J
`
`
`
`Europaisches Patentamt
`European Patent Office
`Office europeen des brevets
`
`© Publication number:
`
`0 3 7 2 7 7 7
`A 2
`
`EUROPEAN PATENT A P P L I C A T I O N
`
`© Application number: 89312270.5
`270.5
`
`© int. CIA A61K 9/12, A61K 9 / 7 2
`
`© Date of filing: 27.11.89
`
`© Priority: 06.12.88 GB 8828477
`
`@ Date of publication of application:
`13.06.90 Bulletin 90/24
`
`® Designated Contracting States:
`BE CH DE ES FR GB IT LI NL SE
`
`© Applicant: RIKER LABORATORIES, INC.
`19901 Nordhoff Street
`Northridge, CA 91324(US)
`
`© Inventor: Purewal, Tarlochan Singh
`196 Radford Road
`Leamington Spa Warwickshire(GB)
`Inventor: Greenleaf, David John
`47 Outwoods Drive
`Loughborough Leicestershire(GB)
`
`© Representative: Bowman, Paul Alan et al
`LLOYD WISE, TREGEAR & CO. Norman
`House 105-109 Strand
`London WC2R OAE(GB)
`
`© Medicinal aerosol formulations.
`
`© A self-propelling aerosol formulation which may be free from CFC's which comprises a medicament, 1 ,1 ,1 ,2-
`tetrafluoroethane, a surface active agent and at least one compound having a higher polarity than 1,1,1,2-
`tetrafluoroethane.
`
`CM
`<
`r s
`r s
`!*«»
`CM
`IN
`CO
`
`Xerox Copy Centre
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1023, p. 1 of 10
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`

`

`EP 0 372 777 A2
`
`MEDICINAL AEROSOL FORMULATIONS
`
`5
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`10
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`75
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`20
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`25
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`This invention relates to medicinal aerosol formulations and in particular to formulations suitable for
`pulmonary, nasal, buccal or topical administration which are at least substantially free of chlorofluorocar-
`bons.
`Since the metered dose pressurised inhaler was introduced in the mid 1950's, inhalation has become
`the most widely used route for delivering bronchodilator drugs and steroids to the airways of asthmatic
`patients. Compared with oral administration of bronchodilators, inhalation 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 bronchial malady.
`The metered dose inhaler is dependent upon the propulsive force of a propellant system used in its
`manufacture. The propellant generally comprises a mixture of liquified chlorofluorocarbons (CFC's) which
`are selected to provide the desired vapour pressure and stability 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
`contribute 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 blowing agents, but heretofore the
`• use of CFC's in medicines, 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 aerosol propellant compositions which consist of a
`mixture of a hydrogen-containing chlorofluorocarbon or fluorocarbon (A), selected from the group consisting
`of CHCIF2 (Freon 22), CH2F2 (Freon 32) and CF3-CH3 (Freon 143a), with a hydrogen-containing fluorocar-
`bon or chlorofluorocarbon (B) selected from the group consisting of: CH2CIF (Freon 31), CCIF2-CHCIF
`(Freon 123a), CF3-CHCIF (Freon 124), CHF2-CCIF2 (Freon 124a), CHCIF-CHF2 (Freon 133), CF3-CH2CI
`(Freon 133a), CHF2-CHF2 (Freon 134), CF3-CH2F (Freon 134a), CCIF2-CH3 (Freon 142b) and CHF2-CH3 -
`(Freon 152a). The compositions may contain a third component (C) consisting of a saturated hydrocarbon
`propellant, 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:
`30 hair lacquers, anti-perspiration products, perfumes, deodorants for rooms, paints, insecticides, for home
`cleaning products, for waxes, etc. The compositions may contain dispersing agents and solvents, e.g.,
`methylene chloride, ethanol etc.
`It has now been found that 1 ,1 ,1 ,2-tetrafluoroethane has particularly suitable properties for use as a
`propellant for medicinal aerosol formulations when used in combination with a surface active agent and an
`adjuvant having a higher polarity than 1 ,1 ,1 ,2-tetrafluoroethane.
