Aerosol compositions containing finely divided solid materials

An aerosol composition capable of dispensing dry particles uniformly in a very fine particle size, comprising solid particles coated with a dry coating of a perfluorinated surfactant, suspended in a propellant. The propellant utilized may be of the perfluorinated environmentally preferred type.

This invention relates to self-propelling, powder dispensing aerosol 
compositions and to a means for dispensing a dry powder in aerosol form 
having controlled, uniformly fine particle size in an improved, uniform 
distribution pattern. This invention also relates to aerosol compositions 
which can be utilized with perfluorinated propellants. The invention also 
relates to a novel method of preparing such improved aerosol compositions. 
Various methods are known in the art to dispense powdered material in 
aerosol form. U.S. Pat. No. 2,868,691 discloses compositions for aerosol 
administration of medicaments which are prepared by rendering the solid, 
active medicament soluble in the liquified propellant by means of a polar 
cosolvent. Unfortunately, as is well recognized in the art (U.S. Pat. No. 
3,014,844), many solids, and particularly certain medicaments, are not 
stable in polar solvents, or they are rendered unstable when in a polar 
solvent and contacted with a metal valve often used in pressurized aerosol 
containers. This is the case with epinephrine. Polar solvent-containing 
systems may also attack and corrode the metal valve closures of the 
containers and interfere with their functioning. In addition, some 
medicaments and other solids cannot be satisfactorily solubilized in the 
usual liquified propellants, even though a cosolvent is employed. 
Accordingly, it has not been possible to provide a polar 
solvent-containing system which provides stable suspensions of powder in a 
liquified propellant for use in aerosol containers. 
To avoid the use of polar solvents an alternative system for providing a 
self-propelling powder-dispensing aerosol composition is disclosed in U.S. 
Pat. Nos. 3,014,844 and 3,169,095. The solid powder is suspended in a 
liquified propellant, in which the solid material is substantially 
insoluble, and a liquid non-ionic non-fluorinated surface-active agent. 
The nature of the surface-active agent is quite critical for production of 
an acceptable aerosol composition and it is required that the 
surface-active agent be soluble or dispersible in the propellant. The 
propellants utilized are fluorinated or chlorofluorinated lower alkanes. 
The viscous liquid surfactants of U.S. Pat. No. 3,014,844 and 3,169,095 
retard the evaporation of the sprayed propellant. The viscous liquid 
surfactants also have a tendency to glue the sprayed solid powdered 
particles together. Both of these effects increase the size of the sprayed 
aerosol particles. 
Thus, the prior art has not provided a stable self-propelling 
powder-dispensing aerosol system which can disperse powdered material in 
as fine a spray as the present invention. In addition, the prior art has 
not disclosed surface-active agents which would be of use in providing a 
very fine spray of powdered material when utilizing the more 
environmentally safe perfluorinated propellants. 
The self-propelling, powder-dispensing aerosol compositions of the present 
invention comprise a finely-divided solid material or powder coated with a 
dry coating of a perfluorinated surface-active dispersing agent and 
suspended in a halogenated propellant, in which the solid material and the 
perfluorinated surface-active dispersing agent are substantially 
insoluble. 
The present invention is an advance over the prior art in that it provides 
aerosol compositions which are capable of dispensing a powdered substrate 
in a particle size which is finer and more uniform than that provided by 
aerosol compositions of the prior art. This feature is of prime importance 
to the area of aerosol compositions for inhalation therapy. Medicaments 
useful for inhalation therapy must be well dispersed in the propellant 
vapor. Smaller particle size permits better dispersion of medicament in 
the propellant vapor and permits more medicament to travel down the throat 
and into the lungs. In addition, smaller particles of medicament uniformly 
dispersed in the propellant provide a composition which is more 
efficiently absorbed in the bronchioles and alveoli than dispersions of 
medicament having larger particle size. 
While we not not wish to be bound by any theory to explain the excellent 
results which are obtained with the aerosol compositions of the present 
invention, the ability to deliver the solid material in a smaller particle 
size than is the case with the prior art is due to the perfluorinated 
surfactants and the manner in which they are used. We have observed that 
in general as surfactant concentration increases so does the droplet size 
of the aerosol particles. Since the practice of the present invention 
results in very little surfactant being used, the droplet size of the 
aerosol particles can be kept at a minimum. In addition the surfactants of 
the present invention utilized as a dry coating on the solid powdered 
material will not retard propellant evaporation and will not glue the 
solid particles together. Thus, the present invention can provide aerosol 
particles having a very small particle size. 
In addition the present invention provides an aerosol composition useful 
with conventional chlorofluorinated propellants as well as perfluorinated 
propellants to provide fine dispersions of powdered substrates. 
