1
`
`3M COMPANY 2001
`Mylan Pharmaceuticals Inc. v. 3M Company
`IPR2015-02002
`
`

`
`I
`
`AEROSOL DRUG FORMULATIONS
`
`5,126,123
`
`This application is a continuation-in-part of applica-
`tion Ser. No. 07/545,437, filed Jun. 28, 1990, now aban-
`doned. This invention relates to aerosol inhalation drug
`formulations comprising one or more drugs and one or
`more soluble surfactants in propellant l34a.
`BACKGROUND OF THE INVENTION
`
`Drugs for treating respiratory and nasal disorders are
`frequently administered in aerosol formulations through
`the mouth or nose. Peter Byron, Respiratory Drug
`Delivery. CRC Press, Boca Raton, FL 1990, provides a
`background for this form of therapy. (As used hereinaf-
`ter the terms “aerosol drug formulation" and “inhala-
`tion drug formulation" are synonymous and refer to one
`or more physiologically active chemical compounds in
`combination with excipients such as surface-active
`agents, “surfactants" and propellants.)
`One widely used method for dispensing such an aero-
`sol drug formulation involves making a suspension for-
`mulation of the drug as a finely divided powder in a
`liquefied gas known as a propellant. The suspension is
`stored in a sealed container capable of withstanding the
`pressure required to maintain the propellant as a liquid.
`The suspension is dispensed by activation of a dose
`metering valve affixed to the container. A metering
`valve may be designed to consistently release a fixed,
`predetermined amount of the drug formulation upon
`each activation. As the suspension is forced from the
`container through the dose metering valve by the high
`vapor pressure of the propellant, the propellant rapidly
`vaporizes leaving a fast moving cloud of very fine pani-
`cles of the drug formulation. This cloud is usually di-
`rected into the body of the patient by a channeling
`device, e.g., a cylinder like or cone like passage, with
`one of its ends attached to the outlet of the pressurized
`container, and the other end inserted in the mouth or
`nose of the patient. Concurrently with the activation of
`the aerosol dose metering valve, the patient inhales the
`drug formulation particles into the lungs or nasal cavity.
`Systems for dispensing drugs in this way are known as
`“metered dose inhalers (MDI‘s)." [Ibid Byron, Pages
`167-207.]
`'
`Many materials, including drug formulations, have a
`tendency to aggregate (also referred to as “flocculate"
`or “clump-up") when stored as fine particles having
`dimensions of a few microns in a suspension. For an
`aerosol delivery system to work properly the particle
`size should generally not exceed about five microns. As
`the particle size exceeds five microns, it becomes in-
`creasing difficult to maintain an efficacious aerosol dose
`with a predicable dispersion pattern upon activation of
`the metering valve. Further. the suspension should be
`uniform, that is, substantially free from large aggregates
`of the drug particle and be substantially homogenous
`throughout the container.
`To minimize or prevent the problem of aggregation
`of fine particles, compounds known as surface active
`agents, or surfactants, are used to coat the surfaces of
`the fine particles and assist in wetting the particles with
`an aerosol propellant..The use of surfactants in this way
`to maintain substantially unifonn suspensions is said to
`“stabilize" the suspensions. An ideal surfactant should
`have a relative high affinity for the suspended drug
`formulation and be chemically and physically compati-
`ble with the propellant as well as the drug formulation.
`
`l0
`
`15
`
`20
`
`‘25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`If it does not have these properties, the surfactant can
`possibly destabilize the suspension. Additionally, it must
`be essentially nontoxic.
`For several years the chlorofluorocarbons (CFC‘s),
`for example. trichloromonofluoromethane, dichlorotet-
`rafluoroethane
`and
`dichlorodifluoromethane,
`also
`known as “propellant 11“ or “P 11", “propellant 114 or
`“P 114" and "propellant 12" or “P 12“, respectively,
`have gained widespread acceptance as the propellants
`of choice for inhalation drug formulations. They are
`nonflammable, have low toxicity and reactivity, are
`compatible with many drug formulations and have the
`requisite physical attributes. See John Sciarra and
`Anthony Cutie, Theory and Practice of Industrial Phar-
`macy, Pages 589-619, Lea and Febiger, Philadelphia,
`l986. However, in the past few years CFC’s have been
`shown to cause depletion of the ozone layer of the
`atmosphere, a serious environmental problem. Scien-
`tists and governmental officials around the world have
`called for a phase-out of the use of CFC‘s. Some
`countries, e.g., Sweden, have completely banned the
`use of CFCs for aerosol products, while other counties
`have levied substantial taxes on them to encourage the
`use of other, environmentally safer propellants. See
`Dalby, et al., Pharmaceutical Technology, Mar. 26,
`1990.