`According to the present invention there is provided an aerosol formulation comprising a medicament, a
`surfactant, 1,1,1 ,2-tetrafluoroethane and at least one compound having a higher polarity than 1,1,1 ,2-
`tetrafluoroethane.
`It has been found that 1 ,1 ,1 ,2-tetrafluoroethane, hereinafter 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 alcohol, isopropyl alcohol, propylene glycol, hydrocarbons such as propane, butane, isobutane,
`pentane, isopentane, neopentane, and other propellants such as those commonly referred to as Propellants
`45 11, 12, 114, 113, 142b, 152a 124, and dimethyl ether. The combination of one or more of such adjuvants
`with Propellant 134a provides a propellant system which has comparable properties to those of propellant
`systems based on CFC's, allowing use of known surfactants and additives in the pharmaceutical formula-
`tions 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
`significantly ozone depleting agents as they are broken down in the lower atmosphere. Such compounds
`have a higher polarity composition of the invention. Examples of such compounds include 2-bromo-2-
`2-chloro-2-
`and
`chloro-1 ,1 ,1 ,-trifluoroethane,
`2-chloro-1 -(difluoromethoxy)-l ,1 ,2-trifluoroethane
`(difluromethoxy)-l ,1 ,1-trifluoroethane.
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`EP 0 372 777 A2
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`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 propellant composition. The compositions are preferably
`free from CFC's.
`The particular adjuvant(s) used and the concentration of the adjuvant(s) is selected according to the
`particular medicament used and the desired physical properties of the formulation.
`It has been found that the use of Propellant 134a and drug as a binary mixture or in combination with a
`conventional surfactant such as sorbitan trioleate does not provide formulations having suitable properties
`for use with pressurised inhalers. It has been established that the physical parameters of polarity, vapour
`10 pressure, density, viscosity and interfacial tension are all important 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 formulations using Propellant 134a may be prepared.
`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 dissolved compared to their solubility in
`75 Propellant 134a alone. The presence of increased amounts of solubilised surfactant allows the preparation
`of stable, homogenous suspensions of drug particles. The presence of large amounts of solubilised
`surfactant may also assist in obtaining 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 measured 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 hydrocarbon solvents having a boiling point over 40* C. The
`method has been modified as described below for application to more volatile substances such as is
`required for propellant.
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`20
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`25
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`30
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`40
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`45
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`50
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`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-butanol value lower than 40, it is more appropriate to use a single
`reference standard of 75% n-heptane : 25% toluene. The concentration of Kauri-butanol solution is adjusted
`until a titre between 35ml and 45mi of the reference standard is obtained 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 aerosol 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 transfer 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 following formula:
`
`V -
`
`(W2
`
`- Wx)
`
`d
`
`^»
`
`4 0
`
`B
`
`in which:
`W2 = weight of aerosol bottle after titration (g)
`W1 = weight of aerosol bottle before titration (g)
`d = density of sample (g/ml)
`
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1023, p. 3 of 10
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`EP 0 372 777 A2
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`B is as defined in the ASTM standard and = ml of heptane-toluene blend required to titrate 20g of
`Kauri-butanol solution.
`If a titre (V) is obtained by precipitation of the Kauri resin out of solution, then a higher Kauri-butanol
`valve represents a sample of higher polarity.
`If the sample and Kauri-butanol solution are immiscible, this is most likely to be due to the immiscibility
`of 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 polarity is to be regarded as lower than that of any
`w material which would give a proper titre into Kauri-butanol solution.
`The particular selection of adjuvant and concentration preferably provides the resulting mixture with a
`solubility parameter of from 6.0 to 8.5 (cal/cm3)1/2. A propellant system having a solubility parameter below
`6.0 (cal/cm3)1'2 is a poor solvent for surfactants, resulting 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)1'2.
`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
`20 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 temperatures 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
`25 makes very little 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 10.3 x
`10s 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 sedimentation or "creaming" 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 10cP.
