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Патент USA US3039941

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United States Patent 0
3,039,929
Patented June 19, 1962
1
2
3,039,929
accordance with the teachings of this invention, it is now
provided that aerosol mixtures can be prepared for use
STABLE ISOPROTERONOL COMPOSITIONS
in self-propellent embodiments wherein the isoproteronol
George L. Stanko, Waukegan, 111., assignor to Abbott
Laboratories, North Chicago, 111., a corporation of
is maintained in stable form in a mixture of alcohol and
Illinois
compressed-liquid gas ?uorinated hydrocarbons by the
No Drawing. Filed Mar. 17, 1960, Ser. No. 15,549
10 Claims. (Cl. 167-65)
presence of small amounts of ascorbyl palmitate.
Aerosol compositions of isoproteronol require that said
active ingredient be dissolved in an alcohol vehicle be
This invention relates to novel compositions contain
cause such alcohol vehicles .are miscible vw'th various
ing the well-known bronchodilator, isoproteronol. In
particular, this invention is concerned with composition
liquid, compressed-gas, ?uorinated hydrocarbons. Such
?uorinated hydrocarbon liquids are commercialy known
forms wherein said isoproteronol is maintained in stable
as various Freons, lsotron, Genetron and by other names.
These foregoing gas propellents are particularly useful
for aerosol compositions wherein the active medicament
years as a useful bronchodilator or a medicament of par
ticular applicability to the treatment of asthma. Iso 15 must be expelled in small particle size. However, as stat
ed hereinbefore, the active ingredient in such aerosol mix
proteronol is identi?ed by the chemical name, oz-(iSO
tures must be portected against degradation. It is now
propylaminomethyl)protocatechuyl alcohol. This fore
provided that this agent is ascorbyl palmitate. It is
going bronchodilator is most usefully employed to relieve
known that ascorbic acid is an antioxidant, but ascorbic
bronchiol constrictions and has attained widespread use
and high popularity both among physicians and distressed 20 acid is non-operable for the foregoing aerosol mixtures
because it is incompatible therein. The ascorbic acid
patients. The bene?cial properties of this active ingredi
form over extended periods of time.
Isoproteronol has been known to the art for many
ent do not reside in permanent relief or cure of the et?ic
comes out of alcohol solution in the presence of the fore
tion, but in temporary relief; consequently, the asthmatic
going ?uorinated hydrocarbon liquid gases and, there
after, the isoproteronol quickly succumbs to the deterior
must repeatedly administer isoproteronol to himself dur
ing the periods of demand.
It can be seen from the foregoing discussion that a
composition form is desired which is readily and conven
iently administered to the distressed subject. One of the
means used to administer this bene?cial medicament has
‘been a mechanical inhalator. The mechanical inhalator
is a closed body section having an open end which is
25
ating elements. The ascorbyl palmitate has been sur
prisingly and unexpectedly found not to possess this dis
advantage.
It is provided by this invention that ascorbyl palmitate
is peculiarly operable for the aerosol mixtures, but that
the inherent properties of ascorbic acid are bene?cial for
stabilizing isoproteronol.
Such bene?cial properties are
unique because many other antioxidants that are known
designed to be placed in the mouth of the patient. The
to the art are inoperable for stabilizing and protecting
body section, at the other extremity, has a constricted
isoproteronol. Among other antioxidants which have
portion which separates a substantially bulbar-shaped
body from the remaining body section. Proximate to the 35 been found undesirable are butylated hydroxy anisole,
propyl gallate, nor-dihydroguaretic acid, sodium meta
constricted portion is a cartridge which contains isopro
bisul?te, ethyl hydroca?eate, di-tert-butylparacresol and
teronol. In the bulbar-shaped body there is a small
others.
weight which can be placed in motion by the suction cre
The advantages of this invention are realized by in
ated from inhalation by the patient. The patient places
the open end of the apparatus in his mouth, inhales forc 40 corporating at least about 0.05% Weight per volume of
ascorbyl palmitate in the areosol mixture. A useul and
ibly and causes the small weight to move and strike the
preferred concentration of the ascorbyl palmitate is about
cartridge, thereby shaking loose the isoproteronol there
0.5% weight per volume in the aerosol mixture; but it
from. It is apparent that this method of administering
isoproteronol has many disadvantages, among which can 45 should be understood that once the prescribed minimum
concentration is exceeded, continual increases will not
be numbered inefficient introduction of the active ingredi
deleteriously affect the accomplishments of this invention.
ent to the bronchiols, aggravated physical stress on an al
The upper limits of the ascorbyl palmitate concentration
ready distressed patient and general awkwardness in han
will be determined by the obvious reluctance of the prac
dling and manipulation.
