US 20100063016A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0063016 A1 Lulla et al. (43) Pub. Date: Mar. 11, 2010

(54) PHARMACEUTICAL COMBINATIONS (30) Foreign Application Priority Data (75) Inventors: Amar Lulla, Mumbai (IN); Geena Feb. 19, 2007 (IN) ...... 314/MUMA2007 Malhotra, Mumbai (IN) Aug. 27, 2007 (IN). ... 1642AMUMA2007 Nov. 1, 2007 (IN) ...... 2179/MUM/2007 Correspondence Address: CONLEY ROSE, PC. Publication Classification 5601 GRANITE PARKWAY, SUITE 750 (51) Int. Cl PLANO, TX 75024 (US) A6II 3/56 (2006.01) A6IP II/00 (2006.01) (73)73) AssigneeA CIPLA LIMITED,, Mumbai (IN)(IN A6IP II/08 (2006.01) (21) Appl. No.: 12/527,096 (52) U.S. Cl...... S14/171 (22) PCT Filed: Feb. 19, 2008 (57) ABSTRACT (86). PCT No.: PCT/GB2O08/OOOST8 A pharmaceutical combination comprising (a) a combination of two or more ; or (b) a combination of at S371 (c)(1), least one in combination with at least one (2), (4) Date: Oct. 29, 2009 corticosteroid. US 2010/006301.6 A1 Mar. 11, 2010

PHARMACEUTICAL COMBINATIONS since most of the are in the form of aerosols, the patient is required to carry several formulations and dispens TECHNICAL FIELD CS. 0015 Thus there remains a need to formulate and also 0001. The present invention relates to combinations of offer to the patient a combination that needs to be taken once inhalable medicaments for simultaneous or sequential admin a day and where the patient does not have to take another dose istration in the prevention or treatment of respiratory, inflam of beta-agonist or any other to Substantiate the combination matory or obstructive airway disease. dose.

