(19)
(11)EP 3 297 607 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
22.07.2020 Bulletin 2020/30

(21)Application number: 16731322.0

(22)Date of filing:  17.05.2016
(51)International Patent Classification (IPC): 
A61K 9/00(2006.01)
A61K 31/439(2006.01)
(86)International application number:
PCT/IB2016/000783
(87)International publication number:
WO 2016/185282 (24.11.2016 Gazette  2016/47)

(54)

TIOTROPIUM INHALATION SOLUTION FOR NEBULIZATION

TIOTROPIUMINHALATIONSLÖSUNG FÜR VERNEBLUNG

SOLUTION D'INHALATION DE TIOTROPIUM À NÉBULISER


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 18.05.2015 IN 1945MU2015

(43)Date of publication of application:
28.03.2018 Bulletin 2018/13

(73)Proprietor: Glenmark Specialty S.A.
2300 La Chaux-de-Fonds (CH)

(72)Inventors:
  • DHUPPAD, Ulhas
    Nashik Maharashtra 422101 (IN)
  • KOPPENHAGEN, Franciscus
    Deerfield Beach, FL 33441 (US)
  • CHAUDHARI, Sunil
    Nashik Maharashtra 422101 (IN)
  • RAJURKAR, Suresh
    Nashik Maharashtra 422101 (IN)
  • DHATRAK, Chandrakant
    Nashik Maharashtra 422101 (IN)
  • KASLIWAL, Alkesh
    Nanded Maharashtra 431809 (IN)

(74)Representative: HGF 
1 City Walk
Leeds LS11 9DX
Leeds LS11 9DX (GB)


(56)References cited: : 
US-A1- 2003 149 007
US-A1- 2004 019 073
US-A1- 2003 215 396
US-A1- 2005 058 606
  
      
    Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


    Description

    FIELD OF THE INVENTION



    [0001] The present invention relates to a sterile pharmaceutical composition comprising tiotropium or a pharmaceutically acceptable salt thereof, for inhalation via nebulization to a subject (e.g. a human). The invention also relates to a process for preparing the pharmaceutical composition and its use in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) in a subject.

    BACKGROUND OF THE INVENTION



    [0002] Anticholinergic agents are believed to inhibit vagally-mediated reflexes by blocking acetylcholine at the cholinergic receptor. Anticholinergic agents are also believed to inhibit secretions of the serous and sero-mucous glands of the nasal mucosa. Anticholinergic agents for the treatment or control of respiratory disorders include tiotropium, oxitropium, ipratropium, glycopyrrolate, aclidinium, and salts thereof.

    [0003] One known anticholinergic agent is tiotropium bromide, the chemical name of which is (1α, 2β, 4β, 5α, 7β)-7-[(hydroxydi-2-thienylacetyl) oxy]-9, 9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1.02, 4] nonane bromide monohydrate. Tiotropium bromide is commercially marketed in the United States by Boehringer Ingelheim Pharmaceuticals, Inc. as SPIRIVA® capsules containing lactose and 18 µg tiotropium (equivalent to 22.5 µg tiotropium bromide monohydrate) and inhalation solution SPIRIVA® RESPIMAT containing tiotropium bromide, water for injection, edetate disodium, benzalkonium chloride and hydrochloric acid. Tiotropium bromide is indicated for the maintenance treatment of bronchospasm associated with COPD and for reducing COPD exacerbations.

    [0004] US 2004/0019073 discloses an aqueous inhalation solution comprising tiotropium and the preservative benzalkonium chloride.

    [0005] Inhalation solutions generally contain preservatives such as benzalkonium chloride. Frequent exposure to low concentrations of benzalkonium chloride may lead to adverse effects. Some studies (Beasley et al., 1987, British Medical Journal, Vol 294, 1197 - 1198; Beasley et al., 1988, Br. J. Clin. Pharmac. 25, 283 -287; Miszkiel et al., 1988, Br. J. Clin. Pharmac. 25, 157 - 163) also suggest that repeated use of COPD treatments with benzalkonium chloride may result in paradoxic bronchoconstriction, as benzalkonium chloride has bronchoconstrictor properties 7.4 times less potent than histamine. Moreover, exposure to benzalkonium chloride may lead to occupational asthma and may also cause dose-dependent bronchoconstriction.

    [0006] US 2005/058606 relates to a tiotropium containing stable pharmaceutical solution formulations suitable for aerosol administration. US 2004/019073 relates to a propellant-free aerosol formulation of a pharmaceutically acceptable salt of tiotropium dissolved in water. US 2003/215396 relates to pharmaceutical preparations in the form of aqueous solutions for the production of propellant-free aerosols for inhalation. US 2003/0149007 relates to a dual bronchodilator inhalation solution, system, kit and method for relieving bronchospasm in patients suffering from chronic obstructive pulmonary disease.

    [0007] Treatments for COPD often come in multiple dosage units and must be diluted to specific concentrations suitable for treating patients, or be directly delivered with the help of a costly and complicated device. This poses several problems while preparing the final dose and/or device for delivery. For example, COPD treatments requiring administration of a single dose unit from multiple dosage units sometimes lack proper mixing or diluting instructions, or the instructions for preparing and using the COPD treatment may be hard to follow or can be easily lost. Of even greater concern is haphazard diluting or mixing of COPD medications, which can result in administering the wrong dosage. This could be especially harmful for patients those are less tolerant to higher dosages of asthma medications. Incorrect mixing can also result in treatment failure such that additional medical attention is required, thereby increasing the time, expense and personnel costs associated with therapy.

    [0008] There is, therefore, a need for an improved inhalation solution, system, kit and method for relieving symptoms associated with COPD.

    SUMMARY OF THE INVENTION



    [0009] In a first aspect, the present invention relates to a container comprising a pharmaceutical composition, being a solution and being suitable for administration with a nebulizer comprising (i) 0.0005% to 0.008% w/w of tiotropium or a pharmaceutically acceptable salt thereof; (ii) water; (iii) a complexing agent, the complexing agent being disodium EDTA and present at a concentration of 0.01% by weight; and (iv) 0.9% by weight sodium chloride; wherein the pH of the composition ranges from 2.2 to 2.9, and said composition is free of quaternary ammonium preservatives.

