EA045879B1 - SPRAYED TIOTROPIUM - Google Patents

Description

This application claims the benefit of Indian Provisional Patent Application No. 201621039057, filed November 16, 2016, which is incorporated herein by reference in its entirety.

Technical field

The invention relates to therapeutic methods for administering tiotropium using a nebulizer. The invention also relates to methods of treating inflammatory or obstructive airway diseases by administering a sterile nebulized tiotropium composition using a nebulizer.

State of the art

Respiratory diseases include a range of diseases of the airways. Asthma and chronic obstructive pulmonary disease (COPD) are among the most common and life-threatening conditions.

COPD is a chronic disease that is characterized by loss of elasticity of the airways and air sacs, destruction of the alveolar walls, inflammation of the airways, and high levels of mucus production in the airways. All of these effects lead to blockage of the airways, making it difficult for the patient to breathe. Asthma, on the other hand, is a chronic disease affecting the airways of the lungs, characterized by coughing, wheezing, and shortness of breath.

Currently available treatment options include corticosteroids, beta-agonists, anticholinergics, and expectorants.

Tiotropium is approved in the United States under the brand name Spiriva Respimat® as a propellant-free metered-dose inhalation product. This product is approved with the Respimat device. The device is complex and requires the patient to coordinate breathing with the device.

There is a need for additional therapeutic options for the treatment of inflammatory or obstructive airway diseases and, in particular, for more convenient and better therapeutic options for patients suffering from COPD and asthma.

The essence of the invention

The present invention relates to a method of treating an inflammatory or obstructive airway disease by administering a nebulized composition of tiotropium or a pharmaceutically acceptable salt thereof using a nebulizer.

One embodiment provides a method of delivering to a subject in need thereof a therapeutically effective amount of tiotropium or a pharmaceutically acceptable salt thereof (such as tiotropium bromide) using a nebulizer.

Another embodiment provides a method of treating an inflammatory or obstructive airway disease comprising administering to a subject in need thereof tiotropium or a pharmaceutically acceptable salt thereof (such as tiotropium bromide) using a nebulizer.

A further embodiment provides a kit for treating an inflammatory or obstructive airway disease in a subject, comprising (i) an effective amount of tiotropium or a pharmaceutically acceptable salt thereof (such as tiotropium bromide), (ii) a nebulizer, and (iii) instructions for use in treatment of inflammatory or obstructive airway disease.

Another embodiment relates to a method of delivering to a subject in need thereof a nebulized composition of tiotropium or a pharmaceutically acceptable salt thereof (such as tiotropium bromide) using a nebulizer.

A further embodiment provides a method of treating an inflammatory or obstructive airway disease comprising administering to a subject in need thereof a nebulized composition of tiotropium or a pharmaceutically acceptable salt thereof (such as tiotropium bromide) using a nebulizer.

Another embodiment provides a kit for treating an inflammatory or obstructive airway disease in a subject, comprising (i) a nebulizer composition containing an effective amount of tiotropium or a pharmaceutically acceptable salt thereof (such as tiotropium bromide), (ii) a nebulizer, and ( iii) instructions for use in the treatment of inflammatory or obstructive airway diseases.

In one embodiment, the nebulized composition is a single-dose pharmaceutical inhalation solution containing tiotropium or a pharmaceutically acceptable salt thereof (such as tiotropium bromide). The nebulized composition is preferably sterile.

In one preferred embodiment, the sprayable composition contains little or no preservatives, including, but not limited to, quaternary ammonium preservatives such as a benzalkonium salt (eg, benzalkonium chloride).

Another embodiment is a sterile nebulized pharmaceutical inhalation solution containing tiotropium or a pharmaceutically acceptable salt thereof (eg,

- 1 045879 tiotropium bromide), and the solution contains little or no complexing agent (such as ethylenediaminetetraacetic acid (EDTA) and its salts). For example, the pharmaceutical solution may contain less than about 0.1% by weight of complexing agent (e.g., less than about 0.05%, less than about 0.02%, or less than about 0.008%) based on the total weight of the composition or solution . The pharmaceutical solution may also contain no or substantially no preservatives, including, but not limited to, quaternary ammonium salt preservatives such as benzalkonium salt (eg, benzalkonium chloride).

One embodiment is a sprayable composition containing (i) tiotropium or a pharmaceutically acceptable salt thereof (eg, tiotropium bromide); and (ii) water, wherein the composition contains little or no preservative and/or complexing agent. The sprayable composition is preferably a solution.

Another embodiment is a sterile nebulized pharmaceutical solution for inhalation by nebulization containing tiotropium or a pharmaceutically acceptable salt thereof (e.g., tiotropium bromide), wherein the solution contains little or no (a) EDTA or a salt thereof, (b) a benzalkonium salt such as benzalkonium chloride, or (c) both.

Another embodiment is a pharmaceutical solution suitable for administration by nebulizer, consisting essentially of (a) from about 0.0005% to about 0.008% w/w. tiotropium or a pharmaceutically acceptable salt thereof (such as tiotropium bromide), (b) from about 0% to about 0.008% w/w. disodium EDTA;

(c) from about 0% to about 0.9% w/w. sodium chloride; and (d) water, based on 100% of the total weight of the pharmaceutical solution, the pH of the pharmaceutical solution being from about 2 to about 4 (eg, about 2.7).

In another embodiment, the sprayable composition contains from about 0.002% to about 0.01% wt./wt. tiotropium or any pharmaceutically acceptable salt thereof (such as tiotropium bromide), from about 0% to about 0.01% w/w. EDTA and about 0.9% w/w. sodium chloride, wherein the composition contains no or substantially no preservative, and wherein the composition has a pH in the range of about 2.0 to about 4.0.

The sprayable composition or solution provided herein is preferably sterile. The sprayable composition or solution provided herein may have a long shelf life, that is, it is stable during long-term storage. The sprayable composition may contain more than about 80%, such as more than about 85%, more than about 90%, more than about 95%, or more than about 98% of the original amount of tiotropium or a salt thereof in the composition after storage for 3 or 6 months, or 1. 2 or 3 years at 25°C in a suitable LDPE container, cyclic olefin polymer container, cyclic olefin copolymer container or glass container. Stability can be determined using Arrhenius kinetics.

