U.S. patent number 3,897,779 [Application Number 05/374,177] was granted by the patent office on 1975-08-05 for triamcinolone acetonide inhalation therapy.
This patent grant is currently assigned to American Cyanamid Company. Invention is credited to Lloyd Frank Hansen.
United States Patent |
3,897,779 |
Hansen |
August 5, 1975 |
Triamcinolone acetonide inhalation therapy
Abstract
An aerosol container carrier and deceleration chamber for
dispensing powdered triamcinolone acetonide with inhaled particles
predominantly below 10 microns in size at a low velocity gives a
comparatively high degree of topical effect in the lungs as
compared with systemic effect from triamcinolone acetonide absorbed
in the mouth or upper throat. The suspension of triamcinolone
acetonide in dichlorodifluoromethane is preferably subjected to
sonic waves at about -40.degree.C, resulting in a suspension having
increased physical stability. A suspending agent such as anhydrous
ethanol or sorbitan trioleate also increases stability.
Inventors: |
Hansen; Lloyd Frank (Campbell
Hall, NY) |
Assignee: |
American Cyanamid Company
(Stamford, CT)
|
Family
ID: |
23475634 |
Appl.
No.: |
05/374,177 |
Filed: |
June 27, 1973 |
Current U.S.
Class: |
128/203.15;
222/402.2; 222/182; 424/46 |
Current CPC
Class: |
A61M
15/009 (20130101); A61M 15/0086 (20130101); C07D
295/215 (20130101); A61K 9/008 (20130101); A61K
9/0075 (20130101); Y10S 514/826 (20130101) |
Current International
Class: |
A61M
15/00 (20060101); A61M 015/02 () |
Field of
Search: |
;128/266,187,185,208,209
;222/420.20,402.17,192 ;259/DIG.41 ;424/46 ;239/338 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Physician's Desk Reference, 1973, 27 Edition, p. 979-988, Decadron,
Sept. 15, 1972. .
Physician's Desk Reference, 1973, 27 Edition, p. 807-814,
Aristocort, July 1972. .
Lancet, Sept. 5, 1959, The Dosage of Dexamethasone and
Triamcinolone in Bronchial Asthma, p. 257-258..
|
Primary Examiner: Gaudet; Richard A.
Assistant Examiner: Recla; Henry J.
Attorney, Agent or Firm: Walker; Samuel Branch
Claims
I claim:
1. A method of treating asthma which comprises
dispensing a measured dose through a metering valve into a
deceleration chamber of
a suspension in a chlorofluoroalkane propellant of finely divided
triamcinolone acetonide having 95% by weight within the particle
size range of about 0.5 to 10 microns, the individual particles of
which are substantially separated,
mixing with additional air, and inhaling, by inspirational air
velocity only, into the lungs of the subject, holding the inspired
air for a short time to permit a substantial portion of the
particles of triamcinolone acetonide to be deposited along the lung
surface, and exhaling.
Description
BACKGROUND OF THE INVENTION
The inhalation of medicaments has long been known. There is a
continuing effort to secure uniform comparatively accurately
measured dosages in selected areas. Large particles have a tendency
to be deposited in the mouth or upper throat. Small particles,
below about 10 microns, have a tendency to go deeper into the
lungs. The problem is to secure the desired dose in the desired
area of a desired medicament at the desired time. sometimes the
systemic effect of a drug on other organs is of dubious
effectiveness or actually undesired. Steroids such as triamcinolone
acetonide have a systemic effect if administered orally and a local
effect on the lungs themselves, so it is desirable to be able to
administer the triamcinolone acetonide to the surfaces of the lungs
only.
SUMMARY OF THE INVENTION
The present invention is based upon the discovery that the
discharge from an aerosol container having therein a suspension of
triamcinolone acetonide in a propellant can be suspended in dry
vaporized propellant mixed with air by the use of a deceleration
chamber which is big enough to serve as a carrier for the aerosol
container in a storage and transportation configuration and which
has a neckeddown mouth-piece at one end and a neckeddown spray
system at the other.