Perfluorinated propellants are preferred by environmentalists because they 
are known not to cause adverse environmental effects associated with 
chlorofluorinated propellants. 
The perfluorinated surface-active dispersing agents of the present 
invention (hereinafter referred to as "perfluorinated surfactants" or 
"surfactants") are insoluble in the propellant. This insolublity is due to 
the relatively ionic character of one end of the surfactant molecule. This 
ionic group is compatible with the solid powdered material and enables the 
surfactant to wet the solid material. Although the perfluorinated 
surfactant is insoluble in the propellants, when coated on the solid 
material, the outermost perfluorinated groups of the surfactant allow the 
solid coated material to be dispersed in the propellant due to the 
compatibility between the perfluorinated groups and the propellant. 
Perfluorinated surfactants most useful in the compositions of the present 
invention include perfluorinated alcohol phosphate esters and their salts; 
perfluorinated sulfonamide alcohol phosphate esters and their salts; 
perfluorinated alkyl sulfonamide alkylene quaternary ammonium salts; 
N,N-(carboxyl-substituted lower alkyl) perfluorinated alkyl sulfonamides; 
and mixtures thereof. By "perfluorinated" it is meant that the surfactant 
contains at least one perfluorinated alkyl group. Particularly preferred 
perfluorinated alcohol phosphate esters are the free acids of the 
diethanolamine salts of mono- and 
bis(1H,1H,2H,2H-perfluoroalkyl)phosphates. The phosphate salts, available 
under the tradename "Zonyl RP" from E. I. Dupont de Nemours and Company, 
Wilmington, Del., are converted to the corresponding free acids by the 
method described in Examples 9 and 10. 
Preferred perfluorinated sulfonamide alcohol phosphate esters are described 
in U.S. Pat. No. 3,094,547, and have the general formula: 
##STR1## 
wherein R is hydrogen or an alkyl group having from 1 to about 12, 
preferably from 1 to 6, carbon atoms; R' is an alkylene bridging group 
containing 2 to about 12 carbon atoms, preferably from 2 to 8 carbon 
atoms; R.sub.f is perfluoroaliphatic C.sub.n F.sub.2n+1 or 
perfluorocycloaliphatic C.sub.n F.sub.2n-1 ; n is an integer from 1 to 18, 
preferably from 6 to 12; and m is an integer from 1 to 3. 
Although the mono-, di- and triesters are useful, the diester is most 
readily available commercially. Particularly preferred perfluorinated 
sulfanomide alcohol phosphate esters and salts of these include 
perfluoro-n-octyl-N-ethylsulfonamidoethyl phosphate, 
bis(perfluoro-n-octyl-N-ethylsulfonamidoethyl)phosphate, the ammonium salt 
of bis(perfluoro-n-octyl-N-ethyl-sulfonamidoethyl)phosphate, 
bis(perfluorodecyl-N-ethyl sulfonamidoethyl)phosphate and 
bis(perfluorohexyl-N-ethyl sulfonamidoethyl)phosphate. The above named 
preferred surfactants are of particular use in medicinal aerosol 
compositions due to their non-irritating and non-toxic nature. 
The particularly preferred perfluorinated alkyl sulfonamide alkylene 
quaternary ammonium salt for use in the preparation of aerosol medicaments 
according to the present invention is 
N,N-dimethyl-N-decyl-N-(perfluoro-n-octylsulfonamidopropyl)ammonium 
bromide. 
A particularly preferred N,N-bis(carboxyl-substituted lower 
alkyl)perfluorinated alkyl sulfonamide for use with medicaments in aerosol 
compositions of the present invention is 
N,N-bis(4-carboxyl-n-butylperfluoro-n-octylsulfonamide. 
The perfluorinated surfactant may constitute from about 0.1 to 20%, 
desirably between about 0.25 and 5%, and preferably, for medicinal 
purposes, between about 0.25 and 1%, by weight of the solid material to be 
suspended. However, the minimum amount of perfluorinated surfactant 
required is dependent upon the concentration of solid material present. 
For best results, the concentration of perfluorinated surface-active agent 
is kept at a minimum as it may tend to increase the droplet size of the 
aerosol particles. 
The compositions of the present invention are useful for a wide variety of 
powder dispersing applications. They are advantageously used to disperse 
medicaments in aerosol form. The solid substrate to be dispensed may also 
be a cosmetic substance such as talc, an antiperspirant such as aluminum 
chlorohydrate and the like, a polishing material such as jeweler's rouge, 
a dye such as the approved food colorings, a lubricant such as graphite 
and other finely-divided materials and other useful substances. 
When the solid substrate to be dispensed is a medicament it may be an 
antiallergic, analgesic, bronchodilator, antihistamine, antitussive, 
anginal preparation, antibotic antiinflammatory, hormone, or sulfonamide, 
such as, for example, a vasoconstrictive amine or its acid-addition salts, 
an enzyme, alkaloid, or steroid, and synergetic combinations of these. 
