U.S. patent number 3,809,294 [Application Number 05/374,176] was granted by the patent office on 1974-05-07 for dispensing lung contacting powdered medicaments.
This patent grant is currently assigned to American Cynamid Company. Invention is credited to William Lee Torgeson.
United States Patent |
3,809,294 |
Torgeson |
May 7, 1974 |
**Please see images for:
( Certificate of Correction ) ** |
DISPENSING LUNG CONTACTING POWDERED MEDICAMENTS
Abstract
A combination aerosol container carrier and deceleration chamber
carries an aerosol container in one configuration and in another
dispenses powdered medicament from the aerosol container with
inhaled particles predominantly below 10 microns in size at a low
velocity which gives a comparatively high degree of topical effect
in the lungs as compared with systemic effect from powders absorbed
in the mouth. The lungs may be used as an effective administration
route for systemic medicament effect.
Inventors: |
Torgeson; William Lee
(Minneapolis, MN) |
Assignee: |
American Cynamid Company
(Stamford, CT)
|
Family
ID: |
23475640 |
Appl.
No.: |
05/374,176 |
Filed: |
June 27, 1973 |
Current U.S.
Class: |
222/182;
222/402.2; 128/203.15 |
Current CPC
Class: |
A61M
15/009 (20130101); A61M 15/0086 (20130101); A61M
2202/064 (20130101) |
Current International
Class: |
A61M
15/00 (20060101); A61m 015/02 () |
Field of
Search: |
;222/182,183,402.2
;128/201,203,208 ;239/350 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Reeves; Robert B.
Assistant Examiner: Martin; Larry H.
Attorney, Agent or Firm: Walker; Samuel Branch
Claims
1. An aerosol dispenser for dispensing uniform dosages of a
finely-divided powdered medicament suspended in a propellant at a
low velocity in inhalable dry aerosol form in the particle size
range of 0.5 to 10 microns, comprising
a circular cylindrical container carrier and deceleration chamber
consisting essentially of a cylindrical barrel, and, at one end
thereof, a mouthpiece and a mouthpiece-to-chamber flare, the
mouthpiece being adapted to fit into a human mouth, said mouthpiece
being cylindrical, and positioned coaxial with the cylindrical
barrel by said flare,
a mouthpiece cap, adapted to removably engage and close the
mouthpiece in dust excluding relationship,
and at the other end of said chamber a removable container holder,
adapted to close the deceleration chamber in essentially air tight
relationship, comprising a holder flange, adapted to fit in sealing
relationship with the cylindrical barrel of said chamber, a
container holding sleeve effectively coaxial and integral with
theholder flange and of a size to hold a circular the holder
aerosol container with a friction-fit, and a button holder coaxial
with the holder flange with means to hold an actuating button on an
aerosol container in indexed relationship to discharge axially with
the deceleration chamber, in dose administering position,
means to close the button holding means in dust excluding
relationship in a carrier configuration,
and a circular cylindrical aerosol container having a dose metering
valve having thereon an actuating button, which button fits into
said button holding means in a dispensing configuration and which
container fits interiorly of the cylindrical deceleration chamber
in a storage
2. The aerosol dispenser of claim 1 in which the base of the
aerosol container fits into the container holding sleeve and the
actuating button extends towards and is shielded by the mouthpiece
cap, when in the storage
3. The aerosol dispenser of claim 1 in which the ferrule end of the
aerosol container fits into the container holding sleeve, and the
actuating button extends into the button holder, when in the
storage and carrying configuration.
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. For instance, many steroids
have a systemic effect is administered orally and a local effect on
the lungs themselves so it is desirable with certain therapeutic
programs to be able to administer the steroids 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 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 mouthpiece at one end and a neckeddown spray
system at the other.
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 dispersed powder, absorb the
aerosol jet momentum before the suspended 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 powder with air, and
give uniform and acceptable powder losses, so that uniform 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 actuation of the actuation button. A considerable percentage
of loss is acceptable if reliably uniform. With the present system,
losses of about 25 to 50 percent of the total medicament doses
occur. The deceleration chamber traps much of the medicament that
would deposit in the mouth of the user, so that a relatively small
amount of the medicament is deposited in the mouth as compared to
the amount that reaches the lungs, and is effective 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 adapted to the use of such drugs as
triamcinolone acetonide and N,N-diethyl-4-methyl-l-piperazine
carboxamide pamoate(diethylcarbamazine pamoate), both of which are
of value in the treatment of asthma and both of which are 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 the
possibility of increasing the concentration of drugs administered
to the desired location, as compared to that obtained when the
drugs are administered systemically.