BACKGROUND & PRIOR ART OBJECT OF THE INVENTION 0002 Chronic obstructive pulmonary disease (COPD) is a 0016. It is an object of the present invention is to provide preventable and treatable disease state characterized by air combinations of inhalable medicaments for administration in flow limitation that is not fully reversible. the prevention or treatment of respiratory, inflammatory or 0003. The airflow limitation is usually progressive and is obstructive airway disease. associated with an abnormal inflammatory response of the 0017. It is another object of the present invention to pro lungs to noxious particles or gases, primarily caused by ciga vide combinations of inhalation medicaments for administra rette Smoking. tion once daily. 0004. It is expected to be the third leading cause of death 0018. It is yet another object of the present invention to by 2020. Approximately 14 million Indians are currently provide a method of formulating such novel combinations. suffering form COPD. Currently there are 94 million smokers in India. 10 lakh Indians die in a year due to Smoking related SUMMARY diseases 0019. According to a first aspect of the present invention 0005. Although COPD affects the lungs, it also produces there is provided a pharmaceutical combination comprising significant systemic consequences. at least two active Substances for once daily administration by 0006 Various therapies are currently used for the treat inhalation route. ment of COPD. Bronchodilators and steroids form the major 0020. According to another aspect of the present invention classes of drugs used. there is provided a method of manufacturing said pharmaceu 0007 WO0139745 discloses dry powder inhalation com tical combination comprising at least two active substances prising and its salts or derivatives thereof and for once daily administration by inhalation route. pharmaceutically acceptable particulate diluent. 0021. According to still another aspect of the present 0008. A combination therapy is described in patent num invention there is provided a pharmaceutical combination ber WOO176601, using short acting ipratro comprising at least two active substances for once daily pium bromide and long acting B-agonist are. administration by inhalation route administration in the pre 0009. A further combination therapy, using steroid along vention or treatment of respiratory, inflammatory or obstruc with and beta agonist, has been described in tive airway disease. U.S. Pat. No. 6,423,298 and WO0207672. 0010 WO0207672 relates to a medicinal aerosol formu DESCRIPTION lation and more particularly, to a medicinal aerosol formula 0022. As discussed above, there is a long felt want in the tion containing a particulate drug, or combination of at least art for an effective once daily formulation. The present inven two particulate drugs a propellant and a stabilizing agent tion provides novel combinations comprising two or more comprising water. The medicament is selected from the group actives for administration once daily. consisting of albuterol, atropine, , cromolyn, epi 0023 The actives may be selected from various classes nephrine, , fentanyl, , formoterol, iprat consisting of bronchodilators and corticosteroids and mix ropium bromide, isoproterenol, , prednisone, tures thereof. The bronchodilators may be either beta-ago , acetonide, salmeterol, nists or anticholinergics or both. amiloride, , (-) 4-amino-3,5-dichloro-a-6 (2py 0024. The present inventors have surprisingly found that a ridinyl)ethoxyhexylaminomethylbenzene-methanol and combination of two or more bronchodilators and/or combi pharmaceutically acceptable salts, esters, hydrates and sol nation of two or more bronchodilators in combination with Vates of the foregoing. corticosteroids shows a synergistic effect by relaxing both the 0011 U.S. Pat. No. 6,423.298 relates to pharmaceutical central and peripheral air pathways improving the airflow formulations for aerosols with at least two or more active obstruction, prolonged bronchodilation and provides rapid Substances for administration by inhalation or by nasal route. onset of action with reduced exacerbations. 0012 WO2004019985 discloses certain other drug phar 0025 Pharmaceutically active agents useful in the present maceutical formulations for aerosols. invention include one or more of drugs selected from various 0013 Various other combinations are known in the art. classes consisting of bronchodilators and corticosteroids and But a problem associated with these drugs is that not all are mixtures thereof. The bronchodilators may be beta-agonists once a day formulations and also if some are, they require an and/or anticholinergics. The terms “beta-agonist agent” or additional dose of a beta agonist to Substantiate the combina “beta-agonist' or “anticholinergic agent' or “corticosteroids' tion. are used in broad sense to include not only the beta-agonist or 0014) Even from the patient compliance point of view, the anticholinergic agent per se but also their pharmaceutically treatment calls for the patient to comply with different dosage acceptable salts, pharmaceutically acceptable Solvates, phar regimens, different frequencies of administration, etc. Also, maceutically acceptable hydrates, pharmaceutically accept US 2010/006301.6 A1 Mar. 11, 2010 able enantiomers, pharmaceutically acceptable derivatives, by conventional methods, for example by grinding in an air pharmaceutically acceptable polymorphs, pharmaceutically jet mill, ball mill or vibrator mill, microprecipitation, spray acceptable prodrugs, etc. drying, lyophilization or recrystallization from Supercritical 0026. The beta-agonists may be selected from formoterol, media. AR-formoterol, , carmoterol, and the 0035. According to a preferred embodiment, the above dry like. Formoterol may be present in an amount ranging from powder composition may be manufactured by any convenient about 4.5-96 mcg, AR-formoterol may be present in an means wherein the process comprises of two or more drugs amount ranging from 1.25-96 mcg, carmoterol may be being mixed optionally with a pharmaceutically acceptable present in an amount ranging from 0.5-16 mcg, and inda carrier and providing the ingredients in a Suitable dry powder caterol may be present in an amount ranging from 25-800 inhaler. mcg. 0036. In case of inhalation solutions or nebulizing solu 0027. The anticholinergic may be aclidinium, ipratro tions, the drugs may be combined with Suitable excipients pium, tiotropium, oxitropium and the like. Tiotropium may be Such as wetting agents, tonicity adjusting agents, pH regula present in an amount ranging from 4.5-160 mcg. Aclidinium tors, buffering agents and chelating agents, in a Suitable may be present in an amount ranging from 50-900 mcg. vehicle. The wetting agents may be selected from the group 0028. The corticosteroid may be budesonide, , consisting of sodiumdioctylsulfoSuccinate; polysorbates mometasone, beclomethasone and the like. Ciclesonide may such as polysorbate 20, polysorbate 40, polysorbate 60, be present in an amount ranging from 40-2880 mcg and polysorbate 80, polysorbate 65, polysorbate 85; sorbitan fatty mometasone present in an amount ranging from 25-2000 acid esters such as Span 20, Span 40, Span 60 Span 80, Span mcg. 120; sodium lauryl sulfate; polyethoxylated castor oil; poly 0029. In one preferred embodiment of the present inven ethoxylated hydrogenated castor oil and the like. The pre tion, the beta agonist is carmoterol, the corticosteroid is ferred wetting agent is one or more polysorbates, either alone ciclesonide and the anticholinergic is tiotropium. In another or in combination with another wetting agent. The amount of preferred embodiment of the present invention, the beta ago wetting agent (especially when it includes a polysorbate) is in nist is carmoterol and the corticosteroid is ciclesonide. In yet a range of 0.001 to 0.1% w/v of the composition. another preferred embodiment of the present invention, the 0037. The tonicity-adjusting agent, which may be used in anticholinergic is tiotropium and the beta agonist is carmot the present invention, may include one or more of Sodium erol. In yet another preferred embodiment of the present chloride, potassium chloride, Zinc chloride, calcium chloride invention, the anticholinergic is aclidinium and the beta ago and mixtures thereof. The preferred tonicity adjusting agentis nist is formoterol and/or AR-formoterol. sodium chloride. 0030 The formulations of the present invention are suit 0038. The pH regulator may be selected from pharmaco able for use in metered dose inhalers (MDI) (or aerosols). logically acceptable inorganic acids or organic acids, such as MDIS are compact drug delivery systems that use a liquefied Sodium hydroxide, sodium carbonate, sodium bicarbonate, propellant to atomize a precisely metered Volume of a phar magnesium carbonates, aluminium hydroxide, aluminum maceutical formulation into particles, which are small carbonate, aluminium bicarbonate, calcium carbonate and enough to penetrate deep into the patient's lungs. MDIs allow calcium hydroxide, calcium bicarbonate and the like. The for targeted delivery of drug to the desired site of the thera preferred inorganic acids are selected from the group consist peutic effect—the lung. ing of hydrochloric acid, hydrobromic acid, nitric acid, Sul 0031. The pharmaceutical combination may further be phuric acid, phosphoric acid and the like. The preferred combined with one or more pharmaceutically acceptable organic acids are selected from the group consisting of ascor excipients in order to provide a suitable formulation. The bic acid, citric acid, malic acid, tartaric acid, maleic acid, combination may, for example, beformulated as a propellant Succinic acid, fumaric acid, acetic acid, formic acid and pro free inhalation solution for nebulization, as an aerosol com pionic acid. The most preferred inorganic acids are hydro position (with propellant), or as dry powder composition for chloric acid & Sulphuric acid, while, for the organic acids, inhalation. ascorbic acid, citric acid and fumaric acid are the most pre 0032. In case of dry powder inhalation formulations, the ferred. drugs may be used alone or optionally together with a finely 0039. The pH regulators may be selected from pharmaco divided pharmaceutically acceptable carrier, which is prefer logically acceptable inorganic bases or organic bases. The ably present and may be chosen from materials known as preferred inorganic bases are selected from the group consist carriers in dry powder inhalation compositions, for example ing of Sodium hydroxide, potassium hydroxide, ammonium saccharides, including monosaccharides, disaccharides, hydroxide, sodium carbonate, calcium hydroxide. The pre polysaccharides; and Sugar alcohols such as arabinose, glu ferred organic bases are selected from the group consisting of cose, fructose, ribose, mannose. Sucrose, trehalose, lactose, methyl amine, ethyleneimine, hydroquinone, ethylamine, maltose, starches, dextran or mannitol. dimethylamine, ethanolamine, butylamine, diethylamine. 0033 Preferably, the pharmaceutically acceptable carrier The most preferred base is sodium hydroxide. in the dry powder inhalation formulation is lactose. The car 0040 Preferably a nasal inhalation formulation as pro rier is preferably present in an amount not less that 75% by vided by the present invention has a pH in the range of 3.0 to weight of the formulation. 7.0. 0034. The dry powder may be provided in capsules of 0041. In a preferred embodiment, suitable chelating or gelatin or HPMC or in blisters or alternatively, the dry powder complexing agents are used in the inhalation solutions, and may be contained as a reservoir either in a single dose or may be molecules which are capable of entering into complex multi-dose dry powder inhalation device. The particle size of bonds. Preferable those compounds should have the effect of the active ingredient and that of the carrier where present in complexing cations most preferably metal cations. The for dry powder compositions, can be reduced to the desired level mulations according to the invention preferably contain US 2010/006301.6 A1 Mar. 11, 2010

