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US 20150250713A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0250713 A1 Malhotra et al. (43) Pub. Date: Sep. 10, 2015

(54) PHARMACEUTICAL COMPOSITION Publication Classification (71) Applicant: CIPLA LIMITED, Mumbai (IN) (51) Int. Cl. A619/00 (2006.01) (72) Inventors: Geena Malhotra, Mumbai (IN); A647/06 (2006.01) Shrinivas Purandare, Mumbai (IN) A613 L/46 (2006.01) (73) Assignee: CIPLA Limited, Mumbai (IN) (52) U.S. Cl. CPC ...... A61 K9/008 (2013.01); A61 K3I/46 (21) Appl. No.: 14/431,561 (2013.01); A61 K47/06 (2013.01) (22) PCT Fled: Oct. 23, 2013 (57) ABSTRACT (86) PCT NO.: PCT/GB2O13/OOO454 S371 (c)(1), The present invention relates to a pharmaceutical composi (2) Date: Mar. 26, 2015 tion comprising tiotropium, a hydrofluoroalkane (HFA) pro pellant, and optionally one or more pharmaceutically accept (30) Foreign Application Priority Data able excipients; to a process for preparing such a pharmaceutical composition, and the use thereof in medicine, Oct. 23, 2012 (IN) ...... 3092AMUMA2012 in particular for the prophylaxis and treatment of respiratory Jan. 31, 2013 (IN) ...... 28OFMUMA2013 disorders. Patent Application Publication US 2015/0250713 A1

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Patent Application Publication Sep. 10, 2015 Sheet 2 of 3 US 2015/0250713 A1

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US 2015/0250713 A1 Sep. 10, 2015

PHARMACEUTICAL COMPOSITION HC NN1-- CH FIELD OF THE INVENTION 0001. The present invention relates to a stable pharmaceu tical composition comprising tiotropium with at least one hydrofluoroalkane (HFA) propellant. The present invention also relates to the process of preparing the same and its use for the treatment of , COPD and other respiratory disor ders thereof.

BACKGROUND AND PRIOR ART 0002 Chronic obstructive pulmonary disease (COPD) is a 0009 Tiotropium has a longer duration of action of up to severe respiratory condition that is increasing its prevalence 32 hours. Also, tiotropium exhibits an improvement in dysp worldwide. In India, the estimated prevalence is about 12.36 nea and ceases the need for rescue therapy. Tiotropium in million. It is currently the fourth leading cause of death in the combination with pulmonary rehabilitation (PR) associated UK & US and is predicted to rank third in the “global impact with an increased exercise endurance time produces clini of disease” by the year 2020. cally meaningful improvements in dyspnea and health status as compared to pulmonary rehabilitation alone in COPD 0003 Chronic obstructive pulmonary disease (COPD) is a patients. preventable and treatable disease state characterized by air 0010 Tiotropium is an extremely moisture sensitive drug. flow limitation that is not fully reversible. The airflow Therefore, formulations containing tiotropium undergo obstruction is usually progressive and associated with an hydrolytic degradation which results in an unstable formula abnormal inflammatory response of the lungs to noxious par tion thus deteriorating its required efficacy. ticles or gases primarily caused by cigarette Smoking. 0011. Several attempts have been made by formulators to Although COPD affects the lungs, it also produces significant stabilize such formulations of tiotropium by adding addi systemic consequences. COPD is associated with mucus tional excipients such as mineral acids, lower branched or hyper secretion, emphysema and bronchiolitis. linear alkyl (C1-C4) alcohols and active adjuvant complexes. 0004 Asthma is a major cause of chronic morbidity and (0012 For example, EP2201934 discloses stable tiotro mortality with an estimated 300 million affected individuals pium HFA aerosol solution formulations wherein stability is worldwide and 250,000 annual deaths are attributed to the achieved by addition of a mineral acid Such as hydrochloric, disease. People of all ages in most countries are affected by phosphoric, nitric and Sulphuric acid in the formulation. this chronic disease. However, to improve the stability, it is not only necessary to add Small amounts of mineral acids but it is also important to 0005 Asthma is a chronic inflammatory disorder of the select the type of the container, metering valve and sealing airways associated with airway hyper responsiveness that gaskets which may be in contact with the formulation. Fur leads to recurrent episodes of wheezing, breathlessness, chest ther, the addition of mineral acids may increase the toxicity of tightness and coughing. An increased inflammatory response the