Some medicaments are conveniently administered by inhalation, for a
systemic effect. Penicillin has been administered by inhalation, as
more convenient than by injection. Many drugs are absorbed through
the lugs, if a suitable system of dispensing for inhalation is
available. The inhalation of gases, such as ether, or liquids is
much more common.
DESCRIPTION OF THE PRIOR ART
Certain representative patents in this very crowded field
include:
U. S. Pat. No. 2,533,065, Taplin and Bryan, Dec. 5, 1950,
"Micropulverized Therapeutic Agents" shows the use of powdered
penicillin, of a particle size of less than one micron, for
inhalation therapy. The penicillin is disclosed as absorbed in the
lungs with high efficiency.
U. S. Pat. Nos. 2,721,010, Meshberg, Oct. 18, 1955, "Aerosol
Containers And Valves Therefor," and U.S. Pat. No. 2,968,427,
Meshberg, Jan. 17, 1961, "Valve For Aerosol Container" show
metering valves for aerosol container. Small uniform charges of the
contents are dispensed on each separate actuation.
Such valves, among others, may be used for metering doses for the
present invention.
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
system, 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 percent ethanol, for inhalation and ophthalmic 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.
U. S. Pat. No. 3,727,806, Wilmot, Apr. 17, 1973, "Valve Assembles
For Aerosol Containers," shows a metering valve assembly in which a
hollow member fits over the inner end of the valve stem and moves
therewith to create a capillary gap to aid in avoiding wastage as
the container contents become exhausted. This container is used in
a valve down position.
U. S. Pat. No. 2,467,895, Kushner and Brancone, Apr. 19, 1949,
"Piperazine Derivatives and Method of Preparing The Same", shows
1-methyl-4-piperazine-N,N-diethyl carboxamide, and its salts, which
may also be named as 1-diethylcarbamyl-4-methyl-piperazine,
commonly called diethylcarbamazine, and is sold as its dihydrogen
citrate salt under the trademark HETRAZAN.
Triamcinolone acetonide,
9.alpha.-Fluoro-11.beta.,16.alpha.,17,-21-tetrahydroxypregna-1,4-diene-3,2
0-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.
U. S. Pat. No. 3,457,350, Mallen, July 22, 1969, "Method Of
Treating Asthma," shows the use of
N,N-diethyl-4-methyl-l-piperazinecarboxamide (commonly called
diethylcarbamazine) for asthma. The dihydrogen citrate salt is
disclosed specifcally.
SUMMARY OF THE INVENTION
A dispensing 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 a powdered medicament suspended in the
propellant and discharging the nozzle into the entrance of a
deceleration chamber having a cylindrical barrel portion, a
mouthpiece at the exit end, and container h0lder-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.
Because some medicaments may be used only under conditions of
stress or at irregular hours, it is highly advantageous that the
assembly be completely protected in the storage and transportation
configuration and readily and rapidly convertible to the dose
administering configuration when medicament is to be
administered.
Other advantages will be appreciated by those skilled in the art
from the detailed description of the device.
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 0.002 inch 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 1/8 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 5/1000ths 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 disbursed 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 bottom 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
plstic 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 medicament 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 25 percent of
discharge doses are found to be higher than the last 25 percent so
that the user is receiving more medication 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 the medicament.
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 medicament 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 medicament
through the mouthpiece. A large portion of the medicament 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 medicament may be fairly expensive, the dosages are
so small that about a 25 to 50 percent 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.
With many drugs it is very important that the desired quantity be
administered to the user. 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.
Other configurations can be used providing that the deceleration
chamber is large enough to decelerate the dispensed aerosol charge
and permit the inhalation velocity from the inhalation of the user
to be the sole factor in controlling the rate of administration at
the time of use. 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
of the drug to be administered, and this fine aerosol is inhaled
into the lungs.
A smoke is normally defined as a suspension of fine solid particles
in a gas such as may be produced by a fire with the particle sizes
being in the colloidal range. Here the particle sizes range from an
overlap of the colloidal range at the small end to slightly larger
than a true colloid. The definitions as to particle size ranges are
somewhat overlapping.
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 medicament deposits on the walls of the
deceleration chamber, the chamber should be washed
occasionally.
The insure adequate dispersion of the powdered medicament in the
propellant, 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 percent,
functions as a lubricant to keep valve action reliable. Some
medicament in propellant systems function reliably without a
lubricant.
