1
`
`3M COMPANY 2004
`Mylan Pharmaceuticals Inc. v. 3M Company
`IPR2015-02002
`
`

`
`1
`
`MEDICINAL AEROSOL FORMULATIONS
`
`5,225,183
`
`2
`It has now been found that 1,1,l,2-tetrafluoroethane
`has particularly suitable properties for use as a propel-
`lant for medicinal aerosol formulations when used in
`combination with a surface active agent and an adju-
`vant having a higher polarity than l,1,1,2-tetrafluoroe-
`thane.
`
`SUMMARY OF THE INVENTION
`
`According to the present invention there is provided
`an aerosol formulation comprising a medicament, a
`surfactant, 1,l,l,2-tetrafluoroethane and at
`least one
`compound having a higher polarity than 1,l,1,2-tetra-
`fluoroethane.
`It has been found that 1,l,1,2-tetrafluoroethane, here-
`inafter referred to as Propellant 134a, may be employed
`as a propellant for aerosol formulations suitable for
`inhalation therapy when used in combination with a
`compound (hereinafter an “adjuvant”) having a higher
`polarity than Propellant 134a. The adjuvant should be
`miscible with Propellant 134a in the amounts employed.
`Suitable adjuvants include alcohols such as ethyl alco-
`hol, isopropyl alcohol, propylene glycol, hydrocarbons
`such as propane, butane, isobutane, pentane, isopentane,
`neopentane, and other propellants such as those com-
`monly referred to as Propellants 11, 12, 114, 113, 142b,
`152a 124, and dimethyl ether. The combination of one
`or more of such adjuvants with Propellant 134a pro-
`vides a propellant system which has comparable prop-
`erties to those of propellant systems based on CFC’s,
`allowing use of known surfactants and additives in the
`pharmaceutical formulations and conventional valve
`components. This is particularly advantageous since the
`toxicity and use of such compounds in metered dose
`inhalers for drug delivery to the human lung is well
`established. Preferred adjuvants are liquids or gases at
`room temperature (22‘’ C.) at atmospheric pressure.
`Recently it has been established that certain CFC’s
`which have been used as anaesthetics are not signifi-
`cantly ozone depleting agents as they are broken down
`in the lower atmosphere. Such compounds have a
`higher polarity than Propellant 134a and may be em-
`ployed in the composition of the invention. Examples of
`such compounds include 2-bromo-2-ch1oro-1,l,1,-tri-
`fluoroethane,
`2-chloro-l-(difluoromethoxy)-1,l,2-tri-
`fluroethane
`and
`2-chloro-2-(difluromethoxy)-l,1-tri-
`fluoroethane.
`In contrast to the prior art the compositions of the
`invention do not require the presence of Freon 22,
`Freon 32 or Freon 143a to provide useful properties;
`these propellants are preferably absent or present in
`minor amounts of less than 5% by weight of the propel-
`lant composition. The compositions are preferably free
`from CFC’s.
`The particular adjuvant(s) used and the concentra-
`tion of the adjuvant(s) is selected according to the par-
`ticular medicament used and the desired physical prop-
`erties of the formulation.
`It has been found that the use of Propellant 134a and
`drug as a binary mixture or in combination with a con-
`ventional surfactant such as sorbitan trioleate does not
`provide formulations having suitable properties for use
`with pressurised inhalers. It has been established 10 that
`the physical parameters of polarity, vapour pressure,
`density, viscosity and interfacial tension are all impor-
`tant in obtaining a stable aerosol formulation, and by a
`suitable selection of a compound having a polarity
`higher than that of Propellant 134a stable aerosol for-
`mulations using Propellant 134a may be prepared.
`
`is a continuation of application Ser. No.
`This
`07/442,119 filed Nov. 28, 19989, now abandoned.
`FIELD OF THE INVENTION
`This invention relates to medicinal aerosol formula-
`tions and in particular to formulations suitable for pul-
`monary, nasal, buccal or topical administration which
`are at least substantially free of chlorofluorocarbons.
`BACKGROUND TO THE INVENTION
`
`Since the metered dose pressurised inhaler was intro-
`duced in the mid l950’s, inhalation has become the most
`widely used route for delivering bronchodilator drugs
`and steroids to the airways of asthmatic patients. Com-
`pared with oral administration of bronchodilators, inha-
`lation offers a rapid onset of action and a low instance of
`systemic side effects. More recently, inhalation from a
`pressurised inhaler has been a route selected for the
`administration of other drugs, e.g., ergotamine, which
`are not primarily concerned with treatment of a bron-
`chial malady.