The self-propellant inhalators or aerosols have also 50 titioner to add amounts in addition to that amount which
accomplishes the desired object. An operative and prac
been used to administer isoproteronol. Such embodi
tical range comprises from about 0.1% to about 0.25%
ments require the use of liquid-compressed gases, such
weight per volume of ascorbyl palmitate in the ?nished
as those known in the art as ?uorinated hydrocarbons
aerosol mixture.
(Freons), to expel the active ingredient in small particle
size. Such particular embodiments would be highly de 55 The aerosol mixture will contain a therapeutic amount
of isoproteronol HCl which amount can be selected from
sira-ble, but prior hereto, the isoproteronol was not main
the range of about 0.1% to about 0.3% weight per vol
tained in sustained stability in the mixed alcohol solution
ume in the ?nished aerosol mixture. Such amounts of
and liquid-compressed gas ?uorinated hydrocarbons.
active ingredient will be stabilized by the ascorbyl palmi
An object of this invention is to provide composition
tate as described supra. It has been additionally found
forms wherein isoproteronol is maintained in stable form
60 that a particular salt form of isoproteronol may be an
for extended periods of time.
incompatible element of the aerosol mixture, e.g., iso~
Another object of this invention is to provide such
stable compositions in forms which are el?ciently admin
istered and pleasingly accepted.
proteronol sulfate will come out of the aerosol mixture.
Isoproteronol hydrochloride has been found to be com
Still another object of this invention is to provide a 65 patible and useful for the aerosol mixtures described.
herein.
The foregoing and following description and disclo
compressed-liquid gases to expel isoproteronol in stable
useful, self-propellent pharmaceutical form which utilizes
form.
‘
sure of the aerosol compositions makes use of the terms
“alcohol solution,” “?uorinated hydrocarbons” and “aero<
It is yet another object of this invention to provide an
sol
mixture.” The term “alcohol solution” shall mean
aerosol mixture wherein isoproteronol is present and re 70 a substantially
anhydrous alcohol such as ethanol which
tained in stable form.
has dissolved therein the isoproteronol and the ascorbyl
In the accomplishment of the foregoing objects and in
palmitate. The ?uorinated hydrocarbons shall mean al
3,039,929
4
3
kanes of 1-2 carbons with ?uoro or both- chloro and
and 500 cc. of the liquid, compressed-gas, ?uorinated hy
?uoro groups attached thereto. Such ?uorinated hydro
drocarbons. The aerosol mixture is then said to con
tain 50% volume per volume of the alcohol solution and
carbons are known commercially as Freons and among
50% volume per volume of the fluorinated hydrocar
bons. Samples of this aerosol mixture are then placed
positions are Freon 11 (trichloromono?uoromethane),
in aerosol containers at a temperature of about —20°
Freon 12 (dichlorodi?uoromethane), Freon 11'3 (mono
F. by placing in each container 10-11 gms. of the aero
chlorotri?uoromethane), Freon 21 ‘(dichloromono?uoro
sol mixture and then crimping on each container a suit
methane) and Freon 114 (dichlorotetra?uoroethane).
able release valve mechanism. The ?nished aerosol mix
The amount of any particular fluorinated hydrocarbon or
the selection of any particular mixture of fluorinated hy 10 ture is compounded to contain 0.25% of isoproteronol
hydrochloride, 0.2% of ascorbyl palmitate and 0.5%
drocarbon gases will be determined by the gauge pres~
such Freons which are gainfully adapted to aerosol com
water.
sures desired for the aerosol container. Reference may
be made to US. 2,868,691 wherein a more detailed dis
cussion of the various Freons and their properties in aero
The stability of isoproteronol in both the alcohol solu
tion and the aerosol mixture is evaluated by the method
sol may be found. The type of aerosol container, the 15 of photo?uorescence as determined with the aid of an
Amico-Bowman Spectrophoto?uorometer. This appara
type of valves crimped thereon and ‘the method of ?lling
tus ?uoresces the active material at a particular wave
such containers may be ascertained by reference to well
length of ultra-violet light. Only the undegraded isopro
known portions of the art dealing with this subject.
teronol ?uoresces at that particular ultra-violet wave
Among such references may be mentioned the foregoing
US. 2,868,691; U.S. 2,728,495; U.S. 2,721,010; Aerosol 20 length.
Age, volume 2, No. 9, page 191?, page 33ft, page 44ft
(September 1957), and other works available to the art.