`In recent years a nonchlorinated propellant chemi-
`cally identified as 1,l,1,2-tetrafluoroethane also known
`as "propellant 134a" or “P 134a” has been promoted by
`major chemical manufacturers, notably DuPont and
`ICI, as an environmentally acceptable alternative to
`CFC propellants. Propellant 134a has physical proper-
`ties comparable with P 12. Although like P 12 it is
`nonflammable and has a relatively low potential for
`interaction with a wide variety of products normally
`sold in aerosol form,
`its other chemical and solvent
`properties are different from P 12. For example P 1343
`is much less stable chemically than P 12 according to
`Dalby, et al. (see above).
`'
`Thiel in US. Pat. No. 4,357,789 teaches the use of
`propellan insoluble perfluorinated surface-active dis-
`persing agents in CFC and perfluorinated propellants
`although P 134a is not specifically mentioned. These
`agents include perfluorinated sulfonamide alcohol phos-
`phate esters and their salts, perfluorinated alkyl sulfona-
`mide alkylene quaternary ammonium salts and perfluo-
`rinated alcohol phosphate esters and their salts. Thiel
`teaches that surfactants must insoluble in the propellant.
`Further, he teaches that the drug must be coated with
`the surfactant in an organic solvent dried, then added to
`the propellant mixture.
`DESCRIPTION OF THE INVENTION
`
`It has now been found that P 134a-soluble surfactants,
`especially soluble perfluorinated surfactants, effectively
`improve the stability of micronized inhalation drug
`suspensions in P 134a. (As used herein the tenns “per-
`fluorinated" and “perfluoro” mean that for at lease one
`alkyl group essentially all of the hydrogens are substi-
`tuted with fluorine.) Accordingly, when a micronized
`drug,
`i.e., a drug having an average particle size of
`about 5 microns or below and a miximum particle size
`of less than about 10 microns, and a P 134a soluble
`surfactant are placed in P 134a in a pressurized con-
`tainer, there is considerably less tendency for the drug
`particles to aggregate and separate from the suspension
`than the drug formulation without such surfactant or
`with a P 134a hydrocarbon surfactant commonly used
`
`2
`
`

`
`5,126,123
`
`3
`with a CFC propellant. Thus it is now possible with the
`present invention to prepare aerosol formulations of
`inhalation drugs with P 134a which have sufficient
`stability for the purposes ofthis invention to deliver the
`active drug in the desired way as presently marketed
`MDI‘s, but without the environmental problems associ-
`ated with CFC‘s. As used herein the term "sufficient
`stability“ means that the aerosol drug formulation re-
`mains as a suspension after shaking at least long enough
`to allow activation of MDI and administration by the
`patient. The time between shaking and administration is
`typically about 10 sec. and generally for the formula-
`tions of this invention the period of stability is at least
`about 30 sec.
`
`An aspect of this invention is the use of one or more
`P 134a soluble surfactants to stabilize an inhalation drug
`in P 13421. A second aspect is an aerosol inhalation drug
`formulation comprising a physiologically effective
`amount of a micronized inhalation drug and one or
`more P 134a soluble surfactants in suspension in P 134a.
`In a preferred aspect the invention provides an aero-
`sol drug formulation comprising a physiologically ef-
`fective amount of micronized inhalation drug and one
`or more Pl34a soluble surfactants in suspension in
`P1342; which formulation is substantially free of Pl34a
`insoluble surfactant.
`In a further or alternative aspect the invention pro-
`vides an aerosol drug formulation comprising a particu-
`late drug and one or more Pl34a soluble surfactants in
`suspension in P13-4a, which formulation is substantially
`free of drug which has been coated with surfactant
`prior to addition to the propellant mixture.
`The drugs useful in this invention include those drug
`adaptable to inhalation administration,
`for example,
`antiallergic, respiratory (e.g. antiasthmatic and bron-
`chodilating), antibiotic, antiinflammatory, antifungal,
`analgesic, antiviral, and cardiovascular drugs. Espe-
`cially useful drugs include the respiratory drugs al-
`buterol, salmeterol and amiloride, fluticasone esters,
`beclomethasone esters and (— )-4-amino-3,5-dichloro-
`a~[[[6-(2-pyridinyl)ethoxy]hexyl]amino]methyl]ben-
`zenemethanol.