    [0010] In a second aspect, the present invention relates to a pharmaceutical solution suitable for administration with a nebulizer consisting essentially of (i) 0.0005% to 0.008 % w/w tiotropium or a pharmaceutically acceptable salt thereof, (ii) a complexing agent, the complexing agent being disodium EDTA; and (iii) 0.9% sodium chloride; and (iv) water, wherein the pH of the pharmaceutical solution ranges from 2.7 2.2 to 2.9, said pharmaceutical solution is free of quaternary ammonium preservatives, and the concentration of the complexing agent is present at a concentration of 0.01% by weight.

    [0011] In a third aspect, the present invention relates to a process of preparing a container or pharmaceutical composition according to the first or the second aspect, wherein the process comprises the steps of: (a) dissolving tiotropium or its salt in water; (b) addition of a complexing agent and sodium chloride to the solution of step (a); (c) adjusting the pH of the solution to 2.7 to 2.9; (d) filtering the solution (for example, with a 0.2 micron filter); and (e) filling a suitable container with the solution.

    [0012] In a fourth aspect, the present invention relates to a kit comprising a nebulizer, instructions for using the nebulizer and a unit dose vial, wherein the unit dose vial is a container or comprises a pharmaceutical solution according to the first, second or third aspects; optionally wherein the nebulizer is selected from a jet nebulizer, ultrasonic nebulizer, vibrating mesh nebulizer and a breath actuated nebulizer.

    [0013] The present invention relates to a sterile pharmaceutical composition for inhalation via nebulization to a patient (e.g., a human). The pharmaceutical composition comprises about 0.0005% to about 0.008% w/w of tiotropium or its salt (a pharmaceutically acceptable salt) and water. The pharmaceutical composition is a solution. The pharmaceutical composition of the first aspect is contained within a container suitable for nebulization. The pharmaceutical composition may be administered in nebulized form to relieve bronchospasm in patients suffering from COPD or for reducing COPD exacerbations.

    [0014] In one embodiment a sterile pharmaceutical composition is a unit dose nebulizable pharmaceutical solution for inhalation comprising 0.0005% to 0.008% w/w of tiotropium or a pharmaceutically acceptable salt thereof. The pharmaceutical solution may be administered in nebulized form to relieve bronchospasm in a subject, such as a subject suffering from COPD.

    [0015] In a preferred embodiment, the pharmaceutical composition or solution is free, or substantially free, of preservative including, but not limited to, quaternary ammonium preservatives, such as a benzalkonium salt, (e.g., benzalkonium chloride). For example, the pharmaceutical composition or solution may contain less than about 0.1% by weight of preservative (or quaternary ammonium preservative) (such as less than about 0.05%, less than about 0.02%, or less than about 0.008%), based on 100% total weight of composition or solution.

    [0016] Yet another embodiment is a sterile, unit dose nebulizable pharmaceutical solution suitable for administration with a nebulizer comprising 0.0005% to 0.008 % w/w tiotropium or a pharmaceutically acceptable salt thereof, wherein the composition comprises the complexing agent disodium EDTA at a concentration of 0.01% by weight.

    [0017] Variants of the disclosure relate to a sterile nebulizable pharmaceutical solution for inhalation via nebulization comprising tiotropium or its salt, wherein the composition is free, or substantially free, of (a) EDTA or a salt thereof and (b) a benzalkonium salt, such as benzalkonium chloride.

    [0018] In a preferred embodiment, the tiotropium salt in the pharmaceutical composition or pharmaceutical solution described herein is tiotropium bromide, such as tiotropium bromide monohydrate ((1α,2β,4β,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane bromide, monohydrate).

    [0019] In another embodiment, the tiotropium salt in the pharmaceutical composition or pharmaceutical solution described herein is amorphous tiotropium bromide.

    [0020] In another embodiment, the tiotropium salt in the pharmaceutical composition or pharmaceutical solution described herein is anhydrous tiotropium bromide.

    [0021] In another embodiment, the tiotropium salt in the pharmaceutical composition or pharmaceutical solution described herein is anhydrous amorphous tiotropium bromide.

    [0022] The pharmaceutical composition or solution may include from about 0.001 mg to about 0.3 mg of tiotropium or its salt (such as tiotropium bromide), such as from about 0.010 mg to about 0.280 mg; about 0.020 mg to about 0.260 mg; about 0.025 mg to about 0.240 mg; about 0.005 mg to about 0.1 mg; about 0.005 mg to about 0.05 mg; about 0.01 mg to about 0.04 mg; about 0.02 to about 0.07 mg; about 0.04 mg to about 0.08 mg; about 0.04 mg to about 0.10 mg; about 0.05 mg to about 0.15 mg; about 0.10 mg to about 0.19 mg; about 0.15 mg to about 0.20 mg; about 0.20 mg to about 0.25 mg; or from about 0.26 mg to about 0.30 mg tiotropium or its salt. The pharmaceutical composition or solution may include from about 0.001 mg to about 0.3 mg of tiotropium or its salt (such as tiotropium bromide), such as from about 0.010 mg to about 0.280 mg; about 0.020 mg to about 0.260 mg; about 0.025 mg to about 0.240 mg; about 0.005 mg to about 0.1 mg; about 0.005 mg to about 0.05 mg; about 0.01 mg to about 0.04 mg; about 0.02 to about 0.07 mg; about 0.04 mg to about 0.08 mg; about 0.04 mg to about 0.10 mg; about 0.05 mg to about 0.15 mg; about 0.10 mg to about 0.19 mg; about 0.15 mg to about 0.20 mg; about 0.20 mg to about 0.25 mg; or from about 0.26 mg to about 0.30 mg tiotropium per unit dosage of pharmaceutical composition or solution.

    [0023] The pharmaceutical composition or solution includes from 0.0005% to 0.008% by weight tiotropium or its salt (such as tiotropium bromide), such as from about 0.001 wt % to about 0.005 wt % tiotropium or its salt, based on 100% total weight of pharmaceutical composition or solution. In variants of the disclosure the pharmaceutical composition or solution may include from about 0.0002 wt% to about 0.02 wt%; about 0.0003 wt% to about 0.01 wt%; about 0.0002 wt% to about 0.001 wt%; about 0.006 wt % to about 0.010 wt %; about 0.011 wt % to about 0.015 wt %; about 0.016 wt % to about 0.020 wt %; about 0.021 wt % to about 0.025 wt %; or from about 0.026 wt % to about 0.030 wt % tiotropium or its salt, based on 100% total weight of pharmaceutical composition or solution.