`The metered dose inhaler is dependent upon the pro-
`pulsive force of a propellant system used in its manufac-
`ture. The propellant generally comprises a mixture of
`liquified chlorofluorocarbons (CFC’s) which are se-
`lected to provide the desired vapour pressure and stabil-
`ity of the formulation. Propellants 11, 12 and 114 are the
`most widely used propellants in aerosol formulations
`for inhalation administration.
`In recent years it has been established that CFC’s
`react with the ozone layer around the earth and contrib-
`ute towards its depletion. There has been considerable
`pressure around the world to reduce substantially the
`use of CFC’s, and various Governments have banned
`the “non-essential" use of CFC’s. Such “non-essential"
`uses include the use of CFC’s as refrigerants and blow-
`ing agents. but heretofore the use of CFC’s in medi-
`cines, which contributes to less than 1% of the total use
`of CFC’s, has not been restricted. Nevertheless, in view
`of the adverse effect of CFC’s on the ozone layer it is
`desirable to seek alternative propellant systems which
`are suitable for use in inhalation aerosols.
`U.S. patent specification No. 4,174,295 discloses aero-
`sol propellant compositions which consist of a mixture
`of a hydrogen-containing chlorolluorocarbon or fluoro-
`carbon (A), selected from the group consisting of
`CI-ICIF2 (Freon 22), CH2F2 (Freon 32) and CF3—CH3
`(Freon 143a), with a hydrogen-containing fluorocarbon
`or chlorolluorocarbon (B) selected from the group con-
`sisting of: CH2ClF (Freon 31), CCIF2-CHCIF (Freon
`123a), CF3-CHCI (Freon 124), Cl-IF;-CClF2 (Freon
`124a), CHCIF-CHF2 (Freon 133), CF3-CH2Cl (Freon
`133a), CI-IF;-CHF2 (Freon 134), CF3-Cl-12F (Freon
`134a), CCIF2-CH3 (Freon l42b) and CHF2-CH3 (Freon
`152a). The compositions may contain a third compo-
`nent (C) consisting of a saturated hydrocarbon propel-
`lant, e.g., n-butane, isobutane, pentane and isopentanes.
`The propellant compositions comprise 5 to 60% of (A),
`5 to 95% of (B) and 0 to 50% of (C) and are said to be
`suitable for application in the fields of: hair lacquers,
`anti-perspiration products, perfumes, deodorants for
`rooms, paints, insecticides, for home cleaning products,
`for waxes, etc. The compositions may contain dispers-
`ing agents and solvents, e.g., methylene chloride, etha-
`nol etc.
`
`5
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`10
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`15
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`20
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`25
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`30
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`35
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`45
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`50
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`55
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`5,225,183
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`4
`the sample with butanol resulting from an excessively
`low polarity. However,
`it
`is feasible that excessively
`high polarity could result in immiscibility. This is tested
`by checking the miscibility of the sample with water. If
`the sample is immiscible with water and immiscible
`with Kauri-butanol solution,
`then the Kauri-butanol
`value is deemed too low to be measured, and the polar-
`ity is to be regarded as lower than that of any material
`which would give a proper titer into Kauri—butanol
`solution.
`The particular selection of adjuvant and concentra-
`tion preferably provides the resulting mixture with a
`solubility parameter of from 6.0 to 8.5 (cal/cm3)i. A
`propellant system having a solubility parameter below
`6.0 (cal/cm3)¥ is a pooor solvent for surfactants, result-
`ing in unstable suspension formulations of drug. The
`preferred solubility parameter for the propellant system
`comprising Propellant 134a and adjuvant is in the range
`6.5 to 7.8 (cal/cm3)§.
`The vapour pressure of a propellant system is an
`important factor as it provides the propulsive force for
`the medicament. The adjuvant is selected to moderate
`the vapour pressure of Propellant 134a so that it
`is
`within the desired range. This allows for advantages in
`the manufacture of the dosage form and gives greater
`flexibility to obtain and vary the target vapour pressure
`at room temperature. Another factor in the choice of
`the adjuvant is that, whilst it should allow moderation
`of the vapour pressure of Propellant 134a, it should not
`easily demix when the mixture is cooled to lower tem-
`peratures for the purposes of manufacture of the aerosol
`formulation and filling the containers.
