Technical Field of the Invention
This invention relates to a stable aerosol composition comprising a combination of Ciclesonide and one or more other active ingredients.
Background of the Invention
Bronchoconstriction occurs due to bronchial smooth muscle spasm and airway inflammation with mucosal edema. Asthma and other related disorders, have been known to be treated with ß-2 adrenergic receptor agonists (ß-2 agonist) as they provide a bronchodilator effect to the patients, resulting in relief from the symptoms of breathlessness. ß-2 Agonists can be short acting for immediate relief, or long acting for long-term prevention, of asthma symptoms. Short acting ß-2 agonists currently available include: salbutamol, biltolterol, pirbuterol and terbutaline. Long acting B-2 agonists currently available include salmeterol and formoterol.
Whilst it is also known that B-2 agonists provide symptomatic relief of bronchoconstriction in patients, another component of asthma, i. e. inflammation, often requires separate treatment. Typically this involves treatment with a steroid. Indeed, treatment with a corticosteroid is considered one of the most potent and effective therapies currently available for persistent asthma. Currently available corticosteroids include: ciclesonide, beclomethasone, budesonide. flunisolide, fluticasone, mometasone and triamcinolone.
Especially, GB 247680 discloses Ciclesonide and their use in the treatment of inflammatory conditions. Ciclesonide shows excellent antiasthmatic activity and the concentration of the drug in the lungs is high and metabolism by liver oxidases is very high, giving the drug a low plasma half-life. Systemic activity of ciclesonide is three times lower than that of budesonide, but anti-inflammatory activity is higher for the former.
Bronchoconstriction and inflammation are also associated with bronchial plugging with secretions, which may be treated with anti-cholinergic agents, such as troventol, ipratropium, oxitropium and tiotropium.
These medicaments can be administered in different ways, however inhalation has become the primary route of administration in the treatment of asthma. This is because, besides providing direct access to the lungs, medication delivered through the respiratory tract provides rapid and predictable onset of action and requires lower dosages compared to the oral route. Typical delivery systems for inhalable drugs are the pressurized metered-dose inhaler (pMDI) comprising a suspension of fine drug particles in a propellant gas, and the dry powder inhaler (DPI) comprising fine drug particles as dry powder typically admixed with coarser excipient such as lactose.
Pharmaceutical agents administered by means of pMDIs are usually bronchodilators or corticosteroids or anticholinergics or combinations thereof.
Typical metered dose inhaler formulations contain chlorofluorocarbon propellants, the active ingredient(s) and ethanol, which is soluble in the propellant, and sometimes also contain a surfactant such as oleic acid for maintaining a stable suspension, lubrication of the metering valve and other functions. Traditionally, the propellant system has consisted of a mixture of chlorofluorocarbons (CFCs) which are selected to provide the desired vapor pressure and suspension stability. Currently, CFCs such as Freon 11, Freon 12, and Freon 114 are the most widely used propellants in aerosol formulations for inhalation administration. While such systems may be used to deliver solubilized drug, the selected active ingredient is typically incorporated in the form of a fine particulate to provide a dispersion. To minimize or prevent the problem of aggregation in such systems, surfactants are often used to coat the surfaces of the active ingredient and assist in wetting the particles with the aerosol propellant. The use of surfactants in this way to maintain substantially uniform dispersions is said to "stabilize" the suspensions.
Unfortunately, traditional chlorofluorocarbon propellants are now believed to deplete stratospheric ozone and, as a consequence, are being phased out. This, in turn, has led to the development of aerosol formulations for pulmonary drug delivery employing so-called environmentally friendly propellants. Classes of propellants which are believed to have minimal ozone-depletion potential in comparison with CFCs are perfluorinated compounds (PFCs) and hydrofluoroalkanes (HFAs). While selected compounds in these classes may function effectively as biocompatible propellants, many of the surfactants that were effective in stabilizing drug suspensions in CFCs are no longer effective in these new propellant systems. As the solubility of the surfactant in the HFA decreases, diffusion of the surfactant to the interface between the drug particle and HFA becomes exceedingly slow, leading to poor wetting of the active ingredient particles and a loss of suspension stability. This decreased solubility for surfactants in HFA propellants is likely to result in decreased efficacy with regard to any incorporated active ingredient(s).