Preferably, the triamcinolone acetonide is finely divided, to about
0.5 to 10 microns, and is suspended in dichlorodifluoromethane to
give a comparatively high pressure system with improved spray
characteristics. If anhydrous ethanol or sorbitan trioleate is used
with an ultrasonic energy input, the dispersion of the
triamcinolone acetonide in the propellant is improved so as to give
a larger proportion of fine particles and fewer larger aggregates;
and reduce static effects.
The deceleration chamber is about the same volume as the human oral
cavity, with the mouth open. It serves to decelerate the aerosol
charge to give a low velocity to the triamcinolone acetonide
powder, absorb the aerosol jet momentum before the triamcinolone
acetonide powder enters the user's mouth, complete the vaporization
of the aerosol propellant, eliminating the possibility of liquid
propellant reaching the mouth, dilute the propellant and suspended
triamcinolone acetonide powder with air, and give uniform and
acceptable powder losses, so that uniform triamcinolone acetonide
doses are administered. It is desirable that a major portion of a
discharged medicament be administered to the user, but it is more
important that each dose be of consistent and predictable size and
absorbability so that a known uniform dose is administered with
each depression of the actuation button. A considerable percentage
of loss is acceptable if reliably uniform. With the present system,
losses of about 25 to 50% of the total triamcinolone acetonide dose
occur. The deceleration chamber traps much of the triamcinolone
acetonide that would deposit in the mouth of the user, so that a
relatively small amount of the triamcinolone acetonide is deposited
in the mouth as compared to the amount that reaches the lungs, and
is effective locally in the lungs.
Additionally, a trap system is used to submerge the metering valve
to insure that the metering valve is immersed in the propellant at
all times so that the metering chamber does not drain and, in
effect, lose its prime. This at times is referred to as a
drain-free trap.
The system is particularly effective for use with triamcinolone
acetonide which is of value in the treatment of asthma, and which
is desirably administered in small known uniform accurate dosages
which are absorbed primarily in the lung system as contrasted with
the nose and throat. The physiological effectiveness is augmented
by increasing the concentration of triamcinolone acetonide
administered to the lungs, as compared to that obtained when
administered systemically.
DESCRIPTION OF THE PRIOR ART
Certain representative patents in this very crowded field
include:
U.S. Pat. No. 2,992,645, Fowler, July 18, 1961, "Disperser For
Powders," in Column 2 has a table showing the effect of particle
size on the zone of deposition of a powder in the respiratory
tract. Powder sizes of 1 and 3 microns are shown to go deeply into
the lungs.
U.S. Pat. No. 3,012,555, Meshberg, Dec. 12, 1961, "Dispensing
Package For Material Under Pressure" shows an aerosol liquid
dispenser with an operating spray button assembled to the valve
stem, which button, with spray orifice, fits removably into an
applicator nozzle. In one configuration the applicator nozzle is
used for spray control; in another for protective storage.
U.S. Pat. No. 3,219,533, Mullins, Nov. 23, 1965, "Aerosol Solid
Medicament In Propellant And Low-Level Ethanol Avoiding
Higher-Level Ethanol Dispersed-Solid Reflocculation" shows many
solid medicaments, including such steroids as hydrocortisone,
prednisolone and dexamethasone dispersed in the particle size range
of 0.5 to 10 microns in certain chlorofluoroalkanes using 0.5 to
5.0 % ethanol, for inhalation and opthalmic therapy.
U.S. Pat. No. 3,236,458, Ramis, Feb. 22, 1966, "Aerosol Apparatus,"
shows an aerosol liquid dispenser using coaxial concentric
extendable tubes for particle size control. The tubes in collapsed
position function as a container carrier for storage. In extended
position, the mass of air in the tubes impedes the forward flow of
a spray and serves as a partial barrier to the discharge jet. The
inside diameter is preferably 18 to 30 mm. and the length 3 to 10
times the diameter, preferably 5 to 7 times.
The aerosol container and valve are taken out of the stored
position, and the valve stem is inserted into a dispensing spray
head which forms the end of the inner tube at the time of use.