EDTA or one of the known salts thereof, e.g. sodium EDTA or lant 12 (monofluorotrichloromethane), Propellant 114, 1,1,1, disodium EDTA dihydrate, as complexing agent. The pre 2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoroethane ferred agent is ethylenediaminetetraacetic acid (EDTA) or a 0051. In one embodiment of the present invention the salt thereof. Such as the disodium salt. actives may be combined with either propellant 11 or propel 0042. In a preferred embodiment, suitable buffering lant 114 or a combination thereof of and propellant 12 with agents that may be used in the inhalation solutions include Surface-active agents known in the art. citric acid and sodium or potassium citrates; or phosphates 0.052 The surfactants may be selected from the vast class like trisodium phosphate, disodium or trisodium hydrogen known in the art like oils such as corn oil, olive oil, cottonseed phosphate, sodium dihydrogen phosphate, potassium hydro oil and sunflower seed oil, mineral oils like liquid paraffin, gen phosphate, potassium dihydrogen phosphate, tripotas oleic acid and also phospholipids such as lecithin, or Sorbitan sium hydrogen phosphate and the like. fatty acid esters like sorbitan trioleate or Tween 20, Tween 60, 0043 Suitable liquid vehicles for use in the compositions Tween 80, PEG-25 Glyceryl trioleate, PVP. citric acid, PFDA of the invention (particularly inhalation Solutions or Suspen (per fluoro-n-decanoic acid) The use of Surfactants leads to sions) include polar solvents, such as compounds that contain comparatively good Suspension quality. One of the preferred hydroxyl groups or other polar groups. Such solvents may Surfactants is lecithin. The Surfactant can be used in a con include water or alcohols, such as ethanol, isopropanol, and centration of 0.001-100%. Preferably in a range of 1%-50%. glycols including propylene glycol, polyethylene glycol, More preferably in a concentration of 5%-30%. These con polypropylene glycol, glycol ether, glycerol and polyoxyeth centrations are based on the weight of the active material(s). ylene alcohols. 0053. In another embodiment of the present invention the 0044 Suitable polar solvents also include protic solvents, actives and the Surfactant can be micro-milled with propel Such as water, one or more aqueous saline Solutions with one lant, preferably propellant 11 or propellant 114 or a combi or more pharmaceutically acceptable salt(s), one or more nation thereof, to form a slurry and then the slurry can be filled alcohols, one or more glycols or a mixture thereof. For a in canisters. The actives can be micro-milled separately or saline Solution as the solvent or as a component thereof, together with the propellant. Micro-milling can be done to particularly Suitable salts are those which display no or only improve the Suspension quality which inum results in a better negligible pharmacological activity after administration. FPD. 0045 An anti-microbial preservative agent may be added 0054 There is also provided by the present invention a for multi-dose packages. Suitable preservatives will be appar method for the manufacture of CFC aerosol which process ent to the skilled person, particularly benzalkonium chloride comprises: (a) optionally micro-milling the drugs and surfac or benzoic acid or benzoates such as Sodium benzoate, Sorbic tant with a propellant, preferably either propellant 11 or pro acid or Sorbates such as potassium Sorbates in the concentra pellant 114 or a combination thereof (b) filling the slurry in tion known from the prior art. The most preferred preservative the canisters; (c) crimping with a suitable valve; and (d) is benzalkonium chloride. charging with a propellant, preferably propellant 12, through 0046 According to a preferred embodiment, the above the valve. inhalation or nebulizer composition may be manufactured by 0055. In yet another embodiment of the present invention any convenient means wherein the process comprises dis the aerosol composition may comprise actives and either Solving two or more drugs and optionally chelating agents, 1,1,1,2-tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-hep tonicity adjusting agents and any other Suitable ingredient in tafluoroethane (HFA227) or a combination thereof. a vehicle and adjusting the pH using a suitable pH adjusting 0056. Another embodiment of the present invention may agent. Further, finally, providing the said composition in a comprise actives, propellant and a cosolvent. In Such a case Suitable dispensing container (such as a nebulizer) for inha the cosolvent has a greater polarity than the propellant. Typi lation. cally the cosolvent is present in a proportion of 0.2 to 20% by 0047 According to another preferred embodiment, the weight of the total formulation. The cosolvent used may be above composition can be manufactured by convenient selected from the group consisting of glycols, particularly means wherein the process comprises sterilization of the propylene glycol, polyethylene glycol and glycerolorethanol active/s by known processes such as dry heat sterilization, and mixtures thereof. Typically the cosolvent is ethanol. moist heat sterilization, gamma radiation. The sterilized 0057 The present invention also provides a method for the active/s is/are placed in a container and sterile bulk of other manufacture of the above composition which method com pharmaceutically acceptable ingredients comprising one or prises (a) Addition of the active ingredients to the canister. (b) more of wetting agents, tonicity adjusting agents, pH regula Addition of the cosolvent optionally to (a) and Sonication of tors, chelating agents, buffering agents are transferred asep the same. (c) Crimping the canister with the metered valve (d) tically in the container with the API. The mixture may then be charging the canister with the propellant. Subjected to mixing either by Sonication or magnetic stirring 0058. In yet another embodiment the present invention or by other means known in the art and finally, adding the may comprise the actives, propellant, Surface-active agent above Solution to the remaining bulk. and cosolvent. 0.048. In case of formulations which are in the form of 0059. The surface-active agent stabilizes the formulation pressurized aerosols using. MDIs, the formulations may com and helps in the lubrication of a valve system in the inhaler. prise one or more of cosolvents, antioxidants, Surfactants, Some of the most commonly used Surface active agents are bulking agents and lubricants, in addition to the actives and those known in the art and can be selected from among propellant. various polysorbates such as Polysorbate 20, Polysorbate 40, 0049. In one embodiment of the present invention the Polysorbate 80; Acetylated monoglycerides like Myvacet actives may be combined with one or more propellants. 9-45 and Myvacet 9-08; isopropylmyristate, oleic acid, Poly 0050. The present invention includes at least one propel oxyethylene ethers, ethyloleate, glyceryl trioleate, glyceryl lant such as propellant 11 (dichlorodifluoromethane), propel monolaurate, glyceryl monooleate, glyceryl monosterate, US 2010/006301.6 A1 Mar. 11, 2010

