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(12) Patent Application Publication (10) Pub. No.: US 2015/0250713 A1 Malhotra Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2015/0250713 A1 Malhotra Et Al 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 (assow6)NETwHNIwºHwnido?iuoju Patent Application Publication Sep. 10, 2015 Sheet 2 of 3 US 2015/0250713 A1 (dS/93W6)(BTwHNiwy??Wnido?,Lou auruavisnonoumanusiasassiouºva:Isa. Patent Application Publication Sep. 10, 2015 Sheet 3 of 3 US 2015/0250713 A1 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 asthma, 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 bronchodilators such as B2 agonists, anticholinergics, COSt. inhaled corticosteroids (ICS) or combinations thereof. 0016 Considering the above limitations, there stillarises a 0008 Tiotropium bromide is one such anticholinergic need to develop a pharmaceutical composition oftiotropium bronchodilator 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
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