Obviously, the size of the container and the size of the metering
chamber can vary widely depending upon the dosage desired for
actuation, and the number of doses desired to be given to a patient
for administration.
Certain medicaments which may be effectively administered are
illustrated by the following examples.
EXAMPLE I
Diethylcarbamazine Pamoate
At room temperature, a 2.0 gm (0.005 mole) portion of
diethylcarbamazine (N,N-diethyl-4-methyl-1-piperazinecarboxamide)
dihydrogen citrate is dissolved in 20 ml. of water. A 2.16 gm
(0.005 mole) portion of the disodium salt of pamoic acid is added.
A crystalline precipitate separates immediately, but after standing
for about 5 hours at room temperature this disappears and is
replaced by an amorphous precipitate. On further standing for 2
days, the amorphous precipitate gradually changes to a crystalline
form which is collected and dried yielding 2.5 gm.
Repetition of this procedure, with the exception that the sodium
pamoate is added as an aqueous solution rather than a dry powder,
results in the immediate precipitation of an amorphous solid that
gradually crystallizes over a 2 day period. The solid is collected
and air dried yielding 2.7 gm, M.P. 215.degree.-220.degree.C. with
decomposition. Calculated: C, 67.44; H, 6.35; N, 7.15 Found: C,
66.90; H, 6.26; N, 7.05
EXAMPLE II
Diethylcarbamazine Pamoate From Pamoic Acid
At room temperature, 15.4 Kg. (32.4 mole) of technical grade
disodium pamoate monohydrate is added to 175 liters of methanol in
a 100 gallon stainless steel kettle, and the mixture stirred until
maximum, but not complete, solution is obtained. 1.5 Kg. of
activated charcoal and 1.5 Kg. of diatomaceous earth are added and
the mixture is stirred for one hour. The mixture is filtered
through diatomaceous earth. The cake is washed with three 2 liter
portions of methanol. The filtrate and washes are charged in a 100
gallon glass lined kettle, 21 liters of water added, and 10.9
liters (130 moles) of concentrated hydrochloric acid is added
fairly rapidly. A bright yellow solid precipitates immediately.
Stirring is continued at room temperature for 1 1/2 hours. Free
pamoic acid is recovered by filtration and washed with three 20
liter portions of water. The cake is slurried with about 80 liters
of water for 1 hour, solids filtered off, the solids washed with
three 2 liter portions of water and then with three 4 liter
portions of methanol. The solid is then dried for 2 days at
50.degree.-55.degree.C. The crude pamoic acid (11.8 Kg.) is
dissolved in 61 liters of dimethylformamide at
85.degree.-90.degree.C. Two pounds of diatomaceous earth are added
and the mixture is stirred for one-half hour before filtering
through pre-heated funnels. The cake is washed with three 3 liter
portions of dimethylformamide. The filtrate is added to 70 liters
of water in a 50 gallon glass lined kettle. An additional 20 liters
of water is added and the resulting mixture is stirred for 1 1/2
hours while being cooled to below 25.degree.C. The purified pamoic
acid is filtered off, pressed dry and then washed with three 6
liter portions of water followed by three 4 liter portions of
methanol. The pamoic acid is dried to a constant weight of 10.8 Kg.
(86 percent based on 95 percent real starting disodium salt).
A 10.1 Kg. (25.8 moles) portion of diethylcarbamazine dihydrogen
citrate is dissolved in 80 liters of water and the solution is
filtered.
A 1.96 Kg. (49.0 moles) portion of sodium hydroxide is dissolved in
100 liters of water and 10.0 Kg. (25.8 moles) of purified pamoic
acid, prepared as described in this example, is added. The pamoic
acid-sodium hydroxide mixture is stirred for one-half hour, 2
pounds of diatomaceous earth is added, stirring is continued for 1
hour and the mixture is clarified by filtration.
