Download Basics of Compounding Inhalation Preparations

G E N E R A L
I N T E R E S T
Basics of Compounding
Table 1. General Formula Components for Oral,
Inhalation
Inhalation, and Nasal Aerosol Preparations.
Preparations
Loyd V. Allen, Jr, PhD, RPh
Drugs can be introduced into the lungs easily by the patient’s inhaling a dose of a drug in a properly designed dosage form that is
caught up in the flow of air and carried into the deep recesses of the
pulmonary environment. Drugs in the form of a vapor, a very fine
powder, or a solution in the form of an aerosol can usually be transported by the airstream into the respiratory bronchioli and the alveolar region. An aerosol is generally a dispersed system consisting of
a solid or liquid internal phase in an outer gaseous phase. Examples
of a natural aerosol are a mist (water/air) or a dust (solid/air). Products administered by inhalation can produce either a local or a systemic effect. Drugs commonly administered for respiratory purposes
include bronchodilators, corticosteroids, antitussives, expectorants,
surfactants, respiratory stimulants, and therapeutic gases.
There are numerous advantages to using oral inhalation products,
including a rapid onset of action, elimination of the first-pass effect, avoidance of drug degradation in the gastrointestinal tract, use
of low dosages that minimize adverse reactions, dose titration capability, flexibility in dosing, and providing an alternate route of
administration when other drugs may chemically or physically interact with concurrent drugs or when drugs with erratic oral or parenteral administration pharmacokinetics are used. The ultimate deposition of inhalation aerosols is dependent on the product’s
formulation; the design of components, packaging, and container; the administration skills and techniques of the product user; and
the anatomic and physiologic status of the respiratory system.
Numerous terms are used to describe the various dosage forms
and methods of drug administration by inhalation, including
aerosols, atomizers, inhalations, insufflations, metered dose inContinuing Education
Goal: To provide pharmacists, pharmacy students, and pharmacy
technicians with supportive information on the basics of
extemporaneous compounding various types of inhalation
products.
Objectives: After reading and studying the article, the reader will
be able to:
1. define the different types of inhalation products.
2. discuss the methods of extemporaneously preparing
inhalation products.
3. detail the preliminary steps involved in preparing to
extemporaneously compound.
4. use appropriate equipment and techniques to prepare and appropriately package various types of inhalation products.
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Component
Active ingredient
Solvents
Antioxidants
Preservatives
Buffers
Tonicity adjustment
Surfactants
Vehicle
Example
Solubilized or suspended
Ethyl alcohol, propylene glycol,
purified water
Ascorbic acid, bisulfites
Benzalkonium chloride
Phosphate buffers
Sodium chloride
Sorbitan esters
Purified water
halers, nebulizers, and vaporizers.
By definition, an aerosol is a colloidal dispersion of a liquid or a
solid in a gas. Oral inhalation and nasopharyngeal medications
can both be administered in the form of an aerosol. Those products are commonly produced by means of manual sprays or from
pressurized packages. Aerosols have become so widespread in use
that the term now refers to a self-contained product that is sprayed
and that has either a liquefied or a compressed gas as a propelling
force. For pulmonary delivery, particles greater than 60 µ are usually deposited in the trachea, and those greater than 20 µ are deposited between the trachea and the bronchioles (but not into the
bronchioles). Particles that are about 1µ in size often remain airborne and are exhaled. Consequently, particles that are from about
5 to 20 µ are desired if the bronchioles are to be reached. Inhalation aerosols are the largest group of oral aerosol products formulated
either as solutions or suspensions. Factors influencing the deposition of inhalation aerosols include the formulation, the device,
the administrative technique of the user, and the anatomic and physiologic status of the respiratory system.
An atomizer is an instrument used to disperse a liquid in a fine spray.