“Aerosol mixtures" shall mean a mixture of the alco
hol solution and the ?uorinated hydrocarbon or hydro
carbons. A further feature of this invention provides 25
that the alcohol solution and ?uorinated hydrocarbon or
hydrocarbons shall be combined in substantially a 1:1
volume ratio, or 50% volume per volume of both the
?uorinated hydrocarbon and the alcohol solution. This
allows the surprising and unexpected stabilization effects 30
of the‘ascorbyl palmitate to operate. It has been found
that substantial departures from this ratio will result in
a haze or precipitate in the aerosol mixture.
Stability of Various Samples
Time After Preparation
6 Months.“
Aerosol
Mixture,
R.’I‘.
40
40
5.00
5.06
5. 26
2.86
2. 89
2.89
RT
514
__________ __
mgJml.
mg./ml.
EXAMPLE II
The vol
Percent
In an alternative aerosol mixture, a small amount of
water in the range of about 1% may be present in order
to place the active ingredient more quickly into solution.
The ascorbyl palmitate is dissolved in the alcohol por
Alcohol
Solution,
A. ALCOHOL SOLUTION
ume per volume units are meant to represent their usual
pharmaceutical meaning. Thus, in a 10 ml. volume of 35
aerosol mixture, 50% volume per volume of alcohol solu
tion means that 5 ml. of said alcohol solution is present
therein.
Temp, ° 0
Ingredient
Amount
0.5 __________ _.
Isoproteronol Hydrochloride __________ ._
60 gms.
0.4 __________ __
Ascorbyl Palmitate ___________ __
__-
48 gms.
1.0 __________ __
Distilled Water _______________ __
_._
120 cc.
Ethyl Alcohol (200 Proof), q.s _________ __ 12,000 00.
B. FLUORLNA’I‘ED HYDROCABBONS
20 ___________ _. Dichlorodi?uorornethane (Freon 12)_.___ 3,564 gms.
80 ___________ __ Dichlorotetra?uoroethane (Freon 114)-“ 15,408 guns.
tion of the composition, but provides its bene?cial ef
fects in stabilizing isoproteronol, despite the small pres
The solution was prepared according to the procedures
ence of water. It is to be remembered that this small 45 set forth in Example I. The ?nished aerosol mixture is
amount of water will not hamper the'excellent stabiliza
compounded to contain 0.25% of isoproteronol HCl,
tion of isoproteronol with ascorbyl palmitate in alcohol
0.2% of ascorbyl palmitate and 0.5% water. The ini~
to solutions.
tial alcohol solution assay showed ‘an isoproteronol con
The following examples are presented to illustrate vari
tent of 5.83 mg./ml. or 116.6% of theory. After three
ous embodiments of the invention. It ‘is understood that 50 months at room temperature, the isoproteronol content
such examples do not represent and are not intended to
was 5.80 mg./ml. or 116.0% of theory. A sample that
represent exclusive embodiments; such examples serve
stood at room temperature for one year was assayed and
merely to illustrate the practice of this invention.
found to contain 5.7 mg. of isoproteronol per ml. or
114% of theory.
EXAMPLE I
A_ ALCOHOL SOLUTION
55
The following examples employ the same process steps
of preparation and are presented to teach operable vari
Percent
Ingredient
150 roteronol H drochloride __________ __
Asgn‘byl Palmtyate _____ __
Distilled Water ____________ ._
Amount
2 5 gins
2'0 gms
ations in the practice of the invention.
EXAMPLE III
‘
60
A. ALCOHOL SOLUTION
_
Ethyl Alcohol (200 Proof) q-SB- FLUORINATED HYDROCARBONS
Percent
Ingredient
0.4 ____________ __
Isoproteronol Hydrochloride __________ __
20 mg.
0.2 ____________ __
Ascorbyl Palmitate ___________ _.
10 mg.
65
15 _____________ __
85 _____________ __
___
Ethyl Alcohol (200 Proof), q.s _________ __ 5 cc.
Dichlorodi?uoromethane (Freon 12)_____ 112.0 ms.
Dichlorotetra?uoroethane (Freon 114)-.. 680.0 gms.
The medicament is moistened with water and added to
Amount
B. FLUORINATED HYDROCARBONS
15
Dichlomdmuommethane (Freon 12)
1 12 gms
the alcohol followed by addition of ascorbyl palmitate. 70 85111111111111 Dichlorotetratluoroethane (Freon 115:: 6180 gins:
Both the foregoing alcohol solution and the ?uorinated
hydrocarbons are cooled to about —20° F. by means of
refrigeration equipment and ‘are then mixed. The com
bined volume of the mixture is about 1000 cc. which
The foregoing formulation results in an aerosol mix
ture having a volume of 10 cc. wherein the isoproteronol
hydrochloride has ‘a ?nal concentration of .2%, and the
consists substantially of 500 cc. of the alcohol solution 75 ascorbyl palmitate has a ?nal concentration of .1%.