`The vapour pressure may also be increased if desired
`depending on the choice of the adjuvant. It has been
`found that some of the propellant mixtures deviate from
`Raoult’s Law. The addition of certain alcohols makes
`verylittle change to the vapour pressure of the mixture
`with Propellant 134a at room temperature. However
`addition of certain hydrocarbons having a lower vapour
`pressure than Propellant 134a can result in a mixture
`having a higher vapour pressure.
`The vapour pressure of the formulations at 25' C. is
`generally in the range 20 to 150 psig (1.4 to 1.3)<lO5
`N/m2) preferably in the range 40 to 90 psig (2.8 to
`6.2 X 105 N/m2).
`The selection of adjuvant may also be used to modify
`the density of the formulation. Suitable control of the
`density may reduce the propensity for either sedimenta-
`tion or “crearning” of the dispersed drug powders. The
`density of the formulations is generally in the range 0.5
`to 2.0 g/cm3, preferably in the range 0.8 to 1.8 g/cm3,
`more preferably in the range 1.0 to 1.5 g/cm3.
`The selection of adjuvant may also_be used to adjust
`the viscosity of the formulation which is desirably less
`than 10 cP.
`_
`The selection of adjuvant may also be used to adjust
`the interfacial tension of the propellant system. In order
`to optimise dispersion of drug particles and stability the
`interfacial tension of the formulation is desirably below
`70 dynes/cm.
`Propellant 134a is generally present in the aerosol
`formulations in an amount of at least 50% by weight of
`the formulation, normally 60 to 95% by weight of the
`formulation.
`Propellant 134a and the component of higher polarity
`are generally employed in the weight ratio 50:50 to 99:1
`Propellant 134a : high polarity component, preferably
`
`3
`The addition of a compound of higher polarity than
`Propellant 134a to Propellant 134a provides a mixture
`in which increased amounts of surfactant may be dis-
`solved compared to their solubility in Propellant 134a
`alone. The presence of increased amounts of solubilised 5
`surfactant allows the preparation of stable, homogenous
`suspensions of drug particles. The presence of large
`amounts of solubilised surfactant may also assist in ob-
`taining stable solution formulations of certain drugs.
`The polarity of Propellant 134a and of an adjuvant
`may be quantified, and thus compared, in terms of a
`dielectric constant, or by using Maxwell’s equation to
`relate dielectric constant to the square of the refractive
`index—the refractive index of materials being readily
`measurable or obtainable from the literature.
`Alternatively, the polarity of adjuvants may be mea-
`sured using the Kauri-butanol value for estimation of
`solvent power. The protocol is described in ASTM
`Standard: Designation 1133-86. However, the scope of
`the aforementioned test method is limited to hydrocar- 20
`bon solvents having a boiling point over 40‘ C. The
`method has been modified as described below for appli-
`cation to more volatile substances such as is required for
`propellant.
`
`Standardisation
`
`In conventional testing the Kauri resin solution is
`standardised against
`toluene, which has an assigned
`value of 105, and a mixture of 75% n-heptane and 25%
`toluene by volume which has an assigned value of 40.
`When the sample has a Kauri-butano] value lower than
`40, it is more appropriate to use a single reference stan-
`dard of 75% n-heptane: 25% toluene. The concentration
`of Kauri-butanol solution is adjusted until a titer be-
`tween 35ml and 45ml of the reference standard is ob-
`tained using the method of the ASTM standard.
`
`Method for Volatile Compounds
`The density of the volatile substance under test is
`calculated to allow a volumetric titration from the
`added weight of the sample after testing.
`Kauri-butanol solution (20g) is weighed into an aero-
`sol bottle. A non—metering value is crimped onto the
`bottle and the weight of bottle and sample measured.
`Following the procedure detailed in ASTM standards
`as closely as possible, successive amounts of the volatile
`sample are transferred from an aerosol bottle via a trans-
`fer button until the end point is reached (as defined in
`ASTM). The aerosol bottle with titrated Kauri-butanol
`solution is re-weighed.