`U.S. Pat. No. 3,644,353, incorporated herein by refer-
`ence, teaches a group of bronchodilating compounds
`that are particularly useful in the treatment of asthma
`and other respiratory diseases. The preferred com-
`pound taught
`therein is at1-tert-butylaminomethyl-4-
`hydroxy-m-xylene-a‘, a3-diol, also known in the United
`States by its generic name, “albuterol“ and,
`in most
`other countries, “salbutamol.” This compound, espe-
`cially in aerosol form, has been widely accepted by the
`medical community in the treatment of asthma.
`Salmeterol, chemically named 4-hydroxy-a’-[[[6[(-1»
`phenylbutyl)oxy]hexyl]amino]methyl]-1,3-bcn-
`zenedimethanol, disclosed in British Patent Application
`No. 8,310,477,
`is a second generation bronchodilator
`which is longer acting and more potent than albuterol.
`This compound is in not yet marketed in the United
`States, but clinical trials in other countries indicate that
`a preferred mode of administration is by way of aerosol
`inhalation.
`The genetic disease cystic fibrosis is characterized by
`abnormalities that produce excessive pulmonary secre-
`tion which can make breathing difficult. U.S. Pat. No.
`4,501,729, incorporated herein by reference. discloses
`the use of the drug amiloride in an aerosol formulation
`to reduce the excess secretion.
`
`4
`United Kingdom Patent Specification No. 2088877
`discloses fluticasone esters. Fluticasone esters are cor-
`ticosteriods having topical anti-inflammatory action.
`Corticosteroids may be used in the management of pa-
`tients whose asthma is inadequately treated by broncho-
`dilators and/or sodium cromoglycate.
`A further class of corticosteroids having topical anti-
`inflammatory action, beclomethasone esters, are de-
`scribed in United Kingdom Patent Specification No.
`1
`047 519.
`(-)-4—Amino-3,5-dichloro-a-[[[6-[2-(2-pyridinyl)e-
`thoxy]hexyl]amino]methyl]benzenemethanol is a bron-
`chodilator.
`Where appropriate the drugs may be used in the form
`of salts (e.g. as alkali metal or amine salts or as acid
`addition salts) or as esters (e.g. as lower alkyl esters).
`For use in the invention, albuterol will preferably be
`in the form of the sulphate salt or the free base and
`salmeterol will preferably be in the form of its 1-
`hydroxy-2-naphthoate salt. The preferred fluticasone
`ester for use in the invention is fluticasone propionate,
`and the preferred beclomethasone ester is beclometha-
`sone dipropionate.
`In addition to surfactants it may be desirable to add
`other excipients to an aerosol formulation to improve
`drug delivery, shelf life and patient acceptance. Such
`optional excipients include, but are not limited to, color-
`ing agents, taste masking agents, buffers, antioxidants
`and chemical stabilizers.
`Inhalation drugs, or a pharmaceutically acceptable
`salt hereof, may be micronized by, for example, conven-
`tional jet mill micronizing to particles ranging from
`about 0.1 to about 10.0 microns and preferably from
`about 0.5 to about 5.0 microns. The micronized inhala-
`tion drug or combination of drugs are mixed with one
`or more P 134a-soluble surfactants and, optionally,
`other excipients and then placed in a suitable container
`capable of withstanding the vapor pressure of P 134a
`and fitted with a metering valve. The propellant is then
`forced as a liquid through the valve into the container.
`The completed MDI is shaken vigorously to form the
`suspension.
`Alternatively, an MDI can also be produced by add-
`ing drug, surfactant and liquefied propellant
`134a
`(chilled below it’s boiling point) to the container and
`then a metering valve fitted to the container. The com-
`pleted MDI can then be brought to ambient tempera-
`ture and shaken vigorously to form the suspension.
`MD1’s prepared according to the teachings herein
`may be used in the same way as currently marketed
`MDI's which use CFC’s or hydrocarbon propellants.
`For example, in the case of albuterol, amount of drug,
`surfactant and propellant can be adjusted to deliver 90
`pg per valve actuation, the dose delivered in currently
`marketed albuterol MDI‘s.