More particularly, the active ingredient(s) suspended in the propellants tend to aggregate rapidly. If the particle size of the suspended material cannot be regulated and aggregation 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 unwanted aggregation or flocculation may lead to improper dosages which can lead to undesirable results, particularly in the case of highly potent, low dose active ingredient(s). Moreover, particle aggregation also leads to fast creaming or sedimentation of the suspension. The resulting phase separation is generally addressed by vigorously shaking the MDI device immediately before use. However, patient compliance is difficult to control and many commercially available suspensions are so unstable that even slight delays between shaking and use can affect dosage uniformity.
To overcome the difficulties associated with forming stabilized dispersions using environmentally compatible propellants generally involve the addition of HFA-miscible co-solvents (i.e. ethanol) and/or the inclusion of various surfactant systems. For example, several attempts have dealt with improving suspension stability by increasing the solubility of surface-active agents in the HFA propellants. To this end U.S. Pat. No.
5,118,494, WO 91/11173 and WO 92/00107 disclose the use of HFA soluble fluorinated surfactants to improve suspension stability. Mixtures of HFA propellants with other perfluorinated cosolvents have also been disclosed as in WO 91/04011.
EP 1870090 Al discloses the formulation with 0.30%w/w of ethanol and 0.050% w/w of oleic acid as a dispersing agent. It is been mentioned that the suspended particles of active agents are stable with very small quantities of ethanol and the valves were compatible with the formulation.
Certain of the steroids have significant solubility in ethanol. When there is insufficient ethanol present for maintaining a solution of these drugs in an aerosol canister, the normal temperature fluctuations encountered during storage and use can cause repeated solubility increases and decreases of a saturated solution. Each time the drug substance becomes less soluble, such as in a period of ambient temperature decrease, it tends to crystallize and, due to the typical slow rate of temperature change, grows into crystals much larger than those which can be properly dispensed-particularly when the drug is intended for delivery to the bronchia or lungs. In general, drug particle sizes from about 1 to about 5 micrometers are preferred for administration to the lower airway, with particles smaller than about 0.5 micrometers frequently being exhaled without complete deposition on tissues, while particles larger than about 10 micrometers can exhibit considerable deposition in the mouth and/or pharynx and therefore not reach the lower airway. Very large particles cannot pass through a metering valve and will not be reliably dispensed. However, the presence of any ethanol is discouraged in many countries, due to the prevalence of alcoholism and the ease with which ethanol is systemically absorbed from lower airway tissues. Any products intended for use by children generally should have low ethanol content as possible.
Other attempts at stabilization involved the inclusion of nonfluorinated surfactants. In this respect. U.S. Pat. No. 5,492,688 discloses that some hydrophilic surfactants (with a hydrophilic/lipophilic balance greater than or equal to 9.6) have sufficient solubility in HFAs to stabilize medicament suspensions. Increases in the
solubility of conventional nonfluorinated MDI surfactants (e.g. oleic acid, lecithin) can also reportedly be achieved with the use of co-solvents such as alcohols, as set forth in U.S. Pat. Nos. 5,683,677 and 5,605,674, as well as in WO 95/17195. Unfortunately, as with the prior art co-solvent systems previously discussed, merely increasing the repulsion between particles has not proved to be a very effective stabilizing mechanism in nonaqueous dispersions, such as MDI preparations.
Whilst surfactants such as oleic acid and sorbitan trioleate serve to improve formulation stability and efficacy, the use of such surfactants in conjunction with the aluminum containers typically used to store and dispense aerosol formulations has proved problematic. Reactions between the oleate surfactant and the aluminum walls of the container result in the formation over time of metal oleates, causing product degradation.