3,039,929
5
6
EXAMPLE IV
EXAMPLE VIII
A. ALCOHOL SOLUTION
A. ALCOHOL SOLUTION
Percent
Ingredient
_
Amount
Isoproteronol Hydrochloride __________ -_
10 mg.
Ascorbyl Palmltate _________ __
Distilled Water _____________ __
10 mg.
250 mg
__
Percent
Ingredient
Isoproteronol Hydrochloride __________ __
_
Ascorbyl Palmitate ______ __
Distilled Water __________ __
Ethyl Alcohol (200 Proof), q.s _________ __ 5 cc.
Ethyl Alcohol (200 Proof), q.s _________ __
10
B. FLUORINATED HYDROCARB ONS
Amount
B. FLUORINATED HYDROCARBONS
Dichlorotetra?uoroethane (Freon 114)-.. 6.0 gms.
Dichlorodi?uoromethane (Freon 12)..-“ 1.90 gms
_ Dichlorodi?uoromethane (Freon 12)_____ 1.12 gms.
_ Dichlorotetra?uoroethane (Freon 114).-. 6.80 gins.
The ?nal aerosol mixture has a concentration of 10 cc., 15
EXAMPLE IX
and the isoproteronol hydrochloride is present therein
in a concentration of .l% and the ascorbyl palmitate is
A. ALCOHOL SOLUTION
also present therein in a concentration of .l%.
EXAMPLE V
Percent
Ingredient
Amount
Isoproteronol Hydrochloride __________ __ 20 mg
A. ALCOHOL SOLUTION
_
Ascorbyl Palmitate _______ __
____
5 mg.
Distilled Water ___________ .-
_.__
500 mg
Ethyl Alcohol (200 Proof), q.s _________ __ 5 cc.
Percent
Ingredient
Amount
B. FLUORlNATED HYDROOARBONS
Isoproteronol Hydrochloride __________ __ 25 mg.
_
Ascorbyl Palmitate _____ __
Distilled Water __________ __
10 mg.
___
25
Dichlorodi?uoromethane (Freon 12)-.." 7.4 gms.
250 mg.
Ethyl Alcohol (200 Proof), q.s _________ _- 5 cc.
EXAMPLE X
B. FLUORINATED HYDROCARBONS
A. ALCOHOL SOLUTION
30
15 _____________ __ Dlchlorodlduoromethane (Freon 12)".-- 1.12 gms.
85 _____________ __ Dichlorotetra?uoroethane (Freon 114)-.. 6.80 grus.
Percent
Ingredient
Amount
isoproteronol Hydrochloride
'Ihe ?nal aerosol mixture contains a volume of 10
_ Ascorbyl Palmitate
Distilled Water_____
cc. in which the isoproteronol hydrochloride is present in
Ethyl Alcohol (200 Pr
a concentration of .25 %, and the ascorbyl palmitate is
present in a concentration of .1%.
In the following examples various embodiments are
presented wherein individual or mixed ?uorinated hydro
Trichloromono?uoromethane (Freon 11) ‘ 0
.
carbons are variously compounded in the aerosol mix 40
Dichlorodi?uorornethane (Freon 12).-.. 0.7 gms.
ture. In each of the following examples the alcohol solu
tion listed under “part A” comprises a volume of 5 cc.,
Others may practice the invention in any of the numer
and the ?uorinated hydrocarbon liquids also comprise a
ous Ways which will be suggested by this disclosure to
volume of 5 cc. under the same temperature conditions
one skilled in the art. All such practice of the invention
of ——20° F. The ?uorinated hydrocarbons represent
is considered to be a part hereof provided it falls within
about 50% volume per volume of the ?nal aerosol mix
the scope of the appended claims.
ture. The weight per volume percentage of the active
I claim:
ingredient and the ascorbyl palmitate in the ?nal aero
1. A stable isoproteronol aerosol composition compris
sol mixture are determined by dividing the listed per
ing a mixture of about equal volumes of substantially
cent ?gures by two.
50 anhydrous ethanol and a lique?ed ?uorinated hydrocar
bon characterized in having at least one ?uorine atom and
EXAMPLE VI
not more than two carbon atoms; said mixture containing
A. ALCOHOL SOLUTION
Percent
Ingredient
0.5 _______________ __
0.4 ______________ __
Amount
Isoproteronol Hydrochloride __________ _Ascorbyl Palnn'tate ___________________ __
25 mg.