Ramis teaches that for inhalation therapy, the particles of the
therapeutic agent should be between 0.5 and 5 microns in size,
since particles above 5 microns may not reach the air-cells in the
lungs while particles below 0.5 microns may fail to be deposited in
the lungs. Ramis teaches using dichloro-difluoro-methane as the
propellant in which the active product is dissolved or kept in a
homogeneous emulsion suspension. The disclosures are limited to
soluble products.
Triamcinolone acetonide, 9.alpha.-Fluoro-117/8 ,16.alpha.
-17,-21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal
with acetone is described and the formula given in The Merck Index,
Eighth Edition, Merck & Co., Rahway, N.J. (1968), pages 1064
and 1065.
In this invention a dispersing package for therapeutic agents under
pressure such as shown in Meshberg, U.S. Pat. No. 3,012,555, supra,
is modified by adapting a valve to dispense powdered triamcinolone
acetonide suspended in the propellant and discharging the nozzle
into the entrance of a deceleration chamber having a cylindrical
barrel portion, a mouth-piece at the exit end, and container
holder-actuating button holder to hold the spray nozzle system.
Preferably, the deceleration and expansion chamber is adapted to
completely enclose and hold the aerosol container during storage
with the system being assembled in one configuration for storage
and transportation and another for use. By having dust covers and
sealing means, the assembly in storage and transportation position
is protected from contaminating dust and may be conveniently
carried in the pocket of a user and yet be rapidly assembled with
minimum risk of contamination of the contents at the time of
use.
Other advantages will be appreciated by those skilled in the art
from the detailed description of a device which permits dispensing
of triamcinolone acetonide for lung administration.
DRAWINGS
FIG. 1 is a pictorial view of the aerosol dispenser assembled in
dose administering configuration.
FIG. 2 is a view in partial section showing the dispenser in the
storage and transportation configuration.
FIG. 3 is an enlarged view in section showing the valve assembled
to the expansion chamber cover and particularly, an anti-drain tank
to insure that the metering valve is continuously immersed in the
propellant and, thus, protected from partial draining and resulting
irregular dosages.
FIG. 4 shows the same valve assembly in compressed position after a
dose in which the valve stem has been depressed.
FIG. 5 is a second configuration in which the actuating button fits
into a movable applicator nozzle for storage.
As shown in FIG. 1, the biggest element of the aerosol dispenser is
the deceleration chamber 11, preferably of a plastic such as
polyethylene. The deceleration chamber has a cylindrical barrel 12
which conveniently may be about 2 3/4 inches in length and 1 1/2
inches in internal diameter with a shell wall thickness of around
one sixteenth inch. At one end is a mouthpiece 13 conveniently
about seven eighths inch in outside diameter and five-eighths inch
long which is a size conveniently held in the lips of the user with
the lips forming an essentially airtight seal with the mouthpiece.
The mouthpiece is joined to the cylindrical barrel 12 by a
chamber-to-mouthpiece flare 14. Conveniently, but not necessarily,
the mouthpiece, the chamber-to-mouthpiece flare, and the
cylindrical barrel are molded in one piece from a plastic such as
linear polyethylene. This gives an economical method of manufacture
and a smooth, easily cleanable working surface. A mouthpiece cap 15
fits removably on the mouthpiece in dust excluding relationship.
The cap may slide on either interiorly or exteriorly with a finger
friction fit. The term "finger friction fit" is used to note a
frictional relationship which will hold pieces together under
normal handling conditions, but may be readily disengaged or
engaged by finger pressure only. The exterior surface of the
mouthpiece cap may be roughened or knurled for easier grasping by
the fingers. The edges of the mouthpiece cap and the mouthpiece may
be "broken" or slightly rounded in accordance with conventional
practice for ease in assembly, as may other edges. Either the
mouthpiece or the mouthpiece cap may have small ribs of the order
of 0.002inch to reduce friction and ease engagement. By having such
small raised portions or beads on frictionally engaging portions,
the natural resilience of plastic such as polyethylene is utilized
to give a frictional engagement which may be readily disengaged
with the fingers without expensive requirements as to accuracy in
sizing of the pieces. Similar assembly details may be used
elsewhere in the present dispenser, and are conventional in the
plastics molding art.