glyceryl monoricinoleate, cetylalcohol, sterylalcohol, 0070 The MDI formulations may be in plain aluminium cetylpyridinium chloride, block polymers, natural oils, poly cans or SS (stainless steel) cans. Some aerosol drugs tend to vinyl pyrrolidone, Sorbitan fatty acid esters such as Sorbitan adhere to the inner Surfaces, i.e., walls of the cans and valves, trioleate, polyethoxylated sorbitan fatty acid esters (for of the MDI. This can lead to the patient getting significantly example polyethoxylated Sorbitan trioleate), Sorbimacrogol less than the prescribed amount of the active agent upon each oleate, synthetic amphotensides (tritons), ethylene oxide activation of the MDI. Coating the inner surface of the con ethers of octylphenolformaldehyde condensation products, tainer with a suitable polymer can reduce this adhesion prob phosphatides such as lecithin, polyethoxylated fats, poly lem. Suitable coatings include fluorocarbon copolymers such ethoxylated oleotriglycerides and polyethoxylated fatty alco as FEP-PES (fluorinated ethylene propylene and polyether hols. sulphone) and PFA-PES (perfluoroalkoxyalkane and poly 0060. The surface-active agents are preferably used in a etherSulphone), epoxy and ethylene. concentration of 0.02-10% by weight of the active ingredi 0071 Alternatively, the inner surfaces of the cans may be entS. anodized. 0061 The present invention also provides a method for the 0072 The following examples are for the purpose of illus manufacture of the above composition which method com tration of the invention only and are not intended in any way prises: (a) addition of the active ingredients to the canister; (b) to limit the scope of the present invention. addition of the cosolvent and the Surfactant solution to (a) and 0073. It will be readily apparent to one skilled in the art Sonication of the same; (c) crimping the canister with a that varying Substitutions and modifications may be made to metered valve; and (d) charging the canister with the propel the invention disclosed herein without departing from the lant. scope of the invention. Thus, it should be understood that 0062 Another embodiment of the present invention com although the present invention has been specifically disclosed prises the actives along with bulking agent and propellant. by the preferred embodiments and optional features, modifi 0063. The bulking agent acts as a carrier for the drug to cation and variation of the concepts herein disclosed may be reach the lungs. The bulking agent may be present in a con resorted to by those skilled in the art, and such modifications centration of 10-500% by weight of the active. More prefer and variations are considered to be falling within the scope of ably in a range of 10-300% by weight of the active. The the invention. bulking agent may be selected from the class of saccharides, including monosaccharides, disaccharides, polysaccharides; Example 1 and Sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, Sucrose, trehalose, lactose, maltose, 0074 An aerosol formulation was prepared using formot starches, dextran or mannitol. The preferred bulking agent is erol and aclidinium or a salt thereof, preferably aclidinium lactose. bromide, with a propellant, which is preferably HFA P227. 0064. The present invention also provides a method for the The amounts of the materials is preferably as shown in the manufacture of the above aerosol composition which method table: comprises: (a) addition of the active ingredients to the canis ter; (b) addition of the bulking agent to (a); (c) crimping the canister with a metered valve; and (d) charging the canister with the propellant. Ingredients Qty/Can Formoterol 0.96 mg 0065. Yet another embodiment of the present invention 32 mg comprises the actives along with Surfactant and propellant. Propellant HFA P227 11.2 gm 0066. The surfactant may be selected from the class of salts of Stearic acids or esters such as ascorbyl palmitate, isopropyl myristate and tocopherol esters. The Surfactant is preferably the magnesium salt of Stearic acid or isopropyl Example 2 myristate. Most preferably the Surfactant is magnesium Stear ate. The Surfactant is preferably used in a concentration of 0075 An aerosol formulation was prepared using formot 0.01% to 10% by weight of the active. erol and aclidinium or a salt thereof, preferably aclidinium 0067. The present invention also provides a method for the bromide, with lactose and a propellant, which is preferably manufacture of the above aerosol composition which method HFA 134a. The amounts of the materials is preferably as comprises: (a) addition of the active ingredients to the canis shown in the table: ter; (b) addition of the Surfactant to (a); (c) crimping the canister with a metered valve; and (d) charging the canister with the propellant. Ingredients Qty/Can 0068. In yet another embodiment one or more actives can Formoterol 0.96 mg be spray-coated or spray-dried or co-precipitated. The spray Aclidinium Bromide 32 mg coating, spray drying or co-precipitation may be done by Lactose 38 mg mixing the active in a solution of Surface active agents in a Propellant HFA134a 9.6 g. Suitable non-polar solvent and further removing the solvent. 0069. In a further aspect of the present invention there is provided a method for the treatment in a mammal. Such as a Example 3 human, of chronic obstructive pulmonary disease, which method comprises administration of a therapeutically effec 0076 An aerosol formulation was prepared using formot tive amount ranging from a pharmaceutical composition erol and aclidinium or a salt thereof, preferably aclidinium according to the present invention. bromide (spray coated with PVP), with lactose and a propel US 2010/006301.6 A1 Mar. 11, 2010