    [0024] The pharmaceutical solution suitable for administration with a nebulizer consisting essentially of
    1. (a) 0.0005% to 0.008% w/w tiotropium or a pharmaceutically acceptable salt thereof,
    2. (b) 0.01 % by weight disodium EDTA;
    3. (c) 0.9% by weight sodium chloride; and
    4. (d) water,
    based upon 100% total weight of the pharmaceutical solution, wherein the pH of the pharmaceutical composition ranges from 2.2 to 2.9 (such as about 2.7). The pharmaceutical solution is free of quaternary ammonium preservatives. In another preferred embodiment, the pharmaceutical solution is free, or substantially free, of preservatives.

    [0025] In one embodiment, the pharmaceutical composition or solution provided herein has a long shelf life, i.e., it is stable during long term storage. The pharmaceutical composition or solution may contain greater than about 80%, such as greater than about 85%, greater than about 90%, greater than about 95% or greater than about 98% of the initial amount of tiotropium or its salt in the pharmaceutical composition or solution after being stored for 3 or 6 months or 1, 2 or 3 years at 25° C when stored in a suitable low density polyethylene (LDPE) container.

    [0026] Yet another embodiment is a container containing a pharmaceutical composition or solution of the present invention, wherein the volume of the composition or solution is 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 tiotropium solution of the present invention 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.

    [0027] In variants of the disclosure the pharmaceutical composition or solution may have a pH of between about 2.0 and about 6.0. For example, the pharmaceutical composition or solution may have a pH of from about 2.0 to about 4.0. The preferred pH range of tiotropium bromide solutions is from about 2.0 to about 4.5, preferably from about 2.5 to 3.5, most preferably from about 2.7 to about 3.2.
    The inhalation solution of the invention has a pH from about 2.2 to about 2.9.

    [0028] The osmolality of the pharmaceutical composition or solution may be from about 200 to about 500 mOsm/kg. In other embodiments of the present invention, the osmolality of the solution may be between about 275 and about 325 mOsm/kg.

    [0029] In variants of the disclosure, the pharmaceutical composition of the present invention comprises about 0.002% to about 0.01 % w/w tiotropium or any pharmaceutically acceptable salt thereof, about 0% to about 0.01% w/w EDTA, about 0.9 % sodium chloride, wherein the composition is free of preservative and wherein the composition has a pH in the range of about 2.0 to about 4.0.

    [0030] Another embodiment is a prepackaged, sterile, premixed, premeasured tiotropium bromide inhalation solution. Preferably, the solution is a ready-to-use solution which does not require any mixing or dilution by the subject prior to administration. The solution may be administered for the relief of bronchospasm in a subject suffering from COPD.

    [0031] Yet another embodiment is one or more prefilled containers containing a pharmaceutical composition or solution of the present invention. In one embodiment, each container comprises a single unit dose of a pharmaceutical composition or solution of the present invention comprising a therapeutically effective amount of tiotropium or its salt for the treatment of COPD. In one embodiment, each container includes a sterile, premixed, premeasured, substantially benzalkonium chloride free inhalation solution comprising a single unit dose of a therapeutically effective amount of tiotropium or its salt in a single container.

    [0032] Also disclosed herein is a method of administering tiotropium or a salt thereof comprising administering by inhalation to a subject a pharmaceutical composition or solution of the present invention.

    [0033] Also disclosed herein is a method of relieving bronchospasm (such as that associated with COPD) comprising administering by inhalation to a subject in need thereof a pharmaceutical composition or solution of the present invention.

    [0034] Yet another embodiment is a kit and/or system for administering a bronchodilator to relieve bronchospasm, for instance, bronchospasm associated with COPD. The kit and/or system may comprise a pharmaceutical composition or solution of the present invention. In one embodiment, the kit and/or system comprises an inhalation solution of the present invention comprising a therapeutically effective amount of tiotropium in a prepackaged, premeasured, premixed and/or single unit dose form for the treatment of COPD. In another embodiment, the prepackaged inhalation kit and/or system comprises one or more premixed, premeasured single unit dose vials comprising a pharmaceutical composition or solution of the present invention containing a therapeutically effective amount of tiotropium for the treatment of bronchospasm (such as that associated with COPD), and instructions for using the same.

    [0035] The kit comprises a nebulizer, instructions for using the nebulizer and the unit dose vials containing the pharmaceutical compositions of the present invention.

    [0036] Yet another embodiment is a kit for the treatment, prevention or amelioration or one or more symptoms of diseases or disorders associated with bronchoconstriction which comprises:
    1. (i) a nebulizer;
    2. (ii) a nebulizable composition for the treatment, prevention or amelioration or one or more symptoms of diseases or disorders associated with bronchoconstriction (such a pharmaceutical composition or solution of the present invention) which comprises:
      1. (a) tiotropium or its salt; and
      2. (b) water.


    [0037] A further embodiment of the present invention is to provide a process for making an inhalation solution comprising tiotropium for use in relieving bronchospasm associated with COPD. The process comprises the steps of:
    1. (a) dissolving tiotropium or its salt in water;
    2. (b) addition of a complexing agent and sodium chloride to the solution of step (a);
    3. (c) adjusting the pH of the solution to 2.7 to 2.9 (for example, the solution of step (a) or step (b)) with a pharmaceutically acceptable acid;
    4. (d) filtering the solution (for example, with a 0.2 micron filter); and
    5. (e) filling a suitable container with the solution.


    [0038] Another embodiment of the invention relates to a device comprising tiotropium or a salt thereof, for example, for use in relieving the symptoms of COPD.

    [0039] Also disclosed herein is a method for improving user compliance and/or quality of life as compared to conventional treatments for COPD. The method comprises initiating treatment with the pharmaceutical composition or solution of the present invention, or a container, kit, or system of the present invention. The present invention provides convenient, fast and reliable treatment for COPD that represents an improvement over traditional COPD treatments.

    [0040] Other objects, features and advantages of the present invention will be apparent to those of ordinary skill in the art in view of the following detailed description of the invention and accompanying drawings.

    DETAILED DESCRIPTION OF THE INVENTION



    [0041] Salts of tiotropium include, but are not limited to, acid addition salts and base salts thereof, solvates thereof, and any mixture 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. The preparation of the tiotropium bromide monohydrate is described in U.S. Patent No. 6,777,423Tiotropium and its salts can be administered to provide a bronchodilation effect and relief from symptoms associated with COPD.