Exemplary of the medicaments which may be employed are: Isoproterenol 
[alpha-(isopropylaminomethyl)protocatechuyl alcohol] hydrochloride or 
sulfate, phenylephrine bitartrate or hydrochloride, phenylpropanolamine, 
glucagon, adrenochrome, trypsin, epinephrine bitartrate, ephedrine, 
narcotine, codeine, atropine, heparin, morphine, dihydromorphinone, 
ergotamine, scopolamine, methapyrilene, cyanocobalamin, terbutaline, 
rimiterol, salbutamol, beclomethazone, flunisolide, and colchicine. Others 
are antibiotics, such as neomycin, streptomycin, penicillin, procaine 
penicillin, tetracycline, chlorotetracycline and hydroxytetracycline; 
adrenocorticotropic hormone and adrenocortical hormones; such as 
cortisone, hydrocortisone, hydrocortisone acetate and prednisolone; 
insulin, antiallergy compounds such as cromolyn sodium, etc. 
Presently preferred medicaments for use in the compositions of the 
invention are isoproterenol sulfate or hydrochloride, epinephrine 
bitartrate, and phenylephrine bitartrate or hydrochloride. 
For pharmaceutical purposes the particle size of the powder should 
desirably be uniform and not greater than 100 microns diameter, since 
larger particles may tend to agglomerate, separate from the suspension and 
may clog the valve or orifice of the container. Preferably the particle 
size should be less than 25 microns in diameter. Desirably the particle 
size of the finely-divided solid powder should for physiological reasons 
be less than 25 microns and preferably less than about 10 microns in 
diameter. The present invention can provide epinephrine in an aerosol 
spray having a mass median diameter of between 1.5 and 2.0 microns. 
There is no lower limit on particle size except that which is imposed by 
the use to which the aerosol produced is to be put. Where the powder is a 
solid medicament, the lower limit of particle size is that which will be 
readily adsorbed and retained on or in body tissues. When particles of 
about one-half micron in diameter are administered by inhalation they tend 
to be exhaled by the patient. 
Desirably the finely divided solid materials should be substantially 
insoluble in both the liquified propellant and the surface-active agent. 
Finely-divided solid materials which are predominantly polar in nature 
provide most satisfactory compositions when used with chlorofluorinated 
propellants. Although, both polar and nonpolar solid materials provide 
satisfactory compositions when used with perfluorinated propellants. If 
the solid material is substantially soluble in the propellant, the 
particle size of the aerosolized material when dispensed cannot be 
controlled. If the particle size of the suspended solid material cannot be 
regulated and agglomeration takes place, the valve orifice of the aerosol 
container may clog, rendering the dispensing device inoperative, or if a 
metering valve is employed, it may be rendered inaccurate. This may lead 
to inaccurate dosages, which in the case of highly potent medicinals may 
lead to undesirable results. In addition to increasing the particle size 
and clogging orifices, agglomeration may make the suspension unstable, an 
obviously undesirable result particularly in the case of aerosolized 
medicinals. 
The finely-divided solid material may constitute up to about 20% by weight 
of the total composition. Desirably it shall constitute up to about 10%, 
and preferably up to about 3%, by weight of the total composition. The 
minimum concentration of the solid material is governed by its specific 
activity and in the case of highly active material can be as low as 0.001% 
by weight of the total composition although a concentration of 0.01% is 
preferred. 
The halogenated propellant useful in the practice of the invention is one 
which is a gas at room temperature (25.degree. C.) at atmospheric pressure 
(760 millimeters of mercury), i.e., it has a boiling point below 
25.degree. C. at atmospheric pressure. For use in compositions intended to 
produce aerosols for medicinal or cosmetic use, the propellant should be 
essentially non-toxic. Among the most suitable propellants which may be 
employed are the fluorinated and chlorofluorinated lower alkanes, such as 
are sold under the trademark "Freon", and certain straight or branched 
chain or cyclic perfluorinated alkanes, ethers, amines, sulfides and 
sulfones. Mixtures of the above propellants may be suitably employed. 
It is contemplated that the fluorinated or chlorofluorinated lower alkanes 
shall contain not more than 4 carbon atoms and at least 1 fluorine atom. 