The nebulizable compositions described herein can be delivered by a jet nebulizer, an ultrasonic nebulizer, a mesh nebulizer, or a breath-actuated nebulizer.

Another embodiment is a method of preparing an inhalation solution containing tiotropium or a pharmaceutically acceptable salt thereof (eg, for use in relieving bronchospasm associated with COPD). In one embodiment, the method includes the steps of:

(a) dissolving tiotropium or its salt in water;

(b) optionally adding one or more pharmaceutically acceptable excipients, eg, a buffer, complexing agent, tonicity regulator, or any combination thereof, to the solution of step (a);

(c) optionally adjusting the pH of the solution (eg, the solution of step (a) or step (b)) with a pharmaceutically acceptable acid (eg, to a pH of 2 to 4);

(d) optionally, filtering the solution (eg, using a 0.2 micron filter); and (e) filling a suitable container with the solution.

In another embodiment, the method includes the steps of:

(a) dissolving tiotropium or its salt in water;

(b) optionally adding to the solution of step (a) one or more pharmaceutically acceptable excipients, for example a buffer, a complexing agent, a tonicity regulator, or any combination thereof;

(c) optionally adjusting the pH of the solution (eg, the solution of step (a) or step (b)) with a pharmaceutically acceptable acid (eg, to a pH of 2 to 4);

(d) filtering the solution (eg using a 0.2 micron filter); and (e) filling a suitable container with the solution.

- 2 045879

Other objects, features and advantages of the present invention will be apparent to those skilled in the art in view of the following detailed description of the invention and the accompanying drawings.

Detailed Description of the Invention

Methods of administration

One embodiment of the present invention is a method of administering tiotropium or a pharmaceutically acceptable salt thereof to a subject in need thereof by administering tiotropium or a pharmaceutically acceptable salt thereof to the subject using a nebulizer. The method may include administering a sprayable composition (eg, a sprayable solution) described herein using a nebulizer.

Preferably, the method includes administering a therapeutically effective amount of tiotropium or a pharmaceutically acceptable salt thereof.

Treatment options

Another embodiment is a method of treating an inflammatory or obstructive airway disease (such as asthma and COPD) by administering tiotropium or a pharmaceutically acceptable salt thereof to a subject in need thereof via a nebulizer. The method may include administering a sprayable composition (eg, a sprayable solution) described herein using a nebulizer.

Kit

Another embodiment is a kit for treating an inflammatory or obstructive airway disease in a subject, comprising (i) a nebulized composition containing an effective amount of tiotropium or a pharmaceutically acceptable salt thereof, (ii) a nebulizer, and (iii) instructions for use for the treatment inflammatory or obstructive airway diseases.

Tiotropium

A preferred tiotropium salt is tiotropium bromide (eg, in its monohydrate form). Tiotropium bromide has a molecular weight of 472.416 g/mol and an empirical formula of C ₁₉ H ₂₂ BrNO ₄ S ₂ . Tiotropium bromide ((1а,2в,4в,7в)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3oxa-9-azoniatricyclo[3.3.1.02,4]nonane bromide) is sparingly soluble in water and soluble in methanol. The established chemical structure of tiotropium bromide monohydrate is:

Tiotropium salts include, but are not limited to, its acid addition salts and base salts, and any mixture thereof. Suitable tiotropium salts include, but are not limited to, halides such as bromide, chloride and iodide. These and other salts are described, for example, in US Pat. No. RE 39820, which is incorporated herein by reference in its entirety.

The various forms of tiotropium include crystalline forms, amorphous form, monohydrate form and amorphous form. The preparation of tiotropium bromide monohydrate is described in US Pat. No. 6,777,423, which is incorporated herein by reference in its entirety. Tiotropium and its salts may be administered to provide a bronchodilation effect and relieve symptoms associated with COPD. In one preferred embodiment, the sprayable composition or solution contains tiotropium in the form of amorphous tiotropium bromide (such as amorphous anhydrous tiotropium bromide).

Sprayable composition

Tiotropium may be provided in a variety of pharmaceutically acceptable carriers, including, but not limited to, an aqueous or aqueous-alcoholic solution or any other aqueous solution containing a pharmaceutically acceptable amount of an osmotic agent.

The spray composition (such as a spray solution) may include from about 0.001 mg to about 0.3 mg of tiotropium or a salt thereof (eg, tiotropium bromide), such as from about 0.010 mg to about 0.280 mg; from about 0.020 mg to about 0.260 mg; from about 0.025 mg to about 0.240 mg; from about 0.005 mg to about 0.1 mg; from about 0.005 mg to about 0.05 mg; from about 0.01 mg to about 0.04 mg; from about 0.02 mg to about 0.07 mg; from about 0.04 mg to about 0.08 mg; from about 0.04 mg to about 0.10 mg; from about 0.05 mg to about 0.15 mg; from about 0.10 mg to about 0.19 mg; from about 0.15 mg to about 0.20 mg; from about 0.20 mg to about 0.25 mg; or about 0.26 mg to about 0.30 mg tiotropium or a salt thereof (e.g., tiotro bromide

- 3 045879 piya) per unit dose of a pharmaceutical composition or solution.

In another embodiment of the present invention, a therapeutically effective amount of tiotropium may include from about 0.0001% to about 0.030% by weight of tiotropium bromide, including the following intermediate tiotropium bromide ranges: from about 0.0002% by weight to about 0.02% by weight of tiotropium. ; from about 0.0003 to about 0.01 wt.%; from about 0.0005 to about 0.008 wt.%; from about 0.0002 wt.% to about 0.001 wt.%; from about 0.001 wt.% to about 0.005 wt.%; from about 0.006 wt.% to about 0.010 wt.%; from about 0.011 wt.% to about 0.015 wt.%; from about 0.016 wt.% to about 0.020 wt.%; from about 0.021 wt.% to about 0.025 wt.%; or from about 0.026 wt.% to about 0.030 wt.%.