In order to address this problem, attempts have been made to reduce the quantity of surfactant used in the formulation, so as to minimize the rate of formation of oleates. However, this is not a preferred solution to the problem, as a reduction in surfactant quantity has an adverse effect both on control of mist generation by the MDI on dispersal of the formulation, and on the lubrication of the dispenser and valve mechanism used to disperse the formulation. Impaired valve lubrication, resulting from diminished surfactant levels, may give rise to excess friction between the working parts of the valve, which may damage the valve and/or may generate particulate matter that will contaminate the formulation.
EP 0504112 A discloses examples of pharmaceutical compositions for aerosol use comprising formoterol fumarate.
WO 93/11747 discloses a pharmaceutical suspension formulation suitable for aerosol administration, consisting essentially of a therapeutically effective amount of a drug and a propellant selected from the group consisting of HFA 134a, HFA 227, and a mixture thereof, the formulation being further characterized in that it exhibits substantially no growth in particle size or change in crystal morphology of the drug over
a prolonged period, is substantially and readily redispersible, and upon redispersion does not flocculate so quickly as to prevent reproducible dosing of the drug. The application specifically discloses formulations of formoterol fumarate in HFA 134a, HFA 227 and 1: 1 mixtures of HFA 134a and HFA 227.
WO 93/11745 discloses pharmaceutical aerosol formulations, substantially free of surfactant containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellants and up to 5% of a polar co-solvent. Preferred propellants are HFA 134a and HFA 227, which are preferably used alone. The preferred polar co-solvent is ethanol and it is stated that in general only small quantities e. g. 0.05 to 3.0% w/w of polar co-solvent are required to improve the dispersion and the use of quantities in excess of 5% w/w may disadvantageously tend to dissolve the medicament.
WO 97/47286 discloses a pharmaceutical suspension formulation suitable for aerosol administration, consisting essentially of: (a) from 0.0025 to 0. 1% w/w of micronized formoterol, or an acid addition salt thereof and (b) from 0.1 to 5.0% w/w ethanol, (c) HFA 134a, HFA 227 or a mixture of HFA 227 and HFA 134a and optionally (d) a surfactant other than a monoacetylated or diacetylated monoglyceride, the for-mutation being further characterized in that it exhibits substantially no growth in particle size or change in crystal morphology of the drug over a prolonged period, is substantially and readily redispersible, and upon redispersion does not flocculate so quickly as to prevent reproducible dosing of the drug. The application specifically discloses formulations comprising formoterol fumarate dispersed in HFA 134a, HFA 227 or mixtures thereof and 1 to 3% ethanol. It is stated that it is important to ensure the formoterol fumarate does not come into contact with high concentrations e. g. above 10% w/w. of ethanol since the drug would dissolve leading to instability and crystal growth problems in the final formulation and that the maximum concentration of ethanol during formulation is preferably less than 5%. It is stated that aerosol compositions consisting of formoterol fumarate, HFA 134a and ethanol have proved to be extremely sensitive to ethanol concentration and an ethanol concentration of 3.5% w/w may cause unacceptable crystal growth.
WO 98/52542 discloses a pharmaceutical compositions comprising a therapeutical effective amount of ciclesonide and a hydrofluorocarbon propellant, preferably selected from 1,1, 1, 2-tetrafluoroethane, 1,1,1,2, 3,3, 3-heptafluoropropane and a mixture thereof, and cosolvent, preferably ethanol, in an amount effective to solubilize the ciclesonide and optionally a surfactant. The application specifically discloses solution formulations comprising ciclesonide (1 to 5 mg/ml) in HFA 134a, HFA 227 or mixtures of HFA 134a and HFA 227 and 5 to 20% by weight ethanol.