    [0042] Tiotropium bromide has a molecular weight of 472.416 g/mol and the empirical formula C19H22BrNO4S2. Tiotropium bromide monohydrate is sparingly soluble in water and soluble in methanol. The established chemical structure of tiotropium bromide monohydrate is as follows:



    [0043] The term "tiotropium" as used herein, include acids, salts, esters, hydrates, polymorphs, hemihydrates, solvates, and derivatives thereof.

    [0044] 2-hydroxy-2,2-dithiophen-2-ylacetic acid is an impurity of Tiotropium identified as Impurity A in the present invention.

    [0045] In the present invention, tiotropium may be provided in a variety of pharmaceutically acceptable vehicles, including, but not limited to, water or hydroalcoholic solution or any other aqueous solution comprising a pharmaceutically acceptable amount of an osmotic agent.

    [0046] In a preferred embodiment, the tiotropium salt in the pharmaceutical composition or pharmaceutical solution described herein is tiotropium bromide, such as tiotropium bromide monohydrate ((1α,2β,4β,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane bromide, monohydrate).

    [0047] In another embodiment, the tiotropium salt in the pharmaceutical composition or pharmaceutical solution described herein is amorphous tiotropium bromide.

    [0048] In another embodiment, the tiotropium salt in the pharmaceutical composition or pharmaceutical solution described herein is anhydrous tiotropium bromide.

    [0049] In another embodiment, the tiotropium salt in the pharmaceutical composition or pharmaceutical solution described herein is anhydrous amorphous tiotropium bromide.

    [0050] To treat indications with a therapeutic agent, an "effective amount" of a therapeutic agent will be recognized by clinicians and persons of ordinary skill in the art, and includes an amount effective to treat, reduce, alleviate, ameliorate, eliminate or prevent one or more symptoms of the condition sought to be treated, or alternately, the condition sought to be avoided, or to otherwise produce a clinically recognizable favorable change in the condition or its effects.

    [0051] In another embodiment, the present invention provides sterile pharmaceutical composition of tiotropium for inhalation wherein the composition is substantially free of preservative, preferably substantially benzalkonium chloride free to treat bronchospasm associated with COPD.

    [0052] A composition is "substantially benzalkonium chloride free" 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 pharmaceutical composition or solution. Moreover, in a "substantially benzalkonium chloride free" or "substantially free of benzalkonium chloride" composition, benzalkonium chloride may be present in concentration less than 0.008% w/w based on total weight of composition or solution. The term "substantially free of preservative" denotes that preservative may be present in concentration less than 0.008% w/w based on total weight of composition or solution.

    [0053] Generally, pharmaceutical inhalation solutions contain a preservative such as benzalkonium chloride. One problem with these solutions is that the benzalkonium chloride may cause paradoxic bronchoconstriction if the solution is administered repeatedly over short intervals and frequent exposure to benzalkonium chloride may lead to occupational asthma. Another problem is that, when inhaled by patients, the benzalkonium chloride can cause dose-dependent bronchoconstriction. The inhalation solutions of the present invention may be provided without benzalkonium chloride, thereby making them suitable, especially in situations where the inhalation solution is administered repeatedly over a short period of time. Also, administering a substantially benzalkonium chloride-free inhalation solution to a patient reduces the concomitant liability of adverse effects associated with benzalkonium chloride alone or in combination other excipients and/or tiotropium. It also negates the toxicity and other side effects associated with benzalkonium chloride.

    [0054] The inhalation solutions of the present invention may also be provided in sterile, unit dose treatments.

    [0055] The disclosure provides a sterile, unit dose pharmaceutical solution composition for inhalation via nebulization comprising tiotropium or its salt wherein the composition is substantially free of a complexing agent such as ethylene diamine tetra-acetic acid (EDTA).

    [0056] One embodiment is a pharmaceutical composition comprising
    1. (i) tiotropium or its pharmaceutically acceptable salts thereof
    2. (ii) water
    wherein said composition is free of preservative and complexing agent.

    [0057] Low pH levels, particularly below 3.2, are preferred for the long-term stability of the tiotropium salts in the formulation. The absence of or reduction in the concentration of the additive EDTA also helps to reduce the paradoxic effect associated with cough.

    [0058] In variants of the disclosure, the inhalation solution has a pH of from about 2.0 to about 6.0. The solution has a pH of from about 2.0 to about 4.0. The preferred pH range of tiotropium bromide solutions is from about 2.0 to about 4.5, preferably from about 2.5 to 3.5, most preferably from about 2.7 to about 3.2.

    [0059] The inhalation solution of the invention has a pH from about 2.2 to about 2.9.

    [0060] The pH may be 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. In one embodiment, the pH is adjusted with IN hydrochloric acid or IN sulfuric acid. In another embodiment, the pH is adjusted with one or more organic acids selected from ascorbic acid, fumaric acid and citric acid. A preferred organic acid is citric acid. If desired, mixtures of the abovementioned acids may also be used, particularly in the case of acids which have other properties in addition to their acidifying properties, e.g., those which act as flavorings or antioxidants, such as for example citric acid or ascorbic acid.

    [0061] The inhalation solution of the present invention 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) to control pH.

    [0062] The inhalation solution may optionally include a buffer. General and biological buffers in the pH range of about 2.0 to about 8.0 include, but are not limited to, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, McIlvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen), 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 buffers.

    [0063] In another embodiment of the present invention, a therapeutically effective amount of tiotropium may include from about 0.001 mg to about 0.3 mg of tiotropium bromide. Therapeutically effective amounts may also include the following intermediate ranges of tiotropium bromide: from about 0.010 mg to about 0.280 mg; about 0.020 mg to about 0.260 mg; about 0.025 mg to about 0.240 mg; about 0.005 mg to about 0.1 mg; about 0.005 mg to about 0.05 mg; about 0.01 mg to about 0.04 mg; about 0.02 to about 0.07 mg; about 0.04 mg to about 0.08 mg; about 0.04 mg to about 0.10 mg; about 0.05 mg to about 0.15 mg; about 0.10 mg to about 0.19 mg; about 0.15 mg to about 0.20 mg; 0.20 mg to about 0.25 mg; and about 0.26 mg to about 0.30 mg. The pharmaceutical composition or solution may include from about 0.001 mg to about 0.3 mg of tiotropium or its salt (such as tiotropium bromide), such as from about 0.010 mg to about 0.280 mg; about 0.020 mg to about 0.260 mg; about 0.025 mg to about 0.240 mg; about 0.005 mg to about 0.1 mg; about 0.005 mg to about 0.05 mg; about 0.01 mg to about 0.04 mg; about 0.02 to about 0.07 mg; about 0.04 mg to about 0.08 mg; about 0.04 mg to about 0.10 mg; about 0.05 mg to about 0.15 mg; about 0.10 mg to about 0.19 mg; about 0.15 mg to about 0.20 mg; about 0.20 mg to about 0.25 mg; or from about 0.26 mg to about 0.30 mg tiotropium per unit dosage of pharmaceutical composition or solution.