In another embodiment, the amount of tiotropium or a salt thereof (e.g., tiotropium bromide) in the nebulized tiotropium composition is from about 1 μg to about 100 μg, or from about 10 μg to about 80 μg, such as about 5 μg, about 10 μg, about 15 μg , about 20 μg, about 25 μg, about 30 μg, about 35 μg, about 40 μg, about 45 μg, about 50 μg, about 55 μg, about 60 μg, about 65 μg, about 70 μg, about 75 μg, about 80 mcg, about 85 mcg, about 90 mcg, about 95 mcg, or about 100 mcg (based on the equivalent amount of tiotropium free base).

The sprayable composition may contain tiotropium bromide and one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to, pH adjusting agents, isotonicity agents, chelating agents, surfactants, antioxidants and pharmaceutically acceptable carriers.

The sprayable composition may be substantially free or free of a preservative (such as benzalkonium and its salts), and preferably substantially free of benzalkonium chloride. The term substantially free of a relatively preservative (eg, substantially free of benzalkonium chloride) means that the preservative is not present in an amount sufficient to materially act as a preservative for the sprayable composition. The composition is substantially free of benzalkonium chloride or substantially free of benzalkonium chloride when the amount of benzalkonium chloride is not an amount sufficient to materially act as a preservative for the sprayable composition. In one embodiment, benzalkonium chloride may be present at a concentration of less than 0.008% w/w. based on the total weight of the composition. In another embodiment, one or more preservatives may be present in a total concentration of less than 0.008% w/w. based on the total weight of the composition.

Typically, sprayable compositions contain a preservative such as benzalkonium chloride. A common problem with benzalkonium chloride is that it can cause paradoxical bronchoconstriction if the solution is administered repeatedly at short intervals and repeated exposure to benzalkonium chloride can lead to occupational asthma. Another concern is that when patients inhale benzalkonium chloride, it can cause dose-dependent bronchial constriction. The nebulizable compositions of the present invention can be provided without benzalkonium chloride, making them suitable for repeated administration over a short period of time. In addition, administering to a patient a nebulized composition that does not contain benzalkonium chloride reduces the associated likelihood of adverse effects associated with the use of benzalkonium chloride alone or in combination with other excipients and/or active agents. It also negates the toxicity and other side effects associated with benzalkonium chloride.

The sprayable composition may contain little or no complexing agents such as ethylenediaminetetraacetic acid (EDTA) and their salts. The absence or reduction of the concentration of EDTA supplement and its salts helps reduce the paradoxical effect associated with cough.

Suitable complexing agents include, but are not limited to, EDTA and its salts, such as disodium edetate. The sprayable tiotropium composition may contain about 0.001% w/w. complexing agent, about 0.01% wt./wt. complexing agent or about 0.02% complexing agent. The nebulized tiotropium composition may contain about 0.01 mg/ml complexing agent, about 0.1 mg/ml complexing agent, or about 0.2 mg/ml complexing agent.

The sprayable tiotropium composition may contain about 0.001% w/w. disodium edetate, about 0.01% w/w. edetate disodium or about 0.02% edetate disodium. The nebulized tiotropium composition may contain about 0.01 mg/ml disodium edetate, about 0.1 mg/ml disodium edetate, or about 0.2 mg/ml disodium edetate.

The sprayable composition may contain:

(i) tiotropium or pharmaceutically acceptable salts thereof; and (ii) water, wherein the composition contains little or no preservative, complexing agent, or both. In one preferred embodiment, the composition contains little or no preservative and complexing agent.

- 4 045879

The sprayable composition may have a pH of from about 2.0 to about 6.0, such as from about 2.0 to about 4.0. The preferred pH range for tiotropium bromide compositions is from about 2.0 to about 4.5, such as from about 2.5 to 3.5 or from about 2.7 to about 3.2. Low pH levels, for example below about 3.2, are preferred for long-term stability of the tiotropium salts in the spray composition. In another embodiment, the sprayable composition has a pH of from about 2.2 to about 2.9. The pH value can be adjusted by adding one or more pharmaceutically acceptable acids. Examples of suitable pharmaceutically acceptable acids include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid, and any combination of any of the foregoing. Examples of other suitable pharmacologically acceptable acids include, but are not limited to, organic acids such as ascorbic acid, citric acid, malic acid, maleic acid, tartaric acid, succinic acid, fumaric acid, acetic acid, formic acid, propionic acid, and any combination any of the above. In one embodiment, the pH is adjusted with 1N. hydrochloric acid or 1 N. sulfuric acid. In another embodiment, the pH is adjusted using one or more organic acids selected from ascorbic acid, fumaric acid and citric acid. The preferred organic acid is citric acid. If desired, a mixture of the above acids can also be used, especially in the case of acids which have other properties in addition to their acidifying properties, for example those which act as flavoring agents or antioxidants, such as for example citric acid or ascorbic acid. The spray composition may contain sodium citrate at a concentration of about 0.1 to about 1.0% (w/w) and citric acid at a concentration of about 0.1 to 1.0% (w/w) for control. pH.

In some embodiments, the pH of the sprayed tiotropium composition may be from about 2.0 to about 6.0, preferably from about 2.0 to about 4.5, more preferably from about 2.5 to about 3.5, such as from about 2 .5 to about 3.0. The sprayable tiotropium composition may have a pH of about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3 , about 3.4 or about 3.5. In one preferred embodiment, the pH is about 2.7.

The sprayable composition may optionally contain a buffer. Common and biological buffer solutions in the pH range from about 2.0 to about 8.0 include, but are not limited to, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, McIlwain , phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Theorella-Stenhagen), veronal acetate, MES, BIS-TRIS, ADA, ACES, PIPES, MOpSo, BIS-TRIS PROPANE, BES, MOPS, TES, HEPES, DIPSO, MOBS, TAPSO, TRIZMA, HEPPSO, POPSO, TEA, EPPS, TRICINE, GLY-GLY, BICINE, HEPBS, TAPS and AMPD.