`Particular 134a-soluble surfactants include pert1uori-
`nated surfactants, especially perfluoroalkanoic acid
`surfactants having greater than 4 but 20 or less carbons,
`preferably from 8 to 10 carbons. Also particularly suit-
`able are a mixture of potassium perfluoroalkyl sulfo-
`nates and a mixture of ammonium perfluoroalkyl car-
`boxylates available under the trademarks FC-95 and
`FC-143, respectively, from 3M Corporation, Saint Paul,
`Minn. Most suitable are the perfluoroalkanoic acids,
`perfluorooctanoic acid and perfluorodecanoic acid.
`The ratio of surfactant to drug is from about l:l(X) to
`about 1:0.5 by weight, preferably in the range of about
`1:50 to about 1:1 and most preferably in the range of
`
`10
`
`15
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`3
`
`

`
`5
`about 1:25 to about H by weight. The amount ofP 134a
`can be varied according to the amount of drug formula-
`tion to be delivered with each activation of the dose
`
`5,126,123
`
`6
`TABLE 1
`
`Approximate
`Time Before
`Significant
`Flocculation
`Observed
`(sec)
`<2
`
`<2
`
`<2
`
`30
`
`30
`
`30
`
`30
`
`30
`
`30
`
`30
`
`30
`
`30
`
`H30
`
`180
`
`240
`
`80
`
`25
`
`40
`
`150
`
`Drug (amount)
`albuterol
`(50 mg)
`albuterol
`(50 mg)
`albuterol
`(50 mg)
`albuterol
`(50 mg)
`albuterol
`(50 mg)
`albuterol
`(50 mg)
`albuterol
`(50 mg)
`albuterol
`(50 mg)
`albuterol
`(50 mg)
`albuterol
`(50 mg)
`albuterol
`(50 mg)
`albuterol
`(50 mg)
`Example 10 salmeterol
`(20 mg)
`salmeterol
`(20 mg)
`salmeterol
`(10 mg)
`Example l3 salmeterol
`(10 mg)
`salmeterol
`(10 mg)
`salmeterol
`(l0 mg)
`perlluorodecanoic
`Example l6 amiloride HCI
`acid (20 mg)
`(100 mg)
`Example l7 amiloride HCl
`perfluorodecanoic
`150
`
`(100 mg)
`acid (70 mg)
`Fropellani l3-ta weight is 18 g in each control and example.
`‘Trademark of 3M Co. for a mixture of ammonium pcrfluoroalkyl carboxylatcs
`=Trademark of 3M Co. for a mixture of potassium perfluoroalkyl sulfonaies
`
`metering valve. Typically for an inhalation drug the
`amount of P 134a for each formulation of active drug
`depends on the volume of the metering valve and the
`dose desired. However the ratio of active drug or drugs
`to P 134a is in the range from about 1:100 to about
`124000 by weight. For example, for albuterol in an aero-
`sol inhalation system outfitted with a Bespak Bl(300
`valve, 18 g of!’ 134a are utilized per 50 mg of albuterol
`to deliver an effective dose of albuterol.
`
`The instant invention thus provides an aerosol inhala-
`tion drug formulation comprising a physiologically
`effective amount ofa micronized drug suitable for inha-
`lation therapy and a propellant 134a-soluble surfactant
`in suspension in propellant 134a and optionally other
`excipients.
`The following examples are presented for illustration
`of the invention and are not to be construed as a limita-
`tion thereto.
`
`EXAMPLES
`
`General Procedure
`
`Micronized drug and surfactant (if used) are weighed
`into a 15 mL transparent aerosol vial (No. S-241:6, pro-
`duced by Wheaton Industries, NJ). A metering valve
`(Bespak valve No. BK30O produced by Bespak plc,
`England) is crimped onto each vial. Finally, Propellant
`134a (from E. I. DuPont de Nemours and Company,
`Wilmington Del.) is added to the vial through the valve.
`Vials are then vigorously shaken for 30 min with a
`wrist-action shaker.
`
`the suspension in the
`Immediately after shaking.
`transparent vial is very milky or turbid. If left undis-
`turbed,
`the drug particles eventually flocculate and
`concentrate at the gas/liquid interface (creaming) or at
`the bottom of the vial (settling) leaving behind a rela-
`tively clear Propellant 134a region. By shaking a formu-
`lation that has separated,
`it quickly re-disperses to a
`milky suspension. Suspension stability is assessed by
`monitoring the rate at which the drug particles floccu-
`lates as evidenced by the time required for the suspen-
`sion to become coarse and/or to develop a relatively
`clear propellant region. If significant flocculation oc-
`curs, that is, a cognizable coarseness and/or clear re-
`gion can be observed,
`in less than about 15 sec., the
`suspension is deemed not stable enough for a practical
`aerosol inhalation drug formulation.
