NEBULIZATION COMPOSITION COMPRISING TIOTROPIUM AND ITS METHOD OF ADMINISTRATION

RELATED APPLICATIONS

This application claims the benefit of Indian Provisional Application No. 202121039037 filed on August 28, 2021; which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a method of treating moderate to severe chronic obstructive pulmonary disease by administering a nebulization composition of tiotropium to a subject in need thereof.

BACKGROUND OF THE INVENTION

Chronic Obstructive Pulmonary Disease (COPD) is on the rise with respect to prevalence, disease burden and mortality cases. Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death worldwide, causing 3.23 million deaths in 2019. The mortality rates due to COPD continue to rise worldwide. COPD can be broadly defined into two states, emphysema and chronic bronchitis. Emphysema is characterized by irreversible enlargement of the air spaces distal to the terminal bronchioles leading to alveolar wall destruction. There is no evidence of fibrosis in emphysema. Chronic bronchitis on the other hand, is characterized by persistent productive cough in the absence of any other cause of excessive sputum generation. All of these effects lead to clogging of the airways making it difficult for the patient to breathe.

The severity of COPD can be assessed using the GOLD (Global Initiative on Obstructive Lung Disease) classification system. The GOLD classification system bases the stage of COPD using, among other things, spirometry, a test that checks the amount (volume) of air and speed (flow) that the patient can exhale. Forced expiratory volume (FEV-1) shows how much air a patient can exhale from his or her lungs in one second. FEV1 is often reported as a percentage of the predicted normal value.

Stage 1 - mild: FEV1/FVC less than 70% and FEV1 of 80% or above predicted.

Stage 2 - moderate: FEV1/FVC less than 70% and FEV1 of 50-79% predicted.

Stage 3 - severe: FEV1/FVC less than 70% and FEV1 of 30-49% predicted. Stage 4 - very severe: FEV1/FVC less than 70% and FEV1 of below 30% predicted (or FEV1 less than 50% but with chronic respiratory failure).

Tiotropium bromide monohydrate is approved in the U.S. under the brand name Spiriva Respimat® as an aqueous formulation for oral inhalation with a metered dose inhaler. The recommended dose of Spiriva Respimat® is two inhalations once daily, for a total daily dose of 5 mcg of tiotropium daily. The prescribing information for Spiriva Respimat® instructs patients not to take more than one dose (2 inhalations) in 24 hours.

The metered dose inhaler device is complex and requires the patient to co-ordinate breathing with the device during administration of medication. Nebulization formulation is convenient and easy to administer to the patients having Chronic Obstructive Pulmonary Diseases (COPD) through nebulizer and obtain better medication compliance in such patients.

Therefore, there is a need for improved methods of treating moderate to severe COPD using tiotropium bromide administered as a nebulization solution.

SUMMARY OF THE INVENTION

The present invention provides a method of treating moderate to severe chronic obstructive pulmonary disease (COPD) in a subject in need thereof by administering to the subject a nebulization composition of tiotropium or a pharmaceutically acceptable thereof. In one embodiment, a therapeutically effective amount of tiotropium or a pharmaceutically acceptable salt thereof to treat the moderate to severe COPD is administered.

In one embodiment, the nebulization composition is administered once a day or twice a day to the subject. In a preferred embodiment, the nebulization composition is administered once a day to the subject.

In one more embodiment, the nebulization composition is administered daily over a period of 12 weeks.

In an embodiment, the subject is 12 to 95 years of age. In a preferred embodiment, the subject is 40 to 75 years of age.

In one embodiment, the subject has a FEV1/FVC ratio less than 80%.

In a preferred embodiment, the subject has a FEV1/FVC ratio less than 70%.

In another embodiment, the subject has a FEV1 of greater than 30% of the predicted normal values.