Despite the various approaches used in formulating drugs for use in aerosol inhalation, a number of serious difficulties and uncertainties are still often encountered in attempting to develop a physically and chemically stable HFA based formulation that reliably delivers an accurate dose of drug having the proper particle size range. In particular, an aerosol composition comprising a combination of Ciclesonide and one or more other actives has poor stability.
Summary of the Invention
The primary object of the present invention is to provide an aerosol composition comprising a combination of Ciclesonide and one or more other active ingredients that is chemically and physically stable.
Hence, it is one of the aspects to provide a stable aerosol composition comprising: (i) therapeutically effective amount of ciclesonide or its pharmaceutically
acceptable salt, solvate or physiologically function derivative thereof, (ii) therapeutically effective amount of formoterol or its pharmaceutically
acceptable salt, solvate or physiologically function derivative thereof, (iii) polyvinylpyrolidone in an amount effective to stabilize the composition, and (iv) a propellant selected from 1.1,1,2-tetrafluoroethane, 1,1.1,2,3,3,3-
heptafluoropropane and a mixture thereof.
It is another aspect to provide a stable composition comprising:
(i) therapeutically effective amount of ciclesonide or its pharmaceuticaliy
acceptable salt, solvate or physiologically function derivative thereof, (ii) therapeutically effective amount of formoterol or its pharmaceuticaliy
acceptable salt, solvate or physiologically function derivative thereof, (iii) therapeutically effective amount of tiotropium or its pharmaceuticaliy
acceptable salt, solvate or physiologically function derivative thereof, (iv) polyvinylpyrolidone in an amount effective to stabilize the composition, and (v) a propellant selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3.3-
heptafluoropropane and a mixture thereof.
Embodiments of the compositions may have one or more of the following features. For example, the compositions additionally comprise ethanol as a co-solvent. The presence of ethanol assists in the stability, the general performance and in the manufacturing of the composition. Ethanol is present in an amount from about 0.5 to about 5.0% w/w of the composition, particularly from about 0.5 to about 3.0% w/w, and more particularly from about 0.5 to about 1.0% w/w of the composition.
In one embodiment, the polyvinylpyrolidone (PVP) is present in the composition as a stabilizer, in an amount from about 0.0005 to about 0.1% w/w of the composition, particularly from about 0.0005 to about 0.5% w/w and more particularly it is from about 0.0005 to about 0.1% w/w of the composition.
The composition of the invention may be in the form of a suspension, a particulate suspension or a clear solution, contained in canisters having part of all of the internal surfaces made of anodised aluminium, stainless steel or lined with an inert organic coating.
It is yet another aspect to provide a method for the prophylaxis or treatment of a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory
tract disease, by administering the aerosol composition of comprising a combination of Ciclesonide and one or more other active ingredients.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and claims.
Description of the Invention
The invention provides aerosol composition comprising a combination of Ciclesonide and one or more other active ingredients, particularly compositions suitable for use in metered dose inhalers.
The composition of the present invention exhibit substantially no growth in particle size or change in crystal morphology of the formoterol, ciclesonide and/or tiotropium over a prolonged period, are readily redispersible, and upon redispersion do not flocculate so quickly as to prevent reproducing dosing of formoterol, ciclesonide and/or tiotropium. In addition to stability the formulations according to the invention provide a significant unexpected therapeutic benefit, particularly a synergistic therapeutic benefit, in the treatment of inflammatory or obstructive airways diseases.
Ciclesonide is the INN for a compound with the chemical name [11 i, 16a (R)]-16, 17- [(Cyclohexylmethylen) bis (oxy)]-l l-hydroxy-21- (2-methyl-l-oxoprop- oxy) pregna-I,4-dien-3, 20-dion. Ciclesonide as used herein also includes, pharmaceutical acceptable salts of ciclesonide, solvates of ciclesonide, physiologically functional derivatives of ciclesonide or solvates thereof. By the term "physiologically functional derivative" is meant a chemical derivative of ciclesonide having the same physiological function as ciclesonide, for example, by being convertible in the body thereto or by being an active metabolite of ciclesonide. Physiological functional derivatives of ciclesonide which may be mentioned in connection with the invention are for example the 21-hydroxy derivative of ciclesonide with the chemical name 16a , 17-(22R, S)-
CycloheXylmethylendioxy-118, 21-dihydroxypregna-l,4-dien-3, 20-dion, in particular 16a , 17-(22R)-Cyclohexylmethylendioxy-l IB, 21-dihydroxypregna-l,4-dien-3, 20-dion.