    [0064] A therapeutically effective amount of tiotropium may include from about 0.0001% to about 0.030% by weight tiotropium bromide, including the following intermediate ranges of tiotropium bromide: about 0.0002 wt% to about 0.02 wt%; about 0.0003 wt% to about 0.01 wt%; about 0.0005 wt% to about 0.008 wt%; about 0.0002 wt% to about 0.001 wt%; about 0.001 wt % to about 0.005 wt %; about 0.006 wt % to about 0.010 wt %; about 0.011 wt % to about 0.015 wt %; about 0.016 wt % to about 0.020 wt %; about 0.021 wt % to about 0.025 wt %; or about 0.026 wt % to about 0.030 wt %.

    [0065] One embodiment is a pharmaceutical solution suitable for administration with a nebulizer consisting essentially of
    1. (a) about 0.0005% to about 0.008% w/w tiotropium or a pharmaceutically acceptable salt thereof,
    2. (b) 0.01% by weight disodium EDTA;
    3. (c) 0.9% by weight sodium chloride; and
    4. (d) water,
    based upon 100% total weight of the pharmaceutical solution, wherein the pH of the pharmaceutical composition is about 2.2 to about 2.9 (such as about 2.7). The pharmaceutical solution is free of quaternary ammonium preservatives. In another preferred embodiment, the pharmaceutical solution is free, or substantially free, of preservatives.

    [0066] In one embodiment, the pharmaceutical composition or solution provided herein has a long shelf life, i.e., it is stable during long term storage. The pharmaceutical composition or solution may contain greater than about 80%, such as greater than about 85%, greater than about 90%, greater than about 95% or greater than about 98% of the initial amount of tiotropium or its salt in the pharmaceutical composition or solution after being stored for 3 or 6 months or 1, 2 or 3 years at 25° C when stored in a suitable LDPE container, cyclic olefin polymer container, cyclic olefin copolymer container, or glass container. The stability may be determined using Arrhenius kinetics.

    [0067] Another embodiment is a container containing a pharmaceutical composition or solution of the present invention, wherein the volume of the composition or solution is 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 tiotropium solution of the present invention 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.

    [0068] In variants of the disclosure, the pharmaceutical composition of the present invention comprises about 0.002% to about 0.01 % w/w tiotropium or any pharmaceutically acceptable salt thereof, about 0% to about 0.01% w/w EDTA, about 0.9 % sodium chloride, wherein the composition is free of preservative and wherein the composition has a pH in the range of about 2.0 to about 4.0.

    [0069] Another embodiment is a prepackaged, sterile, premixed, premeasured tiotropium inhalation solution for the relief of bronchospasm in patients suffering from COPD.

    [0070] Another embodiment of the present invention is to provide a substantially benzalkonium chloride free tiotropium inhalation solution to treat bronchospasm associated with COPD. In another embodiment, the present invention comprises one or more prefilled containers. Each container comprises a single unit dose of an aqueous solution comprising a therapeutically effective amount of tiotropium for the treatment of COPD. In another embodiment, the present invention relates to a sterile, premixed, premeasured, substantially benzalkonium chloride free inhalation solution comprising a single unit dose of a therapeutically effective amount of tiotropium in a single container.

    [0071] A further embodiment of the present invention is to provide a method for treating or relieving bronchospasm associated with COPD comprising administering to a patient in need thereof a tiotropium inhalation formulation according to any of the embodiments described herein.

    [0072] An additional embodiment of the present invention is to provide a kit and/or system for administering a bronchodilator to relieve bronchospasm associated with COPD. In an alternative embodiment, the kit and/or system of the present invention comprises an inhalation solution comprising a therapeutically effective amount of tiotropium in a prepackaged, premeasured, premixed and/or single unit dose form for the treatment of COPD. In another alternative embodiment, the prepackaged inhalation kit and/or system of the present invention provides one or more premixed, premeasured single unit dose vials comprising a therapeutically effective amount of tiotropium for the treatment of bronchospasm associated with COPD, and instructions for using the same.

    [0073] More specifically, the present invention provides a kit for the treatment, prevention or amelioration or one or more symptoms of diseases or disorders associated with broncho constriction which comprises:
    1. (i) a nebulizer;
    2. (ii) a nebulizable composition for the treatment, prevention or amelioration or one or more symptoms of diseases or disorders associated with bronchoconstriction which comprises:
      1. (a) tiotropium or a salt thereof; and
      2. (b) water.


    [0074] The kit comprises a nebulizer, instructions for using the nebulizer and the unit dose vials containing the pharmaceutical compositions of the present invention.

    [0075] In another embodiment of the present invention, the osmolality of the inhalation solution may be from about 200 to about 500 mOsm/kg. In another embodiment, the osmolality of the solution may be from about 275 to about 325 mOsm/kg. In a further embodiment, the compositions of the present invention may comprise about 0.4 to about 1.0 weight percent ionic salt.

    [0076] Suitable tonicity adjusting agents may include, but are not limited to, ammonium carbonate, ammonium chloride, ammonium lactate, ammonium nitrate, ammonium phosphate, ammonium sulfate, ascorbic acid, bismuth sodium tartrate, boric acid, calcium chloride, calcium disodium edetate, calcium gluconate, calcium lactate, citric acid, dextrose, diethanolamine, dimethyl sulfoxide, edetate disodium, edetate trisodium monohydrate, fluorescein sodium, 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, urethan, uridine, zinc sulfate, and mixtures thereof.