One embodiment relates to a method of treating moderate to severe COPD in a subject in need thereof comprising administering via a nebulizer to the subject a daily dose of from about 10 to about 80 mcg of tiotropium or a pharmaceutically acceptable salt thereof (on the weight basis of tiotropium free base). The tiotropium is administered in the form of the nebulization compositions described in US 2016/0339003. The tiotropium is administered once daily or in divided doses twice daily. In one preferred embodiment, the tiotropium is administered once daily.

Another embodiment relates to a method of treating moderate to severe COPD in a subject in need thereof comprising administering via a nebulizer to the subject a daily dose of about 10 mcg of tiotropium or a pharmaceutically acceptable salt thereof (on the weight basis of tiotropium free base). In a preferred embodiment, the tiotropium is administered once daily.

Yet another embodiment relates to a method of treating moderate to severe COPD in a subject in need thereof comprising administering via a nebulizer to the subject a daily dose of about 20 mcg of tiotropium or a pharmaceutically acceptable salt thereof (on the weight basis of tiotropium free base). In a preferred embodiment, the tiotropium is administered once daily.

One more embodiment relates to a method of treating moderate to severe COPD in a subject in need thereof comprising administering via a nebulizer to the subject a daily dose of about 40 mcg of tiotropium or a pharmaceutically acceptable salt thereof (on the weight basis of tiotropium free base). In a preferred embodiment, the tiotropium is administered once daily.

Yet another embodiment is a method of delivering a therapeutically effective amount of tiotropium or a pharmaceutically acceptable salt thereof to a subject in need thereof while minimizing adverse side effects comprising administering via a nebulizer a therapeutically effective amount of tiotropium or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective doses are safe and well tolerated.

One embodiment is a nebulization composition comprising 10 mcg to 80 mcg tiotropium or a pharmaceutically acceptable thereof for the treatment of moderate to severe chronic obstructive pulmonary disease (COPD) in a subject in need thereof, wherein the nebulization composition is administered once daily.

Another embodiment is a nebulization composition comprising 10 mcg tiotropium or a pharmaceutically acceptable thereof for the treatment of moderate to severe chronic obstructive pulmonary disease (COPD) in a subject in need thereof, wherein the nebulization composition is administered once daily.

One more embodiment is a nebulization composition comprising 20 mcg tiotropium or a pharmaceutically acceptable thereof for the treatment of moderate to severe chronic obstructive pulmonary disease (COPD) in a subject in need thereof, wherein the nebulization composition is administered once daily. Yet another embodiment is a nebulization composition comprising 40 mcg tiotropium or a pharmaceutically acceptable thereof for the treatment of moderate to severe chronic obstructive pulmonary disease (COPD) in a subject in need thereof, wherein the nebulization composition is administered once daily.

In a preferred embodiment, the tiotropium is present as tiotropium bromide, such as anhydrous tiotropium bromide or tiotropium bromide monohydrate.

In an embodiment, the nebulization composition, upon administration of a dose from about 10 mcg to 40 mcg of tiotropium in a subject, results in (a) a Cmax SS of about 1 pg/ml to about 25 pg/ml, (b) a AUC SS of about 15h*pg/ml to about 150h*pg/ml, or (c) any combination of any of the foregoing.

In another embodiment, the nebulization composition, upon administration of a dose from about 20 mcg of tiotropium in a subject, results in (a) a Cmax SS of about 1 pg/ml to about 15 pg/ml, (b) a AUC SS of about 15h*pg/ml to about 35h*pg/ml, or (c) any combination of any of the foregoing.

A preferred embodiment is a method of treating moderate to severe COPD in a subject in need thereof who is 40 to 75 years of age comprising administering to the subject via a nebulizer once daily about 10 mcg, about 20 mcg, or about 40 mcg of tiotropium bromide (such as anhydrous tiotropium bromide or tiotropium bromide monohydrate). The subjects have a FEV1/FVC ratio less than 70%, and a FEV1 greater than 30% of the predicted normal values.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method of treating moderate to severe chronic obstructive disease by administering a nebulization composition of tiotropium once a day to a subject in need thereof.