The osmolality of the nebulized composition may be about 200-500 mOsm/kg. The sprayable composition may contain a tonicity adjusting agent such as an ionic salt (eg, from about 0.0001% w/w to about 264% w/w ionic salt). Suitable tonicity agents include, but are not limited to, ammonium carbonate, ammonium chloride, ammonium lactate, ammonium nitrate, ammonium phosphate, ammonium sulfate, ascorbic acid, sodium bismuth tartrate, boric acid, calcium chloride, calcium disodium edetate, calcium gluconate , calcium lactate, citric acid, dextrose, diethanolamine, dimethyl sulfoxide, edetate disodium, edetate trisodium monohydrate, sodium fluorescein, fructose, galactose, glycerin, lactic acid, lactose, magnesium chloride, magnesium sulfate, mannitol, polyethylene glycol, potassium acetate, potassium chlorate, potassium chloride, potassium iodide, potassium nitrate, potassium phosphate, potassium sulfate, propylene glycol, silver nitrate, sodium acetate, sodium bicarbonate, sodium biphosphate, sodium bisulfite, sodium borate, sodium bromide, sodium cacodylate, sodium carbonate, sodium chloride, sodium citrate, sodium iodide, sodium lactate, sodium metabisulfite, sodium nitrate, sodium nitrite, sodium phosphate, sodium propionate, sodium succinate, sodium sulfate, sodium sulfite, sodium tartrate, sodium thiosulfate, sorbitol, sucrose, tartaric acid, triethanolamine, urea, urethane, uridine , zinc sulfate and any combination of any of the above.

The sprayable composition may contain an osmotic control agent. Suitable osmoticity adjusting agents include, but are not limited to, sodium chloride, potassium chloride, zinc chloride, calcium chloride, and any combination of any of the above. Other osmotic control agents include, but are not limited to, mannitol, glycerol, dextrose, and any combination of any of the above.

The pharmaceutically acceptable carrier in the spray composition contains water and optionally a co-solvent. Any cosolvent that is suitable for inhalation and is capable of dissolving or solubilizing tiotropium (or a salt thereof) in a mixture of cosolvent and water can be used. Examples of suitable cosolvents include, for example, alcohols, ethers, hydrocarbons and perfluorocarbons. Preferably, the cosolvent is a short chain polar alcohol. More preferably, the co-solvent is an aliphatic alcohol having from one to six carbon atoms, such as ethanol or isopropanol. The preferred co-solvent is ethanol. Non-limiting examples of suitable hydrocarbons include n-butane, isobutane

- 5 045879 tan, pentane, neopentane and isopentanes. Non-limiting examples of suitable ethers include dimethyl ether and diethyl ether. Non-limiting examples of suitable perfluorocarbons include perfluoropropane, perfluorobutane, perfluorocyclobutane and perfluoropentane.

Suitable surfactants include, but are not limited to, _C5-20 fatty alcohols, _C5-20 fatty acids, _C5-20 fatty acid esters, lecithin, glycerides, propylene glycol esters, polyoxyethylenes, polysorbates , sorbitan esters, carbohydrates and any combination of any of the above. Preferred are _C5-20 fatty acids, propylene glycol diesters of _C5-20 fatty acids, _C5-20 fatty acid triglycerides and _C5-20 fatty acid sorbitans. In one preferred embodiment, the surfactant is selected from oleic acid, sorbitan mono-, di- or trioleates, and any combination of any of the above.

Suitable antioxidants include, but are not limited to, ascorbic acid, vitamin A, vitamin E, tocopherols, and any combination of any of the above.

The volume of the composition may be from about 0.1 ml to about 5 ml, for example from about 1 ml to about 3 ml or from about 1.5 ml to about 2.5 ml. In another embodiment, the volume of the composition is from about 0.05 ml to about 1.0 ml; such as from about 0.1 ml to about 0.9 ml; from about 0.1 ml to about 0.8 ml; from about 0.1 ml to about 0.7 ml; from about 0.1 ml to about 0.6 ml; from about 0.1 ml to about 0.5 ml; from about 0.1 ml to about 0.4 ml; from about 0.1 ml to about 0.3 ml; or from about 0.1 ml to about 0.2 ml.

A sprayable composition suitable for administration via a nebulizer consists essentially of (a) from about 0.0005% to about 0.008% w/w. tiotropium or a pharmaceutically acceptable salt thereof (such as tiotropium bromide), (b) from about 0% to about 0.008% w/w. disodium EDTA;

(c) from about 0% to about 0.9% w/w. sodium chloride; and (d) water, based on 100% of the total weight of the solution sprayed, the pH of the composition being from about 2 to about 4 (eg, about 2.7).

The sprayable composition may contain from about 0.002% to about 0.01% wt./wt. tiotropium or a pharmaceutically acceptable salt thereof (eg, tiotropium bromide), from about 0% to about 0.01% wt./wt. EDTA and about 0.9% w/w. sodium chloride, wherein the composition is substantially free of a preservative, such as benzalkonium chloride, and wherein the composition has a pH in the range of about 2.0 to about 4.0.

In one embodiment, the sprayable composition contains (a) from about 10 to about 80 μg of tiotropium bromide, (b) about 0.9% wt./wt. sodium chloride, (c) about 0.001% w/w. disodium edetate, (d) hydrochloric acid and (e) water. The composition preferably has a pH of about 2.7. In one embodiment, the volume of the composition sprayed is 2 ml. In another embodiment, the sprayable composition contains (a) about 10 to about 80 μg of tiotropium bromide, (b) about 18,000 μg of sodium chloride, (c) 20 μg of disodium edetate, (d) hydrochloric acid, and (e) water. The volume of the composition may also be from about 0.1 ml to about 5 ml, such as from about 1 ml to about 3 ml, or from about 1.5 ml to about 2.5 ml. In another embodiment, the volume of the composition is from about 0.05 ml to about 1.0 ml; such as from about 0.1 ml to about 0.9 ml; from about 0.1 ml to about 0.8 ml; from about 0.1 ml to about 0.7 ml; from about 0.1 ml to about 0.6 ml; from about 0.1 ml to about 0.5 ml; from about 0.1 ml to about 0.4 ml; from about 0.1 ml to about 0.3 ml; or from about 0.1 ml to about 0.2 ml.