The preferred lower alkane compounds may be represented generally by the 
formula C.sub.m H.sub.n Cl.sub.y F.sub.z, wherein m is an integer equal to 
or less than 4, n is an integer or zero, y is an integer or zero, and z is 
an integer, such that n+y+z=2m+2. Examples of useful fluorinated 
propellants include 
dichlorodifluoromethane ("Freon 12"), 
1,2-dichlorotetrafluoroethane ("Freon 114"), 
trichloromonofluoromethane ("Freon 11"), 
dichloromonofluoromethane ("Freon 21"), 
monochlorodifluoromethane ("Freon 22"), 
trichlorotrifluoroethane ("Freon 113"), 
trichloromonofluoroethane, monochlorotrifluoromethane ("Freon 13"), 
chloroheptafluoropropane ("Freon 217") and chloropentafluoroethane ("Freon 
115"). Perfluorinated alkanes and cycloalkanes which are useful include 
perfluoropropane, perfluoro-n-butane, perfluoroisobutane, 
perfluorocyclopropane and perfluorocyclobutane ("Freon C-318"). Other 
useful perfluorinated propellants include perfluorodimethyl ether, 
perfluorodiethyl ether, perfluorofuran, perfluorotrimethylamine, 
bis(trifluoromethyl)sulfone, bis(trifluoromethyl)sulfide, 
trifluoromethylpentafluorosulfide and the like. 
Presently preferred propellants are selected from three classes, 
chlorofluorinated lower alkanes, perfluorinated alkanes and straight chain 
or cyclic perfluorinated ethers. Chlorofluorinated lower alkanes are 
readily available at low cost. They are safe for use with biological 
systems, i.e. with medicaments, although they may have a detrimental 
effect on the environment because they may cause depletion of atmospheric 
ozone. Perfluorinated alkanes, such as perfluoropropane, are readily 
available commercially and they have not been cited for potential 
environmental damage. Straight-chain and cyclic perfluorinated ethers are 
readily available commercially and possess improved stability relative to 
chlorofluorinated alkanes. They also are thought to be safer to biological 
systems than chlorofluorinated alkanes. 
The vapor pressure of the propellant system should be at least 13 pounds 
per square inch gauge (p.s.i.g.) at 70.degree. F. Pressures up to 65 
p.s.i.g. at 70.degree. F. may safely be used with metal containers and up 
to 40 p.s.i.g. at 70.degree. F. with specifically reinforced glass 
containers. It may frequently be desirable to select a propellant system 
having a low specific gravity to aid in preparing a satisfactory 
dispersion of light finely divided powders. Propellants with improved 
solvating characteristics, specific gravity, and vapor pressure may be 
obtained by using certain mixtures of compatible propellants. 
A particularly preferred propellant mixture for the powdered substrate 
isoproterenol sulfate is comprised of about 50% perfluoropropane and 50% 
perfluorofuran. These amounts may be varied by about 10% while retaining 
excellent propellant characteristics. 
In producing the compositions of the present invention a novel and 
surprisingly effective method is utilized. The active powder ingredient is 
dispersed in a solution of the perfluorinated surfactant in a solvent in 
which the powder substrate is substantially insoluble. Suitable solvents 
are, for example chloroform, dichloromethane, isopropanol, ethanol, and 
trichlorotrifluoroethane ("Freon 113"). A dispersion of the powder is 
produced by, for example, homogenization. The dispersed powder is then 
collected by filtration, decantation, or centrifugation, and subsequently 
dried. This procedure fosters uniform wetting of the powder particles by 
the surfactant. 
In producing the aerosol packages of the invention a container equipped 
with a valve is filled with a propellant containing the dried, 
surfactant-coated powdered material, in suspension. The dried 
surfactant-coated powder may be dispersed in the cooled liquified 
propellant by mixing or homogenization. Alternatively, it may be more 
convenient to homogenize the coated powder in a small quantity of 
compatible inert fluid to form a concentrated paste which is then 
dispersed in the propellant. The inert fluid must be soluble in the 
propellant. Preferred inert fluids are fluorocarbon liquids. Particularly 
preferred fluorocarbon liquids include perfluorotri-n-butylamine, 
available under the tradename "FC-47" (medical grade) and "FC-43" 
(commercial grade) from the 3M Company, St. Paul, Minn., and the 
perfluorinated dimer of methylcyclopentadiene, available under the 
tradename "FC-48", from the 3M Company. Propellant is added to the aerosol 
package by either the cold filling method or by pressure filling through 
the valve nozzle. On operating the valve of the aerosol container, the 
powder will be dispensed in a stream of propellant, which will vaporize 
providing an aerosol of dry powder. Throughout the preparation of the 
product care is desirably exercised to minimize the absorption of moisture 
where the powder is water-soluble. This may be accomplished by operating 
in a dehumidified atmosphere using only dry materials and equipment. 