formulation. is a major part of the pathophysiology of acute asthma and (0013 WO2010052466 discloses a stable pharmaceutical regular preventive treatment is important. aerosol composition oftiotropium complexed with an adju 0006. The major goals of the therapy for the prevention vant (PVP) for the treatment of respiratory disorders. and treatment of COPD, asthma and other respiratory disor 0014 EP 1870090 discloses a novel stable formulation of ders include Smoking cessation, relief of symptoms, improve Suspended aerosols and hydrofluorocarbons as propellants ment in physiological functions and limiting complications wherein stability is achieved by adding a dispersion coadju Such as abnormal gas exchange and exacerbation of disease. vant such as ethanol in very Small quantities (lower than However, an integrated approach to the treatment involves the 0.30% w/w) and the use of valves provided with seals com combination of healthcare maintenance Such as Smoking ces patible with the formulation. However, by increasing or sation, avoidance of indoor as well as outdoor pollutants and decreasing the quantity of ethanol, the values of FPF (Fine allergens, avoidance of occupational exposure to allergens Particle Fraction) and MMAD (Mass Median Aerodynamic and use of drugs and Supplemental therapies in a step-wise Diameter) would vary drastically. fashion as the disease progresses. 0015. Although the above prior arts cover various tech niques to preparestable formulations oftiotropium, the use of 0007 Currently, the therapy for the treatment or preven excipients in lower quantities, specific types of containers and tion of COPD and asthma includes the use of one or more long valves may limit the ease of the manufacture and vary the acting such as B2 agonists, , COSt. inhaled corticosteroids (ICS) or combinations thereof. 0016 Considering the above limitations, there stillarises a 0008 is one such need to develop a pharmaceutical composition oftiotropium that antagonises the M1, M2 and M3 musca which can be produced by simple manufacturing techniques rinic receptors. Tiotropium is chemically known as (1C, 2B, and which also exhibit improved stability. 4?. 5C, 7B)-7-(Hydroxydi-2-thienylacetyl)oxy-9, 9-dim 0017 Although the use of HFA propellants has been very ethyl-3-oxa-9-azoniatricyclo 3.3.1.02.4 nonane bromide well disclosed in the prior art, the inventors have Surprisingly monohydrate and is represented as: found that compositions comprising tiotropium and specifi US 2015/0250713 A1 Sep. 10, 2015 cally HFA-227 as a propellant, exhibit improved stability as position comprising tiotropium and a HFA propellant, such as compared to other HFA propellants, particularly HFA-134 HFA-227 optionally along with pharmaceutically acceptable (a). excipients. 0028. According to another aspect of the present inven OBJECT OF THE INVENTION tion, there is provided the use of a pharmaceutical composi 0018. An object of the present invention is to provide a tion comprising tiotropium and a HFA propellant, Such as pharmaceutical composition comprising tiotropium and a HFA-227, optionally along with pharmaceutically acceptable HFA propellant, such as HFA-227, optionally with one or excipients for the prophylaxis or treatment of asthma, chronic more pharmaceutically acceptable excipients. obstructive pulmonary disease or related respiratory disor 0019. Another object of the present invention is to provide ders. a pharmaceutical composition comprising tiotropium and a 0029. According to another aspect of the present inven HFA propellant, such as HFA-227, optionally with one or tion, there is provided the use of a pharmaceutical composi more pharmaceutically acceptable excipients, which compo tion comprising tiotropium and a HFA propellant, Such as sition exhibits improved stability. HFA-227, optionally along with pharmaceutically acceptable 0020. Yet another object is to provide a process for the excipients in the manufacture of a medicament for the pro preparation of a pharmaceutical composition comprising phylaxis or treatment of asthma, chronic obstructive pulmo tiotropium and a HFA propellant, such as HFA-227, option nary disease or related respiratory disorders. ally with one or more pharmaceutically acceptable excipi BRIEF DESCRIPTION OF THE DRAWINGS entS. 0021. Another object of the present invention is to provide 0030 Studies were carried out on pharmaceutical compo a method for prophylaxis or treatment of asthma, chronic sitions comprisingtiotropium, a HFA propellant (either HFA obstructive pulmonary disease or related respiratory disor 227 or HFA 134 (a)) and lactose. ders by administering a pharmaceutical composition com 0031 (A) Stability Data prising tiotropium and a HFA propellant, such as HFA-227. 