In one embodiment, the sprayable composition contains (a) from about 10 to about 80 μg of tiotropium bromide, (b) about 0.9% wt./wt. sodium chloride, (c) about 0.01% w/w. disodium edetate, (d) hydrochloric acid and (e) water. The composition preferably has a pH of about 2.7. In one embodiment, the volume of the composition sprayed is 2 ml. In another embodiment, the spray composition contains (a) about 10 to about 80 μg of tiotropium bromide, (b) about 18,000 μg of sodium chloride, (c) 200 μg of disodium edetate, (d) hydrochloric acid, and (e) water. The volume of the composition may also be from about 0.1 ml to about 5 ml, such as from about 1 ml to about 3 ml, or from about 1.5 ml to about 2.5 ml. In another embodiment, the volume of the composition is from about 0.05 ml to about 1.0 ml; such as from about 0.1 ml to about 0.9 ml; from about 0.1 ml to about 0.8 ml; from about 0.1 ml to about 0.7 ml; from about 0.1 ml to about 0.6 ml; from about 0.1 ml to about 0.5 ml; from about 0.1 ml to about 0.4 ml; from about 0.1 ml to about 0.3 ml; or from about 0.1 ml to about 0.2 ml.

In another embodiment, the sprayable composition contains (a) from about 10 to about 80 μg of tiotropium bromide, (b) about 0.9% wt./wt. sodium chloride, (c) about 0.02% w/w. disodium edetate, (d) hydrochloric acid and (e) water. The composition preferably has a pH of about 2.7. In one embodiment, the volume of the composition sprayed is 2 ml. In another embodiment, the sprayable composition contains (a) from about 10 to about 80 μg of tiotropium bromide,

- 6 045879 (b) about 18000 µg sodium chloride, (c) 400 µg disodium edetate, (d) hydrochloric acid and (e) water. The volume of the composition may also be from about 0.1 ml to about 5 ml, such as from about 1 ml to about 3 ml, or from about 1.5 ml to about 2.5 ml. In another embodiment, the volume of the composition is from about 0.05 ml to about 1.0 ml; such as from about 0.1 ml to about 0.9 ml; from about 0.1 ml to about 0.8 ml; from about 0.1 ml to about 0.7 ml; from about 0.1 ml to about 0.6 ml; from about 0.1 ml to about 0.5 ml; from about 0.1 ml to about 0.4 ml; from about 0.1 ml to about 0.3 ml; or from about 0.1 ml to about 0.2 ml.

In another embodiment, the sprayable composition contains (a) from about 10 to about 80 μg of tiotropium bromide, (b) about 0.9% wt./wt. sodium chloride, (c) about 0.05% w/w. disodium edetate, (d) hydrochloric acid and (e) water. The composition preferably has a pH of about 2.7. In one embodiment, the volume of the composition sprayed is 2 ml. The volume of the composition may also be from about 0.1 ml to about 5 ml, such as from about 1 ml to about 3 ml, or from about 1.5 ml to about 2.5 ml. In another embodiment, the volume of the composition is from about 0.05 ml to about 1.0 ml; such as from about 0.1 ml to about 0.9 ml; from about 0.1 ml to about 0.8 ml; from about 0.1 ml to about 0.7 ml; from about 0.1 ml to about 0.6 ml; from about 0.1 ml to about 0.5 ml; from about 0.1 ml to about 0.4 ml; from about 0.1 ml to about 0.3 ml; or from about 0.1 ml to about 0.2 ml.

Another embodiment is a method of treating an inflammatory or obstructive airway disease, such as COPD, comprising administering, through a vibrating mesh nebulizer, a nebulized composition, wherein the nebulized composition contains (a) from about 10 to about 80 μg of tiotropium bromide, (b) about 0.9% w/w sodium chloride, (c) about 0.001% w/w. disodium edetate, (d) hydrochloric acid and (e) water. The composition preferably has a pH of about 2.7. In one embodiment, the volume of the composition sprayed is 2 ml. In another embodiment, the sprayable composition contains (a) about 10 to about 80 μg of tiotropium bromide, (b) about 18,000 μg of sodium chloride, (c) 20 μg of disodium edetate, (d) hydrochloric acid, and (e) water. The volume of the composition may also be from about 0.1 ml to about 5 ml, such as from about 1 ml to about 3 ml, or from about 1.5 ml to about 2.5 ml. In another embodiment, the volume of the composition is from about 0.05 ml to about 1.0 ml; such as from about 0.1 ml to about 0.9 ml; from about 0.1 ml to about 0.8 ml; from about 0.1 ml to about 0.7 ml; from about 0.1 ml to about 0.6 ml; from about 0.1 ml to about 0.5 ml; from about 0.1 ml to about 0.4 ml; from about 0.1 ml to about 0.3 ml; or from about 0.1 ml to about 0.2 ml.

Another embodiment is a method of treating an inflammatory or obstructive airway disease, such as COPD, comprising administering, through a vibrating mesh nebulizer, a nebulized composition, wherein the nebulized composition contains (a) from about 10 to about 80 μg of tiotropium bromide, (b) about 0.9% w/w sodium chloride, (c) about 0.01% w/w. disodium edetate, (d) hydrochloric acid and (e) water. The composition preferably has a pH of about 2.7. In one embodiment, the volume of the composition sprayed is 2 ml. In another embodiment, the sprayable composition contains (a) about 10 to about 80 μg of tiotropium bromide, (b) about 18,000 μg of sodium chloride, (c) 200 μg of disodium edetate, (d) hydrochloric acid, and (e) water. The volume of the composition may also be from about 0.1 ml to about 5 ml, such as from about 1 ml to about 3 ml, or from about 1.5 ml to about 2.5 ml. In another embodiment, the volume of the composition is from about 0.05 ml to about 1.0 ml; such as from about 0.1 ml to about 0.9 ml; from about 0.1 ml to about 0.8 ml; from about 0.1 ml to about 0.7 ml; from about 0.1 ml to about 0.6 ml; from about 0.1 ml to about 0.5 ml; from about 0.1 ml to about 0.4 ml; from about 0.1 ml to about 0.3 ml; or from about 0.1 ml to about 0.2 ml.