    [0077] Suitable osmotic adjusting agents that may be used include, but are not limited to, sodium chloride, potassium chloride, zinc chloride, calcium chloride and mixtures thereof. Other osmotic adjusting agents may also include, but are not limited to, mannitol, glycerol, dextrose and mixtures thereof.

    [0078] Any cosolvent that is suitable for inhalation and capable of dissolving or solubilizing the tiotropium in the 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 cosolvent is an aliphatic alcohol having from one to six carbon atoms, such as ethanol or isopropanol. The most preferred cosolvent is ethanol. Examples of suitable hydrocarbons include n-butane, isobutane, pentane, neopentane and isopentanes. Examples of suitable ethers include dimethyl ether and diethyl ether. Examples of suitable perfluorocarbons include perfluoropropane, perfluorobutane, perfluorocyclobutane, and perfluoropentane.

    [0079] When ethanol is utilized as the cosolvent, the cosolvent is usually present in an amount of from about 1% to about 40% by weight, based on the total weight of the formulation. The ethanol should be present in an amount which fully dissolves or solubilizes tiotropium in the mixture of ethanol and water. Preferably, ethanol is present in amount sufficient to fully maintain the tiotropium in solution at freezing temperatures, such as 0° C. In general, as the temperature is decreased, the solubility of active ingredient in ethanol is decreased. Therefore, an excess of ethanol over the amount required to fully dissolve or solubilize active ingredient at ambient or room temperature is preferred. In this regard, ethanol is preferably present in an amount of at least 10% by weight, more preferably at least 15% by weight, even more preferably at least 20% by weight, and most preferably at least 25% by weight. Based on the disclosure provided herein, one skilled in the art will recognize that lower concentrations of active ingredient usually require lower concentrations of cosolvent, and vice versa, in order to form a stable solution.

    [0080] Suitable surfactants that may be used include, but are not limited to, C5-20-fatty alcohols, C5-20-fatty acids, C5-20-fatty acid esters, lecithin, glycerides, propyleneglycol esters, polyoxyethylenes, polysorbates, sorbitan esters and/or carbohydrates. C5-20-fatty acids, propyleneglycol diesters and/or triglycerides and/or sorbitans of the C5-20-fatty acids are preferred, while oleic acid and sorbitan mono-, di- or trioleates are particularly preferred.

    [0081] Suitable antioxidants that may be used include, but are not limited to, ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins or pro-vitamins occurring in the human body.

    [0082] The inhalation solution may be contained in a unit-dose, low-density polyethylene (LDPE) container, polypropylene container, or a cyclic polyolefin container. Each unit-dose container may be disposed in a foil pouch, and each foil pouch may contain 2 or more unit-dose containers. Each foil pouch containing the unit dose container may be disposed in a shelf carton. The inhalation solution comprises a single unit dose of a therapeutically effective amount of tiotropium. Such system and/or kit may provide such containers in prepackaged form. The container with a TWIST-FLEX™ top prefer, such top comprising an easy-to-grip tab-like handle such that the container may be opened, for example, by twisting off the tab by hand. The TWIST-FLEX™ top is advantageous in that it allows for easy dispensing of the solution, prevents spillage and eliminates the need to open the container or tearing by cutting or tearing off the top, or the like, thereby reducing cross-contamination. One or more of the semi-permeable single unit dose containers may be prepackaged in aluminum foil pouch, such that the foil provides a protective barrier against environmental contaminants and light as it helps to improves the shelf-life and stability of the inhalation solution. Dispensing vials may include, but are not limited to, any container comprising glass, low density polyethylene, polypropylene, cyclic polyolefins or any other material capable of preventing the solution from leaking out of the container. The vial may be enclosed by any conventional means including, but not limited to, screw cap, heat seal, snap-on top, flip-top, twist-off stopper, peel away top, and the like.

    [0083] The inhalation solution of the present invention may be administered by nebulizer. Suitable nebulizers include, but are not limited to, a jet nebulizer, an ultrasonic nebulizer, vibrating mesh nebulizer and a breath actuated nebulizer. Preferably, the nebulizer is a jet nebulizer connected to an air compressor with adequate airflow. The nebulizer being equipped with a mouthpiece or suitable face mask. The inhalation solution may be administered by nebulizers manufactured, designed or sold by Omron, such as the Omron MICRO AIR™ Ultrasonic Nebulizer. Other nebulizers may also include those manufactured, designed, or sold by Aerogen. Additionally, the formulations described herein can also be nebulized using inhalers other than those described above, for example jet-stream inhalers.

    [0084] The following non-limiting examples suitably illustrate the pharmaceutical compositions of the present invention.

    EXAMPLE 1



    [0085] The pharmaceutical compositions of the invention may include the following ingredients in amounts as provided in the following table:
    Sr. No.IngredientsRange (% w/w)
    1 Tiotropium Bromide 0.0005 to 0.1
    2 Benzalkonium Chloride 0 to 0.008
    3 Di Sodium EDTA 0.001 to 0.008
    4 Sodium Chloride 0 to 0.9
    5 1N HCl 0 to 1.4
    6 Water for injection q.s.

    EXAMPLE 2



    [0086] The pharmaceutical compositions of the invention may include following ingredients and amounts:
    Sr. No.IngredientsRange (%w/w)
    1 Tiotropium Bromide 0.0005 to 0.1
    2 Citric acid 0 to 0.008
    3 Sodium citrate 0.001 to 0.008
    4 Sodium Chloride 0 to 0.9
    5 1N HCl 0 to 1.4
    6 Water for injection q.s.


    [0087] The pharmaceutical compositions from Example 1 and Example 2 may be sterilized by filtration (through a 0.2 micron filter) and filled into a suitable container. The solution compositions may be inserted into a suitable nebulizer and the patient breathes into the nebulizer to deliver the dosage into the lungs.

    EXAMPLE 3



    [0088] The pharmaceutical compositions of the invention may include the following:
    Sr. NoIngredients10mcg/ 2ml20mcg/ 2ml40mcg/ 2ml80mcg/ 2ml
    Quantity (%w/w)
    1 Tiotropium bromide anhydrous eq. to Tiotropium 0.0005 0.001 0.002 0.004
    2 Sodium chloride 0.9
    3 Disodium edetate 0.001
    4 Hydrochloric acid as IN HCl solution q. s. to pH 2.7
    5 Water for injection q. s.