lant, which is preferably HFA P227. The amounts of the Example 7 materials is preferably as shown in the table: 0080. An aerosol formulation was prepared using formot erol and aclidinium or a salt thereof, preferably aclidinium bromide, with absolute alcohol, sorbitan trioleate, citric acid Ingredients Qty/Can and a propellant, which is preferably HFA 134a. The amounts of the materials is preferably as shown in the table: Formoterol 0.96 mg Aclidinium Bromide (spray 32 mg coated with PVP) Lactose 38 mg Propellant P227 11.2 g Ingredients Qty/Can Formoterol 0.96 mg Aclidinium Bromide 32 mg Absolute Alcohol 1.44 g Example 4 Sorbitan trioleate 0.11 mg Citric acid For pH adjustment 0077. An aerosol formulation was prepared using formot Propellant HFA 134a 8.16 g erol and aclidinium or a salt thereof, preferably aclidinium bromide, with PEG 100 and a propellant, which is preferably HFA 134a. The amounts of the materials is preferably as Example 8 shown in the table: I0081. An aerosol formulation was prepared using formot erol and aclidinium or a salt thereof, preferably aclidinium bromide, with absolute alcohol, lecithin, hydrochloric acid, Ingredients Qty/Can and a propellant, which is preferably HFA 134a. The amounts Formoterol 0.96 mg of the materials is preferably as shown in the table: Aclidinium Bromide 16 mg PEG 1 OO 0.0288 g Propellant HFA 134a 9.6 g. Ingredients Qty/Can Formoterol 0.96 mg Example 5 Aclidinium Bromide 32 mg Absolute Alcohol 1.44 g Lecithin 0.11 mg 0078. An aerosol formulation was prepared using formot Hydrochloric acid For pH adjustment erol and aclidinium or a salt thereof, preferably aclidinium Propellant HFA 134a 8.16 g bromide, with absolute alcohol, oleic acid, and a propellant, which is preferably HFA 134a. The amounts of the materials is preferably as shown in the table: Example 9 I0082 An aerosol formulation was prepared using AR formoterol and aclidinium or a salt thereof, preferably aclid Ingredients Qty/Can inium bromide, with a propellant, which is preferably HFA Formoterol 0.96 mg P227. The amounts of the materials is preferably as shown in Aclidinium Bromide 16 mg the table: Absolute Alcohol 1.44 g Oleic acid 0.11 mg Propellant HFA134a 8.16 g Ingredients Qty/Can AR-formoterol 0.48 mg Example 6 Aclidinium Bromide 32 mg Propellant HFA P227 11.2 gm 0079 An aerosol formulation was prepared using formot erol and aclidinium or a salt thereof, preferably aclidinium bromide, with absolute alcohol, lecithin and a propellant, Example 10 which is preferably HFA 134a. The amounts of the materials I0083. An aerosol formulation was prepared using AR is preferably as shown in the table: formoterol and aclidinium or a salt thereof, preferably aclid inium bromide, with lactose and a propellant, which is pref erably HFA 134a. The amounts of the materials is preferably Ingredients Qty/Can as shown in the table: Formoterol 0.96 mg Aclidinium Bromide 16 mg Absolute Alcohol 0.192 g Ingredients Qty/Can Lecithin 0.004.4 mg Propellant HFA 134a 9.40 g AR-formoterol 0.48 mg Aclidinium Bromide 32 mg US 2010/006301.6 A1 Mar. 11, 2010

lant, which is preferably HFA 134a. The amounts of the -continued materials is preferably as shown in the table: Ingredients Qty/Can Lactose 38 mg Propellant HFA134a 9.6 g. Ingredients Qty/Can AR-formoterol 0.48 mg Aclidinium Bromide 16 mg Absolute Alcohol 0.192 g Example 11 Lecithin 0.004.4 mg 0084 An aerosol formulation was prepared using AR Propellant HFA 134a 9.40 g formoterol and aclidinium or a salt thereof, preferably aclid inium bromide spray coated with PVP with lactose and a propellant, which is preferably HFA P227. The amounts of Example 15 the materials is preferably as shown in the table: I0088 An aerosol formulation was prepared using AR formoterol and aclidinium or a salt thereof, preferably aclid inium bromide, with absolute alcohol, Sorbitan trioleate, cit Ingredients Qty/Can ric acid and a propellant, which is preferably HFA 134a. The amounts of the materials is preferably as shown in the table: AR-formoterol 0.48 mg Aclidinium Bromide (spray 32 mg coated with PVP) Lactose 38 mg Propellant P227 11.2 g Ingredients Qty/Can AR-formoterol 0.48 mg Aclidinium Bromide 32 mg Absolute Alcohol 1.44 g Example 12 Sorbitan trioleate 0.11 mg Citric acid For pH adjustment 0085. An aerosol formulation was prepared using AR Propellant HFA 134a 8.16 g formoterol and aclidinium or a salt thereof, preferably aclid inium bromide, with PEG 100 and a propellant, which is preferably HFA 134a. The amounts of the materials is pref erably as shown in the table: Example 16 I0089. An aerosol formulation was prepared using AR formoterol and aclidinium or a salt thereof, preferably aclid inium bromide, with absolute alcohol, lecithin, hydrochloric Ingredients Qty/Can acid and a propellant, which is preferably HFA 134a. The AR-formoterol 0.48 mg amounts of the materials is preferably as shown in the table: Aclidinium Bromide 16 mg PEG 1 OO 0.0288 g Propellant HFA 134a 9.6 g. Ingredients Qty/Can AR-formoterol 0.48 mg Example 13 Aclidinium Bromide 32 mg Absolute Alcohol 1.44 g I0086. An aerosol formulation was prepared using AR Lecithin 0.11 mg formoterol and aclidinium or a salt thereof, preferably aclid Hydrochloric acid For pH adjustment inium bromide, with absolute alcohol, oleic acid and a pro Propellant HFA 134a 8.16 g pellant, which is preferably HFA 134a. The amounts of the materials is preferably as shown in the table: Example 17 0090. An aerosol formulation was prepared using tiotro Ingredients Qty/Can pium or a salt thereof, preferably mono AR-formoterol 0.48 mg hydrate, carmoterol, or a salt thereof, and ciclesonide, with Aclidinium Bromide 16 mg lecithin and a propellant, which is preferably Propellant 11 Absolute Alcohol 1.44 g and Propellant 12. The amounts of the materials is preferably Oleic acid 0.11 mg as shown in the table: Propellant HFA134a 8.16 g

Example 14 Ingredients Qty can Tiotropium bromide monohydrate 1.980 mg 0087 An aerosol formulation was prepared using AR carmoterol 0.32 mg formoterol and aclidinium or a salt thereof, preferably aclid ciclesonide 0.16 mg inium bromide, with absolute alcohol, lecithin and a propel US 2010/006301.6 A1 Mar. 11, 2010

Example 21 -continued 0094. An aerosol formulation was prepared using tiotro Ingredients Qty can pium or a salt thereof, preferably tiotropium bromide mono hydrate and carmoterol, or a salt thereof, with oleic acid and Lecithin 0.304 mg a propellant, which is preferably Propellant 11 and Propellant Propellant 11 3.22 gms 114 in combination with Propellant 12. The amounts of the Propellant 12 8.0 gms materials is preferably as shown in the table:

Example 18 Ingredients Qty can 0091 An aerosol formulation was prepared using tiotro Tiotropium bromide monohydrate 1.980 mg pium or a salt thereof, preferably tiotropium bromide mono carmoterol 0.32 mg Oleic acid 0.304 mg hydrate and carmoterol, or a salt thereof, with lecithin and a Propellant 11 + Propellant 114 3.22 gms propellant, which is preferably Propellant 11 and Propellant Propellant 12 8.0 gms 114 in combination with Propellant 12. The amounts of the materials is preferably as shown in the table: Example 22 0.095 An aerosol formulation was prepared using carmot Ingredients Qty can erol, or a salt thereof, and ciclesonide, with sorbitan trioleate Tiotropium bromide monohydrate 1.980 mg and a propellant, which is preferably Propellant 11 and Pro carmoterol 0.64 mg pellant 114 in combination with Propellant 12. The amounts Lecithin 0.304 mg of the materials is preferably as shown in the table: Propellant 11 + Propellant 114 3.22 gms Propellant 12 8.0 gms

Ingredients Qty can Example 19 ciclesonide 0.16 mg carmoterol 0.64 mg 0092 An aerosol formulation was prepared using carmot Sorbitan trioleate 0.304 mg erol, or a salt thereof, and ciclesonide, with oleic acid and a Propellant 11 + Propellant 114 3.22 gms propellant, which is preferably Propellant 11 and Propellant Propellant 12 8.0 gms 12. The amounts of the materials is preferably as shown in the table: Example 23 0096. An aerosol formulation was prepared using tiotro pium or a salt thereof, preferably tiotropium bromide mono Ingredients Qty can hydrate, carmoterol, or a salt thereof, and ciclesonide, and a ciclesonide 0.16 mg propellant, which is preferably HFA 134a. The amounts of the carmoterol 0.32 mg materials is preferably as shown in the table: Oleic acid 0.304 mg Propellant 11 3.22 gms Propellant 12 8.0 gms Ingredients Qty can Tiotropium bromide monohydrate 1.980 mg Example 20 carmoterol 0.32 mg ciclesonide 0.16 mg 0093. An aerosol formulation was prepared using tiotro HFA 134a 8.0 gms pium or a salt thereof, preferably tiotropium bromide mono hydrate, carmoterol, or a salt thereof, and ciclesonide, with sorbitan trioleate and a propellant, which is preferably Pro Example 24 pellant 11 and Propellant 12. The amounts of the materials is 0097. An aerosol formulation was prepared using carmot preferably as shown in the table: erol, or a salt thereof, and ciclesonide, with a propellant, which is preferably Propellant P227. The amounts of the materials is preferably as shown in the table: Ingredients Qty can Tiotropium bromide monohydrate 1.980 mg carmoterol 0.64 mg Ingredients Qty can ciclesonide 0.16 mg Sorbitan trioleate 0.304 mg ciclesonide 0.16 mg Propellant 11 3.22 gms carmoterol 0.64 mg Propellant 12 8.0 gms P227 9.6 gms US 2010/006301.6 A1 Mar. 11, 2010

Example 25 0098. An aerosol formulation was prepared using tiotro -continued pium or a salt thereof, preferably tiotropium bromide mono Ingredients Qty can hydrate and carmoterol, or a salt thereof, with ethanol and a Oleic acid 3.08 mg propellant, which is preferably HFA 134a. The amounts of the Ethanol 0.192 gms materials is preferably as shown in the table: HFA134a 9.6 gms

Ingredients Qty can Example 29 Tiotropium bromide monohydrate 1.980 mg 0102) An aerosol formulation was prepared using tiotro carmoterol 0.32 mg Ethanol 0.16 gms pium or a salt thereof, preferably tiotropium bromide mono HFA134a 8.0 gms hydrate, carmoterol, or a salt thereof, and ciclesonide, with lactose and a propellant, which is preferably HFA 134a. The amounts of the materials is preferably as shown in the table: Example 26 0099. An aerosol formulation was prepared using tiotro pium or a salt thereof, preferably tiotropium bromide mono Ingredients Qty can hydrate, carmoterol, or a salt thereof, and ciclesonide, with Tiotropium bromide monohydrate 1.98 mg ethanol and a propellant, which is preferably Propellant P227. carmoterol 0.32 mg ciclesonide 0.16 mg The amounts of the materials is preferably as shown in the Lactose 3.036 mg table: HFA134a 8.0 gm

Ingredients Qty can Example 30 Tiotropium bromide monohydrate 1.980 mg (0103) An aerosol formulation was prepared using carmot carmoterol 0.64 mg Ciclesonide 0.16 mg erol, or a salt thereof, and ciclesonide, with lactose and a Ethanol 0.192 gms propellant, which is preferably Propellant P227. The amounts P227 9.6 gms of the materials is preferably as shown in the table:

Example 27 Ingredients Qty can 0100. An aerosol formulation was prepared using tiotro ciclesonide 0.16 mg pium or a salt thereof, preferably tiotropium bromide mono carmoterol 0.64 mg hydrate and carmoterol, or a salt thereof, with oleic acid, Lactose 3.036 mg ethanol and a propellant, which is preferably Propellant P227. P227 9.6 gms The amounts of the materials is preferably as shown in the table: Example 31 0104. An aerosol formulation was prepared using tiotro Ingredients Qty can pium or a salt thereof, preferably tiotropium bromide mono Tiotropium bromide monohydrate 1.980 mg hydrate and carmoterol, or a salt thereof, with magnesium carmoterol 0.32 mg stearate and a propellant, which is preferably Propellant Oleic acid 0.000616 mg Ethanol 0.192 gms P227. The amounts of the materials is preferably as shown in P227 9.6 gms the table:

Example 28 Ingredients Qty can 0101 Anaerosol formulation was prepared using carmot Tiotropium bromide monohydrate 1.98 mg erol, or a salt thereof, and ciclesonide, with oleic acid, ethanol carmoterol 0.32 mg and a propellant, which is preferably HFA 134a. The amounts Magnesium stearate 0.3035 mg of the materials is preferably as shown in the table: P227 9.6 gms