Another embodiment is a method of treating an inflammatory or obstructive airway disease, such as COPD, comprising administering, through a vibrating mesh nebulizer, a nebulized composition, wherein the nebulized composition contains (a) from about 10 to about 80 μg of tiotropium bromide, (b) about 0.9% w/w sodium chloride, (c) about 0.02% w/w. disodium edetate, (d) hydrochloric acid and (e) water. The composition preferably has a pH of about 2.7. In one embodiment, the volume of the composition sprayed is 2 ml. In another embodiment, the spray composition contains (a) about 10 to about 80 μg tiotropium bromide, (b) about 18,000 μg sodium chloride, (c) 400 μg disodium edetate, (d) hydrochloric acid, and (e) water. The volume of the composition may also be from about 0.1 ml to about 5 ml, such as from about 1 ml to about 3 ml, or from about 1.5 ml to about 2.5 ml. In another embodiment, the volume of the composition is from about 0.05 ml to about 1.0 ml; such as from about 0.1 ml to about 0.9 ml; from about 0.1 ml to about 0.8 ml; from about 0.1 ml to about 0.7 ml; from about 0.1 ml to about 0.6 ml; from about 0.1 ml to about 0.5 ml; from about 0.1 ml to about 0.4 ml; from about 0.1 ml to about 0.3 ml; or from about 0.1 ml to about 0.2 ml.

The sprayable composition provided herein may have a long shelf life, that is, it is stable during long-term storage. The sprayable composition may contain more than about 80%, such as more than about 85%, more than about 90%, more than about 95%, or more than about 98% of the original amount of tiotropium or its salt in the composition after storage for 3 or 6 months,

- 7 045879 or 1, 2 or 3 years at 25°C in a suitable LDPE container, cyclic olefin polymer container, cyclic olefin copolymer container or glass container. Stability can be determined using Arrhenius kinetics.

Sprayable compositions may be contained in a pre-filled container.

The sprayable composition may be contained in a low-density polyethylene (LDPE) unit dose container, a polypropylene unit dose container, or a cyclic polyolefin polymer unit dose container. Each unit dose container may be placed in a foil pouch, and each foil pouch may contain 2 or more unit dose containers. Each foil pouch containing a unit dose container may be placed in a cardboard box for storage.

Spray

Suitable nebulizer devices for use with the nebulizable composition include jet nebulizers, ultrasonic nebulizers, mesh nebulizers and breath-actuated nebulizers, more preferably mesh nebulizers.

Jet atomizers work by passing a stream of air through a Venturi nozzle and spraying a liquid. The negative pressure created by the gas causes the fluid flowing out of the reservoir to increase in velocity. There are baffles that are located behind the jet holes to further reduce the droplet size. The advantages of jet sprayers are that they are easy to use and have a reliable design. However, jet sprayers are noisy and have longer spray times. Commercially available jet sprayers include Acom-I®, Acom-II®, AquaTower®, AVA-NEB®, Cirrhus®, Dart®, DeVilbiss 646®, Downdraft®, Fan Jet®, MB-5®, Misty Neb® , PARILC JET®, PARI-JET®, Salter 8900®, Sidestream®, Updraft-II® and Whisper Jet®.

Ultrasonic nebulizers work based on piezoelectric crystal technology. In short, these atomizers contain a piezoelectric crystal that vibrates at high frequencies to create an aerosol. However, ultrasonic nebulizers suffer from limitations such as device heating (making them unsuitable for heat-labile active agents), large residual volumes, and the inability to nebulize viscous solutions. Commercially available ultrasonic nebulizers include DeVilbiss-Pulmosonic®, Rhone Poulenc-Rorer-Fisoneb®, Omron NE-U1®, and Beurer Nebulizer IH30®.

Mesh nebulizers are relatively new devices and have many advantages over jet and ultrasonic nebulizers. Said atomizer typically uses a mesh plate or plate with holes that are precisely drilled, the diameter of which regulates the size of the aerosol droplets. The piezoelectric element is in contact with a mesh plate, which vibrates when electrical current is applied. The nebulized composition is in direct contact with a mesh plate, which, when vibrated, turns the liquid into aerosol droplets that can be inhaled by the patient. As a result of vibrations, a thick aerosol is formed that can be administered to the patient. Mesh nozzles can be either static mesh nozzles or vibrating mesh nozzles. Static mesh atomizers force liquid through a static mesh under vibration generated by an ultrasonic transducer. Vibrating mesh atomizers use mesh vibrations or mesh deformations to create an aerosol. Commercially available mesh nebulizers include Micro Air® from Omron, i-Neb® from Respironics, Akita® from Activaero, AeroNeb Go®, AeroNeb Pro®, AeroNeb Solo® from Aerogen, and Aerovect Rx® from Aerovect.

The nebulizable composition, when administered via a nebulizer, can achieve an inhaled dose delivery rate of from about 0.25 μg/min to about 20 μg/min.

The spray composition, administered by a vibrating mesh atomizer, can provide an aerosol having a geometric standard deviation of the spray droplet size distribution of the spray composition from about 1 to about 3.

The atomizable composition administered by a vibrating mesh atomizer can provide an aerosol having a mass median aerodynamic droplet size diameter of the atomizable composition from about 2.5 microns to about 10.5 microns.

A method of administering a nebulized composition of tiotropium using a vibrating mesh nebulizer, wherein said composition contains from about 1 μg to about 100 μg of tiotropium, wherein said nebulizable composition, when administered by said vibrating mesh nebulizer, provides an aerosol having a mass median aerodynamic diameter of about 2. 5 microns to about 10.5 microns and a geometric standard deviation of the spray droplet distribution from about 1 to about 3.

The spray composition, administered by a vibrating mesh atomizer, can provide a dose of fine particles that is at least 10%.

Fraction of fine particles obtained by introducing the sprayed composition into sprays

- 8 045879 caster with vibrating mesh, can range from about 10% to about 60%.

Nebulized compositions of the present invention, when administered using a vibrating mesh nebulizer into a breathing simulator (BRS), exhibit a delivered dose of about 10% to about 70%.