A. Definition of terms

As used herein, the term "about" is used synonymously with the term "approximately." Illustratively, the use of the term "about" with regard to a certain therapeutically effective pharmaceutical dose indicates that values slightly outside the cited values, e.g., plus or minus 0.1% to 10%, which are also effective and safe.

As used herein, the terms "comprising", "including", "such as", and "for example" (or "e.g.") are used in their open, non-limiting sense.

As used herein "mcg" means micrograms, and is synonymous with "pg" or "ug". One microgram (mcg) is 0.001 mg, or 0.000001 g. "Bioavailability" as used herein, refers to the amount of unchanged drug that reaches systemic circulation.

"Subject" refers to an animal (especially mammal) or human being treated.

"Nebulizer," as used herein, refers to a device that turns medications, compositions, formulations, suspensions, and mixtures, etc. into a fine mist for delivery to the lungs. Nebulizers is also referred to as atomizers.

The term "treating" and its grammatical variants (e.g. "to treat," "treating," and "treatment") refer to administration of tiotropium to a patient with the purpose of ameliorating or reducing the incidence of one or more symptoms of a condition or disease state in the patient. Such symptoms may be chronic or acute; and such amelioration may be partial or complete.

B. Methods of treatment

The present invention relates to a method of treating moderate to severe chronic obstructive pulmonary disease by administering a nebulization composition of tiotropium or a pharmaceutically acceptable thereof.

The severity of COPD can be assessed using the GOLD (Global Initiative on Obstructive Lung Disease) classification system. The GOLD classification system bases the stage of COPD using, among other things, spirometry, a test that checks the amount (volume) of air and speed (flow) that the patient can exhale. Forced expiratory volume (FEV-1) shows how much air a patient can exhale from his or her lungs in one second. FEV1 is often reported as a percentage of the predicted normal value.

Stage 1 - mild: FEV1/FVC less than 70% and FEV1 of 80% or above predicted.

Stage 2 - moderate: FEV1/FVC less than 70% and FEV1 of 50-79% predicted.

Stage 3 - severe: FEV1/FVC less than 70% and FEV1 of 30-49% predicted.

Stage 4 - very severe: FEV1/FVC less than 70% and FEV1 of below 30% predicted (or FEV1 less than 50% but with chronic respiratory failure).

The present invention provides a method of treating moderate to severe COPD by administering via a nebulizer a nebulization composition of tiotropium.

C. Methods of administration

Relevant terms include:

“FEV1”: Forced Expiratory Volume is the volume of air forcibly exhaled in one second as measured by a spirometer. “Change in FEV1”: Change in FEV1 is calculated as the difference between the FEV1 value measured after dosing and the FEV1 measured immediately prior to dosing. Change in FEV1 is also measured in reference to a placebo. These values may be expressed in absolute terms or in terms of percent change from baseline or placebo.

“FVC”: Forced Vital Capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath.

“FEV1/FVC”: The quotient of FEV1 and FVC represents the proportion of a subject’s vital capacity which he or she is able to expire in the first second of forced expiration.

“Cmax”: peak concentration during a dosing interval.

“CmaxSS”: peak concentration during a dosing interval at steady-state.

“CminSS”: minimum of trough concentration during a dosing interval at steady-state. “CavSS”: average concentration during a dosing interval at steady state.

“tmax”: time of peak drug concentration during a dosing interval.

“AUC”: area under the concentration-time curve.

“AUCO-tau”: area under the concentration-time profile over a dosing interval. “AUCO-tauSS”: area under the concentration-time profile over a dosing interval at steady state. “Aetau”: cumulative amount of unchanged drug excreted into the urine over a dosing interval. “Fe”: fraction of drug excreted into the urine.

“Rac”: Accumulation ratio.