Many of the older pressure-type atomizers used the Bernoulli
principle. When a stream of air moves at a high velocity over the
tip of a dip tube, the pressure is lowered; this results in the liquid’s
being drawn into the airflow. The liquid is broken up into a spray
as it is taken up into the airstream. To produce smaller droplets, a
baffle, a bead, or another device may be put in the flow to break
the droplets into smaller droplets as they collide with the stationary device. Those smaller droplets are then carried by the airflow
into the inhaled stream of air. Many different configurations are
available when the Bernoulli principle is used. A finer spray can be
obtained by using a pressure-type atomizer. Today’s plastic spray
bottles are similar to pressure atomizers. When the plastic bottle
is squeezed, the air inside is compressed, which forces the liquid
up a dip tube into the tip. The liquid stream is mixed with air as it
is emitted from the nozzle, thus producing a spray.
Inhalations are preparations designed to deliver the drug into
the respiratory tree of the patient for local or systemic effect.
G E N E R A L
Rapid relief is obtained when the vapors, the mist, or the droplets
reach the affected area. The USP 24/NF 19 definition of inhalations states that “inhalations are drugs or solutions or suspensions
of one or more drug substances administered by the nasal or oral
respiratory route for local or systemic effect.” The drugs may be
nebulized to produce droplets sufficiently fine and uniform in size
to reach the bronchioles. The mist may be breathed directly from
the nebulizer of a face mask, or a tent or an intermittent positive
pressure breathing (IPPB) machine may be used to produce a contained environment that maximizes the quantity of drug available
in the breathing environment for delivery into the lungs.
Inhalants are drugs that are characterized by a high vapor pressure and that can be carried by an air current into the nasal passage, where they usually exert their effect. The device or container from which the inhalant is usually administered is called an
inhaler. An inhalant consists of cylindrical rolls of a fibrous material that has been impregnated with the drug and that usually contains an aromatic substance in addition to an active substance.
Those devices are often cylindrical and have a cap in place to retard the loss of the medication. When the device is used, the cap
is removed and the inhaler is inserted into a nostril. When the patient inhales, the air passes through the inhaler and carries the vapor
of the medication into the nasal passage. An actual drug vapor is
delivered to the patient. For example, menthol, camphor, amyl nitrite, propylhexedrine, and tuaminoheptane inhalants are of that
type. Another type, the amyl nitrite inhalant, is packaged so that
the drug is contained in a thin glass ampule encased in a gauze netting. When the product is squeezed and the glass ampule is broken, the amyl nitrite is released and is absorbed on the gauze netting for inhalation by the patient.
Nebulae, or spray solutions, were intended for spraying into the
throat and nose. Generally, those were simple solutions. Sprays in
plastic spray bottles work in a manner similar to that of pressure
atomizers. When the flexible plastic container is squeezed, the air
is compressed, which forces the liquid in the container up through
a dip tube into the tip, where it mixes with a stream of air. Droplets
are formed, depending on the geometry of the device and the pressure of the individual who is squeezing the bottle.
The Latin term for mist is “nebula.” A nebulizer is a small, vacuum-type atomizer inside a chamber. When a nebulizer is used, large
droplets strike the walls of the chamber and then fall back and are
reprocessed. The smaller particles are carried in the airstream out
of the unit. The patient using the nebulizer places it into his or her
mouth and inhales while simultaneously squeezing the bulb. For a
nebulizer to be suitable for the administration of inhalation solutions, it must produce droplets sufficiently fine and uniform in size
(optimally 0.5 to 7 µ) to enable the mist to reach the bronchioles.
A vaporizer is an electrical device that produces moist steam that
does or does not contain medication for inhalation. A vaporizer is
often used to soothe upper respiratory irritations but is relatively
ineffective in providing medications to the deeper areas of the
respiratory tract.
I N T E R E S T
Composition
Solution aerosols can be formulated rather easily, but if their formulation is difficult, a suspension or emulsion aerosol can be prepared. Either solution or suspension aerosols are used for oral inhalation. Examples of ingredients in oral inhalation and nasal
aerosol solutions or suspensions are shown in Table 1.