`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
`40 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 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 1 34a 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.
`Patent 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.
`so 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,
`
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1023, p. 4 of 10
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`EP 0 372 777 A2
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`Lauryl polyoxyethylene (4) ether available under the trade name Brij 30,
`Oleyl polyoxyethylene (2) ether available under the trade name Genapol 0-020,
`Block copolymers of oxyethylene and oxypropylene available under the trade name Synperonic,
`
`s
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`Oleic acid, Synthetic lecithin, Diethylene glycol dioleate, Tetrahydrofurfuryl oleate, Ethyl oleate,
`Isopropyl myristate, Glyceryl trioleate, Glyceryl monolaurate, Glyceryl mono-oleate, Glyceryl monostearate,
`Glyceryl monoricinoleate, Cetyl alcohol, Stearyl alcohol, Polyethylene glycol 400, Cetyl pyridinium chloride.
`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, analgesics, bronchodilators, antihistamines.therapeutic
`proteins and peptides, antitussives, anginal preparations, antibiotics, anti-inflammatory preparations, hor-
`mones, or sulfonamides, such as, for example, a vasoconstrictive amine, an enzyme, an alkaloid, or a
`steroid, and synergistic combinations of these. Examples of medicaments which may be employed are:
`Isoproterenol [alpha-(isopropylaminomethyl) protocatechuyl alcohol], phenylephrine, phenylpropanolamine,
`glucagon, adrenochrome, trypsin, epinephrine, ephedrine, narcotine, codeine, atropine, heparin, morphine,
`dihydromorphinone, ergotamine, scopolamine, methapyrilene, cyanocobalamin, terbutaline, rimiterol, sal-
`butamol, flunisolide, colchicine, pirbuterol, beclomethasone, orciprenaline, fentanyl, and diamorphine. Others
`such
`antibiotics,
`20 are
`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.
`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 salbutamol exhibits a greater dispersion stability than
`salbutamol 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, camsylate, car-
`30 bonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, fluceptate, glu-
`conate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate,
`iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methyl-
`nitrate, methylsulphate, mucate,
`nitrate,
`(embonate),
`pantothenate,
`napsylate,
`pamoate
`phosphate\diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulphate, tannate,
`tartrate, and triethiodide.
`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 pharmaceutical^ acceptable,
`e.g. glycine, ethylene diamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine,
`triethylamine, 1-amino-2-propanol-amino-2-(hydroxymethyl)propane-1 ,3-diol and 1-(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 1 0
`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 particles of less than about one-half micron in
`so 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
`metering valves and dispensed in an identical manner to formulations employing CFC's.
`The invention will now be illustrated by the following Examples.
`The following components were used in the Examples:
`Salbutamol Sulphate B.P., micronised - Salbutamol
`Beclomethasone Dipropionate
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`EP 0 372 777 A2
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`Isopropylacohol solvate, micronised - BDP
`Sodium Cromogiycate B.P., micronised - DSCG
`Sorbitan trioleate - Span 85
`Lecithin commercially available under the trade name Lipoid S100 - Lipoid S100
`5 Oleic Acid B.P. - oleic acid
`1,1,1 ,2-Tetrafluoroethane - P1 34a
`Ethyl alcohol B.P. - ethanol
`n-Pentane, standard laboratory reagent - n-pentane
`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 quanity 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.
`
`10
`
`EXAMPLES 1 to 6
`
`20
`
`Formulations containing Salbutamol
`
`The formulations reported in the following Tables were prepared.
`
`Ingredient (g)
`Salbutamol
`Span 85
`Oleic Acid
`Lipoid S100
`n-Pentane
`P134a
`
`1
`0.010
`0.012
`-
`-
`1.240
`3.720
`
`Example No.
`2
`0.010
`
`3
`0.010
`
`0.012
`-
`1.240
`3.720
`
`0.012
`1.240
`3.720
`
`Ingredient (g)
`Salbutamol
`Span 85
`Oleic Acid
`Lipoid S100
`Ethanol
`P134a
`
`4
`0.010
`0.012
`-
`
`1.350
`4.040
`
`Example No.