Formoterol is the compound N- [2-hydroxy-5- (l-hydroxy-2- ( (2- (4-methoxyphenyl)-l-methylethyl) amino) ethyl) phenyl] formamide. Formoterol as used herein also includes pharmaceutical acceptable salts of formoterol, solvates of formoterol, physiologically functional derivatives of formoterol or solvates thereof. As would be appreciated by the skilled person, formoterol may exist in form of different stereoisomers. The present invention includes all stereoisomers of formoterol either in substantially pure form or admixed in any proportions. In one embodiment of the invention, formoterol is present in the formulations according to the invention essentially as R, R-formoterol. Essentially as R, R-formoterol in connection with the present inventions refers to a ratio of R, R-formoterol in a mixture of stereoisomers of formoterol of at least 95%, preferably at least 99%. By the term "physiologically functional derivative" is meant a chemical derivative of formoterol having the same physiological function as the free compound, for example, by being convertible in the body thereto. Suitable salts according to the invention include those formed with both organic and inorganic acids. Pharmaceutically acceptable acid addition salts include but are not limited to those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic succinic, oxalic, fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, p-tolu- enesulphonic, benzenesulphonic, isethionic, and naphthalenecarboxylic, such as l-hydroxy-2- naphthalenecarboxylic acids. Formoterol fumarate and R, R-formoterol fumarate are particularly mentioned in connection with the invention.
Tiotropium as used herein also includes pharmaceutical acceptable salts of tiotropium, solvates of tiotropium, physiologically functional derivatives of tiotropium or solvates thereof. By the term "physiologically functional derivative" is meant a chemical derivative of tiotropium having the same physiological function as the free compound, for example, by being convertible in the body thereto. According to the invention a reference to tiotropium, which is the free ammonium cation, corresponds to a reference to
tiotropium in the form of a salt (tiotropium salt) which contains an anion as counter-ion. Tiotropium salts which may be used within the scope of the present invention are preferably compounds which contain, in addition to tiotropium as counter-ion (anion), chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate, and/or methylsulfate.
The active ingredients (ciclesonide, formoterol and tiotropium respectively) present as particles in the compositions according to the invention should be in a form so as to permit inhalation of substantially all of the active ingredients into the lungs upon administration of the aerosol formulation. Thus the active ingredients should unless obtainable by chemical processes in a suitable size be micronized so as to permit inhalation of substantially all of the active ingredients into the lungs upon administration of the aerosol composition. Thus the active ingredients will have a mean particle size diameter of less than 100 microns, particularly less than 20 microns, and more particularly in the range 1 to 10 microns, for example, 1 to 5 microns.
As with other drugs which have appreciable solubility in ethanol, there is a tendency for formoterol to exhibit crystal growth in ethanol-containing formulations. However, the inventors have discovered formulation parameters which do not promote drug particle size growth. These parameters also provide the advantage of minimizing the required ethanol concentrations, to reduce the potential for unpleasant taste sensations and render the compositions more suitable for use by children and others with low alcohol tolerance.
It is surprisingly found that a certain minimum level of ethanol is needed to provide consistent and predictable delivery of the drug from a metered dose dispenser. This minimum level is from about 0.5 to about 5.0 weight percent of the total composition, particularly from about 0.5 to about 3.0% w/w, and more particularly from about 0.5 to about 1.0% w/w of the composition. Increased amounts of ethanol generally improve drug delivery characteristics. However, for reasons previously discussed, and to prevent drug crystal growth in the formulation, it is necessary to limit the concentration of ethanol.