0032 FIG. 1: Comparative stability data of tiotropium optionally with one or more pharmaceutically acceptable with propellant HFA 134(a) versus tiotropium with propel excipients. lant HFA-227. 0022. Another object of the present invention is to provide 0033. This figure indicates that the drop from the initial % the use of a pharmaceutical composition comprising tiotro L.A. (Labelled Amount)-value to the 6 month96 L.A. value is pium and a HFA propellant, such as HFA-227, optionally substantially lower in the case oftiotropium with propellant with one or more pharmaceutically acceptable excipients for HFA-227 as compared to tiotropium with propellant HFA the treatment of asthma and chronic obstructive pulmonary 134(a). This indicates that the tiotropium HFA-227 compo disease or related respiratory disorders. sition is more stable than the tiotropium HFA 134(a) compo sition. SUMMARY OF THE INVENTION 0034 (B) Particle size distribution studies replicating the 0023. According to a first aspect of the present invention, deposition of particles in the human lung. there is provided a pharmaceutical composition comprising 0035 FIG. 2: Particle size distribution study of propellant tiotropium, preferably tiotropium bromide and a WA propel HFA 134(a) using a Cascade Impactor. lant, preferably HFA-227, optionally with one or more phar 0036 FIG. 3: Particle size distribution study of propellant maceutically acceptable excipients. HFA-227 using a Cascade Impactor. 0024. According to another aspect of the present inven 0037 Stages S3, S4 and S5 are the critical stages which tion, there is provided a pharmaceutical composition com indicate the deep lung deposition oftiotropium. prising tiotropium optionally with one or more pharmaceuti 0038 FIGS. 2 and 3 illustrate that the drop from the initial cally acceptable excipients comprising HFA-227 as a % L.A value to the 6 month % L.A value for the tiotropium propellant. Preferably, the composition is formulated for HFA-227 composition at both the S3 and S4 stage is less than administration using a metered dose inhaler (MDI). for the tiotropium 134(a) composition. This indicates that the 0025. According to another aspect of the present inven tiotropium HFA-227 composition is more stable than the tion, there is provided a pharmaceutical composition com tiotropium HFA 134(a) composition. prising tiotropium and another active ingredient, preferably a beta agonist and/or an inhaled corticosteroid, a DETAILED DESCRIPTION OF THE INVENTION HFA propellant, preferably HFA-227, optionally with one or 0039. The inventors of the present invention have devel more pharmaceutically acceptable excipients. Preferably, the oped a pharmaceutical composition comprising tiotropium composition is formulated for administration using a metered and a HFA propellant, preferably HFA-227, optionally with dose inhaler (MDI). one or more pharmaceutically acceptable excipients. 0026. According to another aspect of the present inven 0040. The present invention provides a process for the tion, there is provided a process for the preparation of a preparation of Such pharmaceutical compositions and also pharmaceutical composition, such process comprising provides their use in the treatment of asthma, chronic obstruc admixingtiotropium along with a HFA propellant, preferably tive pulmonary disease or any other related respiratory disor HFA-227, optionally with one or more pharmaceutically ders. acceptable excipients. 0041. The pharmaceutical compositions of the present 0027. According to another aspect of the present inven invention are preferably aerosol compositions for administra tion, there is provided a method for prophylaxis or treatment tion using a metered dose inhaler (MDI) or the like. of asthma, chronic obstructive pulmonary disease or related 0042. Further, such pharmaceutical compositions may respiratory disorders by administering a pharmaceutical com comprisetiotropium and additional actives, a propellant and US 2015/0250713 A1 Sep. 10, 2015