`5
`0.010
`
`6
`0.010
`
`0.012
`-
`1.350
`4.040
`
`0.012
`1.350
`4.040
`
`so
`
`All formulations comprised a suspension of salbutamol. Examples 4 to 6 containing ethanol appeared to
`be more stable than Examples 1 to 3 containing n-pentane, exhibiting a decreased tendency to settling.
`
`55
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`EXAMPLES 7 to 12
`
`Formulations containing Beclomethasone Dipropionate
`
`6
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`EP 0 372 777 A2
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`The formulations reported in the following Tables were prepared.
`
`Ingredient (g)
`BDP
`Span 85
`Oleic Acid
`Lipoid S100
`n-Pentane
`P134a
`
`7
`0.005
`0.012
`-
`-
`1.240
`3.720
`
`Example No.
`8
`0.005
`
`9
`0.005
`
`0.012
`-
`1.240
`3.720
`
`0.006
`1.240
`3.720
`
`Ingredient (g)
`BDP
`Span 85
`Oleic Acid
`Lipoid S100
`Ethanol
`P134a
`
`10
`0.005
`0.006
`-
`-
`1.350
`4.040
`
`Example No.
`11
`0.005
`
`12
`0.005
`
`0.006
`-
`1.350
`4.040
`
`0.006
`1.350
`4.040
`
`30
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`40
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`50
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`For those formulations containing n-pentane, Examples 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 Cromoglycate
`
`The formulations reported in the following Tables were prepared.
`
`Ingredient (g)
`DSCG
`Span 85
`Oleic Acid
`Lipoid S100
`n-Pentane
`P134a
`
`13
`0.100
`0.024
`-
`-
`1.240
`3.720
`
`Example No.
`14
`0.100
`
`15
`0.100
`
`0.024
`-
`1.240
`3.720
`
`0.024
`1.240
`3.720
`
`7
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`EP 0 372 777 A2
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`Ingredient (g)
`DSCG
`Span 85
`Oleic Acid
`Lipoid S100
`Ethanol
`P134a
`
`16
`0.100
`0.006
`-
`-
`1.350
`4.040
`
`Example No.
`17
`0.100
`
`18
`0.100
`
`0.006
`-
`1.350
`4.040
`
`0.006
`1.350
`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.
`2
`1
`0.012
`
`0.001
`
`
`Ingredient (g)
`
`19
`
`20
`
`Salbutamol
`BDP
`Span 85
`Oleic Acid
`P134a
`neopentane
`Isopropylalcohol
`Isopropylmyristate
`Propellant 11
`Isopentane
`
`0.012
`.
`0.001
`.
`4.98
`0.55
`-
`-
`-
`.
`
`.
`
`.
`
`.
`
`0.012
`.
`0.001
`.
`5.22
`.
`0.58
`-
`-
`
`.
`
`.
`
`.
`
`.
`
`.
`
`5.28
`
`0.59
`-
`
`.
`
`
`
`22
`
`23
`
`0.012
`
`0.001
`
`5.61
`.
`
`o.010
`
`o.001
`5.04
`
`
`0.62
`
`
`q.56
`
`Each Example was 5ml in volume and was in the form of a stable suspension.
`
`EXAMPLE 24
`
`This Example illustrates the use of different surfactants in the following basic formulations:
`
`Salbutamol
`Ethanol
`P134a
`Surfactant
`
`0.01 2g
`0.058g
`5.220g
`A or B
`Volume = 5 ml
`A = 0.005g B = 0.01 2g
`
`The following surfactants were employed to form stable suspensions in the concentrations specified.
`A, B.
`1 . Span 85
`
`8
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1023, p. 8 of 10
`
`

`

`EP 0 372 777 A2
`
`B.
`
`A.
`A.
`
`B.
`
`5
`
`10
`
`75
`
`20
`
`25
`
`A.
`A.
`A.
`A.
`A, B.
`B.