`Alternatively, several suspensions can be shaken si-
`multaneously and the most stable suspension designated
`as the last one to separate. A suspension of drug in
`Propellant 134a with no surfactant is used as a control
`and reference for measuring the stability of the formula-
`tions.
`
`l0
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`The drug and propellant weight ratio is selected
`based on reasonable ranges of marketed products. The
`ratio of surfactant weight to drug weight is varied by
`keeping the drug weight constant and increasing the
`surfactant weight.
`Using the procedure described above, the following
`data shown on Table 1 below was obtained:
`
`65
`
`Control l
`
`Control 2
`
`Control 3
`
`Example I
`
`Example 2
`
`Example 3
`
`Example 4
`
`Example 5
`
`Example 6
`
`Example 7
`
`Example 8
`
`Example 9
`
`Example ll
`
`Example 12
`
`Example 14
`
`Example 15
`
`Surfactant (amount)
`none
`
`oleic acid
`(10 mg)
`perfluorobutyric
`acid (10 mg)
`perfluoroclanoic
`acid (5 mg)
`perfluoroclanoic
`acid (25 mg)
`perfluoroctanoic
`acid (50 mg)
`perlluorodecanoic
`acid (5 mg)
`perfluorodecanoic
`acid (25 mg)
`FC-143' (5 mg)
`
`FC-l43 (50 mg)
`
`F095: (5 mg)
`
`FC-95 (50 mg)
`
`perfluorodecanoic
`acid (5 mg)
`perfluorodecanoic
`acid (50 mg)
`perfluorodecanoic
`acid (0.5 mg)
`perfluorodecanoic
`acid (0.1 mg)
`FC-143 (1 mg)
`
`FC-95 (1 mg)
`
`In the case of albuterol, the rate of particle settling
`after flocculation tended to increase with surfactant
`concentration.
`The following are examples of stable micronized
`drug suspension formulations according to the inven-
`tion.
`
`EXAMPLE 18
`
`Chilled propellant 134a (18 g) was added to per-
`fluorodecanoic acid (25 mg) in a glass aerosol vial. Mi-
`cronised Beclomethansone dipropionate (50 mg) was
`added and a metering valve crimped into place. The
`process was performed in a dry box.
`EXAMPLE 19
`
`Chilled propellant 134a (18 g) was added to per-
`fluorodecanoic acid (50 mg) in a glass aerosol vial. Mi-
`cronised Beclomethanasone dipropionate (50 mg) was
`added and a metering valve crimped into place. The
`process was performed in a dry box.
`EXAMPLE 20
`
`Chilled propellant 134a (18 g) was added to per-
`fluorodecanoic acid (1 mg) in a glass aerosol vial. Mi-
`cronised Albuterol sulphate (32 mg) was added and a
`
`4
`
`

`
`5,126,123
`
`8
`11. A method of claim 10 wherein said drug is se-
`lected from the group consisting of albuterol, sal-
`meterol. amiloride, fluticasone propionate. beclometha-
`sone dipropionate or (-)-4-amino-3,5-dichloro~a-[[[6-
`(2-pyridinyl)ethoxy]hexy]amino]methyl]benzeneme-
`thanol, and said surfact is a l,l,l,2-tetrafluorocthane-
`soluble, -soluble perfluorinated surfactant.
`12. A method of claim 11 wherein said drug is al-
`buterol, salmeterol or amiloride and said surfactant is a
`l,l,1,2-tetrafluoroethane-soluble, perfluorinated surfac-
`tants.
`13. A method of claim 11 wherein said surfactant is a
`
`perfluoroalkanoic acid of greater than 4 carbons but not
`greater than 20 carbons.
`14. A method of claim 11 wherein said surfactant is
`potassium perfluoroalkyl sulfonates ammonium per-
`fluoroalky carboxylates or a combination thereof.
`15. A method of claim 11 wherein said surfactant is
`perfluoroctanoic acid, perfluorodecanoic acid or a com-
`bination thereof and the ratio of surfactant to drug is
`from about 1:40 to about 1:05 by weight and the ratio of
`drug to l.l.l,2-tetrafluoroethane is from about l:l0O to
`about 1:4000 by weight.