optionally one or more excipients. The active ingredient can 0048. The moisture uptake of HFA-134 (a) is six times be selected from the group comprising beta adrenergicago higher compared to HFA-227 (measured values) due to its nists and/or inhaled corticosteroids. higher polarity. This moisture uptake may increase the par 0043. As used herein the terms “tiotropium, albuterol, ticle size oftiotropium leading to a lower fine particle dose , levoalbuterol, butaline, pir (FPD) value which in turn causes lesser bioavailability. buterol, , metaproterenol, , isoproterenol 0049. Further, HFA-134 (a) causes the cold Freon effect (B and B), metaproterenol, , isoetarine, which may ultimately affect patient compliance. mesylate, , , , , 0050 Suitable excipients may be optionally used for for , , , , milveterol, mulating the pharmaceutical composition according to the , , propionate, fluticasone present invention. Examples of Suitable pharmaceutically furoate, fluticaSone Valerate, , , acceptable excipients may comprise one or more, but not beclomethasone, , R-budesonide' are used in a limited to, HFA propellants, non-halogenated hydrocarbon broad sense to include not only the active ingredient perse but propellants, co-solvents, low volatility components, stabiliz also pharmaceutically acceptable derivatives thereof. Suit ers, dispersing agents, pH adjusting agents, antioxidants, pre able derivatives include pharmaceutically acceptable salts, servatives, chelating agents, Surface active agents, bulking pharmaceutically acceptable Solvates, pharmaceutically agents and the like or mixtures thereof. acceptable hydrates, pharmaceutically acceptable isomers, 0051. HFA propellants are carriers which, when mixed pharmaceutically acceptable esters, pharmaceutically accept with the cosolvent(s), form a homogeneous propellant system able anhydrates, pharmaceutically acceptable enantiomers, in which a therapeutically effective amount of the medica pharmaceutically acceptable polymorphs, pharmaceutically ment can be dissolved. The HFA propellant must be toxico acceptable prodrugs, pharmaceutically acceptable tautomers logically safe and must have a vapor pressure which is Suit and/or pharmaceutically acceptable complexes thereof, or able to enable the medicament to be administered via a any combination of such derivatives. A preferred pharmaceu pressurized MDI. Additionally, the HFA propellant must be tically acceptable salt oftiotropium is tiotropium bromide, compatible with the components of the MDI device (such as preferably tiotropium bromide monohydrate or tiotropium containers, valves, and sealing gaskets, etc.) which are bromide anhydrate. employed to administer the medicament. The preferred HFA 0044 Chlorofluorocarbons (CFC) were previously the propellant is 1,1,1,2,3,3,3-heptafluoropropane (HFA-227). most common propellants used in pressurised Metered Dose Other examples of suitable HFA propellants are HFA-32 (dif Inhalers (pMDIs) due to the fact that they are non-toxic, luoromethane), HFA-143(a) (1.1.1 -trifluoroethane) and non-flammable and have high vapor pressure. However HFA-152a (1,1-difluoroethane) and mixtures thereof. CFCs, as propellants, have adverse effects on global warm 0052. Non-halogenated hydrocarbon may be used in com ing and stratospheric ozone destruction due to which the use bination with the HFA propellants of the present invention. of the same has been banned in many countries, which led to Examples of Such non-halogenated hydrocarbons are satu the extensive usage of HFA as propellant systems. rated hydrocarbons, including propane, n-butane, and isobu tane, and ethers, including diethyl ether and the like or mix 0045 Thus, two new hydrofluoroalkanes (HFAs) namely tures thereof. tetrafluoroethane (HFA-134a) and heptafluoropropane 0053. It will also be apparent to those skilled in the art that, (HFA-227), have become the alternative propellants for use although the use of a single HFA propellant is preferred, a with pharmaceutical aerosols delivered in pMDIs. HFAS also mixture of two or more HFA propellants, or a mixture of at have similar advantages to CFCs for use in pMDIs and they least one HFA propellant and one or more non-CFC propel also do not cause any damage to the oZone layer. lants, may be employed in the composition (aerosol Solution 0046. The HFA propellant must be toxicologically safe formulation) of the present invention. and must have a vapor pressure which is suitable to enable the 0054 Suitable co solvents and low volatility components medicament to be administered via a pressurized MDI. Addi that may be employed to increase the compatibility between tionally, the HFA propellant must be compatible with the the drug and the propellant in the pharmaceutical composi components of the MDI device (such as containers, valves, tion may comprise one or more C-Caliphatic alcohols such and sealing gaskets, etc.) which are employed to administer as, but not limited to, ethyl