly used enhancers include DMSO (dimethyl sulfoxide), urea, and triethanolamide.
|Alcohols||methanol, ethanol, propanol, octanol|
|Fatty Alcohols||myristyl alcohol, cetyl alcohol, stearyl alcohol|
|Fatty Acids||myristic acid, stearic acid, oleic acid|
|Fatty Acid Ester||isopropyl myristate, isopropyl palmitate|
|Polyols||propylene glycol, polyethylene glycol, glycerol|
|Anionic surfactants||sodium lauryl sulfate|
|Cationic surfactant||benzalkonium chloride, cetylpyridinium chloride|
|Nonionic surfactants||Spans®, Tweens®, poloxamers, Miglyol®|
There are five (5) classes or types of ointment bases which are differentiated on the basis of their physical composition. These are:
- oleaginous bases
- absorption bases
- water in oil emulsion bases
- oil in water emulsion bases
- water soluble or water miscible bases
Each ointment base type has different physical characteristics and therapeutic uses based upon the nature of its components. The following table summarizes the composition, properties, and common uses of each of the five types. For more information consult Remington’s.
SUMMARY CHART: PROPERTIES OF OINTMENT BASES
|Oleaginous Ointment Bases||Absorption Ointment Bases||Water/Oil Emulsion Ointment Bases||Oil/Water Emulsion Ointment Bases||Water-miscible Ointment Bases|
|Composition||oleaginous compounds||oleaginous base + w/o surfactant||oleaginous base + water (< 45% w/w) + w/o surfactant (HLB <8)||oleaginous base + water (> 45% w/w) + o/w surfactant (HLB >9)||Polyethylene Glycols (PEGs)|
|Water Content||anhydrous||anhydrous||hydrous||hydrous||anhydrous, hydrous|
|Affinity for Water||hydrophobic||hydrophilic||hydrophilic||hydrophilic||hydrophilic|
|Spreadability||difficult||difficult||moderate to easy||easy||moderate to easy|
|Washability||nonwashable||nonwashable||non- or poorly washable||washable||washable|
|Stability||oils poor; hydrocarbons better||oils poor; hydrocarbons better||unstable, especially alkali soaps and natural colloids||unstable, especially alkali soaps and natural colloids; nonionics better||stable|
|Drug Incorporation Potential||solids or oils (oil solubles only)||solids, oils, and aqueous solutions (small amounts)||solids, oils, and aqueous solutions (small amounts)||solid and aqueous solutions (small amounts)||solid and aqueous solutions|
|Drug Release Potential*||poor||poor, but > oleaginous||fair to good||fair to good||good|
|Uses||protectants, emollients (+/-), vehicles for hydrolyzable drugs||protectants, emollients (+/-), vehicles for aqueous solutions, solids, and non-hydrolyzable drugs||emollients, cleansing creams, vehicles for solid, liquid, or non-hydrolyzable drugs||emollients, vehicles for solid, liquid, or non-hydrolyzable drugs||drug vehicles|
|Examples||White Petrolatum, White Ointment||Hydrophilic Petrolatum, Anhydrous Lanolin, Aquabase™, Aquaphor®, Polysorb®||Cold Cream type, Hydrous Lanolin, Rose Water Ointment, Hydrocream™, Eucerin®, Nivea®||Hydrophilic Ointment, Dermabase™, Velvachol®, Unibase®||PEG Ointment, Polybase™|
*Varies depending upon specific content of the ointment base and the relative polarity of the drug(s) incorporated. This table refers more generally to the release of a typical nonelectrolyte (primarily lipophilic) drug.
Prepare 120 g of each of the following five ointments on a w/w basis. One partner should prepare bases #1, 3 and 5 while the other prepares #2 and 4. Make sure that you follow closely the procedures for preparation.
General Comments About Compounding Ointment Bases
- Between 2 and 4 grams of an ointment may be lost in the compounding process. The ointment is lost as it adheres to beakers, ointment tiles, or ointment pads. To compensate for this loss, make an excess of the ointment. Some general rules might be to add 10% or 3 grams excess to the prescribed amount.
- When heat is used to melt ingredients, use a water bath or special low temperature hotplate. Most ingredients used in ointment bases will liquefy around 70°C These two heating devices provide adequate control over the heating and will ensure that the ingredients are not over heated. A water bath will only heat to the boiling point of water which is 100°C. Special “low temperature” hotplates (full range is 25°C to 120°C) are not a standard laboratory type hotplate; those hotplates heat at 125°C to 150°C at their lowest setting.
- When both an oil and aqueous phase are being mixed together to make an ointment, it is helpful to heat the aqueous phase a few degrees higher than the oil phase prior to mixing. The aqueous phase tends to cool faster than the oil phase and may cause premature solidification of some ingredients. However, use the lowest temperature possible and keep the time of heating as short as possible. This will minimize the quantity of water lost through evaporation.