Ingredients Qty can Example 32 ciclesonide 0.16 mg 0105. An aerosol formulation was prepared using tiotro carmoterol 0.64 mg pium or a salt thereof, preferably tiotropium bromide mono hydrate, carmoterol, or a salt thereof, and ciclesonide, with US 2010/006301.6 A1 Mar. 11, 2010 magnesium Stearate and a propellant, which is preferably HFA 134a. The amounts of the materials is preferably as shown in the table: Ingredients Qty unit (mg) Carmoterol Hydrochloride O.OO40 Tiotropium bromide monohydrate O.O225 Ingredients Qty can Lactose 24.973S Tiotropium bromide monohydrate 1.98 mg Total 2S.OOOO carmoterol 0.64 mg Ciclesonide 0.16 mg Magnesium stearate 0.3035 mg HFA134a 8.0 gms Example 36 0110. An dry powder formulation was prepared using car moterol, or a salt thereof, preferably carmoterol hydrochlo Example 33 ride in combination with ciclesonide and lactose. The amount of the materials is preferably as shown in the table: 010.6 An aerosol formulation was prepared using carmot erol, or a salt thereof, and ciclesonide, with isopropyl myristate and a propellant, which is preferably Propellant Ingredients Qty/unit (mg) P227. The amounts of the materials is preferably as shown in the table: Carmoterol Hydrochloride O.004O Ciclesonide O.2OOO Lactose 24.7960

Total 2S.OOOO Ingredients Qty can Ciclesonide 0.16 mg carmoterol 0.32 mg Example 37 Isopropyl myristate 0.3035 mg P227 9.6 gms 0111. An dry powder formulation was prepared using tiotropium or a salt thereof, preferably tiotropium bromide monohydrate, and carmoterol, or a salt thereof, preferably Example 34 carmoterol hydrochloride in combination with ciclesonide and lactose. The amount of the materials is preferably as 0107 An aerosol formulation was prepared using tiotro shown in the table: pium or a salt thereof, preferably tiotropium bromide mono hydrate and carmoterol, or a salt thereof, with isopropyl myristate and a propellant, which is preferably HFA 134a. Ingredients Qty unit (mg) The amounts of the materials is preferably as shown in the Carmoterol Hydrochloride O.OO40 table: Tiotropium bromide monohydrate O.O225 Ciclesonide O.2OOO Lactose 24.7735

Ingredients Qty can Total 2S.OOOO Tiotropium bromide monohydrate 1.98 mg carmoterol 0.64 mg Isopropyl myristate 0.3035 mg Example 38 HFA134a 8.0 gms 0112 An dry powder formulation was prepared using tiotropium or a salt thereof, preferably tiotropium bromide 0108. According to the following examples 35 to 39, the monohydrate, and formoterol, or a salt thereof, preferably present invention may be manufactured by convenient means formoterol fumarate dehydrate in combination with budes wherein the process comprises of one or more drugs being onide and lactose. The amount of the materials is preferably mixed optionally with a pharmaceutically acceptable carrier as shown in the table: and providing the ingredients in a Suitable dry powder inhaler ready for inhalation. Ingredients Qty unit (mg) Example 35 Formoterol fumarate dihydrate O.O12O Tiotropium bromide monohydrate O.O225 0109 An dry powder formulation was prepared using Budesonide O.8000 tiotropium or a salt thereof, preferably tiotropium bromide Lactose 24.1655 monohydrate, and carmoterol, or a salt thereof, preferably Total 2S.OOOO carmoterol hydrochloride in combination with lactose. The amount of the materials is preferably as shown in the table: US 2010/006301.6 A1 Mar. 11, 2010

Example 39 Example 42 0113. An dry powder formulation was prepared using 0117. An inhalation solution formulation was prepared tiotropium or a salt thereof, preferably tiotropium bromide using tiotropium or a salt thereof, preferably tiotropium bro monohydrate, and formoterol, or a salt thereof, preferably mide monohydrate, and carmoterol, or a salt thereof, prefer formoterol fumarate dehydrate in combination with budes ably carmoterol hydrochloride in combination with sodium onide and lactose. The amount of the materials is preferably chloride and water. The amount of the materials is preferably as shown in the table: as shown in the table:

Ingredients Qty unit (mg) Ingredients Quantity Formoterol fumarate dihydrate O.O12O Tiotropium bromide monohydrate O.O225 Carmoterol Hydrochloride 2.000 mcg Ciclesonide O4(OOO Tiotropium bromide monohydrate 9.000 mcg Lactose 24.S6SS Sodium chloride 0.9% wiv Water q.S. to 2 ml Total 2S.OOOO

0114. According to the following examples 40 to 42, the Example 43 present invention may be carried out by a process comprising placing a sterile active(s) in a Suitable container, then, asep tically adding the sterile bulk of other ingredients to the 0118. An aerosol formulation was prepared using tiotro container having the active(s) and mixing the above Solution pium or a salt thereof, formoterol, and budesonide, in com by Sonication or magnetic stirring and finally adding the bination with lecithin and a propellant, which is preferably above mixture to the remaining bulk. Propellant 11 and Propellant 12. The amount of the materials is preferably as shown in the table: Example 40

0115. An inhalation solution formulation was prepared Ingredients Qty can using tiotropium or a salt thereof, preferably tiotropium bro Tiotropium 1.98 mg mide monohydrate, and carmoterol, or a salt thereof, prefer Formoterol 0.96 mg ably carmoterol hydrochloride in combination with budesonide 64 mg ciclesonide, Tween 20, sodium chloride and water. The Lecithin 6.7 mg Propellant 11 3.22 gms amount of the materials is preferably as shown in the table: Propellant 12 8.0 gms

Ingredients Quantity Example 44 Carmoterol Hydrochloride 2.000 mcg Tiotropium bromide monohydrate 9.000 mcg Ciclesonide 200.000 mcg 0119) An aerosol formulation was prepared using tiotro Tween 20 O.005% wiv pium or a salt thereof, formoterol, and ciclesonide, in com Sodium chloride 0.9% wiv bination with lecithin and a propellant, which is preferably Water q.S. to 2 ml Propellant 11 and Propellant 12. The amount of the materials is preferably as shown in the table: Example 41 0116. An inhalation solution formulation was prepared Ingredients Qty can using carmoterol, or a salt thereof, preferably carmoterol Tiotropium 1.98 mg hydrochloride in combination with ciclesonide, Tween 20, Formoterol 0.96 mg sodium chloride and water. The amount of the materials is Ciclesonide 16 mg Lecithin 6.1 mg preferably as shown in the table: Propellant 11 3.22 gms Propellant 12 8.0 gms