The present invention provides a method of treating moderate to severe chronic obstructive pulmonary disease (COPD) in a subject in need thereof by administering to the subject a nebulization composition of tiotropium or a pharmaceutically acceptable thereof. A therapeutically effective amount of tiotropium or a pharmaceutically acceptable salt thereof to treat the moderate to severe COPD is administered.

The nebulization composition is administered once a day or twice a day to the subject. Preferably, the nebulization composition is administered once a day to the subject.

The subject is 12 to 95 years of age, preferably the subject is 40 to 75 years of age. The subject has a FEV1/FVC ratio less than 70%.

The subject has a FEV1 of greater than 30% of the predicted normal values.

The present invention relates to a method of treating moderate to severe COPD in a subject in need thereof comprising administering via a nebulizer to the subject a daily dose of from about 10 to about 80 mcg of tiotropium or a pharmaceutically acceptable salt thereof (on the weight basis of tiotropium free base). The tiotropium is administered in the form of the nebulization compositions described in US 2016/0339003. The tiotropium is administered once daily or in divided doses twice daily. Preferably, the tiotropium is administered once daily.

The present invention also relates to a method of treating moderate to severe COPD in a subject in need thereof comprising administering via a nebulizer to the subject a daily dose of about 10 mcg of tiotropium or a pharmaceutically acceptable salt thereof (on the weight basis of tiotropium free base). Preferably, the tiotropium is administered once daily.

The present invention relates to a method of treating moderate to severe COPD in a subject in need thereof comprising administering via a nebulizer to the subject a daily dose of about 20 mcg of tiotropium or a pharmaceutically acceptable salt thereof (on the weight basis of tiotropium free base). Preferably, the tiotropium is administered once daily.

The present invention relates to a method of treating moderate to severe COPD in a subject in need thereof comprising administering via a nebulizer to the subject a daily dose of about 40 mcg of tiotropium or a pharmaceutically acceptable salt thereof (on the weight basis of tiotropium free base). Preferably, the tiotropium is administered once daily

The present invention encompasses a method of delivering a therapeutically effective amount of tiotropium or a pharmaceutically acceptable salt thereof to a subject in need thereof while minimizing adverse side effects comprising administering via a nebulizer a therapeutically effective amount of tiotropium or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective doses are safe and well tolerated.

Preferably, the tiotropium is present as tiotropium bromide, such as anhydrous tiotropium bromide or tiotropium bromide monohydrate.

The methods of the present invention comprise administration of the nebulization composition over a period of 12 weeks.

The therapeutically effective doses of tiotropium as administered by the method of the present invention are safe and well tolerated.

The present invention relates to a method of treating moderate to severe COPD in a subject in need thereof who is 40 to 75 years of age comprising administering to the subject via a nebulizer once daily about 10 mcg, about 20 mcg, or about 40 mcg of tiotropium bromide (such as anhydrous tiotropium bromide or tiotropium bromide monohydrate). The subjects have a FEV1/FVC ratio less than 70%, and a FEV1 greater than 30% of the predicted normal values.

The present invention relates to a method of treating moderate to severe COPD in a subject in need thereof who is 40 to 75years of age comprising administering to the subject via a nebulizer once daily a nebulization composition comprising about 10 mcg, about 20 mcg, or about 40 mcg of tiotropium bromide (such as anhydrous tiotropium bromide or tiotropium bromide monohydrate). The subjects have a FEV1/FVC ratio less than 70%, and a FEV1 greater than 30 of the predicted normal values.

The present invention relates to a nebulization composition, which upon administration of a dose from about 10 mcg to 40 mcg of tiotropium in a subject, results in (a) a Cmax SS of about 1 pg/ml to about 25 pg/ml, (b) a AUC SS of about 15h*pg/ml to about 150h*pg/ml, or (c) any combination of any of the foregoing.