Citric acid is often used in those formulations as an acidifying
agent. Polysorbate 80 is used as an emulsifying and a solubilizing
agent. Sodium chloride and dextrose are used as tonicity-adjusting agents.
Physicochemical Considerations
When products for oral inhalation are compounded or formulated, the variables to consider include particle size, solubility, vehicles, tonicity, pH, sterility, preservatives, viscosity, buffers, surfactants, and moisture content.
Particle Size
Usually, the particle size should lie within the range of about 0.5
to 10 µ (more preferably between about 3 to 6 µ) for a drug that,
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G E N E R A L
I N T E R E S T
when inhaled, is intended to penetrate to the small bronchioles and
the lung alveoli and to provide a rapid effect. This size range of particles is deposited in the lung by gravitational sedimentation, by
inertial impaction, and by diffusion into terminal alveoli via Brownian motion. With respect to inhalation aerosols, particles 5 to 10
µ are common; for topical sprays, 50 to 100 µ are common.
Solubility
Active drugs that are soluble in the matrix and in the pulmonary
fluids have a rapid onset of action and usually a shorter duration
of action when compared with drugs that are somewhat less soluble in the matrix and in the pulmonary fluids. Drugs that are poorly soluble in the pulmonary fluids may cause problems by irritating the lung tissue. For suspensions, it is best to select a vehicle in
which the drug is not very soluble to minimize the phenomenon
of particle size growth, which occurs when the drug in solution crystallizes out onto the crystals that are present. Polymorphic forms
of crystalline drugs should not be used for suspension aerosols. To
enhance the stability of a suspension aerosol, the selection of a liquid phase with a density similar to that of the suspensoid will minimize the tendency to settle.
Vehicle
Commonly used vehicles that carry the drugs in inhalations include sterile water for inhalation or 0.9% sodium chloride inhalation solution. Some inhalations are simple solutions of nonvolatile
or volatile medications in water or cosolvent mixtures. Small quantities of alcohol or glycerin may be used to solubilize ingredients.
Tonicity
Usually, it is best to have inhalation solutions that are isotonic with
physiologic fluids, ie, that are equivalent to 0.9% sodium chloride,
or an osmolality of about 290 mOsm. To enhance movement of the
fluid and drug through the alveoli, it may be best to have the solution slightly hypotonic. When the solution is hypertonic, fluids
have a tendency to move from the alveoli into the pulmonary space
to reach an isotonic equilibrium. If the solution is hypotonic, the
administered drug solution may have a greater tendency to move
into the tissue, which produces more rapid absorption and greater
therapeutic effect.
pH
A pH in the neutral range similar to that of body fluids minimizes
any cough reflex that might occur when the pH is too low. However, the solubility and stability characteristics of the drug must be
considered.
Sterility
A new requirement for inhalation solutions is sterility. That requirement was instituted as a result of contamination problems with
different inhalation solution products and adverse experience reports of commercially available products. Sterility can be easily accomplished by using 0.2 µ filtration systems designed for extemporaneous compounding.
Preservative
Any preparation that is not in unit dose containers should contain a preservative, especially because of the latest requirement of
sterility for this class of dosage forms. The minimum amount of
preservative that is still effective should be used. If too high a concentration is used, it may initiate a cough reflex in the patient. Also,
too high a concentration of certain preservatives that are also surfactants may result in foaming that may interfere with the delivery of the complete dose.
Viscosity
The viscosity of the external phase for most aerosol products is
very low, and as a result they are very sensitive systems. Evaporation, sedimentation, and an increase in the particle size are processes
that may occur and may change rapidly.
Buffer
A buffer, if used, should be at low buffer strength to maintain the
desired pH and to not induce pH changes in a microenvironment
in the pulmonary cavity.