    MANUFACTURING PROCESS:



    [0089] 
    1. 1. Collect 95% of batch quantity water for injection in manufacturing vessel. Cool water for injection to 15-25°C.
    2. 2. Add and dissolve to it batch quantity of sodium chloride under stirring. Check clarity of the solution.
    3. 3. Add and dissolve to it batch quantity of disodium edetate under stirring. Check clarity of the solution.
    4. 4. Check pH and adjust pH to 2.7 using IN HCl solution.
    5. 5. Add and dissolve to it batch quantity of tiotropium bromide anhydrous under stirring. Check clarity of the solution.
    6. 6. Make up volume of bulk.
    7. 7. Filter bulk through 0.22µ PVDF filter.
    8. 8. Fill in suitable containers.

    EXAMPLE 4



    [0090] The below example illustrates the effect of different concentrations of EDTA on the stability of the composition
    #Ingredients4A4B4C
    mcg/2ml%w/wmcg/2ml%w/wmcg/2ml%w/w
    1 Tiotropium Bromide anhydrous eq. to tiotropium 80 0.004 80 0.004 80 0.004
    2 Disodium EDTA -- -- 20 0.001 200 0.01
    3 Sodium chloride 18000 0.9 18000 0.9 18000 0.9
    5 1N HCl solution q. s. to pH 2.7
    6 Water for injection qs qs qs qs qs qs
    pH of solution 2.69 2.71 2.7
    Stability data
    Related substances
    Impurity A (2-hydroxy-2,2-dithiophen-2-ylacetic acid)
    #4A4B4C
    Initial 0.02 ND 0.01
    1M 2-8°C 0.01 0.03 0.02
    1M_25°C/60% RH 0.05 0.06 0.05
    1M_40°C/75% RH 0.17 0.16 0.2
    Total impurities
    Initial 0.07 ND 0.06
    1M 2-8°C 0.08 0.00 0.12
    1M_25°C/60% RH 0.13 0.09 0.16
    1M_40°C/75% RH 0.26 0.17 0.39
    Assay %
    Initial 101.5 101.1 103.1
    1M 2-8°C 101.1 99.7 102.6
    1M_25°C/60% RH 101.1 100.2 102.4
    1M_40°C/75% RH 100.8 100.6 102.1

    Manufacturing Process:



    [0091] 
    1. 1. 90% batch quantity of water for injection was collected in a vessel.
    2. 2. Batch quantity of sodium chloride was added and dissolved under stirring.
    3. 3. Batch quantity of disodium edetate was added and dissolved under stirring.
    4. 4. pH was checked and adjusted to pH 2.7 using IN HCL solution.
    5. 5. Batch quantity of Tiotropium Bromide was added and dissolved under stirring.
    6. 6. Volume of bulk was made up.

    EXAMPLE 5



    [0092] The below example illustrates the compositions with different pH adjusting agents such as citrate buffer and 1 N HCl
    Sr. No.Ingredients5A5B
    mcg/2ml%w/wmcg/2ml%w/w
    1 Tiotropium Bromide anhydrous eq. to tiotropium 80 0.004 80 0.004
    2 Disodium EDTA 20 0.001 20 0.001
    3 Sodium chloride 18000 0.9 18000 0.9
    4 Citric acid monohydrate 8000 0.40 -- --
    5 Sodium citrate dihydrate 1200 0.06 -- --
    6 1N HCl -- q. s. to pH 2.7
    7 Water for injection qs qs qs qs
    pH of solution 2.65 2.71
    Stability data
    Related substances (Impurity A (2-hydroxy-2,2-dithiophen-2-ylacetic acid)
    # 5A 5B
    Initial 0.02 ND
    1M 2-8°C 0.03 0.03
    1M_25°C/60%RH 0.06 0.06
    1M_40°C/75%RH 0.18 0.16
    Total impurities
    Initial 0.07 ND
    1M 2-8°C 0.16 0
    1M_25°C/60%RH 0.26 0.09
    1M_40°C/75%RH 0.38 0.17
    Assay % 
    Initial 104.9 101.1
    1M 2-8°C 104.2 99.7
    1M_25°C/60%RH 104.4 100.2
    1M_40°C/75%RH 103.5 100.6

    Manufacturing Process (5A)



    [0093] 
    1. 1. 90% batch quantity of water for injection was collected in a vessel.
    2. 2. Batch quantity of sodium chloride was added and dissolved under stirring.
    3. 3. Batch quantity of disodium edetate was added and dissolved under stirring.
    4. 4. Batch quantity of citric acid monohydrate was added and dissolved under stirring.
    5. 5. Batch quantity of sodium citrate dihydrate was added and dissolved under stirring.
    6. 6. Batch quantity of Tiotropium Bromide was added and dissolved under stirring.
    7. 7. Volume of bulk was made up.

    Manufacturing Process (5B)



    [0094] 
    1. 1. 90% batch quantity of water for injection was collected in a vessel.
    2. 2. Batch quantity of sodium chloride was added and dissolved under stirring.
    3. 3. Batch quantity of disodium edetate was added and dissolved under stirring.
    4. 4. pH was checked and adjusted to pH 2.7 using IN HCL solution.
    5. 5. Batch quantity of Tiotropium Bromide was added and dissolved under stirring.
    6. 6. Volume of bulk was made up.

    EXAMPLE 6



    [0095] The below example illustrates the compositions at different pH ranges.
    Sr. NoIngredients6A6B6C6D% w/w
    mcg/ 2mlmcg/ 2mlmcg/ 2mlmcg/ 2ml
    1 Tiotropium Bromide anhydrous eq. to tiotropium 80 80 80 80 0.004
    2 Disodium EDTA 20 20 20 20 0.001
    3 Sodium chloride 18000 18000 18000 18000 0.9
    5 1N HCl q. s. to pH 2.7 q. s. to pH 2.9 q. s. to pH 2.4 q. s. to pH 2.2 --
    6 Water for injection qs qs qs qs qs
    Stability data
    Related substances
    Impurity A (2-hydroxy-2,2-dithiophen-2-ylacetic acid)
    #6A6B6C6D
    Initial 0.03 0.03 0.02 0.03
    1M 2-8°C 0.04 0.05 0.05 0.06
    1M_25°C/60%RH 0.07 0.09 0.09 0.12
    1M_40°C/75%RH 0.21 0.27 0.19 0.23
    Total impurities
    Initial 0.19 0.19 0.19 0.18
    1M 2-8°C 0.18 0.20 0.21 0.18
    1M_25°C/60%RH 0.20 0.13 0.23 0.26
    1M_40°C/75%RH 0.33 0.41 0.33 0.35
    Assay %
    Initial 97.9 102.5 103.1 102.8
    1M 2-8°C 95.6 102.30 102.2 102.2
    1M_25°C/60%RH 95.6 102.3 101.6 101.9
    1M_40°C/75%RH 95.0 101.4 100.8 101.2