The compositions of the invention may be used to dispense consistently 
accurate doses of aerosolized solid medicaments into body cavities such as 
throat or nose. They also provide a means of producing aerosolized 
medicaments suitable for inhalation therapy. Inhalation therapy enables 
drugs to act directly on respiratory sites without engendering undesirable 
systemic effects as often happens when drugs are administered by other 
routes. With very volatile substances inhalation approaches intravenous 
therapy in rapidity of action. The compositions of the present invention 
are of particular efficacy in inhalation therapy since the very small size 
of the medicament particles dispersed uniformly in the propellant are more 
efficiently absorbed in the bronchioles and alveoli than are the larger 
particles of medicament provided by the aerosol compositions of the prior 
art. Also, as illustrated by Example 28, less of the medicament provided 
by the present invention is impacted in the throat and more of the 
medicament is available for inhalation than is the case with the aerosol 
formulations of the prior art. 
The compositions of the present invention are useful with the more 
environmentally safe perfluorinated propellants as well as with 
conventional fluorochlorinated propellants. In contrast, the surfactants 
of the prior art do not perform well as dispersing agents in 
perfluorinated propellants. 
In order more clearly to disclose the nature of the present invention, the 
following examples illustrating compositions in accordance with the 
invention will now be described. It should be understood, however, that 
this is done solely by way of example and is intended neither to delineate 
the scope of the invention nor limit the ambit of the appended claims. In 
the examples which follow, the process described above was employed. In 
the examples which follow and throughout the specification, the quantities 
of material are expressed in terms of percentages by weight of the total 
composition, unless otherwise specified. The range of particle size 
specified is that existing at the time of formulation. Where a constituent 
is described as "micronized," it comprises 90% by weight of particles 
having a particle size range of between 1 and 5 microns.

EXAMPLE 1 
A mixture of 1.0 g of micronized epinephrine bitartrate and 0.5 g of a 
perfluorinated sulfonamide alcohol phosphate ester surfactant, sold under 
the tradename "FC-161" by the 3M Company, St. Paul, Minn. and comprising 
over 90% perfluoro-n-octyl-N-ethyl sulfonamidoethyl phosphate, was 
dispersed mechanically in 50 g of isopropanol. After one to two minutes of 
mechanical agitation the mixture was allowed to settle for five minutes. 
The mixture was filtered and the solid surfactant-coated drug collected 
was dried in a vacuum oven at 58.degree. C. for thirty minutes. 
A sample of the dried solid (0.5 g) was put into a chilled glass bottle and 
49.75 g of "Freon 114" and 49.75 g of "Freon 12" were added and mixed to 
provide an aerosol formulation of: 
______________________________________ 
Percent 
______________________________________ 
Surfactant-coated epinephrine bitartrate 
0.5% 
Freon 114 (50%), Freon 12 (50%) 
q.s. 
______________________________________ 
The contents of the bottle were used to fill aerosol vials and the vials 
were sealed with metering valves. 
EXAMPLE 2 
A solution of 300 mg of the ammonium salt of 
bis(perfluoro-n-octyl-N-ethylsulfonamidoethyl)phosphate was partially 
solubilized by means of a Virtis Homogenizer (available from the Virtis 
Co., Inc., Gardiner, NY) in 60 ml of isopropanol. Undissolved surfactant 
was removed by filtration. 49 G. of the surfactant filtrate was used to 
disperse one gram of micronized epinephrine bitartrate by homogenization. 
The epinephrine solid was separated and dried. The dried powder was used 
to prepare an aerosol formulation in "Freon 114" and "Freon 12" according 
to the procedure of Example 1. 
EXAMPLES 3-8 
In the following table (Table I) several surfactant solutions and 
corresponding aerosol formulations are set forth. 
Surfactant solutions were prepared by dissolving the surfactant in a 
solvent. 5 G of micronized epinephrine bitartrate was coated with the 
surfactant by homogenization in 50 ml of surfactant solution. After 
homogenization the mixture was filtered and the solid coated epinephrine 
bitartrate obtained was dried. 
Aerosol formulations comprising 0.5% and 1.0% coated epinephrine bitartrate 
were prepared by homogenizing 1.0 g or 2.0 g of coated drug in 50 ml of 
"Freon 114" for 2 minutes. Additional "Freon 114" was then added to 
provide the desired concentration of coated drug. The resultant suspension 
was transferred to a bottle and "Freon 12" was added. The bottle was 
capped and shaken. The propellant composition of the aerosol formulations 
was 50% "Freon 114" and 50% "Freon 12". 
TABLE I 
______________________________________ 
Amt. Coated 
Drug in Aerosol 
Formulation 
Example Surfactant Solution (% by wt.) 