alcohol and isopropyl alcohol; the medicament. Examples of suitable HFA propellants for glycols such as, but not limited to, propylene glycol, polyeth use in the present invention are HFA-32 (difluoromethane), ylene glycols, polypropylene glycols, glycol ethers, and HFA-143(a) (1,1,1-trifluoroethane), HFA-134 (1.1.2.2-tet block copolymers of oxyethylene and oxypropylene; and rafluoroethane), and HFA-152a (1,1-difluoroethane), 1,1,1,2- other Substances such as, but not limited to glycerol, isopro tetrafluoroethane (HFA-134(a)) and 1,1,1,2,3,3,3-heptafluo pyl myristate polyoxyethylene alcohols, and polyoxyethyl ropropane (HFA-227), and any mixture thereof. Preferred enefatty acid esters; hydrocarbons such as, but not limited to, HFA propellants are 1,1,1,2-tetrafluoroethane (HFA-134(a)) n-propane, n-butane, isobutane, n-pentane, iso-pentane, neo and 1,1,1,2,3,3,3,-heptafluoropropane (HFA-227) or a mix pentane and n-hexane; ethers such as but not limited to diethyl ture thereof. The terms hydrofluoroalkane (HFA) and hydrof ether and the like or mixtures thereof. The co-solvent is pref luorocarbon (HFC) are used interchangeably throughout this erably present in an amount ranging from 0.1-5% of the specification. composition. 0047. The inventors of the present invention have found 0055 Suitable bulking agents that may be employed in the that the use of HFA-227 specifically as a propellant system pharmaceutical composition of the present invention may resulted in a more stable pharmaceutical composition of comprise Saccharides such as, but not limited to, monosac tiotropium when compared with a pharmaceutical composi charides, disaccharides, oligosaccharides, and polysaccha tion oftiotropium comprising HFA-134 (a) as a propellant rides for example lactose, maltose, glucose, fructose, galac system. This is illustrated in FIGS. 1, 2 and 3. tose arabinose, dextrose, ribose, Sucrose, Sorbitol, mannitol, US 2015/0250713 A1 Sep. 10, 2015

Xylose, trehalose, raffinose, melezitose, glycerol, erythritol, olive oil, cottonseed oil and Sunflower seed oil, mineral oils Xylitol, maltitol, lactitol and D & L series of rare Sugars and like liquid paraffin, oleic acid and also phospholipids such as the like and mixtures thereof The bulking agent is preferably lecithin, or sorbitan fatty acid esters like sorbitan trioleate or present in an amount ranging from 10-500% of the drug. Tween 20, Tween 60, Tween 80, polyethylene glycols such as More preferably, the bulking agent is present in an amount PEG-25, PEG-100, PEG-1000 (preferably in an amount of ranging from 10-300%, 50-300%, 50-200% of the drug (for 0.3% of the total weight of the composition), Glyceryl tri example, tiotropium). Most preferably the bulking agent is oleate, PVP (polyvinylpyrrollidone, e.g. PVP K25 preferably present in an amount of 300% of the drug. in an amount of 0.001% of the total weight of the composi 0056 Suitably, the preservatives that may be employed in tion), citric acid, PFDA (per fluoro-n-decanoic acid) and the the pharmaceutical composition may be present in a range of like or mixtures thereof. 0.00001-0.2%, more preferably 0.01-0.2% of the formula 0060 Suitable dispersing agents that may be employed in tion. The preservative that may be employed in the pharma the pharmaceutical composition may comprise Sorbitan tri ceutical composition may comprise one or more of benzalko oleate, oleyl alcohol, oleic acid, lecithin and the like or mix nium chloride, EDTA, benzoic acid, benzoates such as tures thereof. sodium benzoate and such other preservatives which may be 0061 Suitable antioxidants that may be employed in the known to the person skilled in the art and the like or mixtures pharmaceutical composition may comprise ascorbic acid, thereof. C-tocopherol, BHT (butylhydroxytoluene) and BHA (butyl 0057 Suitably the chelating/complexing agents that may hydroxyanisole) and the like or mixtures thereof. be employed in the pharmaceutical composition may be 0062 Preferably, the composition is essentially free of a present in a range of 0.00001-0.2%, more preferably 0.01-0. mineral acid and/or the composition does not comprise a 2% of the formulation. The chelating agents that may be tiotropium-adjuvant complex, for example a tiotropium-PVP employed in the pharmaceutical composition may comprise complex. In an alternative it is preferable that the composition edetic acid (EDTA) or one of its known salts thereof, e.g. is free of a mineral acid and/or the composition does not sodium EDTA or disodium EDTA dihydrate (sodium edetate) comprise a tiotropium-adjuvant complex, for example a and the like or mixtures thereof. tiotropium-PVP complex. 