Note: Descriptions are shown in the official language in which they were submitted.
~0~a3z~8
BACKGROUND OF IHE INVENTION
_ . .
The inhalation of medicaments has long been known. There is a con-
tinuing effort ~o 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. Some- -~ -
times the systemic effect of a drug on other organs is of dubious effective- - ~-
ness or actually undesired. For instance, many steroids have a systemic
effect if 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.
.:,
'5 DESCRIPTION OF THE PRIOR ART
,l i Certain representative patents in this very crowded field include:
United States Patent No. 2,533,065, Taplin and Bryan, December
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.
2~ United States Patents Nos. 2,721,010, Meshberg, October 18~ 1955,
"Aerosol Containers and Valves Therefor", and 2,968,427, Meshberg, January
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 d~ses for the
present invention.
United States Patent, 2992,645, 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.
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United States Patent No. 3,012,555, Meshberg, December 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.
United States Patent No. 3,219,533, Mullins, November 23, 1965,
"Aerosol Solid Medicament in Propellan~ and Low-Level Ethanol Avoiding
Higher-Level Ethanol Dispersed-Solid Reflocculation" shows many solid medica-
ments, including such steroids as hydrocortisone, prednisolone and dexametha-
sone 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 ophthalmic
therapy.
United States Patent No. 3,236,458, Ramis, February 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 posi-
tion, 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 ther,a~y~ 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-di1uoro-nlethane as the propellant in which the active product is ;
~, dissolved or kept in a homogeneous emulsion suspension. The disclosures are
limited to soluble products.
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United States Patent No. 3,727,806, ~ilmot, April 17, 1~73, "Valve
Assemblies for Aerosol Containers", sho~s 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.
United States Patent No. 2,467,895, Kushner and Brancone, April 19,
1949, "Piperazine Derivatives and Method of Preparing the Same", shows l-methyl- -
4-piperazine-N,N-diethyl carboxamide, and its salts, which may also be named
~- as l-diethylcarbamyl-4-methyl-piperazine, commonly called diethylcarbamazine, :
and is sold as its dihydrogen citrate salt under the trademark HETRAZAN. ~ ~ -
Tri~ncinolone acetonide, 9~-Fluoro-1~ ,16~,17,-21-tetrahydroxypregna-
1,4-diene-3,20-dione cyclic 16,17-acetal with acetone is described and the form- ~ - `
ula given in The Merck Index, Eighth Edition, Merck ~ Co., Rahway, New Jersey - ~
(1968), pages 1064 and 1065. -
United States Patent 3,457,350, Mallen, July 22, 1969, "Method of ;
Treating Asthma", shows the use of N,N-diethyl-4-methyl-1-piperazinecarboxa-
mide tcommonly called diethylcarbamazine) for asthma. The dihydrogen citrate
salt is disclosed specifically,
SUMMARY OF T~IE INVENTION
~0 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 configura-
tion and which has a neckeddo~n mouthpiece at one end znd a neckeddown spray
system at the other.
According to the present invention there is provided an aerosol dis-
penser for dispensing uniform dosages of a finely divided powdered medicament
suspended in a propellant at a low velocity in inhalable dry aerosol form in
`I the particle size range of 0.5 to 10 microns, comprising a circular ~ylindrical
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container carrier and decceleration 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
the holder flange and of a size to hold a circular cylindrical aerosol con-
tainer 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, m0ans 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
conflguration and which container fits interiorly of the cylindrical decelera-
tlon chamber in a storage configuration.
The deceleration chamber 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 vaporiza-
tion of the aerosol propellant, eliminating the possibility of liquid pro-
pellant 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 medica-
ment 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
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considerable percentage of loss is acceptable if reliably uniform. W~th the
present system, losses of about 25 to 50% 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 amou:nt that reaches the lungs, ~ -
and is effective in the lungs.