______________________________________ 
3 1% "FC-161" in 0.5% 
4 isopropanol 1.0% 
5 0.5% bis(perfluoro-n-octyl-N-- 
0.5% 
6 ethyl sulfonamidoethyl)phosphate 
1.0% 
in isopropanol 
7 0.5% "Zonyl RP".sup.1 in 
0.5% 
8 "Freon 113" 1.0% 
______________________________________ 
.sup.1 "Zonyl RP" is a fluorinated surfactant sold by DuPont Co., 
Wilmington, Delaware, and comprises diethanolamine salts of mono and 
bis(1H,1H,2H,2Hperfluoroalkyl)-phosphates where the alkyl group is 
evennumbered in the range C.sub.4 -C.sub.18 and the fluorine content of 
the salts is 52.4% to 54.4% as determined on a solids basis. 
The aerosol suspensions of Examples 3-8 had differing flocculation 
characteristics. The aerosol formulations containing 1% coated drug 
settled more rapidly than those containing 0.5% coated drug. The amount of 
surfactant-coated drug which coated the walls of the aerosol bottle 
increased in the following order: 
Examples 3 and 4&gt;Examples 5 and 6&gt;Examples 7 and 8. 
EXAMPLES 9 AND 10 
"Zonyl RP" obtained commercially from DuPont Co., Wilmington, Del., was 
converted to the purified free acid by acidification with hydrochloric 
acid followed by extraction of the desired product into diethyl ether. 
Surfactant solutions of 0.5% by weight dried extracted "Zonyl RP" in 
"Freon 113" were prepared. 
Micronized epinephrine bitartrate was coated with surfactant by 
homogenizing a 5 g sample in 50 ml of surfactant solution. After 
homogenization, the mixture was filtered and the solid epinephrine 
bitartrate was dried. 
Aerosol suspensions of 0.5% by weight coated drug and 1% by weight coated 
drug were made up, as in Examples 7 and 8, by homogenizing 1.0 or 2.0 g 
samples of the coated drug in 50 ml of "Freon 114", adding "Freon 114" to 
obtain 101 and 102 g of suspension respectively, and then adding "Freon 
12" to provide 201 and 202 g of solution, respectively. 
When compared with the aerosol suspensions of Examples 7 and 8, the 
suspensions of Examples 9 and 10 showed reduced tendency to flocculate. 
EXAMPLE 11 
To 100 ml of chloroform 0.5 g of the surfactant 
bis(perfluoro-n-octyl-N-ethylsulfonamidoethyl)phosphate was added. Into 
this mixture five grams of micronized isoproterenol sulfate was dispersed 
by homogenization. The powder was separated by filtration and dried. A 100 
mg sample of this powder was then dispersed in 200 mg of liquid 
perfluorotri-n-butylamine by mixing in a milling apparatus for one minute. 
A 100 mg portion of this dispersion was transferred to a plastic-coated 
glass aerosol vial. The mixture was placed in a deep-freeze apparatus and 
liquid perfluoropropane was added. The vial was sealed with a 50 
microliter valve. 
The resultant aerosol formulation was: 
______________________________________ 
Percent 
______________________________________ 
Surfactant-coated isoproterenol 
0.33 
sulfate powder 
Perfluorotri-n-butylamine 
0.67 
Perfluoropropane 99.0 
______________________________________ 
EXAMPLE 12 
A surfactant solution of 0.5% "Zonyl RP" (purified and converted to the 
free acid according to the procedures of Examples 9 and 10) in "Freon 113" 
was prepared by dissolving "Zonyl RP" in the solvent. 
Micronized isoproterenol sulfate was coated with surfactant by homogenizing 
a 5 g sample in 50 ml of surfactant solution. After homogenization, the 
mixture was filtered and the solid coated isoproterenol sulfate was dried. 
An aerosol suspension was prepared by homogenizing 0.30 g of coated drug in 
50 ml of "Freon 114" for 2 minutes, adding more "Freon 114" to provide 
80.3 g of mixture and then adding "Freon 115" to provide 200.3 g of 
mixture. 
The aerosol formulation was: 
______________________________________ 
Percent 
______________________________________ 
Surfactant-coated isoproterenol sulfate 
0.15 
"Freon 114" 39.94 
"Freon 115" 59.91 
______________________________________ 
EXAMPLE 13 
A surfactant solution of 0.5% by weight "Zonyl RP" in "Freon 113" was 
prepared, as in Example 12. 
A mixture of micronized isoproterenol hydrochloride (0.572 g) and 
micronized phenylephrine bitartrate (0.858 g) was coated with surfactant 
by homogenization in surfactant solution, followed by filtration, and 
drying of the solid coated drug. 
An aerosol suspension was prepared by homogenizing the solid coated drug 
(1.43 g) in 50 ml of "Freon 114" adding more "Freon 114" to provide 81.43 
g of mixture and then adding "Freon 115" to provide 201.4 g of mixture. 