The filtrate is charged in a 100 gallon glass lined kettle, stirred
and the diethylcarbamazine citrate solution is added as rapidly as
convenient. A very thick cream-colored precipitate forms
immediately. Forty liters of water is added. After 1 hour of
stirring the mixture thins out considerably. Stirring is continued
for 1 more hour. The product is collected by filtration and washed
with three 15 liter portions of water. The material is dried at
50.degree.-55.degree.C., and then micro-milled twice in a fluid
energy mill to give 13.5 Kg. of product. A 10.8 Kg. portion of this
diethylcarbamazine pamoate is dissolved in a mixture of 25 liters
of dimethylsulfoxide and 50 liters of methanol at 65.degree.C. The
hazy solution is filtered through diatomaceous earth and the cake
is washed with three 4 liter portions of methanol. The filtrate and
washes are charged in a 50 gallon glass lined kettle and warmed to
dissolve any separated material. Forty liters of methanol are added
and the solution is chilled to and maintained at
0.degree.C.+-.4.degree.C. overnight. The product is filtered off
and washed three times with 1.5 liters of methanol. After drying at
45.degree.-50.degree.C. the material is micro-milled yielding 8.0
Kg. of diethylcarbamazine pamoate
(N,N-diethyl-4-methyl-1-piperazinecarboxamide pamoate)(equimolar)
having 90 percent or more of the particles 10 microns or less in
size.
EXAMPLE III
To a stirred suspension of 50.5 mg (0.13 mole) of purified pamoic
acid in 400 ml of acetone heated to 50.degree.C. there is added
53.0 gm (0.27 mole) of diethylcarbamazine dihydrogen citrate. The
resulting clear yellow solution is allowed to cool to room
temperature and is then filtered. The filtrate is concentrated to
dryness in vacuo at 50.degree.C. and the resulting product is dried
in vacuo at 75.degree.-80.degree.C. for 16 hours yielding 102.0 gm
of bis-(N,N-diethyl-4-methyl-1-piperazine carboxamide) pamoate as a
yellow amorphous powder, M.P. 101.degree.-105.degree.C. Analysis:
Calculated: C, 65.62; H, 7.44; N, 10.68 C.sub.43 H.sub.58 N.sub.6
O.sub.8 (787) Found: C, 65.22; H, 7.79; N, 10.80
EXAMPLE IV
N, N-diethyl-4-methyl-1-piperazinecarboxamide pamoate was passed
through a fluid energy pulverizing mill and micronized to 0.5 to 10
microns, with 90 percent by weight being in the range of 1 to 5
microns. 300 milligrams thereof in dry form where introduced into a
10 milliliter stainless steel container adapted to be fitted with
an aerosol metering spray nozzle, and thereto was added 0.75 grams
of anhydrous ethanol. Chilled (-40.degree.C) dichlorodifluoro
methane was added from a pressure tank to the open container which
by evaporative cooling rapidly chilled the container and its
contents, enough being added that the container held 15 grams of
dichlorofluoromethane, after which the container was closed with a
metering valve, and the metering valve sealed in place.
A metering valve was used which discharged 50 microliters of
contents per actuation which gives 1.3 milligrams of
N,N-diethyl-4-methyl-1-piperazinecarboxamide pamoate per actuation
with 65 milligrams of dichlorofluoromethane and 3.25 milligrams of
ethanol being simultaneously dispensed. These are volatile and
become mixed with enough air so as to have minimal or no
physiological activity.
Depending upon the degree of severity of an asthmatic attack, one
or more actuations inhaled bring relief. The inhalation
administration gives a rapid and effective method of administration
which is more rapidly effective than systemic administration.
The N,N-diethyl-4-methyl-1-piperazinecarboxamide pamoate is more
effective for prophylactic or long term treatment than for instant
relief. Other drugs are preferred for very rapid relief during an
asthmatic attack. The present
N,N-diethyl-4-methyl-1-piperazinecarboxamide pamoate in doses of
from about 0.5 to 30 milligrams of diethylcarbamazine equivalent
administered three times a day, the dosage level being adapted to
the patient, and the intensity of therapy required, gives good long
term control of many asthmatic conditions.
Because the diethylcarbamazine pamoate is administered directly to
the lungs, a smaller dosage, as the diethylcarbamazine, is normally
required for effective relief than if administered systemically,
i.e., orally, with the circulator system being utilized to carry
the medicament to the lungs.
EXAMPLE V
Triamcinolone acetonide
Triamcinolone acetonide was micronized in a fluid energy mill until
90 percent 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 a
refinement to insure more uniform dispersion in micronized
form.
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 be instructed to actuate the button to release
the medicament into the deceleration chamber, and to inhale so that
only the inspired air imparts velocity to the particles being
absorbed. The patient should hold the inspired dose for a few
seconds to permit absorption on lung surfaces before exhaling. A
minor amount of the medicament is exhaled.
Wherein the propellant in the preceding example is
dichlorodifluoromethane, other chlorofluoroalkanes and their
mixtures may be used.
Other modifications are apparent to those skilled in the art.
* * * * *