- When melting a number of ingredients, melt the ingredient with the highest melting point first. Then gradually reduce the heat to melt the ingredient with the next lowest melting point. Continue this process until all ingredients have been added. This will ensure that the ingredients were exposed to the lowest possible temperature and thus enhance the stability of the final product.
- The cooling step in an ointment’s preparation is an important part of the compounding process.
- Do not accelerate the cooling process by putting the melt in water or ice. This will change the consistency of the final product making it more stiff than desired.
- If adding volatile ingredients such as oils, flavors, or drugs, add them when the product is “cool to the back of the hand.” The melt will still be fluid enough for adequate mixing but not hot enough to evaporate the ingredient.
- Ointments should be cooled until just a few degrees above solidification before they are poured into tubes or jars. They should be thick, viscous fluids. This will minimize “layering” of the ointment in the packaging container. However, this is not the preferred method of packing an ointment tube or jar.
- Most bases achieve their final consistency and texture several hours after they are compounded.
BASE NO. I: Oleaginous Base (White Ointment)
|White Wax||5%||________ g|
|White Petrolatum||95%||________ g|
Procedure for Preparation:
- Melt the white wax on a hot plate. No need to heat beyond 70 – 75°C
- When the wax has completely melted, add the petrolatum and allow the entire mixture to remain on the hot plate until liquefied.
- Following liquefication, remove from heat and allow the mixture to congeal. Stir the mixture until it begins to congeal.
BASE NO. II: Absorption Base
|Stearyl Alcohol||3%||________ g|
|White Wax||8%||________ g|
|White Petrolatum||86%||________ g|
Procedure for Preparation:
- Melt the stearyl alcohol, white wax, and petrolatum together on a hot plate.
- Add the cholesterol to the mixture; stir until completely dissolved.
- Remove the mixture from the hot plate and stir until congealed.
BASE NO. III: W/O Emulsion Base (Cold Cream type base)
|White wax||12.0%||________ g|
|Cetyl Esters Wax (or Spermaceti)||12.5%||________ g|
|Mineral Oil (Sp Gr = 0.9)||56.0%||________ g||________ ml|
|Sodium Borate||0.5%||________ g|
|Water||19.0%||________ g||________ ml|
Procedure for Preparation:
- Melt the white wax and spermaceti on a hot plate.
- Add the mineral oil to this mixture and bring the temperature to 70°C.
- Dissolve the sodium borate in water.
- Heat the sodium borate solution to 70°C.
- When both phases have reached the desired temperature, remove both phases from the hot plate and add the aqueous phase slowly and with constant stirring to the oil phase.
- Stir briskly and continuously until congealed.
BASE NO. IV: O/W Emulsion Base (Hydrophilic Ointment)
|Sodium Lauryl Sulfate||1.0%||________ g|
|Propylene Glycol (SP Gr = 1.035)||12.0%||________ g||________ ml|
|Stearyl Alcohol||25.0%||________ g|
|White Petrolatum||25.0%||________ g|
|Purified Water||37.0%||________ g||________ ml|
Procedure for Preparation:
- Melt the stearyl alcohol and white petrolatum on a hot plate.
- Heat this mixture to 70°C.
- Dissolve remaining ingredients in water and heat the solution to 70° C.
- Add the oleaginous phase slowly to the aqueous phase, stirring constantly.
- Remove from heat and stir the mixture until it congeals.
BASE NO. V: Water Soluble Base
|Polyethylene Glycol 400 (SP Gr = 1.12)||60%||________ g||________ ml|
|Polyethylene Glycol 3350||40%||________ g|
Procedure for Preparation:
- Melt the PEG 400 and Carbowax 3350 on a hot plate.
- Warm the mixture to about 65°C.
- Remove from the hot plate and stir until congealed.
How To Pack An Ointment Jar
Sealing an Ointment Tube
|Prepare the ointment and place inside the tube. Leave about 1″ empty at the bottom of the tube. Flatten about 1″ of the bottom of the tube with a spatula.|
In the next several steps, you will make 3 folds in the ointment tube.
Make a crease about 1/8″ from the bottom of the tube with the edge of the spatula. Fold the tube completely over the spatula.
With the first fold facing up, make a crease about 1/4″ from the bottom of the tube.
|Fold the tube completely over the spatula…|
|…a side view.|
Turn the tube over (i.e., no folds showing), and make a crease about 1/8″ from the bottom of the tube. This time, do not fold the tube completely over the spatula, but only until the tube is perpendicular to the surface.
|A “T” will appear in the bottom of the tube…|
|…a side view.|
|Place the metal clip on the “T”…|
|… and crimp with pliers or a tube crimper.|
|Place the tube in the ointment tube box, and affix appropriate label(s).|
Filling an Ointment Tube
An ointment slab (left) and large metal spatulas should be used for this process. Ointment slabs are either ground glass plates or porcelain and provide a hard, nonabsorbable surface for mixing.