The present invention also relates to a nebulization composition, which upon administration of a dose of 20 mcg of tiotropium in a subject, results in (a) a Cmax SS of about 1 pg/ml to about 15 pg/ml, (b) a AUC SS of about 15h*pg/ml to about 35h*pg/ml, or (c) any combination of any of the foregoing

The present invention further relates to a nebulization composition, which upon administration of a dose of 20 mcg of tiotropium in a subject, results in (a) a Cmax SS of about 1 pg/ml to about 10 pg/ml, (b) a AUC SS of about 15h*pg/ml to about 25h*pg/ml, or (c) any combination of any of the foregoing.

D. Tiotropium

Tiotropium is an anticholinergic agent with specificity for muscarinic receptors. It is chemically described as (la, 213, 413, 5a, 713)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl- 3-oxa-9- zoniatricyclo[3.3.1.02,4] nonane. It is a synthetic, non-chiral, quaternary ammonium compound. Tiotropium has a molecular formula of C19H22NO4S2 and the following structure:

As used herein, the term “tiotropium”, unless otherwise indicated, includes, but is not limited to, tiotropium in any physical form such as the amorphous form and crystalline forms (e.g., anhydrous, hydrate, and other solvate forms). 2-hydroxy-2,2-dithiophen-2-ylacetic acid is an impurity of tiotropium, referred to herein as Impurity A. Salts of tiotropium include, but are not limited to, acid addition salts and base salts thereof. Suitable salts of tiotropium include, but are not limited to, halide salts such as bromide, chloride and iodide salts. These and other salts are described, for example, in U.S. Patent No. RE 39,820, which is hereby incorporated by reference in its entirety. The preparation of tiotropium bromide monohydrate is described in U.S. Patent No. 6,777,423, which is incorporated herein by reference in its entirety. One preferred salt of tiotropium for the nebulization composition is tiotropium bromide, such as in the anhydrous form, amorphous form, or the form of its monohydrate salt (tiotropium bromide monohydrate), anhydrous salt, amorphous salt or as an anhydrous amorphous salt.

E. Nebulization compositions

The nebulization compositions may, for example, have any of the formulations described in International Patent Application No. PCT/IB2016/000783, filed May 17, 2016 (published as WO 2016/185282) or U.S. patent application serial number 15/157,143, filed May 17, 2016 (published as US 2016/0339003), both of which are hereby incorporated for reference.

The present invention relates to a nebulization composition comprising 10 mcg to 80 mcg tiotropium or a pharmaceutically acceptable thereof for the treatment of moderate to severe chronic obstructive pulmonary disease (COPD) in a subject in need thereof, wherein the nebulization composition is administered once daily. The invention further relates to a nebulization composition comprising 10 mcg tiotropium or a pharmaceutically acceptable thereof for the treatment of moderate to severe chronic obstructive pulmonary disease (COPD) in a subject in need thereof, wherein the nebulization composition is administered once daily. It is also an aspect of the invention a nebulization composition comprising 20 mcg tiotropium or a pharmaceutically acceptable thereof for the treatment of moderate to severe chronic obstructive pulmonary disease (COPD) in a subject in need thereof, wherein the nebulization composition is administered once daily. The present invention also relates to a nebulization composition comprising 40 mcg tiotropium or a pharmaceutically acceptable thereof for the treatment of moderate to severe chronic obstructive pulmonary disease (COPD) in a subject in need thereof, wherein the nebulization composition is administered once daily.

The nebulization compositions of tiotropium comprise tiotropium, water and wherein the composition is substantially free of complexing agents such as edetate disodium and preservative such as benzalkonium chloride. The term “substantially free” as used herein means less than about 0.1 % by weight of the complexing agent or the preservative. The nebulization composition optionally contains other excipients such as buffering agents, pH adjusting agents and other such excipients commonly known in the art.

The nebulization composition of tiotropium comprises:

(i) tiotropium or its pharmaceutically acceptable salts thereof (ii) water wherein said composition is free of preservative and complexing agent.