`
`2. Span 80
`3. Span 20
`4. Tween 20
`5. Tween 80
`6. Oleic acid
`7. Epikuron 200
`8. Synthetic lecithin
`A.
`9. Brij 92
`10. Brij 72
`A.
`11. Brij 30
`B.
`A.
`12. Genapol 0-020
`13. Diethylene glycol dioleate
`1 4. Tetrahydrofurfuryl oleate
`15. Ethyl oleate
`A.
`16. Isopropyl myristate
`B.
`17. Glyceryl trioleate
`A, B.
`18. Glyceryl monolaurate
`A.
`19. Glyceryl mono-oleate
`A.
`20. Glyceryl monostearate
`A.
`21 . Glyceryl monoricinoleate
`A.
`22. Cetyl alcohol
`A.
`23. Stearyl alcohol
`B.
`24. Polyethylene glycol 400
`25. Synperonic PE L61
`A.
`26. Synperonic PE L64
`A.
`27. Synperonic PE L92
`A.
`28. Synperonic PE P94
`A.
`29. Cetyl pyridinium chloride
`A.
`30. FC 807 free acids (consisting mainly of bis(perfluoro-n-octyl-N-ethyl sulphonamidoethyl) phos-
`A, B.
`30 phate)
`31. Corn Oil
`
`B.
`
`Claims
`
`35
`
`1. An aerosol formulation comprising a medicament, 1,1,1,2-tetrafluoroethane, a surface active agent
`and at least one compound having a higher polarity than 1,1,1,2-tetrafluoroethane.
`2. An aerosol formulation as claimed in Claim 1 suitable for administration to a patient by oral or nasal
`inhalation, the formulation being in the form of a solution or a suspension of medicament particles having a
`40 median particle size of less than 10 microns.
`3. An aerosol formulation as claimed in any preceding claim in which less than 5% by weight of the
`propellant composition comprises CHCIF2, CH2F2, CF3CH3 and mixtures thereof.
`4. An aerosol formulation as claimed in Claim 3 which is substantially free of CHCIF2, CH2F2, and
`CF3CH3.
`5. An aerosol formulation as claimed in any preceding claim in which the compound having a higher
`polarity than 1,1,1,2-tetrafluoroethane is selected from alcohols, saturated hydrocarbons, and mixtures
`thereof.
`6. An aerosol formulation as claimed in Claim 5 in which the compound is selected from ethyl alcohol,
`isopropyl alcohol, n-pentane, isopentane, neopentane, isopropyl myristate and mixtures thereof.
`7. An aerosol formulation as claimed in any preceding claim in which 1,1,1,2-tetrafluoroethane is
`present in an amount of at least 50% by weight of the formulation and the weight ratio of 1,1,1,2-
`tetrafluoroethane : compound of higher polarity is in the range 50:50 to 99:1.
`8. An aerosol formulation as claimed in Claim 7 in which the 1,1,1,2-tetrafluoroethane is present in an
`amount in the range 60 to 95% by weight of the formulation and the weight ratio of 1 ,1 ,1 ,2-tetrafluoroethane
`: compound of high polarity is in the range 70:30 to 98:2.
`9. An aerosol formulation as claimed in Claim 7 or claim 8 in which the weight ratio of 1,1,1,2-
`tetrafluoroethane : compound of higher polarity is in the range 85:15 to 95:5.
`10. An aerosol formulation as claimed in any preceding claim in which the surface active agent is
`
`45
`
`50
`
`55
`
`9
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1023, p. 9 of 10
`
`

`

`EP 0 372 777 A2
`
`selected from sorbitan trioleate, sorbitan mono-oleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan
`monolaurate, polyoxyethylene (20) sorbitan mono-oleate, natural lecithin, oleyl polyoxyethylene (2) ether,
`stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and
`oxypropylene, Oleic acid, Synthetic lecithin, Diethylene glycol dioleate, Tetrahydrofurfuryl oleate, Ethyl
`oleate, Isopropyl myristate, Glyceryl mono-oleate, Glyceryl monostearate,