Ingredients Quantity Carmoterol Hydrochloride 20.000 mcg Example 45 Ciclesonide 2000.000 mcg Tween 20 O.05% wiv 0.120. An aerosol formulation was prepared using tiotro Sodium chloride 0.9% wiv Water q.S. to 2 ml pium or a salt thereof, formoterol, and budesonide, in com bination with a propellant, which is preferably HFA134a. The amount of the materials is preferably as shown in the table: US 2010/006301.6 A1 Mar. 11, 2010

a propellant, which is preferably Propellant 11 and Propellant 12. The amount of the materials is preferably as shown in the table: Ingredients Qty can Tiotropium 1.98 mg Formoterol 0.96 mg budesonide 64 mg Ingredients Qty can HFA134a 9.6 gms Ciclesonide 16 mg Formoterol 0.96 mg Lecithin 1.7 mg Propellant 11 3.22 gms Example 46 Propellant 12 8.0 gms 0121. An aerosol formulation was prepared using tiotro pium or a salt thereof, formoterol, and budesonide, in com bination with lactose and a propellant, which is preferably Example 50 HFA227. The amount of the materials is preferably as shown in the table: 0.125. An aerosol formulation was prepared using carmot erol or a salt thereof and ciclesonide, in combination with a propellant, which is preferably HFA 134a. The amount of the materials is preferably as shown in the table: Ingredients Qty can Tiotropium 1.98 mg Formoterol 0.96 mg budesonide 64 mg Ingredients Qty can Lactose 16.7 mg Carmeterol 0.16 mg HFA227 11.2 gms Ciclesonide 16 mg HFA134a 4.8 gms Example 47 0.122 An aerosol formulation was prepared using tiotro Example 51 pium or a salt thereof, formoterol, and ciclesonide, in com 0.126 An aerosol formulation was prepared using formot bination with a propellant, which is preferably HFA 134a. erol and ciclesonide, in combination with a propellant, which The amount of the materials is preferably as shown in the is preferably HFA 134a. The amount of the materials is pref table: erably as shown in the table:

Ingredients Qty can Ingredients Qty can Tiotropium 1.98 mg Ciclesonide 16 mg Formoterol 0.96 mg Formoterol 0.96 mg Ciclesonide 16 mg HFA134a 4.8 gms HFA134a 9.6 gms

Example 48 Example 52 0123. An aerosol formulation was prepared using carme I0127. An aerosol formulation was prepared using formot terol, or a salt thereof, ciclesonide, in combination with leci erol and ciclesonide, in combination with ethanol, lecithin thin and a propellant, which is preferably Propellant 11 and and a propellant, which is preferably HFA227. The amount of Propellant 12. The amount of the materials is preferably as the materials is preferably as shown in the table: shown in the table:

Ingredients Qty can Ingredients Qty can Ciclesonide 16 mg Formoterol 0.96 mg Carmeterol 0.16 mg Ethanol 224 mg Ciclesonide 16 mg Lecithin 0.0034 mg Lecithin 1.6 mg HFA227 11.0 gms Propellant 11 3.22 gms Propellant 12 8.0 gms I0128. It is to be understood that the phraseology and ter minology used herein is for the purpose of description and Example 49 should not be regarded as limiting. The use of “including.” “comprising,” or “having and variations thereof herein is 0124. An aerosol formulation was prepared using meant to encompass the items listed thereafter and equiva ciclesonide and formoterol, in combination with lecithin and lents thereofas well as additional items. US 2010/006301.6 A1 Mar. 11, 2010

0129. It must be noted that, as used in this specification, 15. The combination according to claim 1, wherein the the singular forms “a,” “an and “the include plural refer corticosteroid is selected from budesonide, ciclesonide, ences unless the context clearly dictates otherwise. Thus, for mometasone and beclomethasone, or a pharmaceutically example, reference to “a propellant includes a single propel acceptable salt or ester thereof. lant as well as two or more different propellants; reference to 16-17. (canceled) a “cosolvent refers to a single cosolvent or to combinations 18. The combination according to claim 1, wherein the of two or more cosolvents and the like. bronchodilators are carmoterol and tiotropium and the corti costeroidisciclesonide, or a pharmaceutically acceptable salt 0130. It will be appreciated that the invention described or ester thereof. above may be modified within the scope of the claims. 19. The combination according to claim 1, wherein the 1. A pharmaceutical combination comprising (a) a combi bronchodilators are tiotropium and carmoterol, or a pharma nation of two or more bronchodilators for simultaneous or ceutically acceptable salt or ester thereof. sequential administration; or (b) a combination of at least one 20. The combination according to claim 1, wherein the bronchodilator incombination with at least one corticosteroid bronchodilator is carmoterol and the corticosteroid is for simultaneous or sequential administration. ciclesonide, or a pharmaceutically acceptable salt or ester 2. The pharmaceutical combination according to claim 1, thereof. 21. The combination according to claim 1, wherein the comprising a combination of at least two bronchodilators in bronchodilators are aclidinium and formoterol and/or AR combination with at least one corticosteroid. formoterol, or a pharmaceutically acceptable salt or ester 3. The pharmaceutical combination according to claim 1, thereof. wherein (a) the combination comprises bronchodilators 22. The combination composition according to claim 1, selected from anticholinergic agents or beta adrenergicago wherein all the active materials and any excipients are formu nists or a combination thereof or (b) the combination com lated in a single pharmaceutical composition. prises at least one bronchodilator in combination with at least 23. (canceled) one corticosteroid. 24. The combination composition according to claim 1, 4. (canceled) formulated for use in a metered dose inhaler. 5. The combination according to claim 1, wherein at least 25-26. (canceled) one of the bronchodilators is a beta-agonist. 27. The combination composition according to claim 1, 6. The combination according to claim 5, wherein the or formulated for use as a dry powder inhalation formulation. each beta-agonist is selected from formoterol, AR-formot 28-30. (canceled) erol, fenoterol, carmoterol and indacaterol, or a pharmaceu 31. The combination composition according to claim 1, tically acceptable salt or ester thereof. formulated for use as an inhalation Solution. 7-10. (canceled) 32-36. (canceled) 11. The combination according to claim 1, wherein at least 37. A metered dose inhaler comprising a container, a phar one of the bronchodilators is an anticholinergic agent. maceutical combination according to claim 1 disposed within 12. The combination according to claim 11, wherein the the container, and a valve for metering a dose of the pharma anticholinergic agent is selected from aclidinium, ipratro ceutical combination from the container. pium, tiotropium and oxitropium, or a pharmaceutically 38-42. (canceled) acceptable salt or ester thereof. 13-14. (canceled)