20 mg.
Ethyl Alcohol (200 Proof), q.s _________ _. 5 cc.
B. FLUORINATED HYDROCARBONS
therein from about 0.1 % to about 0.3% isoproteronol hy
drochloride and at least about 0.05% ascorbyl palmitate.
2. A stable isoproteronol aerosol composition compris
55
ing a mixture of about equal rvolumes of substantially
anhydrous ethanol and lique?ed ?uorinated hydrocarbons
characterized in having at least one ?uorine atom and not
more than two carbon atoms; said mixture containing
60 therein vfrom about 0.1% to about 0.3% isoproteronol
90 _______________ ._ Dichlorotctra?uoroethane (Freon 114)“. 7.2 ms.
10 _______________ __ Dichlorodi?uoromethane (Freon 12)__-__ .74 gms.
A. ALCOHOL SOLUTION
hydrochloride and at least about 0.05% ascorbyl palmitate.
3. A stable isoproteronol aerosal composition compris
ing a mixture of about equal volumes of anhydrous eth
anol and a lique?ed ?uorinated hydrocarbon characterized
65 in having at least one ?uorine atom and not more than
Percent
Ingredient
Amount
0.5 _______________ __
Isoproteronol Hydrochloride __________ __
25 mg.
0.5 ______________ -_
Ascorbyl Palmitate ___________ __
25 mg.
__
Ethyl Alcohol (200Proot), q.s _________ _.
5 cc.
B. FLUORINATED HYDROCARBONS
two carbon atoms; said mixture containing therein from
about 0.1% to about 0.3% isoproteronol hydrochloride
and at least about 0.05% ascorbyl palmitate.
4. A stable isoproteronol aerosol composition compris
70 ing a mixture of about equal volumes of anhydrous eth
anol and lique?ed ?uorinated hydrocarbons characterized
in having at least one ?uorine atom and not more than
70 _______________ __ Dichlorotetra?uoroethane (Freon 114).-. 5.6 g'ms.
30 _______________ __ Dichlorodi?uoromethane (Freon 12)_____ 2.2 £1115.
two carbon atoms; said mixture containing therein from
about ‘0.1% to about ‘0.3% isoproteronol hydrochloride
75 and at least about 0.05% ascorbyl palmi-tate.
_
3,099,929
7
5. A stable isoproteronol aerosol composition compris
ing a mixture of about equal volumes of anhydrous eth
anol and lique?ed ?uorinated hydrocarbons characterized
in having at least one ?uorine atom and not more than two
carbon atoms; said mixture containing therein from about
0.1% to about 0.2% isoproteronol hydrochloride and
from about 0.1% to about 0.2% ascorbyl palmitate.
8 .
anol and a lique?ed ?uorinated hydrocarbon characterized
in having at least one ?uorine atom and not more than
two carbon atoms; said mixture containing therein about
0.25% isoproteronol hydrochloride and about 0.2% as
corbyl palmitate.
'
9. A stable isoproteronol aerosol composition compris
6. A stable isoproteronol aerosol composition compris
ing a mixture of about equal volumes of anhydrous ethanol
and lique?ed ?uorinated hydrocarbons characterized in
ing a mixture of about equal volumes of substantially an
having at least one ?uorine ‘atom and not more than two
hydrous ethanol and a lique?ed ?uorinated hydrocarbon
characterized in having at least one ?uorine atom and not
carbon atoms; said ‘mixture containing therein about
0.25% isoproteronol hydrochloride and about 0.2% as
more than two carbon ‘atoms; said mixture containing
corbyl palmitate.
therein about 0.25 % isoproteronol hydrochloride, about
10. A composition according to claim 9' wherein the
1% water and about 0.2% ascorby-l palmitate.
lique?ed ?uorinated hydrocarbons consist of a combina
7. A stable isoproteronol aerosol composition compris 15 tion of about eight parts dich-lorotetra?uoroethane and
ing a, mixture ‘of about equal volumes of substantially an
about two parts dichlorodi?uoromethane.
hydrous ethanol and lique?ed ?uorinated hydrocarbons
characterized in having at least one ?uorine atom and not
more than two carbon atoms; said mixture containing
therein about 0.25% isoproteronol hydrochloride, about
1% water and about 0.2% ascorbyl palmitate.
8. A stable isoproteronol aerosol composition compris
ing a mixture of about equal ‘volumes of anhydrous eth
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,350,435
2,868,691
Wells et al _____________ .. June 6, 1944
Porush et ‘a1 ___________ __ Jan. 13, 1959
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