The nebulizable compositions of the present invention, when administered using a vibrating mesh atomizer, exhibit a droplet size distribution in which D10 is no more than about 5 microns, D50 is no more than about 10 microns, D90 is no more than about 20 microns, and the range [ (D90 - D10) / D50] is no more than about 5.

The time required to spray the spray composition from the spray device may range from about 1 to about 15 minutes.

Definitions

As used herein, the words contain and include, and variations such as contains, containing, includes, including, are to be interpreted to mean including, unless the context otherwise requires. That is, the use of these words may imply the inclusion of an element or elements not specifically stated.

The term subject includes, but is not limited to, people.

For treatment of an indication with a therapeutic agent, an effective amount of a therapeutic agent will be recognized by clinicians and those skilled in the art and includes an amount effective to treat, reduce, alleviate, ameliorate, eliminate, or prevent one or more symptoms of the condition being sought. treat, or alternatively, the condition sought to be avoided, or otherwise cause a clinically recognizable beneficial change in the condition or its consequences.

The term inhaled dose delivery rate is the rate at which an inhaled dose of drug is nebulized, administered, and delivered to the patient's lungs.

The term geometric standard deviation represents the geometric width of the best-fitting lognormal function of the particle size data.

The term mass median aerodynamic diameter (MMAD) means the median aerodynamic size of a plurality of particles, usually in a polydisperse population. The term aerodynamic diameter is the diameter of a sphere of unit density having the same settling rate, usually in air, as a powder, and is therefore a useful way to characterize an aerosol powder or other dispersed particle or particulate composition in terms of its behavior during deposition. Aerodynamic diameter covers the particle or particle shape, density, and physical size of the particle or particle. MMAD is defined in this document using cascading effects unless the context indicates otherwise.

The term fine particle dose is the dose, expressed in micrograms or percentage of total dose, of aerosolized drug particles with an aerodynamic diameter <5 microns.

The term fine particle fraction is the ratio of the dose of fine particles to the total dose extracted.

The term D10 represents the particle diameter value below which 10% of the population of particles lies.

The term D50 is the particle diameter value below which 50% of the population of particles lies and above which 50% of the population of particles lies.

The term D90 is the particle diameter value below which 90% of the particle population lies.

The term by weight refers to % w/w. of the total mass of the sprayed composition.

Examples

The following examples further illustrate the invention but are not limiting.

Example 1_______________________________________________________________

Sample number Ingredients Amount (µg/2 ml) 10 mcg/2 ml 20 mcg / 2 ml 40 mcg / 2 ml 80 mcg/2 ml 1 Tiotropium bromide IH 10 20 40 80 2 Sodium Chloride USP 18000 18000 18000 18000 3 Edetate disodium USP 20 20 20 20

- 9 045879

4 Hydrochloric acid USP 0.5N HCl solution in sufficient number of persons up to pH 2.7 in sufficient number of persons up to pH 2.7 in sufficient number of persons up to pH 2.7 in sufficient number of persons up to pH 2.7 5 Water for injections USP in sufficient number of persons up to 2 ml in sufficient number of persons up to 2 ml in sufficient number of persons up to 2 ml in sufficient number of persons up to 2 ml

Way

1. Draw 85% of the quantity of water for injection (WFI) into the production vessel. Cool WFI to 20-25°C.

2. Add and dissolve a batch of sodium chloride while stirring. Check the transparency of the solution.

3. Add and dissolve a portion of edetate disodium in it while stirring. Check the transparency of the solution.

4. Check the pH and adjust the pH to 2.7 using 0.5N HCl solution.

5. Add and dissolve a portion of anhydrous tiotropium bromide while stirring. Check the transparency of the solution.

6. Bring volume to final volume. Submit sample for analysis.

7. Filter the entire resulting solution through a 0.22 micron PVDF filter.

8. Place the resulting solution into HDPE bottles.

The contents of the compositions shown above were poured into the reservoir of a vibrating mesh atomizer such as an Omron Micro Air NE-U22. The compositions were then evaluated using a Next Generation Impactor (NGI) device. The NGI device simulates multiple components of the airway. The data obtained from the NGI device represents the proportion of drug reaching different parts of the respiratory tract. This provides an estimate of the proportion of drug ingested and inhaled, drug remaining in the device, and drug reaching target sites. Evaluation methods include, but are not limited to, fine particle fraction (FPF), fine particle dose (FPD), mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), etc. The following table shows the characteristics of sprayable compositions in a sprayer with a vibrating mesh, for example Omron, Micro Air NE-U22.__________________________________________

No. 10 mcg/2 ml 20 mcg / 2 ml 40 mcg / 2 ml 80 mcg/2 ml % mcg % mcg % mcg % mcg Dose delivered by N.G.I. 74 7.4 78 15.66 82.04 32.82 89.91 71.93 Mass balance 95.31 9.53 91.99 18.4 100.59 40.23 97.43 77.95 FPD 24.27 2.43 26.14 5.23 26.55 10.62 28.32 22.66 FPF 32.8 33.52 32.37 31.5 ISM (Stage 1 to MOS) 7.31 15.41 31.24 69.36 MMAD (µm) 6,637 6,579 6,547 6,749 GSD 1.958 1,902 1.879 1,860 Spray time (min) 8 4.5 4.5-5 4 Remaining in tank (%) ~27 ~21 ~26 ~22

- 10 045879

Example 2

Sample number Ingredients Amount (µg/2 ml) 10 mcg/2 ml 20 mcg / 2 ml 40 mcg / 2 ml 80 mcg/2 ml 1 Tiotropium bromide IH 12.04 24.07 48.14 96.29 2 Sodium chloride USP 18000.00 18000.00 18000.00 18000.00 3 Edetate disodium USP 400.00 400.00 400.00 400.00 4 Hydrochloric acid USP 0.5N HCl in sufficient number of persons pH in sufficient number of persons pH in sufficient number of persons pH in sufficient number of persons pH 5 Water for injection USP in sufficient number of persons up to 2 ml in sufficient number of persons up to 2 ml in sufficient number of persons up to 2 ml in sufficient number of persons up to 2 ml

Way

1. Draw up 85% of the amount of water for injection. Cool the water for injection to 20-25°C.

2. Add and dissolve sodium chloride in it while stirring. Check the transparency of the solution.

3. Add and dissolve disodium edetate in it while stirring. Check the transparency of the solution.

4. Check pH and adjust pH to 2.7 using 1N. HCl solution.

5. Add and dissolve anhydrous tiotropium bromide in it while stirring. Check the transparency of the solution.

6. Bring volume to final volume.

7. Filter the entire resulting solution through a 0.22 micron PVDF filter.

8. Fill HDPE bottles with the resulting solution.

The contents of the compositions presented in Example 2 above were poured into a reservoir of various vibrating mesh nebulizers and then delivery was assessed using a Next Generation Impactor (NGI) device.