The nebulization composition contains tiotropium in amounts of about 0.0001% to about 0.030% by weight tiotropium or its salt (such as tiotropium bromide).

The nebulization compositions of tiotropium have a pH of from about 2.0 to about 6.0 preferably from about 2.7 to about 3.2, further preferably less than 3. The pH is adjusted by the addition of one or more pharmaceutically acceptable acids. Examples of suitable pharmaceutically acceptable acids include inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid, and combinations thereof. Examples of other suitable pharmacologically acceptable acids include organic acids, such as ascorbic acid, citric acid, malic acid, maleic acid, tartaric acid, succinic acid, fumaric acid, acetic acid, formic acid, and/or propionic acid.

Optionally suitable osmotic adjusting agents that used include, but are not limited to, sodium chloride, potassium chloride, zinc chloride, calcium chloride and mixtures thereof. Other osmotic adjusting agents also include, but are not limited to, mannitol, glycerol, dextrose and mixtures thereof.

The present invention further relates to a nebulization composition of tiotropium comprises:

(i) tiotropium or its pharmaceutically acceptable salts thereof

(ii) osmotic adjusting agent

(iii) water wherein said composition is free of preservative and complexing agent.

The present invention further relates to a nebulization composition of tiotropium comprises:

(i) tiotropium or its pharmaceutically acceptable salts thereof

(ii) osmotic adjusting agent

(iii) water wherein said composition is free of preservative.

The present invention further more relates to a nebulization composition of tiotropium comprises:

(i) tiotropium or its pharmaceutically acceptable salts thereof

(ii) osmotic adjusting agent

(iii) complexing agent

(iv) water wherein said composition is free of preservative.

The present invention further more relates to a nebulization composition of tiotropium comprises:

(i) tiotropium or its pharmaceutically acceptable salts thereof

(ii) osmotic adjusting agent

(iii) complexing agent

(iv) pH adjusting agent

(v) water wherein said composition is free of preservative.

The nebulization composition comprises:

(a) about 0.0005% to about 0.008% w/w tiotropium or a pharmaceutically acceptable salt thereof,

(b) about 0 % to about 0.1% edetate disodium;

(c) about 0 % to about 0.9% sodium chloride; and

(d) water, based upon 100% total weight of the nebulization composition, wherein the pH of the pharmaceutical composition is about 2 to about 4.

Example a: Nebulization composition with 0,01% Edetate disodium

Example b: Nebulization composition with 0,02% Edetate disodium

The nebulization compositions can be administered with any suitable nebulizer device. Suitable nebulizer devices for use with the nebulization composition include jet nebulizers, ultrasonic nebulizers, mesh nebulizers and breath actuated nebulizers, preferably, mesh nebulizers, more preferably vibrating mesh nebulizer. The nebulization composition administered by a vibrating mesh nebulizer may provide an aerosol having a Geometric Standard Deviation of emitted droplet size distribution of the nebulization composition.

F. Examples

The examples provided below represent some embodiments of method of administering nebulization compositions of tiotropium once a day for treatment of moderate to severe COPD. Other aspects, which are not specifically described in the following examples are within the scope of the invention and will be apparent to those skilled in the art considering the disclosure herein.

The tiotropium nebulization compositions and its methods of administration as disclosed herein will be evaluated for Phase 3 clinical study, details of which are as below:

Example 1 :

Pharmacodynamic and Pharmacokinetic Dose Ranging Study of Tiotropium Bromide Administered Via Inhalation Solution in Patients with moderate to severe Chronic Obstructive Pulmonary Disease (COPD)

Key objectives:

Primary Objective(s):

The primary objective of the study is to evaluate the efficacy of TIOTROPIUM BROMIDE NEBULIZATION SOLUTION (20 pg) delivered by nebulizer once daily in comparison with Spiriva® Respimat® in subjects with moderate to severe COPD.