`The Kauri-butanol value is calculated using the fol-
`lowing formula:
`
`40
`= (W2 - Wt)
`U. XT
`
`V
`
`-
`
`30
`
`35
`
`45
`
`50
`
`S5
`
`in which:
`W2=weight of aerosol bottle after titration (g)
`W; =weight of aerosol bottle before titration (g)
`d=density of sample (g/ml)
`B is as defined in the ASTM standard and=ml of
`heptane-toluene blend required to titrate 20g of Kauri-
`butanol solution.
`If a titer (V) is obtained by precipitation of the Kauri
`resin out of solution, then a higher Kauri-butanol value 65
`represents a sample of higher polarity.
`If the sample and Kauri-butanol solution are immisci-
`ble, this is most likely to be due to the immiscibility of
`
`60
`
`3
`
`

`
`5
`in the weight ratio 70:30 to 98:2 and more preferably in
`the weight ratio 85:15 to 95:5 Propellant 134a : high
`polarity component. Preferred compounds of higher
`polarity than Propellant 134a include ethanol, pentane,
`isopentane and neopentane.
`The aerosol formulations comprise a surface active
`agent to stabilise the formulation and lubricate the valve
`components. Suitable surface active agents include both
`non-fluorinated surfactants and fluorinated surfactants
`known in the art and disclosed, for example, in British
`Patent Nos. 837465 and 994734 and U.S. Pat. No.
`4,352,789. Examples of suitable surfactants include: oils
`derived from natural sources, such as, corn oil, olive oil,
`cotton seed oil and sunflower seed oil.
`Sorbitan trioleate available under the trade name
`Span 85,
`Sorbitan mono-oleate available under the trade name
`Span 80,
`Sorbitan monolaurate available under the trade name
`Span 20,
`Polyoxyethylene (20) sorbitan monolaurate available
`under the trade name Tween 20,
`Polyoxyethylene (20) sorbitan mono-oleate available
`under the trade name Tween 80,
`lecithins derived from natural sources such as those
`available under the trade name Epikuron particularly
`Epikuron 200.
`Oleyl polyoxyethylene (2) ether available under the
`trade name Brij 92,
`Stearyl polyoxyethylene (2) available under the trade
`name Brij 72,
`Lauryl polyoxyethylene (4) ether available under the‘
`trade name Brij 30,
`Oleyl polyoxyethylene (2) ether available under the
`trade name Genapol 0-O20,
`Block copolymers of oxyethylene and oxypropylene
`available under the trade name Synperonic,
`Oleic acid, Synthetic lecithin, Diethylene glycol di-
`oleate, Tetrahydrofurfuryl oleate, Ethyl oleate, Isopro-
`pyl myristate, Glyceryl trioleate, Glyceryl monolau-
`rate, Glyceryl mono-oleate, Glyceryl monostearate,
`Glyceryl monoricinoleate, Cetyl alcohol, Stearyl alco-
`hol, Polyethylene glycol 4-O0, Cetyl pyridinium chlo-
`ride.
`The surface active agents are generally present in
`amounts not exceeding 5 percent by weight of the total
`formulation. They will usually be present in the weight
`ratio 1:100 to 10:1 surface active agent: drug(s), but the
`surface active agent may exceed this weight ratio in
`cases where the drug concentration in the formulation is
`very low.
`Suitable solid medicaments include antiallergics, an-
`algesics, bronchodilators, antihistamines,
`therapeutic
`proteins and peptides, antitussives, anginal preparations,
`antibiotics, anti-inflammatory preparations, hormones,
`or sulfonamides, such as, for example, a vasoconstric-
`tive amine, an enzyme, an alkaloid, or a steroid, and
`synergistic combinations of these. Examples of medica-
`ments which may be employed are: Isoproterenol [al-
`pha-(isopropylaminomethyl) protocatechuyl alcohol],
`phenylephrine, phenylpropanolamine, glucagon, adre-
`nochrome, trypsin, epinephrine, ephedrine, narcotine,
`codeine, atropine, heparin, morphine, dihydromorphi-
`none, ergotamine, scopolamine, methapyrilene, cyano-
`cobalamin, terbutaline, rimiterol, salbutamol, fluniso-
`lide, colchicine, pirbuterol, beclomethasone, orciprena-
`line, fentanyl, and diamorphine. Others are antibiotics,
`such as neomycin, streptomycin, penicillin, procaine
`
`6
`penicillin, tetracycline, chlorotetracycline and hydrox-
`ytetracycline; adrenocorticotropic hormone and adre-
`nocortical hormones, such as cortisone, hydrocortisone,
`hydrocortisone acetate and prednisolone;
`insulin, an-
`tiallergy compounds such as cromolyn sodium, etc.