At the open end of the cylindrical barrel 12 is a container holder
16. The container holder is a multifunctional element. A holder
flange 17 fits across the open end of the cylindrical barrel 12. A
positioning sleeve 18 engages the end of the cylindrical barrel 12.
Conveniently, but not necessarily, the positioning sleeve fits
interiorly of the cylindrical barrel 12 with a friction fit and the
positioning sleeve is long enough to prevent accidental
disengagement but permit ready removal of the container holder 16.
Conveniently, but not necessarily, the positioning sleeve 18
extends from the holder flange 17 so that its resilience permits
finger frictional engagement with the normal accuracy of molding
parts. A container holding sleeve 19 extends interiorly from the
holder flange 17 and is of a size to fit around, retain, and
position an aerosol container 20. Conveniently, but not
necessarily, the aerosol container 20 is of stainless steel or
aluminum to hold high pressure aerosol propellants. The container
holding sleeve is long enough and of a size to position and retain
the aerosol container assembly inside and axially of the
deceleration chamber 11 during storage and transportation phases of
using the device, and permits ready disengagement from the aerosol
container 20 at the time of administration.
Through the holder flange extend one or more air vents 21 which
provide for the introduction of diluent air during use. Three
vents, each one eighth inch diameter, give good results.
Extending exteriorly from the holder flange 17 is a button holder
22. The button holder is hollow, has a closed end opposite to the
holder flange, and has therein an indexing port 23 which is of a
size and shape to hold an aerosol actuating button 24, which is
described in more detail below. Because the aerosol actuating
button is to be oriented, the shape of the indexing port 23 is such
as to match with the actuating button 24 and hold the actuating
button in an oriented relationship. As shown, the actuating button
is cylindrical with a flat side 25 which flat side cooperates with
an indexing port flat 26 so that the spray is directed axially of
the deceleration chamber. Conveniently, but not necessarily, the
button holder is formed with two indexing ports 23 in diametrically
opposed relationship so that the actuating button 24 can be
inserted from either side and the other port serves such as an
additional air inlet. At the end of the button holder 22 away from
the holder flange 17 is a retaining bead 27 which conveniently
extends up about five one thousandths of an inch above the exterior
cylindrical surface of the button holder. A protective sleeve 28
fits in light frictional engagement over and on the exterior
surface of the button holder. Being made of plastic, there is
sufficient resilience that the protective sleeve 28 may be easily
forced over the retaining bead 27 into position and is not readily
removed so that it is retained in place during the useful life of
the dispenser. The protective sleeve has button apertures 29 to
permit the sleeve 28 to be rotated so that the button apertures 29
index with the indexing ports and permit the button to be inserted
therethrough and yet can be rotated through about 90.degree. to
protect the assembly from the entrance of dust and dirt during
storage and transportation.
In FIG. 2 is shown the dispenser in the carrying configuration for
storage and transportation in which the aerosol container 20 is
held in the container holding sleeve 19 interiorly of the
cylindrical barrel of the deceleration chamber.
The aerosol container 20 is closed with a valve assembly 30 which
includes a ferrule 31 to hold the valve in position and from which
valve assembly extends the actuating button 24.
As shown in FIG. 3, at the time of use, the mouthpiece cap 15 is
removed, the holder flange 17 removed from the other end of the
cylindrical barrel, the aerosol container 20 is removed from the
container holding sleeve 19, the protective sleeve 28 rotated until
the button apertures 29 index with the indexing port 23, and
assembled in dose administering configuration by inserting the
actuating button 24 through the button aperture 29 into one of the
indexing ports 13 so that the spray port 32 is axial and concentric
with the cylindrical barrel 12 of the deceleration chamber, so that
the discharge from the aerosol container is symmetrical with
respect to the deceleration chamber.
As shown in FIG. 3, in the dose administering position the aerosol
container 20 extends upwards so that the medicament in propellant
33 is drawn by gravity against the valve assembly 30.