Ointment pads (right) have the advantage that “clean-up” is quicker, but the ointment can soak into the parchment paper. Further, the paper can absorb liquids and may tear when using sticky or thick ointments. Large metal spatulas are used instead of smaller metal spatulas because they have the proper combination of flexibility and strength for adequate shearing and mixing. Black rubber or plastic spatulas are not used in ointment compounding.
If preparing a large quantity of ointment, a mixing device of some type might be used instead of the ointment slab and spatula. Two options are an ointment mill, and an “electric mortar and pestle.” Ointment mills produce very smooth and elegant ointments. The electric mortar and pestle allows the formulation of the ointment and the dispensing of the formulation to be done in the same container. (Photos courtesy of Professional Compounding Centers of America, Inc., Houston, Texas)
Levigation and Incorporation
Levigating a Powder
Incorporating a Drug into an Ointment
|The drug is usually the smaller quantity of the two ingredients. So geometric dilution will be used to “dilute” the smaller quantity drug into the ointment. The drug in this demonstration is Calamine (the pink powder).|
|Add an amount of the ointment that is approximately equal in size to the Calamine.|
|Spatulate the mixture.|
|Add a second portion of the ointment to the spatulated mixture that is about the same size.|
|Spatulate that mixture.|
|Continue adding portion of the ointment to the spatulated mixture in approximately equal sizes until all of the ointment is used. Spatulate after each addition.|
To incorporate an insoluble drug into these bases, pulverize the powder on the pill tile or with a mortar and pestle (above/right). Use a levigating agent to wet the powder and then incorporate the wetted powder into the ointment base. Generally, the amount of drug to be incorporated into the ointment will be much less than the amount of ointment. In other words, a small amount of drug will be incorporated into a large amount of ointment. The process of geometric dilution will “dilute” the drug into the ointment. Geometric dilution involves a series of dilution steps. It begins by incorporating the drug into an amount of ointment of approximately the same size. Then a second amount of ointment approximately equal to the first mixture is added and mixed. This step-wise dilution process is continued all of the ointment has been used.
A good levigating agent is mineral oil since it is compatible with oleaginous bases. Sometimes using a small quantity of the base itself as the levigating agent is sufficient.
Soluble drugs can be incorporated into oleaginous bases by fusion. The base is liquefied over low heat (not to exceed 70°C) and then the drug is added to the molten base. The mixture is then allowed to cool with occasional stirring.
An absorption base is an oleaginous base that contains a w/o emulsifying agent. When water is taken up into the base, it will form a w/o emulsion. Absorption bases typically can incorporate about 50% of their volume in water.
Incorporating insoluble drugs into these bases can be done mechanically or by fusion. The final destination (internal or external phase of the emulsion) of the drug must be considered when selecting a levigating agent. If the drug will reside in the internal phase (water phase), then the levigating agent should be water soluble or miscible. Water, glycerin, alcohol, or propylene glycol would be suitable levigating agents. If the drug will reside in the external phase, then mineral oil should be used.
Water soluble ingredients can be added to the water phase of the w/o emulsion. If the drug will dissolve in a small amount of water, the aqueous solution can be added directly to the base using a pill tile and spatula. If a larger quantity of water is needed to solubilize the drug or if an aqueous solution is being added to the base, heat may be needed to compound the formulation. It may be necessary to add additional emulsifier to the emulsion to accommodate the added water. Some commercial emulsions do have the necessary excess emulsifier.
W/O Emulsion Bases
Oils and insoluble powders can be directly incorporated into the external phase using a pill tile and spatula. If a levigating agent is to be used with the insoluble powders, it should be miscible with the oil phase; mineral oil would be a suitable agent. Levigating agents may be needed with larger quantities of insoluble powders. If the insoluble powder has a different salt form that is oil soluble, consideration should be given to using that salt form.
The same comments that apply to incorporating water soluble ingredients into absorption bases also apply to w/o emulsion bases.
O/W Emulsion Bases
Water soluble powders can be directly incorporated into the external phase using a pill tile and spatula. If the powder is insoluble, the levigating agent should be water miscible so glycerin, propylene glycol, polyethylene glycol (PEG) 300 or 400, or alcohol would be acceptable. If the insoluble substance has a different salt form that is aqueous soluble, consideration should be given to using that salt form.
It may be more difficult to incorporate oil soluble ingredients into the o/w formulation. A small amount of oil can be incorporated into the base if there is excess emulsifier. Some commercial products do have the necessary excess emulsifier. If a larger portion of oil is to be added, the addition of more emulsifier may be necessary. If heat is used to incorporate the oil, it is important to work quickly so that water is not evaporated from the product. This will cause the product to become stiff and waxy.
Water Miscible Bases
Water soluble drugs can be dissolved in a small quantity of water and incorporated using a pill tile and spatula. Insoluble powders will require a water miscible levigating agent such as glycerin, propylene glycol, or polyethylene glycol 400. Oils can be added into these bases by first mixing the oil with glycerin or propylene glycol, and then incorporating the mixture into the base. Heat may be necessary if the quantity of liquid to add to the base is large.