0058 Suitably, the pH adjusting agent that may be 0063 Preferably, there is provided a pharmaceutical com employed in the pharmaceutical composition may comprise position comprising tiotropium bromide, more preferably one or more of organic or inorganic acids such as, but not tiotropium bromide monohydrate or tiotropium bromide limited to, citric acid, ascorbic acid, hydrochloric acid, sul anhydrate, and HFA-227. The dose oftiotropium bromide, furic acid, nitric acid or phosphoric acid and the like or preferably tiotropium bromide monohydrate, is preferably 9 mixtures thereof. Preferably, the one or more organic or inor micrograms (mcg). ganic acids are non-mineral acids, such as citric acid and 0064. The pharmaceutical composition according to the ascorbic acid. Most preferably, the composition of the present present invention, may further comprise one or more active invention does not comprise a mineral acid, in other words it agents selected from beta adrenergic agonists such as, but not is preferable that the composition is essentially free or free of limited to, albuterol or salbutamol, levoalbuterol, levosalb a mineral acid. utamol butaline, , procaterol, metaproterenol, 0059. One or more surfactants may be employed to stabi fenoterol, isoproterenol (B and B2), metaproterenol, terbuta lize the pharmaceutical composition and to also provide line, isoetarine, bitolterol mesylate, ritodrine, salmeterol, for lubrication to the valve system of the metered dose inhaler. moterol, arformoterol, carmoterol, bambuterol, clenbuterol, The one or more stabilizers is preferably present in a range of indacaterol, milveterol, Vilanterol, olodaterol, or inhaled cor 0.00001-0.5% of the composition, more preferably 0.00001 ticosteroids such as, but not limited to, , 0.2%, even more preferably 0.001-0.3%, and most preferably fluticasone furoate, fluticaSone Valerate, mometaSone, 0.001-0.1%. Some of the most commonly employed surfac ciclesonide, beclomethasone, budesonide, R-budesonide. tants may comprise one or more ionic and/or non-ionic Sur 0065 According to a preferred embodiment of the present factants such as salts of Stearic acids such as magnesium invention, the pharmaceutical composition comprises tiotro Stearate or esters such as ascorbyl palmitate, isopropyl pium, preferably tiotropium bromide, more preferably tiotro myristate or tocopherol esters such as oleic acid, Sorbitan pium bromide monohydrate or tiotropium bromide anhy trioleate, lecithin, isopropyl myristate, tyloxapol, or polysor drate, and is formulated for delivery using a pressurized bates such as polysorbate 80, Polysorbate 20, Polysorbate 40, metered dose inhaler. Preferably the tiotropium concentration vitamin E-TPGS or macrogol hydroxystearates such as mac corresponds to single doses ranging from about 2.5 micro rogol-15-hydroxy Stearate or acetylated monoglycerides like grams to about 18 micrograms, preferably from about 2.5 to My vacet 9-45 and Myvacet 9-08, Polyoxyethylene ethers, about 15 micrograms, more preferably from about 4.5 to ethyloleate, glyceryl trioleate, glyceryl monolaurate, glyceryl about 9 micrograms, characterized by a desirable FPD of the monooleate, glyceryl monosterate, glyceryl monoricinoleate, said active particles/ aerosol particles. Most preferably, the cetylalcohol, sterylalcohol, cetyl pyridinium chloride, block composition comprises tiotropium bromide, preferably polymers, natural oils, Sorbitan fatty acid esters such as Sor tiotropium bromide monohydrate at a concentration of about bitan trioleate, polyethoxylated sorbitan fatty acid esters (for 9 micrograms. example polyethoxylated Sorbitan trioleate), Sorbimacrogol 0066. According to another preferred embodiment of the oleate, synthetic amphotensides (tritons) or ethylene oxide present invention, the pharmaceutical composition comprises ethers of octylphenolformaldehyde condensation products, tiotropium, Such as tiotropium bromide, preferably tiotro phosphatides such as lecithin, polyethoxylated fats, poly pium bromide monohydrate or tiotropium bromide ayhy ethoxylated oleotriglycerides and polyethoxylated fatty alco drate, and is formulated for delivery/administration using a hols. The surfactants may also be selected from the vast class metered dose inhaler or a breath actuated metered dose like oils known in the art Such as, but not limited to, corn oil, inhaler. US 2015/0250713 A1 Sep. 10, 2015