The actuating button 24 has a spray port 32 which is conveniently
counterbored into the button and has a spray orifice 34 through
which the medicament in propellant is discharged. This spray
orifice may either be formed integral with the spray button or a
separate metallic insert may be used. Both are conventional
constructions. The spray orifice should have a diameter such that
the discharged dose is dispersed in finely divided form as a cone
on exit from the spray orifice.
An orifice of about 0.015 to 0.018 inch gives a good spray
pattern.
The actuating button 24 fits snugly on the end of a valve stem 35
which extends into the valve body 36. The valve body 36 has therein
a metering chamber 37 in which the valve stem 35 is slidably
mounted. Between the valve body and the ferrule 31 is a metering
gasket 38 which performs the dual function of serving as a seal
against loss of propellant when the valve stem collar 39 presses
against the metering gasket, and acts as a ring seal around the
valve stem 35 so that as the valve stem is depressed against the
valve spring 40, the metering port 41 in the valve stem passes the
metering gasket and permits the contents of the metering chamber to
pass through the metering port 41, the axial valve stem bore 42,
extending through the valve stem, into the discharge passage 43 in
the actuating button 24 to the spray orifice 34. At the inner end
of the valve stem 35 are charging flutes 44. These cooperate with a
charging gasket 45 which is held against the lower end of the
metering chamber by a stainless steel valve stem washer 46 which,
in turn, is held against the botton of the metering chamber 37 by
the valve spring 40. In operation, as the valve stem 35 is
depressed, the valve stem 35 passes through the charging gasket 45
so that the charging flutes pass through the charging gasket and
the full diameter of the valve stem 35 seals against the charging
gasket 45 so that the metering chamber is filled and closed at the
inner end before the metering port 41 passes the metering gasket 38
which permits the contents of the metering chamber to discharge
through the metering port 41, the axial valve stem bore 42, the
discharge passage 43, and the spray orifice 34.
FIG. 4 shows the actuating button 24 in depressed position with the
valve in the discharge position.
When pressure on the actuating button 24 is released, the valve
stem 35 is pushed outwardly by the valve spring 40 so that the
metering port 41 passes the metering gasket 38 which closes
discharge from the metering chamber, and later the charging flutes
44 pass the charging gasket 45 permitting the propellant containing
the medicament to flow through the charging flutes 44 and again
fill the metering chamber 37.
The valve body 36 has a valve body flange 47 which covers the end
of the aerosol container 20 and is sealed thereto by a container
gasket 48. The ferrule 31 holds the assembly in position against
the end of the aerosol container 20 by the ferrule 31 being swaged
against the stainless steel or aluminum aerosol container 20.
The above construction for a metering valve is one type of metering
valve. Other conventional types of metering valves may be used.
Because the metering valve discharges a comparatively small charge,
for instance about 50 microliters per actuation is a convenient
commercial size, and each discharge has a volume of about that of a
small drop of water, it is important that the metering chamber be
completely filled before each actuation and that the metering
chamber be prevented from draining back into the aerosol container
between actuations. This loss of charge or loss of prime is
prevented by an anti-drain tank 49. The anti-drain tank 49 fits
into a flange sleeve 50 on the valve body flange 47 which flange
sleeve 50 has an interior cylindrical surface against which the
anti-drain tank 49 is a snug friction fit. In the periphery of the
anti-drain tank 49 and between the anti-drain tank and the flange
sleeve 50 is a charging passage 51 which provides for refilling of
the anti-drain tank from the main body of the medicament in
propellant in the aerosol container.
To protect against accidental disengagement of the anti-drain tank
as, for example, by dropping the aerosol container on the floor
during use, the anti-drain tank is sonically welded into position
using an ultrasonic seal in which ultrasonic energy is passed
through the flange sleeve to the anti-drain tank. As the energy
passes through, there is a discontinuity between the anti-drain
tank and the flange sleeve so that energy is reflected and
refracted causing dissipation of ultrasonic energy which reappears
as heat which melts and thereby seals the anti-drain tank to the
flange sleeve. By such ultrasonic sealing, the assembly is
economical and effective. When so sealed, the anti-drain tank
remains in position under any use or abuse that does not damage the
aerosol container itself.