The aerosol formulation was: 
______________________________________ 
Percent 
______________________________________ 
Surfactant-coated drug 
0.71 
"Freon 114" 39.72 
"Freon 115" 59.57 
______________________________________ 
EXAMPLE 14 
A surfactant solution of 1.0% 
bis(perfluoro-n-octyl-N-ethylsulfonamidoethyl)phosphate in "FC-113" was 
prepared, as in Example 11. 
A mixture of micronized isoproterenol hydrochloride (0.572 g) and 
micronized phenylephrine bitartrate (0.858 g) was coated with surfactant 
according to the procedure of Example 13. 
An aerosol suspension of the coated solid mixture in "Freon 114" and "Freon 
115" was prepared according to the procedure of Example 13. 
EXAMPLES 15-17 
Aerosol suspensions were prepared according to the procedures of Examples 
12-14, using twice the concentration of surfactant-coated drug. 
EXAMPLE 18 
A mixture of 3.0 g of micronized epinephrine bitartrate, 0.60 g of 
bis(perfluoro-n-octyl-N-ethylsulfonamidoethyl)phosphate and 30 ml of 
"Freon 113" was homogenized for 2 minutes. The mixture was filtered and 
the surfactant-coated drug was dried. A paste was prepared by mixing the 
coated drug with three times its weight of "FC-48". A vial was rinsed with 
"Freon 11", air dried and 196 mg of the paste was added to the vial. The 
vial was sealed with a rubber septum and 12 ml of a propellant mixture of 
75% "Freon C-318" and 25% "Freon 22" was added by means of a pressure 
syringe. The resultant aerosol formulation was: 
______________________________________ 
Percent 
______________________________________ 
Surfactant-coated epinephrine bitartrate 
0.291 
FC-48 0.873 
"Freon C-318" 75%, "Freon 22" 25% 
q.s. 
______________________________________ 
EXAMPLE 19 
A solution of 1% bis(perfluoro-n-octyl-N-ethylsulfonamidoethyl)phosphate in 
"Freon 113" was prepared. A 3 g sample of epinephrine bitartrate was 
homogenized in 30 ml of the above surfactant solution. The dispersion was 
filtered and dried to provide surfactant-coated drug. 
According to the procedure of Example 18 a paste was prepared of the 
surfactant-coated drug and "FC-48" and this paste was transferred to a 
vial after which the propellant mixture was added. The resultant aerosol 
formulation was: 
______________________________________ 
Percent 
______________________________________ 
Surfactant-coated epinephrine bitartrate 
0.291 
"FC-48" 0.873 
"Freon C-318" 75%, "Freon 22" 25% 
q.s. 
______________________________________ 
EXAMPLES 20-22 
Aerosol formulations were prepared according to the procedure of Example 19 
utilizing micronized phenylephrine hydrochloride, micronized isoproterenol 
hydrochloride and micronized phenylephrine bitartrate as the solid 
particulate active drug. 
EXAMPLE 23 
A 0.5% surfactant solution of 
N,N-dimethyl-N-decyl-N-(perfluoro-n-octylsulfonamidopropyl)ammonium 
bromide in a solvent mixture of 80% chloroform and 20% isopropanol was 
prepared. A mixture of 3 grams of micronized isoproterenol sulfate and 30 
ml of this surfactant solution was homogenized at high speed in a Virtis 
homogenizer for one minute. The solid drug was collected by filtration and 
dried at 60.degree. C. under vacuum for one hour. A paste was prepared by 
mixing together 100 mg of surfactant-coated drug with 300 mg of "FC-48". A 
197 mg portion of the paste was placed in a container and about 10 ml of 
perfluoropropane was added. The resulting aerosol formulation was: 
______________________________________ 
Percent 
______________________________________ 
Surfactant coated isoproterenol sulfate 
0.291 
"FC-48" 0.873 
perfluoropropane q.s. 
______________________________________ 
EXAMPLE 24 
A 0.5% surfactant solution of 
N,N-bis(4-carboxyl-n-butyl)perfluoro-n-octylsulfonamide in a solvent 
mixture of 80% chloroform and 20% isopropanol was prepared. A mixture of 3 
grams of micronized isoproterenol sulfate and 30 ml of this surfactant 
solution was homogenized at high speed in a Virtis homogenizer for one 
minute. The solid drug was collected and dried as in Example 23. A paste 
was prepared by mixing together 100 mg of surfactant-coated drug with 300 
mg of "FC-48". A 197 mg portion of the paste was placed in a container and 
about 10 ml of perfluoropropane was added. The resulting aerosol 
formulation was: 
______________________________________ 
Percent 
______________________________________ 
Surfactant coated isoproterenol sulfate 
0.291 
"FC-48" 0.873 
perfluoropropane q.s. 