Secondary Objective(s):

The secondary objectives of the study are: To evaluate the safety of tiotropium bromide nebulization solution (20 pg) delivered by nebulizer once daily in subjects with moderate to severe COPD in comparison with Spiriva® Respimat®

To compare Tiotropium bromide nebulization solution (20 pg) delivered by nebulizer once daily with Spiriva® Respimat® in subjects with moderate to severe COPD, with respect to: o Change from baseline in trough forced vital capacity (FVC) o Average weekly use of rescue medication o Effect on health status as measured by SGRQ

Patient Population:

The study population will consist of male and female subjects aged between >40 to <75 years with clinical diagnosis of moderate to severe COPD (as defined by the GOLD Guidelines, 2020) and post-bronchodilator FEW FVC <0.70 and post bronchodilator FEV1 >30% predicted and <80% predicted, at screening visit and chronic current or previous cigarette/beedi smokers with a history of cigarette/beedi smoking of at least 10 pack-years.

Planned Duration of Study Participation:

The anticipated maximum total study duration for each subject is approximately 17 weeks. This will consist of a screening period of up to 7 days, a run-in period of 14 days, an open label treatment period of 12 weeks, and a 2-week safety follow-up period.

Key subject selection criteria:

Each subject must meet all of the following criteria to be randomized in the study:

1. Provided written informed consent.

2. Aged >40 years to <75 years at the time of screening.

3. Male or female and must have a primary diagnosis of moderate to severe COPD, defined as post-bronchodilator FEV1/FVC ratio of <0.70 and 30% > FEV1 <80% of predicted normal value, at screening.

4. Willing and able to comply with all aspects of the protocol and demonstrate ability to use the inhalation device appropriately.

5. Must agree to the following requirements during the study: a. If male with a partner of childbearing potential, he must be willing to use condoms in combination with a second effective method of contraception, i.e., spermicide. Each man will be considered as potent unless surgically sterilized (with appropriate post vasectomy documentation of the absence of sperm in the ejaculate). b. Male subjects should agree not to donate sperm for 180 days following administration of the study drug. c. Females subjects of childbearing potential defined as all females physiologically capable of becoming pregnant, are eligible if they are using highly effective methods of contraception during dosing of study treatment; must have a negative serum pregnancy test result within 7 days prior to first dosing and a negative serum pregnancy test at screening. She must be willing to use a highly effective form of contraception for the duration of the study and for at least 3 months after the last dose of study medication. Highly effective contraception methods include:

- Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception, or other form of hormonal contraception that have comparable efficacy (failure rate <1%)

- In case of use of oral contraception, woman should have been stable on the same pill for a minimum of 3 months before taking study treatment

- Intrauterine device (IUD)

- Intrauterine horm one-releasing system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate <1%) for example hormone vaginal ring or transdermal hormone contraception d. Female subjects are eligible to participate if they are of non-childbearing potential defined as premenopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) >40 MIU/mL and estradiol >141 pmol/L is confirmatory (as a precaution a pregnancy test is conducted prior to dosing, a positive test leads to exclusion). Female subjects who have undergone female sterilization (e.g., surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking investigational drug are eligible. In case of oophorectomy alone, female subjects are eligible only when the reproductive status of the woman has been confirmed by follow up hormone level assessment)

6. Current or ex-smoker (cigarette/bidi) with a >10-pack-year smoking history (number of pack years = (number of cigarettes/bidis per day/20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years).

Study Drug, Dose, and Mode of Administration Investigational Product:

Name of Investigational Product: GSP304 (tiotropium bromide) Nebulization Solution

Dosage Form: Inhalation Solution

Dose: 20 pg once daily

Dosage Frequency: Once a day

Mode of Administration: Oral inhalation solution along with nebulizer device

Storage Conditions: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F), Avoid freezing.

Comparator:

Name: Spiriva Respimat

Dosage Form: Inhalation spray

Dosage: Two inhalation once daily (5 pg)

Dosage Frequency: Once a day

Mode of Administration: Oral inhalation using the Respimat device

Storage Conditions: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F), Avoid freezing.