`The drugs exemplified above may be used as either
`the free base or as one or more salts known to the art.
`The choice of free base or salt will be influenced by the
`physical stability of the drug in the formulation. For
`example, it has been shown that the free base of sal-
`butamol exhibits a greater dispersion stability than sal-
`butamol sulphate in the formulations of the invention.
`The following salts of the drugs mentioned above
`may be used; acetate, benzenesulphonate, benzoate,
`bicarbonate, bitartrate, bromide, calcium edetate, cam-
`sylate, carbonate, chloride, .citrate, dihydrochloride,
`edetate, edisylate, estolate, esylate, fumarate, fluceptate,
`gluconate, glutamate, glycollylarsanilate, hexylresorci-
`nate, hydrobromide, hydrochloride, hydroxynaphtho-
`ate,
`iodide,
`isethionate,
`lactate,
`lactobionate, rnalate,
`maleate, mandelate, mesylate, methylbromide, methyl-
`nitrate, methylsulphate, mucate, napsylate, nitrate,
`pamoate (embonate), pantothenate, phosphatediphos-
`phate, polygalacturonate, salicylate, stearate, subace-
`tate, succinate, sulphate, tannate, tartrate, and triethio-
`dide.
`Cationic salts may also be used. Suitable cationic salts
`include the alkali metals, e.g. sodium and potassium, and
`ammonium salts and salts of amines known in the art to
`be pharmaceutically acceptable, e.g. glycine, ethylene
`diamine, choline, diethanolamine, triethanolamine, oc-
`tadecylamine, diethylamine, triethylamine,
`l-amino-2-
`propanol—amino—2-(hydroxymethyI)propane—l,3-diol
`and l-(3.4-dihydroxyphenyl)-2 isopropylaminoethanol.
`For pharmaceutical purposes the particle size of the
`powder should desirably be no greater than 100 microns
`diameter, since larger particles 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 particle size of the powder for inhalation therapy
`should preferably be in the range 2 to 10 microns.
`There is no lower limit on particle size except that
`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
`absorbed and retained on or in body tissues. When parti-
`cles of less than about one-half micron in diameter are
`administered by inhalation they tend to be exhaled by
`the patient.
`The concentration of medicament depends upon the
`desired dosage but is generally in the range 0:01 to 5%
`by weight.
`The formulation of the invention may be filled into
`conventional aerosol containers equipped with meter-
`ing valves and dispensed in an identical manner to for-
`mulations employing CFC’s.
`The invention will now be illustrated by the follow-
`ing Examples.
`The following components were used in the Exam-
`ples:
`
`Salbulamol
`Salbutamol Sulphate B.P.. micronised
`BDP
`Beclomethasone Dipropicnate
`Isopropylacohol solvate, micronised
`
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`8 E
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`-continued
`DSCG
`Sodium Cromoglycate B.P.. micronised
`Span S5
`Sorbitan lrioleate
`Lipoid S100
`Lecithin commercially available
`under the trade name Lipoid S100
`oleic acid
`Oleic Acid B.P.
`P134a
`1.1.1.2-Tetralluoroethane
`ethanol
`Ethyl alcohol E.P.
`n-pentane
`n-Pentane, standard laboratory
`reagent
`
`The formulations in the Examples were prepared by the
`following techniques.
`Each drug and surfactant combination was weighed
`into a small beaker. The required quantity of the higher
`boiling point component of the propellant system e.g.
`ethanol was added and the mixture homogenised using
`a Silverson mixer. The required quantity of the mixture
`was dispensed into a P.E.T. bottle and an aerosol valve
`crimped in place. Propellant 134a was added to the
`required weight by pressure filling.
`EXAMPLES 1 TO 6
`
`Formulations containing Salbutamol
`The formulations reported in the following Tables
`were prepared.
`
`Example No.