The polyvinylpyrolidone (PVP) used in the compositions as a stabilizer, for purposes such as assisting with maintaining a stable suspension of the drug and lubricating the metering valve. PVP used in the compositions required for maintenance of ready dispersability (such as by moderate agitation immediately prior to use), as the drug forms loose flocculates in the propellant and does not exhibit a tendency to settle or compact. Upon undisturbed storage, the drug particles merely remain in their flocculated state.
Particularly the PVP used in the composition is PVP K25, in an amount from about 0.0005 to about 0.1% w/w of the composition, particularly from about 0.0005 to about 0.5% w/w and more particularly it is from about 0.0005 to about 0.1% w/w of the composition.
The propellant used in the compositions to deliver the actives from the aerosol container is hydrofluorocarbon based propellants, particularly selected from the group of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and mixtures thereof.
Compositions of the invention are made according to processes customary in the art for other aerosol compositions. Typically, all the ingredients except the propellant are mixed and introduced into aerosol containers. The containers can then be chilled to temperatures below the boiling point of the propellant, and the required amount of the chilled propellant added before the metering valve is crimped onto the container. Alternatively, the containers can be fitted with a metering valve before being filled with propellant and the required quantity of propellant will be introduced through the valve.
Canisters generally comprise a container capable of withstanding the vapour pressure of the propellant, such as plastic or plastic-coated glass bottle or a metal can, for example an aluminium can which may optionally be anodised, lacquer-coated and/or plastic-coated, which container is closed with a metering valve. The canisters may have part of or all of the internal surfaces made of anodised aluminium, stainless steel or lined with an inert organic coating. Examples of coatings are epoxy-phenol resins.
perfluoroalkoxyalkane, perfluoroalkoxyalkylene, perfluoroalkylenes such as polytetrafluoroethylene, fluorinated-ethylene-propylene, polyether sulfone and a copolymer fluorinated-ethylene-propylene polyether sulfone. Other suitable coatings could be polyamide, polyimide, polyamideimide, polyphenylene sulfide or their combinations.
The metering valves are designed to deliver a metered amount of the composition per actuation and incorporate a gasket to prevent leakage of propellant through the valve. The gasket may comprise any suitable elastomeric material such as for example low density polyethylene, chlorobutyl, black and white butadiene acrylonitrile rubbers, butyl rubber and neoprene. The composition of the invention is actuated by a metering valve capable of delivering a volume of between 50 µl and 100 µl
Valve seals, especially the gasket seal and also the seals around the metering chamber, will preferably be manufactured of a material, which is inert to and resists extraction into the contents of the composition, especially when the contents include ethanol. Valve materials, especially the material of manufacture of the metering chamber, will preferably be manufactured of a material which is inert to and resists distortion by contents of the composition, especially when the contents include ethanol. Examples of suitable materials for use in manufacture of the metering chamber include polyesters e.g. polybutyleneterephthalate (PBT) and acetals, especially PBT.
The present invention is illustrated below by reference to the following example. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention.
The following examples illustrate the invention:
EXAMPLES 1 & 2: (Table Removed)
Procedure:
i) Polyvinylpyrrolidone (PVP K-25) was dissolved in ethanol and added to the
manufacturing vessel, ii) Ciclesonide and Fomoterol fumarate were mixed together and charged in the
manufacturing vessel, iii) The total batch quantity of propellant was transferred to the manufacturing vessel
(which was already saturated with vapour phase of the propellent) and stirred iv) The mixture of step (iii) was homogenized for sufficient time to give a homogenous
suspension, v) The suspension of step (iv) was filled in aluminum cans internally coated with
epoxy-phenol resin, vi) The filled cans of step (v) were crimped with metering valves, designed to deliver
80µg of ciclesonide and 6µg of formoterol on each actuation for Example 1, and
160µg of ciclesonide and 6µg of formoterol on each actuation for Example 2.