The system is particularly adapted to the use of such drugs as
triamcinolone acetonide and N,N-diethyl-4-methyl-1-piperazine carboxamide -~-~
pamoate (diethylcarbamazine pamoate), both of which are of value in the
treatment of asth~a and both of which are desirably administered in small
known uniform accurate dosages which are absorbed primarily in the lung sys-
tem 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 ~ocation, 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 lungs, if ~ :
a suitable system of dispersing for inhalation is available. The inhalation
of gases, such as ether, or liquids is much more common.
DRAWINGS `
In the accompanying drawings which illustrate exemplary embodiments
of the present invention:
Figure 1 is a pictorial view of the aerosol dispenser assembled in
dose administering configuration;
Figure 2 is a view in partial section showing the dispenser in the '
storage and transportation configuration;
Figure 3 is an enlarged view in section showing the valve assembled
to the expansion chamber cover and particularly, an anti-drain tank to ensure
that the metering valve is continuously immersed in the propellant and, thus, :
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protected from partial draining and resulting irregular dosages;
Figure 4 S}IOWS the same valve assembly in compressed position after
a dose in which the valve stem has been depressed; and
~ Figure 5 is a second configuration in which the actuating button
: fits into a movable applicator nozzle for storage.
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cylindrical barrel 12 which conveniently may be about 2 3/4" in
length and 1 1/2" in internal diameter with a shell wall thick-
ness of around 1/16". At one end is a mouthpiece 13 conveniently
about 7/8" in outside diameter and 5/8" long which is a size con-
veniently held in the lips of the user with the lips forming anessentially 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
~ 10 molded in one piece from a plastic such as linear polyethylene.
; This gives an economical method of manufac~ure and a smooth,
easily cleanable working surface. A mouthpiece cap 15 fits re-
movably 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 fi~" 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
~0 by the fingers. The edges of the mouthpiece cap and the mouth-
piece may be "broken" or slightly rounded in accordance with con-
ventional 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" to reduce friction and ease engagement.
, 25 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 re-
quirements as to accuracy in sizing of the pieces. Similar ass-
embly details may be used elsewhere in the present dispenser,
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and are conventional in the plastics molding art.
At the open end of the cylindrical barrel 12 is a con-
tainer holder 16. The container holder is a multifunctional ele-
ment. A holder flange 17 fits across the open end of the cylin-
drical barrel 12. A positioning sleeve 18 engages the end of thecylindrical 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 po-
sitioning 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 s~eel
or aluminum to hold high pressure aerosol propellants. The con-
tainer 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 o~ 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.
~ xtending 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 o~ a size and shape to hold an aerosol actuating button
24, which is described in more detail kelow. Because the aerosol
. ~ .
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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 actu-
atin button is cylindrical with a flat side 25 which flat side co-
operates with an indexing port flat 26 so that the spray is direc-
ted 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/lOOOths of an inch above
the exterior cylindrical surface of the button holder. A pro-
tective sleeve 28 fits in light frictional engagement over and on
lS 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 o~ 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 to protect the assembly from the entrance of dust and
dirt during storage and transportation.
In FIGURE 2 is shown the dispenser in the carrying con-
figuration for storage and transportation in whiah the aerosol
container 20 is held in the container holding sleeve 19 interiorly
;` o~ the cylindrical barrel of the deceleration chamber.
The aerosol container 20 is closed with a valve assem-
b~y 30 which includes a ferrule 31 to hold the valve in position
9 _
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and from which valve assembly extends the actuating button 24.
As shown in FIGURE 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 in-
serting 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 decel-
eration chamber, so that the discharge from the aerosol container
is symmetrical with respect to the decleration chamber.,
As shown in FIGURE 3, in the dose administering posi-
~ tion the aerosol container 20 extends upwards so that the medica-
- 15 ment in propellant 33 is drawn by gravity against the valve assem-
bly 30.
The actuatin~ 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.