______________________________________ 
EXAMPLE 25 
A solution of 1.8 g of bis(perfluoro-n-octyl-N-ethyl 
sulfonamidoethyl)phosphate and 0.20 g of bis(perfluorodecyl-N-ethyl 
sulfonamidoethyl)phosphate in 100 ml of "Freon 113" was prepared. A 
mixture of 3 g of micronized isoproterenol sulfate and 30 ml of the above 
surfactant solution was homogenized. The mixture was filtered and dried to 
provide surfactant-coated drug. A paste was prepared by mixing 100 mg of 
the coated drug with 300 mg of "FC-48". 197 Mg of the paste was placed in 
a container and about 10 ml of perfluoropropane was added. The resultant 
aerosol formulation was: 
______________________________________ 
Percent 
______________________________________ 
Isoproterenol sulfate 
0.291 
"FC-48" 0.873 
Perfluoropropane q.s. 
______________________________________ 
EXAMPLE 26 
A solution of 0.025 g of 
bis(perfluorohexyl-N-ethylsulfonamidoethyl)phosphate, 0.20 g of 
bis(perfluoro-n-octyl-N-ethylsulfonamidoethyl)phosphate and 0.025 g of 
bis(perfluorodecyl-N-ethyl sulfonamidoethyl)phosphate in 100 ml of 
chloroform was prepared. A mixture of 3 g of micronized isoproterenol 
sulfate and 30 ml of the above surfactant solution was homogenized. The 
mixture was filtered and dried to provide surfactant-coated drug. A paste 
was made by mixing the coated drug with three times its volume of "FC-48". 
197 Mg of the paste was placed in a container and about 10 ml of 
perfluoropropane was added. The resultant aerosol formulation was: 
______________________________________ 
Percent 
______________________________________ 
Surfactant coated isoproterenol sulfate 
0.291 
"FC-48" 0.873 
Perfluoropropane q.s. 
______________________________________ 
EXAMPLE 27 
A solution of 1% bis(perfluoro-n-octyl-N-ethyl sulfonamidoethyl)phosphate 
and 0.25% "Zonyl RP" in "Freon 113" was prepared. 
A mixture of 3 g of micronized epinephrine bitartrate and 30 ml of the 
above surfactant solution was homogenized. The mixture was filtered and 
dried to provide surfactant-coated drug. A paste was made by mixing the 
coated drug with three times its weight of "FC-48". 560 Mg of the paste 
was placed in a container and about 10 ml of propellant (75% "Freon C-318" 
and 25% "Freon 22") was added. The resultant aerosol formulation was: 
______________________________________ 
Percent 
______________________________________ 
Surfactant-coated epinephrine bitartrate 
1.0 
"FC-48" 3.0 
"Freon C-318" 75%, "Freon 22" 25% 
q.s. 
______________________________________ 
The foregoing Examples 1-27 illustrate compositions of this invention. Such 
compositions exhibit a high degree of stability against any tendency of 
the powdered solid material to agglomerate or to form deposits on the 
walls of the container. 
EXAMPLE 28 
The improved smaller particle size of the compositions of the present 
invention was demonstrated by the use of the "Andersen Sampler" cascade 
impactor, a device available from the Andersen 2000 Company, Atlanta, 
Georgia. This machine is widely used for particle size analysis. The 
following formulations were compared: 
1. A commercial aerosol formulation, useful for inhalation therapy, sold 
under the trademark "Medihaler-Epi" by Riker Laboratories, Inc., 
Northridge, California, comprising 0.5% by weight epinephrine bitartrate 
and 1% by weight sorbitan trioleate in a mixture of 25% 
1,2-dichlorotetrafluoroethane, 50% dichlorodifluoromethane, and 25% 
chlorotrifluoromethane. 
2. A formulation of epinephrine bitartrate prepared as described in Example 
1 in a concentration of 0.5% by weight in a propellant mix comprised of 
50% w/w dichlorotetrafluoroethane and 50% w/w of dichlorodifluoromethane. 
The formulations were sprayed into a glass "throat" attached to the 
impactor. The amount of drug impacted in the "throat" was determined in 
addition to the amount of drug distributed on the stages of the impactor. 
With the use of the impactor the mass median diameter of the aerosolized 
drug was determined. Drug impacted in the "throat" is, of course, not 
available for inhalation. These values are compared below in Table II. 
TABLE II 
______________________________________ 
Formulation of 
"Medihaler-Epi" 
Example 1 
______________________________________ 
Amount impacted 
in throat 58.4% 39.5% 
Amount delivered to 
impactor stages 
41.6% 60.5% 
Mass median diameter 
of delivered aerosol 
2.14 microns 1.87 microns 
______________________________________ 
One concludes from the above table that more of the drug is available for 
delivery to the lungs and more of the drug delivered to the lungs is of an 
acceptable particle size when the novel aerosol formulation of Example 1 
is employed.