No. 10 mcg/2 ml Device 1 Device 2 Device 3 mcg % mcg % mk % Dose delivered by NGI 7.73 98.1 8.75 99.10 9.3 8 93.80 Mass balance 9.81 77.30 9.91 87.50 9.8 2 98.20 FPD 4.13 41.29 3.46 34.57 4.3 43.60 FPF - 53.14 - 39.51 - 46.48 MMAD (µm) 4.62 5.77 5.13 GSD 1.99 1.93 1.68 Spray time (min) 3 minutes 7 minutes 10 minutes

- 11 045879

- 12 045879

Device 2

No. D10 (µm) D50 (µm) D90 (µm) Interval 1 2,564 5.915 11.75 1.553 2 2,518 5,929 11.90 1,582 3 2,454 5.831 11.79 1.601 4 2,253 5,554 11.33 1.635 5 2.335 5,646 11.43 1.611 6 2,252 5,482 11.15 1.624 7 2,313 5,608 11.39 1.619 8 2,342 5,644 11.45 1.614 9 2.265 5,497 11.22 1.629 10 2,100 5,306 11.13 1,701 Average 2,340 5,641 11.45 1.617 %OSO 5.95 3.55 2.39 2.37 Maximum 2,564 5,929 11.90 1,701 Minimum 2,100 5,306 11.13 1.553

Device 3

No. D10 (ppm) D50 (ppm) D90 (ppm) Interval 1 2,834 6,991 14.71 1,698 2 2,550 5,717 11.66 1,593 3 2.616 5.795 11.64 1.558 4 2,346 5,846 12.53 1,742 5 2.452 6.525 14.23 1.805 6 2,470 5,508 11.06 1.559 7 2,572 5.834 11.90 1,599 8 2,634 6.121 12.71 1.645 9 2,496 6,296 13.57 1,759 10 2.326 5,460 11.27 1.638 Average 2,530 6,009 12.53 1,660 %OSO 5.88 7.97 10.11 5.26 Maximum 2,834 6,991 14.71 1.805 Minimum 2.326 5,460 11.06 1.558

Abbreviations

NGI - next generation impactor,

MOC - micro-orifice manifold,

FPD - dose of fine particles,

FPF - fine particle fraction,

ISM is the mass of particles selected by size by the impactor, MMAD is the mass median aerodynamic diameter, GSD is the geometric standard deviation.

Claims (9)

1. A method of administering tiotropium bromide, comprising administering, through a vibrating mesh nebulizer, a nebulizable composition to create an aerosol at an inhalable dose delivery rate of from 0.25 μg/min to 20 μg/min, wherein (i) said nebulizable composition contains (a) bromide tiotropium, (b) 0.9% sodium chloride, (c) 0.01% w/w. disodium edetate and (d) water, (ii) said aerosol has a droplet size distribution with D10 not more than 5 microns, D50 not more than 10 microns, D90 not more than 20 microns, the range [(D90 - D10) / D50] not more than 5, or any combination of any of the foregoing, and (iii) said aerosol has a fine particle dose of not less than 10%, wherein said fine particle dose is the dose, expressed in micrograms or as a percentage of the total dose, of the aerosol drug particles products with an aerodynamic diameter <5 microns. 2. A method of administering tiotropium bromide, comprising administering, through a vibrating mesh nebulizer, a sprayable composition to create an aerosol having one or more of: (i) geometric standard deviations of the spray droplet size distribution of the spray composition from 1 to 3, (ii) mass median aerodynamic droplet diameters of the spray composition from 2.5 microns to 10.5 microns, or (iii) any combination of any of the above, in which ( i) said spray composition contains (a) tiotropium bromide, (b) 0.9% sodium chloride, (c) 0.01% w/w. disodium edetate and (d) water, (ii) said aerosol has a droplet size distribution with D10 not more than 5 microns, D50 not more than 10 microns, D90 not more than 20 microns, the range [(D90 - D10) / D50] not more than 5, or any combination of any of the above, and (ii i) said aerosol has a fine particle dose of not less than 10%, where said fine particle dose is the dose, expressed in micrograms or as a percentage of the total dose, of the aerosol particles drug with an aerodynamic diameter <5 microns. 3. The method according to any one of claims 1 or 2, in which the aerosol has a fraction of fine particles from 10% to 60%. 4. The method according to any one of claims 1 to 3, in which the sprayed composition contains from 1 μg to 100 μg of tiotropium bromide. 5. Method according to any one of claims 1 to 4, wherein the nebulized composition, when administered via a vibrating mesh nebulizer, has a delivered dose of from 10% to 70%. 6. Method according to any one of claims 1 to 5, wherein the time required to spray the sprayable composition is from 1 to 15 minutes. 7. The method according to any one of claims 1 to 6, in which the spray composition contains (a) from 10 to 80 μg tiotropium bromide, (b) 18000 μg sodium chloride, (c) 200 μg disodium edetate, (d) hydrochloric acid and (e) water, the composition having a pH of 2.7. 8. The method according to any one of claims 1 to 6, in which the spray composition contains (a) from 10 to 80 μg of tiotropium bromide, (b) 0.9% wt./wt. sodium chloride, (c) 0.01% w/w. disodium edetate, (d) hydrochloric acid and (e) water, the composition having a pH of 2.7. 9. The method according to any one of claims 1-8, in which the sprayed composition consists of tiotropium bromide, sodium chloride, 0.01% wt./wt. disodium edetate, hydrochloric acid and water.