0067. According to another embodiment of the present EXAMPLE 1. invention, there is provided a method of administering tiotro pium, preferably tiotropium bromide, more preferably tiotro 0.077 pium bromide monohydrate or tiotropium bromide anhy drate, with one or more pharmaceutically acceptable excipients comprising a HFA propellant, preferably HFA Sr. No. Ingredients Quantity/Spray 227, co-solvent, low volatility component, stabilizer, dispers 1 Tiotropium Bromide 9 mcg ing agent, pH adjusting agent, Surface active agent or mix 2 HFAHFC-227 q.S. to make up to 100 mcl tures thereof, to be used with a metered dose inhaler or a breath actuated metered dose inhaler comprising a metering 0078 Process: valve and low orifice actuator ranging from 0.2 mm to 0.6 mm 0079 1) Tiotropium bromide was homogenized with part diameter (preferably 0.4 to 0.5 mm) characterized by a desir quantity of HFA-227. able FPD of the said active particles/aerosol particles. 0080 2) The suspension obtained in step (1) was trans 0068. The pharmaceutical composition according to the ferred to a mixing vessel where the sufficient quantity of present invention may be dispensed in plain aluminum cans HFA-227 was added to make up the required volume of the or SS (stainless steel) cans. The inner surface of these cans Ca can be coated with Suitable polymers. Such polymers include, I0081. 3) The resulting suspension was then mixed, recir but are not limited to, fluorocarbon copolymers such as FEP culated and filled into pre-crimped Aluminium cans. PES (fluorinated ethylene propylene and polyethersulphone), PFA-PES (perfluoroalkoxyalkane and polyethersulphone), EXAMPLE 2 epoxy and ethylene or combinations thereof. Alternatively, 0082 the inner Surfaces of the cans may be anodized also. 0069. The present invention also provides a process for preparing the pharmaceutical composition of the present Sr. No. Ingredients Quantity/Spray invention which process comprises admixingtiotropium with 1 Tiotropium Bromide 9 mcg a HFA propellant. Preferably, the admixing step comprises 2 Lactose 9 mcg admixing one or more pharmaceutically acceptable excipi 3 HFAHFC-227 q.S. to make up to 100 mcl ents with tiotropium, and/or with a HFA propellant. 0070 The present invention also provides a method for the 0083 Process: treatment in a mammal. Such as a human, for treating chronic I0084. 1) Tiotropium bromide was homogenized with lac obstructive pulmonary disease and asthma, which method tose and part quantity of HFA-227. comprises administration of a therapeutically effective I0085 2) The suspension obtained in step (1) was trans amount of pharmaceutical compositions according to the ferred to the mixing vessel where sufficient quantity of HFA present invention. 227 was added to make up the required volume of the can. I0086 3) The resulting suspension was then mixed, recir 0071. The method of treatment may be characterized in that the pharmaceutical compositions according to the culated and filled into pre-crimped Aluminium cans. present invention are administered once or twice a day in EXAMPLE 3 therapeutically effective amounts. 0072. In one aspect, the present invention provides a phar 0087 maceutical composition which may further comprise one or more active agents selected from beta adrenergic agonists Sr. No. Ingredients Quantity/Spray and/or inhaled corticosteroid for treating chronic obstructive 1 Tiotropium Bromide 9 mcg pulmonary disease and asthma. PEG 1 OOO 0.3% of total weight 0073. Accordingly, the present invention provides a phar of composition 3 PVP K 25 0.001% of total weight maceutical composition which may further comprise one or of composition more active agents selected from beta adrenergic agonists for 4 Lactose 9 mcg simultaneous, sequential or separate use. 5 HFAHFC 227 q.S. to make up to 100 mcl 0074 The present invention also provides the use of the pharmaceutical composition for the treatment of chronic 0088 Process: obstructive pulmonary disease and asthma or related respira I0089. 1) PEG and PVP were dissolved in HFA-227. tory disorders. 0090. 2) Tiotropium bromide was homogenized with lac 0075. The present invention also provides a pharmaceuti tose and part quantity of HFA-227. cal composition as substantially described herein by refer 0091 3) The suspension obtained in step (2) was trans ence to the examples. ferred to the mixing vessel where the sufficient quantity of HFA-227 was added to make up the required volume of the 0076. The following examples are for the purpose of illus Ca tration of the invention only and are not intended in any way 0092] 4) The resulting suspension was then mixed, recir to limit the scope of the present invention. culated and filled into pre-crimped Aluminium cans. US 2015/0250713 A1 Sep. 10, 2015