`16. A method of claim 11 wherein said surfactant is
`potassium perfluoroall-tyl sulfonates ammonium perfluo-
`roalkyl carboxylates or a combination thereof and the
`ratio of surfactantyto drug is from about 1:40 to about
`l:0.5 by weight and the ratio of drug to l,1,l,2-tetra-
`fluoroethane is from about 1:100 to about
`l:4000 by
`weight.
`17. An aerosol inhalation drug formulation consisting
`essentially of a physiologically effective amount of mi-
`_cronized drug selected from the group albuterol, sal-
`meterol and amiloride or a pharmaceutically acceptable
`salt
`thereof, a
`l,l,l,2-tetrafluoroethane-soluble, per-
`fluoronated surfactant
`in suspension in 1,1,l,2-tetra-
`fluoroethane wherein the ratio of said surfactant to said
`drug is from about l:10O to about 1:05 by weight and the
`ratio of drug to 1,l,1,2—tetrafluoroethane is from about
`l:10O to about 1:4000 by weight.
`18. A formulation of claim 17 wherein said l,l,l,2—tct-
`rafluoroethane-soluble, perfluoronated surfactant
`is
`perfluoroctanoic acid, perfluorodecanoic acid, ammo-
`nium perfluoroalltyl carboxylates or potassium perfluo-
`roalkyl sulfonates.
`19. A formulation of claim 1 wherein said inhalation
`drug is a fluticasone ester.
`20. A formulation of claim 1 wherein said inhalation
`drug is a beclomethasone ester.
`2]. A formulation of claim 1 wherein said inhalation
`drug is (-)-4-amino-3,5-dichloro-a-[[[6-(2-pyridinyl)e-
`thoxy]hexy]amino]methyl]benzenemethano1.
`3
`I
`O
`t
`1
`
`7
`metering valve crimped into place. The process was
`performed in a dry box.
`EXAMPLE 2l
`
`Micronised fluticasone propionate (50 mg) and per-
`fiuorodecanoic acid (20 mg) were weigh into a glass
`aerosol vial. A metering valve was crimped onto the
`vial and propellant 134a (18 g) added to the vial
`throught the valve.
`
`EXAMPLE 22
`
`Micronised fluticasone propionate (50 mg) and per-
`fiuorodecanoic acid (50 mg) were weigh into a glass
`aerosol vial. A metering valve was crimped onto the
`vial and propellant 134a (18 g) added to the vial
`throught the valve.
`I claim:
`
`1. An aerosol inhalation drug formulation consisting
`essentially of a physiologically effective amount of a
`micronized inhalation drug and a l,1,l,2-tetrafluoroe-
`thanc-soluble. perfluoronated surfactant in suspension
`in l,l.1.2-tetrafluoroethane.
`2. A formulation of claim 1 wherein the ratio of said
`
`l0
`
`l5
`
`20
`
`surfactant to said drug is from about 1210010 about l:0.5
`by weight.
`3. A formulation of claim 1 wherein the ratio of said
`
`25
`
`drug to 1,1,1,2-tetrafluoroethane is from about 1:100 to
`about l:4000 by weight.
`4. A formulation of claim 1 wherein said surfactant is
`a perfluoroalkanoic acid of greater than 4 carbons but
`not greater than 20 carbons.
`5. A formulation of claim 4 wherein said per-
`fluoroalkanonic acid is perfluorooctanoic acid or per-
`fluorodecanoic acid.
`6. A formulation of claim 1 wherein said inhalation
`drug is albuterol or a pharmaceutically acceptable salt
`thereof.
`7. A formulation of claim 1 wherein said inhalation
`drug is salmeterol or a pharmaceutically acceptable salt
`thereof.
`8. A formulation of claim 1 wherein said inhalation
`drug is amiloride or a pharmaceutically acceptable salt
`thereof.
`9. A formulation ofclaim I wherein said l,l,l,2-tetra-
`fluoroethane-soluble, perfluoronated surfactant is potas-
`sium perfluoroalkyl sulfonates, ammonium perfluoroal-
`kyl carboxylates or a combination thereof.
`‘
`10. A method of improving the stability ofa micron-
`ized, aerosol inhalation drug suspension in l,1,l,2-tetra-
`fluoroethane consisting essentially of the addition of a
`1,l,l,2-tetrafluoroethane-soluble, perfluoronated sur-
`factant to said suspension.
`
`30
`
`50
`
`55
`
`65
`
`5