` Ingredient (g) 1 2 3 4 5 6
`
`
`
`
`
`
`Salbutamol
`0.010
`0.010
`0.010
`0.010
`0.010
`0.010
`Span 85
`0.012
`—
`—
`0.012
`—
`-
`Oleic Acid
`—
`0.012
`—
`——
`0.012
`-
`Lipoid S100
`-—
`—
`0.012
`—
`——
`0.012
`n-Pentane
`1.240
`1.240
`1.240
`Ethanol
`1.350
`1.350
`1.350
`
`P134a 4.040 3.720 3.720 3.720 4.040 4.040
`
`
`
`
`
`
`
`
`
`formulations comprised a suspension of sal-
`All
`butamol. Examples 4 to 6 containing ethanol appeared
`to be more stable than Examples 1 to 3 containing :1-
`pentane, exhibiting a decreased tendency to settling.
`EXAMPLES 7 TO 12
`
`Formulations containing Beclomethasone Dipropionate
`The formulations reported in the following Tables
`were prepared.
`
`xample No.
`___?.¢.
`15
`16
`Ingredient (g)
`13
`14
`17
`18
`DSCG
`0.100
`0.100
`0.100
`0.100
`0.100
`0.100
`Span 85
`0.024
`——
`—
`0.006
`—
`—
`Oleic Acid
`——
`0.024
`—
`—
`0.006
`—
`Lipoid S100
`—
`—
`0.024
`—-
`——
`0.006
`n~Pentane
`1.240
`1.240
`1.240
`_
`Ethanol
`1.350
`1.350
`1.350
`
`P1343 4.040 3.720 3.720 3.720 4.040 4.040
`
`
`
`
`
`
`Examples 13 to 18 produced suspension formulations,
`Examples 16 to 18 containing ethanol exhibiting better
`stability properties than Examples 13 to 15 containing
`n-pentane.
`
`EXAMPLES 19 to 23
`
`The following Examples illustrate the use of different
`adjuvants with Propellant 134a.
`
`Example No.
`23
`20
`19
`21
`22
`
`Ingredient (g)
`0.012
`0.012
`0.012
`0.012
`Salbutamol
`BDP
`Span 85
`Oleic Acid
`P134a
`neopentane
`lsopropyl-
`alcohol
`lsopropy1-
`myristate
`0.62
`Propellant 11
`0.56
`lsopentane
`
`0.001
`
`0.CX')1
`
`5.22
`
`4.98
`0.55
`_o_5_g
`
`0.001
`
`5.28
`
`0.001
`
`5.61
`
`_
`
`_
`
`0.010
`
`0.001
`5.04
`
`_
`
`Each Example was 5 ml in volume and was in the
`form of a stable suspension.
`EXAMPLE 24
`
`This Example illustrates the use of different surfac-
`tants in the following basic formulations:
`
`Salbutamol
`0.012 g
`Ethanol
`0.58 g
`Pl34a
`5.220 g
`Surfactant
`A or B
`
`Volume = 5 ml
`A : 0.005 g
`B = 0.012 g
`
`The following surfactants were employed to form
`stable suspensions in the concentrations specified.
`
`F’
`Span 85
`Span 80
`Span 20
`Tween 20
`Tween 80
`Oleic acid
`Epikuron 200
`Synthetic lecithin
`Btij 92
`Brij 72
`. Brij 30
`Genapol 0-020
`Diethylene glycol dioleate
`Tetrahydrofurfuryl oleate
`Ethyl oleate
`Isopropyl myristate
`Glyceryl trioleate
`Glyceryl rnonolaurate
`Glyceryl mono-olcate
`
`???P????F??PF?????>F“F”
`
`5F§3F3?§:5wrs9w+wwr
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`65
`
`5
`
`
`
`%
`0.005
`0.011
`—
`—
`1.240
`
`8
`0.005
`—
`0.012
`-
`1.240
`
`Example No.
`12
`11
`9
`10
`Ingredient (3)
`0.005
`0.005
`0.005
`0.005
`BDP
`—
`—
`—
`0.006
`Span 85
`—
`0.006
`—
`—
`Oleic Acid
`0.006
`_
`0.006
`_
`Lipoid S100
`1.240
`n~Pentane
`1.350
`1.350
`1.350
`Ethanol
`
`
`
`3.720 3.720 3.720 4.040 4.040P134a 4.040
`
`
`
`
`
`
`
`For those formulations containing n-pentane, Exam-
`ples 7 and 8 appeared less turbid than Example 9, and
`Example 8 appeared to form a solution after 4-5 days.
`Examples 10 to 12 produced solution formulations.