Key evaluation criteria (Clinical endpoints)

Primary Efficacy Endpoint(s):

Change from baseline in trough FEV1 at Week 12.

Secondary Efficacy Endpoint(s): a) Proportion of St. George’s Respiratory Questionnaire (SGRQ) responders at Week 4, and Week 12 (>4 points improvement) b) Change from baseline in SGRQ score at Week 4, and Week 12 c) Change from baseline (average of number of puffs used within a week prior to randomization) in weekly average number of puffs of rescue medication used at Week 12 d) Change from baseline in trough FVC at Week 12

Safety Endpoint(s):

Number and percentage of treatment emergent adverse events (TEAEs), vital signs, laboratory parameters, 12-lead electrocardiogram (ECG), physical examination. A nebulization composition of the present invention comprising tiotropium bromide administered via nebulizer to the subject selected based on the key subject selection criteria. The parameters like Cmax SS and AUC SS are processed further. The nebulization composition comprising of a dose from about 10 mcg to 40 mcg of tiotropium upon administration to a patient suffering from moderate to server chronic obstructive pulmonary disease (COPD), provides (a) a Cmax SS of about 1 pg/ml to about 25 pg/ml, (b) a AUC SS of about 15h*pg/ml to about 150h*pg/ml, or (c) any combination of any of the foregoing.

The nebulization composition comprising a dose of 20 mcg of tiotropium in a subject, upon administration to a patient suffering from moderate to server chronic obstructive pulmonary disease (COPD) provides (a) a Cmax SS of about 1 pg/ml to about 15 pg/ml, (b) a AUC SS of about 15h*pg/ml to about 35h*pg/ml, or (c) any combination of any of the foregoing

The nebulization composition comprising a dose of 20 mcg of tiotropium in a subject, upon administration to a patient suffering from moderate to server chronic obstructive pulmonary disease (COPD) provides (a) a Cmax SS of about 1 pg/ml to about 10 pg/ml, (b) a AUC SS of about 15h*pg/ml to about 25h*pg/ml, or (c) any combination of any of the foregoing.

Efficacy Assessments:

Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) (spirometry). FEV1 and FVC assessed on days 1, 15, 29, 57, 85 and 86. FEV1 and FVC recorded, using spirometry, at the following time points relative to the morning dose: 45 min ± 5 min and 15 min ± 5 min pre-morning dose at baseline visit (Visit 1); and 5 min, 15 ± 1 min, 30 ± 2 min, 60 ± 5 min, 90 ± 5 min, and 120 ± 5 min post-morning dose at baseline visit (Visit 1) and at end-of-treatment visit at Week 12 (Visit 5, Day 1). There was no window for the 5 min time point spirometry assessment. FEV1 and FVC were also assessed using spirometry 23hl5min ± 1 hour and 23h45min ± 1 hour after previous day’s dose at Visit 2, Visit 3, Visit 4 and Visit 5-Day 2. 23h45min spirometry was performed 30 ± 5 min after 23hl5min spirometry. Trough FEV1 : It is defined as the mean FEV1 obtained 23 hours 15 min ± 1 hour and 23 hours 45 min ± Ihour post-morning dose of the previous day before the mean is calculated, a time window of 22 to 25 hours post-morning dose applied to these 2 measurements Recordings outside the time window set to missing. Peak FEV1 : It is defined as the maximum FEV1 over the period from 5 min to 2 hours post-morning dose. Baseline FEV1 : It is defined as the average of the pre-dose FEV1 measured at -45 min and -15 min on baseline. Baseline FVC: It is defined as the average of the pre-dose FVC measured at -45 min and -15 min on Day 1.

St. George’s Respiratory Questionnaire (SGRQ), an index to measure and quantify the health status of a subject with chronic airflow limitation (Jones and Forde, 2012).

Weekly average number of puffs of rescue medication use