;l 20 This spray orifice may either be formed integral with the spray
, button or a separate metallic insert may be used. Both are con~
ventional 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" 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
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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 againsk the metering gasket, and acts as a ring
seal around the valve stem 35 so that as the valve stem is depres-
sed 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 ori-
: 10 fice 34. At the inner end of the valve stem 35 are charging
1utes 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
button of the metering chamber 37 by the valve spring 40. In op-
eration, as the valve stem 35 is depressed, the valve stem 35 pas-
ses through the charging gasket 45 50 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
meteriny 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 meter-
ing port ~1, the axi.al valve stem bore 42, the discharge passage
43, and the spray orifice 34.
FIGURE 4 shows the actuating button 24 in depressed
position with the valve in the discharge position.
~hen 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 charg-
ing 1utes 44 pass the charging gasket 45 permitting the propel-
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lant 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
~, 15 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 sur-
face 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 in-
' 30 to position using an ultrasonic seal in which ultrasonic energy
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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 with re-
appears 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 con-
tainer. Thus, a predictable, uniform, accurate dosage is dispen-
sed 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 medicament become charged and affect their disper-
,;
sion and discharge rate. With the anti-drain tank, the effect
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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 thelast twenty-fice percent so that the user is receiving more medi-
cation than anticipated from the new dispenser and less than an-
ticipated 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 medica-
ment.
It is more difficult to measure the effect of electrical
charges within the aerosol container and in the decleration cham-
ber but independent of the theroetical and scientific background
for explaining uniformity of charge, it is found that with the
~i present anti-drain tank, more uniform dosages are dispensed with
the decel~eration chamber in which the mouthpiece has less than
half the cross sectional area of the cylindirical 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 deceler-
ation chamber or are bounced away from the walls so that a dis-
persed powder charge is formed which is mixed with addition dilu-
ent air and inhaled, as the user inhales the finely divided medic-
ment 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 desposi~ed on the walls of the
declerati~n chamber.
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Even though the medicament may be fairly expensive, the
dosages are so small that about a 25 to 50~ loss in the deceler-
ation 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 FIGURE 5 is shown a modification of the aerosol dis-
penser system in which the container holding sleeve of the type
shown in Meshberg, 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 pul-
led outward to hold the actuating button in operating position.
~he details of this construction are shown in said 3,012,555.
Other configurations can be used providing that the
decleration chamber is large enough to declerate the dispensed
aerosol charge and permit the inhalation velocity from the inhal-
ation of the user to be the sole factor in controlling the rate
of administration at the time of use. With a metering trap hold-
ing 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 particles sizes being in the colloidal range. Here the par-
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1~43;~
ticle 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
S mouth or the throat of the user to be preferred for inhalation
therapy. A few particles in this size range are usually not de-
leterious, but contribute disproportionately to systemic absorp-
tion 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.
To insure adequate dispersion of the powdered medica-
ment in the propellant, a comparatively high pressure propellant
system is preferred. DichlorodifluoromethanetFreon 12) which has
a pressure o~ 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
~ 20 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 pla-
stic valve stem is less subject to binding or sticking from powder
being packed around it. A s~all amount ~f alcohol, about 1% to
10%, 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
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given to a patient ~or administration.
Certain medicaments which may be effectively administer-
ed are illustrated by the following examples.
EXAMPLE I
DIETHYLCARBAM~ZINE 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 crytsalline precipitate separates immediately, but after stand-
ing 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 crystal-
line form which is collected and dried yielding 2.5 gm.
- 15 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 ~radually crystallizes over a two day period. The
solid is collected and air dried yielding 2.7 gm, M.P. 215-220C.
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
i 25 At room temperature, 15.4 Kg. (32.4 mole) of technical
grade disodium pamoate monohydrate is added to 175 liters of meth-
1 anol in a 100 gallon stainless steel kettle, and the mixture stir-
-~ red until maximum, but not complete, solution is obtained. 1.5 Kg.