Because of the nature of the propellant composition, when the
actuating button is depressed with the aerosol container in
dispensing position, the contents of the metering chamber are
discharged and as the actuating button is released, a new charge is
drawn from the anti-drain tank into the metering chamber and the
anti-drain tank is refilled through the charging passage 51. The
anti-drain tank remains filled with the propellant containing the
medicament independent of the orientation of the aerosol container.
Thus, a predictable, uniform, accurate dosage is dispensed with
each actuation of the actuating button.
By keeping the fluted end of the valve stem immersed in liquid
propellant at all times, the homogeneity of the solid finely
divided medicament in the propellant is maintained more uniformly,
and more consistent uniform doses are dispersed. The use of a
plastic anti-drain tank appears to aid in neutralizing electrical
charges which would otherwise build up in the system. With a
stainless steel aerosol container 20, the periphery of the
propellant charge is effectively at a single potential, but the
propellant can act as a dielectric so that the individual particles
of triamcinolone acetonide become charged and affect their
dispersion and discharge rate. With the anti-drain tank, the effect
of the stainless steel container is at least in part neutralized so
that static effects are reduced or minimized permitting more
uniform charge characteristics.
In the absence of the anti-drain tank, the first twenty-five
percent of discharge doses are found to be higher than the last
twenty-five percent so that the user is receiving more
triamcinolone acetonide than anticipated from the new dispenser and
less than anticipated from the nearly empty dispenser. With the
present anti-drain tank, the variation in charges are minimized so
that the user is obtaining a more reliably uniform dosage of
triamcinolone acetonide.
It is difficult to measure the effect of electrical charges within
the aerosol container and in the deceleration chamber but
independent of the theoretical and scientific background for
explaining uniformity of charge, it is found that with the present
anti-drain tank, more uniform dosages are dispensed and with the
deceleration chamber in which the mouthpiece has less than half the
cross sectional area of the cylindrical barrel, and the length of
the cylindrical barrel is less than twice its diameter, the
individual dosages of triamcinolone acetonide in propellant are
dispersed into the deceleration chamber and lose the jet velocity
imparted by the propellant spray. If any particles still retain
velocity, they either impinge or are retained by the walls of the
deceleration chamber or are bounced away from the walls so that a
dispersed powder charge is formed which is mixed with additional
diluent air and inhaled, as the user inhales the finely divided
triamcinolone acetonide through the mouthpiece. A large portion of
the triamcinolone acetonide which would otherwise be deposited in
the mouth of the user and, hence, absorbed systemically, are
deposited on the walls of the deceleration chamber.
Even though the triamcinolone acetonide is fairly expensive, the
dosages are so small that about a 25 to 50% loss in the
deceleration chamber is a highly acceptable loss as compared with
the advantages of consistency and uniformity of the dose which is
administered to the patient. Uniformity is important so that the
physician administering knows what adjustments in dosage level need
be made depending on the response of the user.
In FIG. 5 is shown a modification of the aerosol dispenser system
in which the container holding sleeve of the type shown in
Meshberg, U.S. Pat. No. 3,012,555, supra, is used with an
applicator nozzle 52 fitting in the holder flange 53 with the
bottom end of the aerosol container fitting into the applicator
nozzle. Slidably fitting in the other end of the applicator nozzle
is a button holding slide 54 which can be pressed inward for
sealing or pulled outward to hold the actuating button in operating
position. The details of this construction are shown in said U.S.
Pat. No. 3,012,555.
With a metering trap holding about 50 microliters of material, the
energy of discharge is completely dissipated in the deceleration
trap and a fine aerosol, almost a smoke, is formed.
For Applicant's purpose, a particle size range from about 0.5
microns to 10 microns gives good results. Particles larger than
about 10 microns are too apt to be deposited in the mouth or the
throat of the user to be preferred for inhalation therapy. A few
particles in this size range are usually not deleterious, but
contribute disproportionately to systemic absorption rather than
through the lungs.
In use, because part of the triamcinolone acetonide deposits on the
walls of the deceleration chamber, the chamber should be washed
occasionally.