Example 3:
The compositions prepared in Example 1 and Example 2 were subjected to accelerated stability studies at 40 + 2° C with 75 + 5% relative humidity (RH) for the period of one, two and three months, and Long term stability studies at 30 + 2° C with 75
+ 5% relative humidity (RH) for the period of three months. The compositions were checked for related substances (RS) and the results are provided in Table 1.
Table 1: (Table Removed) EXAMPLES 4 & 5: (Table Removed)
Procedure: i) Polyvinylpyrrolidone (PVP K-25) was dissolved in ethanol and added to the
manufacturing vessel, ii) Ciclesonide, Fomoterol fumarate and Tiotropium bromide monohydrate were
mixed together and charged in the manufacturing vessel. iii) The total batch quantity of propellant was transferred to the manufacturing vessel
(which was already saturated with vapour phase of the propellent) and stirred, iv) The mixture of step (iii) was homogenized for sufficient time to give a
homogenous suspension.
v) The suspension of step (iv) was filled in aluminum cans internally coated with
epoxy-phenol resin, vi) The filled cans of step (v) were crimped with metering valves, designed to deliver
80|ig of ciclesonide, 6ug of formoterol and 9ug of tiotropium on each actuation
for Example 4, and 160ug of ciclesonide, 6µg of formoterol and 9µg of
tiotropium on each actuation for Example 5.
Example 6:
The compositions prepared in Example 4 and Example 5 were subjected to accelerated stability studies at 40 + 2° C with 75 + 5% relative humidity (RH) for the period of one, two and three months, and Long term stability studies at 30 + 2° C with 75 + 5% relative humidity (RH) for the period of three months. The compositions were checked for related substances (RS) and the results are provided in Table 2.
Table 2: (Table Removed)

WE CLAIM:
1. A stable aerosol composition comprising:
(i) therapeutically effective amount of ciclesonide or its pharmaceutically acceptable salt, solvate or physiologically function derivative thereof,
(ii) therapeutically effective amount of formoterol or its pharmaceutically acceptable salt, solvate or physiologically function derivative thereof,
(iii) polyvinylpyrolidone in an amount effective to stabilize the composition, and
(iv) a propellant selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and a mixture thereof.
2. A stable aerosol composition comprising:
(i) therapeutically effective amount of ciclesonide or its pharmaceutically
acceptable salt, solvate or physiologically function derivative thereof, (ii) therapeutically effective amount of formoterol or its pharmaceutically
acceptable salt, solvate or physiologically function derivative thereof, (iii) therapeutically effective amount of tiotropium or its pharmaceutically
acceptable salt, solvate or physiologically function derivative thereof, (iv) polyvinylpyrolidone in an amount effective to stabilize the composition, and (v) a propellant selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-
heptafluoropropane and a mixture thereof.
3. The composition according to claim 1 and 2, wherein the polyvinylpyrolidone is present in amount from about 0.0005% to about 0.1% w/w.
4. The composition according to claim 1 and 2, wherein the formoterol is in the form of its fumarate dihydrate salt.
5. The composition according to claim 2, wherein the tiotropium is in the form of its bromide monohydrate salt.
6. The composition according to claim 1 and 2, wherein the composition further
comprises ethanol as a co-solvent.
7. The composition according to claim 6, wherein the ethanol is present in amount from about 0.5% to about 5.0% w/w.
8. The composition according to claim 1 and 2, wherein the composition is contained in canisters having a part of or all of the internal surfaces said canister consist of anodised aluminium, stainless steel or lined with an inert organic coating.
9. The composition according to claim 8, wherein part or all of the internal surfaces of
the canister is coated with epoxy-phenol resins.
10. A stable aerosol composition comprising a combination of ciclesonide and one or
more other active ingredients substantially as described and illustrated herein.