1
of activated charcoal and 1.5Kg. of diatomaceous earth are added
;` 30 and the mix~ure is stirred for one hour. The mixture is filtered
,.~
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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 lit-
ers 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 two days at
50-55C. The crude pamoic acid (11. 8 Kg.) is dissolved in 61
liters of dimethylformamide at 85-90C. Two pounds of diatoma-
ceous earth are added and the mixture is stirred for 1/2 hour be-
fore 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 o water is added and the resulting mix-
ture is stirred for 1 1/2 hours while being cooled at below 25C.
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
weiyht of 10.8 Kg. (86% based on 95% 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
`Idissolved 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
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3~
1/2 hour, two 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 pre-
cipitate 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 50-55C., 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 mix-
ture of 25 liters of dimethylsulfoxide and 50 liters of methanol
, at 65C. 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 lit-
ers o~ methanol are added and the solution is chilled to and main-
tained at 0~4C. overnight. The product is filtered oil and
washed three times with 1.5 liters of methanol. After drying at
45-50C. the material is micro-mîlled yielding 8.0 Kg. of diethyl-
carbamazine pamoate(N,N-diethyl-4-methyl-1-piperazinecarboxamide
pamoate)(equimolar) having 90~ 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 puri-
- ~ied pamoic acid in 400 ml of acetone heated to 50C. there is
: ' .
added 53.0 gm (0.27 mole) o~ diethylcarbamazine dihydrogen citrate.
I 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 50C. and the resulting product is dried in
vacuo at 75-80C. 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. 101-1~5C.
Analysis: Calculated: C, 65.62; H, 7.44; N, 10.68
C43~58N6O8(787) Found: C, 65.22; H, 7.79; N, 10.80
EXAMPLE IV
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~ by weight being in the range of 1
to 5 microns. 300 milligrams thereof in dry form were introduced
into a 19 milliliter stainless steel container adapted to be fit-
ted with an aerosol metering spray nozzle, and thereto was added
0.75 grams of anhydrous ethanol. Chilled (-40C) dichlorodifluoro-
methane was added from a pressure tank to the open container which
by evaporative cooling rapidly chilled the container and its con-
tents, enough being added that the container held 15 grams of di-
chlorofluoromethane, 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 microlit-
ers 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 atuations inhaled bring relief. The inhala-
tion administration gives a rapid and effective method of admini-
stration which is more rapidly effective than systemic administra-
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tion.
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 re-
lief during an asthmatic attack. The present N,N-diethyl-4-
methyl-l-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 con-
trol of many asthmatic conditions.
Because the diethylcarbamazine pamoate is administereddirectly to the lungs, a smaller dosage, as the diethylcarbamazine,
is normally required for effective relief than if administered
systemically, i.e., orally, with the circulatory system being uti-
lized to carry the medicament to the lungs.
EXAMPLE V
Triamcinolone acetonide
Triamcinolone acetonide was micronized in a fluid ener-
gy mill until 90% by weight was in the particle size range of 1
to 5 microns.
A 10 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 dichloro-
difluoromethane at -40C, evaporation serving to chill the cont-
ainer, and the excess being added to allow for evaporation. Thefilled containers were closed with a metering valve, as above de-
, .
scribed, and sealed. Dispersion in the propellant is improvedwhen the filled containers are immersed in an ultrasonic bath
that transfers energy from the transducer to the contents of the
aerosol container.
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Good results are normally obtained by shaking to disperse the tri-
amcinolone acetonide in the system. Ultrasonic dispersal is a re-
finement 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 rungs, 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 ex-
haled, slightly more than 1 mg. a day is administered for a typ-
ical patient. A systemic dose for a patient is about 8 mg. The
; 15 lower level and delivery to the preferred site is a major advan-
tage.
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 par-
ticles being absorbed. The patient should hold the inspired dosefor a few seconds to permit adsportion on lung surfaces before
exhaling. A minor amount of thë medicament is exhaled.
Wherein the propellant in the preceding example is di-
chlorodifluoromethane, other chlorofluoroalkanes and their mixtures
may be used.
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