To insure adequate dispersion of the powdered triamcinolone
acetonide, a comparatively high pressure propellant system is
preferred. Dichlorodifluoromethane (Freon 12) which has a pressure
of about 80 pounds per square inch absolute at room temperature
gives good results. A stainless steel or aluminum container is
preferred for such pressures to avoid damage from breakage. Glass
containers, or plastic containers, or a plastic covered and
protected glass container may be used, but these are more
conventional at lower pressures, of the order of 30 to 50 pounds
per square inch gage.
A plastic valve stem is preferred to metal, as the plastic valve
stem is less subject to binding or sticking from powder being
packed around it. A small amount of alcohol, about 1 to 10%,
functions as a lubricant to keep valve action reliable.
Obviously, the size of the container and the size of the metering
chamber can vary widely depending upon the dosage desired per
actuation, and the number of actuations desired in the
dispenser.
Example I
Triamcinolone acetonide aerosol
Triamcinolone acetonide was micronized in a fluid energy mill until
90% by weight was in the particle size range of 1 to 5 microns.
A 19 ml. stainless steel container had charged thereto 30 mg. of
the micronized triamcinolone acetonide, 0.244 ml. of anhydrous
ethanol and was cold filled with 19.5 grams of
dichlorodifluoromethane at -40.degree.C, evaporation serving to
chill the container, and an excess being added to allow for
evaporation. The filled containers were closed with a metering
valve, as above described, and sealed. Dispersion in the propellant
is improved when the filled containers are immersed in an
ultrasonic bath that transfers energy from the transducer to the
contents of the aerosol container.
Good results are normally obtained by shaking to disperse the
triamcinolone acetonide in the system. Ultrasonic dispersal is
preferred to insure more uniform dispersion in micronized form, and
reduce the number of aggregates.
The components can be mixed, treated ultrasonically, and pressure
filled. Pressure filling is more complex for small scale runs, but
often preferred for large size runs, and saves loss of the
propellant. The valve needs to be specifically designed for such
pressure fill.
Each actuation of the valve button delivers about 0.1 mg. of
triamcinolone acetonide. Five actuations four times a day gives a
dosage of about 2 mg. of triamcinolone acetonide. As a portion is
retained in the deceleration chamber, and some is exhaled, slightly
more than 1 mg. a day is administered for a typical patient. A
systemic dose for a patient is about 8 mg. The lower level and
delivery to the preferred site is a major advantage.
The patient should hold inspired triamcinolone acetonide for a few
seconds to permit the particles to contact the walls of the
air-sacs and passages deep in the lungs.
Example II
A suspension was prepared of:
Example II ______________________________________ A suspension was
prepared of: ______________________________________ Triamcinolone
acetonide, micronized (0.5-5 400 mg. microns)
Dichlorodifluoromethane 100 ml. Sorbitan trioleate 6.9 mg.
______________________________________
The triamcinolone acetonide and sorbitan trioleate were placed in a
beaker, and the dichlorodifluoromethane was added at -40.degree.C.
A suspension was formed. The mixture was sonified, that is, treated
with a Sonifier, manufactured by the Branson Sonic Power Co., Eagle
Road, Danbury, Connecticut, as model LS75 at a current input of 9
amperes for 2 minutes. Additional cold dichlorodifluoromethane was
added as necessary to keep the volume at 100 ml. The mixture was
uniformly dispersed, and had increased stability resulting from the
sonification.
19 cc stainless steel containers were filled with 15 ml. of the
cold mixture, valves as described above inserted and the valves
sealed in place.
On warming, after storage, the triamcinolone acetonide remained
dispersed, and after merely casual shaking, gave uniform doses of
finely divided triamcinolone acetonide.
Good results are obtained on inhalation by asthmatics.
Example III
The procedure of Example II was repeated substituting 1.24 ml. of
anhydrous ethanol for the sorbitan trioleate. The suspension was
stable on filling and on storage. Shaking to uniformly disperse
before using is recommended.
The dispenser gave comparatively uniform doses from the initial
actuation until empty. Five actuations four times a day, for a
total of about 2 mg. of triamcinolone acetonide per patient is
recommended as an initial program, with the dose rate subject to
adjustment based on clinical results in a particular patient.
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