0093. The use of “qs' in the tables above refers to the 7. A pharmaceutical composition according to claim 1, amount of the propellant which is required to make up the further comprising one or more active agents selected from desired volume of the inhaler, excluding the volume of the albuterol, salbutamol, levoalbuterol, levosalbutamolbutaline, other components stated. pirbuterol, procaterol, metaproterenol, fenoterol, isoproter 0094. It will be readily apparent to one skilled in the art enol (B and B), metaproterenol, terbutaline, isoetarine, that varying Substitutions and modifications may be made to bitolterol mesylate, ritodrine, salmeterol, formoterol, arfor the invention disclosed herein without departing from the moterol, carmoterol, bambuterol, clenbuterol, indacaterol, spirit of the invention. Thus, it should be understood that milveterol, vilanterol, olodaterol, fluticasone propionate, flu although the present invention has been specifically disclosed ticasone furoate, fluticasone Valerate, mometaSone, by the preferred embodiments and optional features, modifi ciclesonide, beclomethasone, budesonide, R-budesonide or cation and variation of the concepts herein disclosed may be their pharmaceutically acceptable derivatives thereof. resorted to by those skilled in the art, and such modifications 8. A pharmaceutical composition according to claim 7. and variations are considered to be falling within the scope of wherein the pharmaceutically acceptable derivative is a salt, the invention. Solvate, complex, hydrate, isomer, ester, tautomer, anhydrate, 0095. It is to be understood that the phraseology and ter enantiomer, polymorph or prodrug. minology used herein is for the purpose of description and 9. A pharmaceutical composition according to claim 1, should not be regarded as limiting. The use of “including, whereinthetiotropium is present in an amount from about 2.5 “comprising or “having and variations thereof herein is micrograms to about 18 micrograms. meant to encompass the items listed thereafter and equiva 10. A pharmaceutical composition according to claim 1, lents thereofas well as additional items. formulated for administration using a metered dose inhaler or 0096. It must be noted that, as used in this specification a breath actuated metered dose inhaler. and the appended claims, the singular forms “a” “an and “the include plural references unless the context clearly 11. A pharmaceutical composition according to claim 10, dictates otherwise. wherein the inhaler comprises a metering valve and low ori 1. A pharmaceutical composition comprising tiotropium, a fice actuator ranging from 0.2 mm to 0.6 mm diameter. hydrofluoroalkane (HFA) propellant, and optionally one or 12. A process for preparing a pharmaceutical composition more pharmaceutically acceptable excipients. according to claim 1, which process comprises admixing 2. A pharmaceutical composition according to claim 1, tiotropium with a HFA propellant. comprising tiotropium in the form of a pharmaceutically 13. A process according to claim 12, wherein the admixing acceptable derivative thereof. step comprises admixing one or more pharmaceutically 3. A pharmaceutical composition according to claim 2, acceptable excipients with tiotropium, and/or with a HFA wherein the pharmaceutically acceptable derivative is a salt, propellant. Solvate, complex, hydrate, isomer, ester, tautomer, anhydrate, 14. (canceled) enantiomer, polymorph or prodrug. 15. (canceled) 4. A pharmaceutical composition according to claim 1, 16. A method for the prophylaxis or treatment of asthma, wherein the HFA propellant is HFA-227. chronic obstructive pulmonary disease and related respira 5. A pharmaceutical composition according to claim 1, tory disorders in a patient in need thereof, which method wherein the tiotropium is in the form oftiotropium bromide. comprises administering a pharmaceutical composition 6. A pharmaceutical composition according to claim 1, according to claim 1. wherein the one or more pharmaceutically acceptable excipi ents is selected from HFA propellants, non-halogenated 17. A method according to claim 16, wherein the pharma hydrocarbon propellants, co-solvents, low volatility compo ceutical composition is administered using a metered dose nents, stabilizers, dispersing agents, pH adjusting agents, inhaler. antioxidants, preservatives, chelating agents, Surface active 18. (canceled) agents, bulking agents, or mixtures thereof.