`EXAMPLES 13 to 18
`
`Formulations containing Sodium Crornoglycate
`The formulations reported in the following Tables
`were prcpared._
`
`

`
`9
`-continued
`. Glyceryl monostearate
`. Glyceryl monoricinoleate
`Cetyl alcohol
`Stearyl alcohol
`Polyethylene glycol 400
`Synperonic PE L61
`Synperonic PE L64
`Synperonic PE L92
`Synperonic PE P94
`Cetyl pyridinium chloride
`FC 807 free acids
`(consisting mainly of
`bis(perfluoro-n-octyl-N-
`ethyl sulphonamidoethyl)
`phosphate)
`Com Oil
`
`9'?‘-l3'3824.
`
`25.
`26.
`27.
`28.
`29.
`30.
`
`31.
`
`?.>E>?’.>?‘F°F"?*?*?’ 51"
`
`B,
`
`We claim:
`
`1. An aerosol formulation comprising:
`(a) a therapeutically effective amount of a medica-
`ment;
`
`5,225,183
`
`5
`
`10
`
`»
`
`15
`
`10
`(b) a propellant substantially free of chlorofluorocar-
`bons,
`said propellant comprising 1,1,1,2-tetra-
`fluoroethane;
`(c) a surface active agent in an amount sufficient (i) to
`stabilize the formulation or (ii) lubricate a valve
`stem in a metering valve; and
`(d) at least one compound selected from the group
`consisting of ethyl alcohol, isopropyl alcohol, n-
`pentane,
`isopentane, neopentane,
`isopropyl, and
`myristate,
`said compound being present
`in an
`amount such that it is miscible with the l,l,1,2-tet-
`rafluoroethane and such that said surface active
`agent
`is soluble in the formulation in a greater
`amount than in 1,1,1,2-tetrafluoroethane.
`2. The formulation of claim 1 wherein the weight
`ratio of l,l,l,2-tetrafluoroethane to compound (d) is in
`the range of 50:50 to 99:1.
`3. The formulation of claim 1 wherein said medica-
`ment is a member selected from the group consisting of
`20 salbutamol, beclomethasone dipropionate, disodium
`cromoglycate,
`pirbuterol,
`isoprenaline,
`adrenaline,
`rimiterol, and ipratropium bromide.
`I
`C
`l
`I
`*
`
`-
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`6
`
`

`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`CERTIFICATE OF CORRECTION
`
`PATENTNO.
`
`DATED
`
`:
`
`:
`
`5.2251133
`
`July 6, 1993
`
`|NVENTon$);
`
`Tarlochan S. Purewal et al.
`
`kkcmfifiwtmtwmrwpmminmemnwdmnmmdpmmnmmtmtwwLummPmmukhmwy
`corrected as shown nelow:
`4
`
`Col. 1, 5, "l9989" should read --1989--.
`
`Col. 1,
`
`line 54,
`
`"CB3-CHCl" should read --CF3—CHC1F—-.
`
`Col. 2,
`
`line 45-46, "-1,1—trifluoroethane" should read
`
`---1,1,1-trifluoroethane-—.
`
`Col. 2,
`
`line 62, delete "lo".
`
`Col. 4,
`
`line 44, "1.3" should read --10.3--.
`
`Col. 6,
`
`lines 23-24, "phosphatediphosphate" should read
`
`—-phosphate/diphosphate--.
`
`Signed and Sealed this
`
`
`
`Fourteenth Day of June, 1994
`
`flwwk
`
`BRUCE LEI-[MAN
`
`
`
`
`Commisxioner of Patent: and Trademarks
` Arresting Oflicer
`
`
`
`7
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`CERTIFICATE OF CORRECTION
`
`PATENT NO.:
`
`5,225,183
`
`DATED:
`
`July 6, 1993
`
`lNVENTOR(S): Tadocan S. Purewal et al.
`
`It is certified that error appears in the above-identified patent and that said Letters Patent is hereby
`corrected as shown below:
`
`Col. 10, lines 9-10, “isopropyl. and myristate," should read --isopropyl myristate.-.
`
`Signed and Sealed this
`
`Eleventh Day of March, 1997
`
`flwzmx
`
`BRUCE LEHMAN
`
`Arresting Oflicer
`
`C(7IIlIlIIh‘.Vf(7IlCI' of P11I('nr.\' and 'l‘ruzlmnarkx
`
`8