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Surfactants
Surfactants can be used as dispersing agents for suspensions, as
solubilizing agents to enhance the solubility of the drug, and as
spreading agents when the drug is deposited in the lungs. The sorbitan esters (especially sorbitan trioleate) are used, as well as
lecithin derivatives, oleyl alcohol, and others. One should be cautious and should keep the surfactant concentration as low as possible to minimize foaming that might interfere with proper administration.
Moisture Content
For inhalation dispersion aerosols in general, the moisture
content should be kept extremely low for all active and inactive
ingredients. The ingredients should be anhydrous to minimize
caking.
Preparation Methods
and Techniques
1. Calculate the quantity of the individual ingredients required for
the total amount to be prepared.
2. Accurately weigh/measure each of the ingredients.
3. Dissolve the solids in about 2/3 of the volume of vehicle for
4.
5.
6.
7.
I N T E R E S T
the preparation.
Add the liquid ingredients and mix well.
Add sufficient vehicle to volume and mix well.
Filter through a 0.2 µ filter system into sterile containers.
Package and label.
Specific Quality Control
Solutions should be checked for precipitation, discoloration,
haziness, gas formation caused by microbial growth, final volume,
and sterility.
Storage and Labeling
Usually, oral inhalation preparations should be stored at either
room temperature or refrigerated temperature.
Stability
Without stability information that is applicable to a specific drug
and preparation, a beyond-use date for water-containing formulations should be not later than 14 days when stored at cold temperatures for products prepared from ingredients in solid form. A
similar commercially available product with an extended date can
be taken into consideration. However, a maximum of 6 months
should be used for compounded preparations. ■
Examples
The example formulas illustrated here are for preservative-free formulations. These should be packaged as single-use or unit-dose
products. Formulations are provided for 100 mL quantities for ease of calculations. The formulas should be reduced or expanded according to the total quantity to be compounded. These solutions can be preserved by the addition of 4 mg benzalkonium chloride per
100 mL of solution (this would be 3 mL of a benzalkonium chloride 1:750 solution).
Albuterol Sulfate 0.5% Inhalant
Solution (Preservative Free)
Albuterol sulfate
Citric acid, anhydrous
Sodium chloride
Sterile water for inhalation qs
500 mg
100 mg
800 mg
100 mL
Beclomethasone Dipropionate
0.042% Nasal Solution (Preservative Free)
Beclomethasone dipropionate,
monohydrate
42 mg
Dextrose
5.4 g
Polysorbate 80
1 mL
Hydrochloric acid
(3% - 5%)
Adjust to pH 7
Ethanol, 95%
13 mL
0.9% Sodium chloride
solution
qs 100 mL
Flunisolide 0.025% Inhalation Solution
(Preservative Free)
Flunisolide
25 mg
Ethanol, 95%
2 mL
0.9% Sodium chloride
solution
qs 100 mL
Ipratropium Bromide 0.02% Solution
(Preservative Free)
Ipratropium bromide
20 mg
Citric acid, anhydrous
50 mg
0.9% Sodium chloride
solution
qs 100 mL
Terbutaline 0.1% Inhalant Solution
(Preservative Free)
Terbutaline sulfate
100 mg
Citric acid, anhydrous
100 mg
0.9% Sodium chloride
solution
qs 100 mL
Albuterol-Cromolyn-Betamethasone
for Inhalation (Preservative Free)
Albuterol sulfate
500 mg
Cromolyn sodium
1g
Betamethasone sodium
phosphate
250 mg
Citric acid, anhydrous
100 mg
Sodium chloride
800 mg
Sterile water for inhalation qs 100 mL
Adjust pH to 6.8 - 7.0
Albuterol-Ipratropium for Inhalation
(Preservative Free)
Albuterol sulfate
100 mg
Ipratropium bromide
20 mg
Citric acid, anhydrous
50 mg
Sterile water for inhalation qs 100 mL
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