    Manufacturing Process:



    [0096] 

    1. 90% batch quantity of water for injection was collected in a vessel

    2. Batch quantity of sodium chloride was added and dissolved under stirring.

    3. Batch quantity of disodium edetate was added and dissolved under stirring.

    4. pH was checked and adjusted as desired using IN HCL solution

    5. Batch quantity of Tiotropium Bromide was added and dissolved under stirring.

    5. Volume of bulk was made up.


    EXAMPLE 7



    [0097] The below example illustrates compositions with different fill volumes per unit dosage form
    Sr. No.Ingredients7A7B7C
    80mcg/1ml%w/w80mcg/2ml%w/w80mcg/3ml%w/w
    1 Tiotropium Bromide anhydrous eq. to tiotropium 80 0.008 80 0.004 80 0.0026
    2 Disodium EDTA 20 0.002 20 0.001 20 0.0006
    3 Sodium chloride 9000 0.9 18000 0.9 27000 0.9
    4 1N HCl q. s. to pH 2.7
    5 Water for injection q. s 1 ml q.s 2 ml q.s 3 ml
    pH of solution 2.69 2.71 2.68
    Related substances
    Impurity A (2-hydroxy-2,2-dithiophen-2-ylacetic acid)
    # 7A 7B 7C
    Initial ND ND ND
    1M 2-8°C 0.01 ND ND
    1M_25°C/60%RH 0.04 0.09 0.04
    1M_40°C/75%RH 0.15 0.17 0.15
    Total impurities
    Initial 0.09 0 0
    1M 2-8°C 0.11 0.16 0
    1M_25°C/60%RH 0.17 0.19 0.04
    1M_40°C/75%RH 0.29 0.28 0.15
    Assay %
    Initial 103.2 102.9 104.1
    1M 2-8°C 102.9 102.7 103.4
    1M_25°C/60%RH 101.8 101.8 102.1
    1M_40°C/75%RH 100.9 102.1 101.4

    Manufacturing process:



    [0098] 
    1. 1. 90% batch quantity of water for injection was collected in a vessel.
    2. 2. Batch quantity of sodium chloride was added and dissolved under stirring.
    3. 3. Batch quantity of disodium edetate was added and dissolved under stirring.
    4. 4. pH was checked and adjusted to pH 2.7 using IN HCL solution.
    5. 5. Batch quantity of Tiotropium Bromide was added and dissolved under stirring.
    6. 6. Volume of bulk was made up.


    [0099] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention.


    Claims

    1. A container comprising a pharmaceutical composition, being a solution and being suitable for administration with a nebulizer comprising

    (i) 0.0005% to 0.008% w/w of tiotropium or a pharmaceutically acceptable salt thereof;

    (ii) water;

    (iii) a complexing agent, the complexing agent being disodium EDTA and present at a concentration of 0.01% by weight; and

    (iv) 0.9% by weight sodium chloride

    wherein the pH of the composition ranges from 2.2 to 2.9, and said composition is free of quaternary ammonium preservatives.
     
    2. A container according to claim 1, wherein the pH of the composition ranges from 2.7 to 2.9.
     
    3. A container according to claim 1 or claim 2, wherein the container is a low-density polyethylene container.
     
    4. A container according to claims 1-3, wherein the composition comprises greater than 95% of the initial amount of tiotropium or a pharmaceutically acceptable salt thereof after being stored for 3 months at 25° C in the container.
     
    5. A container according to claims 1-4, wherein the composition is a solution.
     
    6. A pharmaceutical solution suitable for administration with a nebulizer consisting essentially of

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

    (ii) a complexing agent, the complexing agent being disodium EDTA; and

    (iii) 0.9% sodium chloride; and

    (iv) water,

    wherein the pH of the pharmaceutical solution ranges from 2.2 to 2.9, said pharmaceutical solution is free of quaternary ammonium preservatives, and the concentration of the complexing agent is present at a concentration of 0.01% by weight.
     
    7. A pharmaceutical solution according to claim 6, wherein the pH of the composition or solution ranges from 2.7 to 2.9.
     
    8. A container according to claim 5 or a pharmaceutical solution according to claim 6 or claim 7, wherein tiotropium is present in the composition in an amount of 0.001 mg to 0.3 mg.
     
    9. A container or a pharmaceutical solution according to claim 5 to 8, wherein the pH of the composition or solution is 2.7.
     
    10. A container or a pharmaceutical solution according to any of claims 5-9, wherein the osmolality of the composition is between about 275 mOsm/kg to about 325 mOsm/kg.
     
    11. A container or a pharmaceutical solution according to any of claims 7-10, wherein the composition does not require any mixing or dilution prior to administration.
     
    12. A container or pharmaceutical solution according to any of claims 5-11 for use in relieving bronchospasm associated with chronic obstructive pulmonary disease.
     
    13. A container or pharmaceutical solution according to claim 12, wherein the composition is administered in nebulized form.
     
    14. A process of preparing a container or pharmaceutical solution according to any of claims 1-13, wherein the process comprises the steps of:

    (a) dissolving tiotropium or its salt in water;

    (b) addition of a complexing agent and sodium chloride to the solution of step (a);

    (c) adjusting the pH of the solution to 2.7 to 2.9;

    (d) filtering the solution (for example, with a 0.2 micron filter); and

    (e) filling a suitable container with the solution.


     
    15. A process according to claim 14, wherein step (b) comprises adding sodium chloride and di sodium EDTA as complexing agent in the aqueous solution of tiotropium bromide.
     
    16. A kit comprising a nebulizer, instructions for using the nebulizer and a unit dose vial, wherein the unit dose vial is a container or comprises a pharmaceutical solution according to any of claims 1-15; optionally wherein the nebulizer is selected from a jet nebulizer, ultrasonic nebulizer, vibrating mesh nebulizer and a breath actuated nebulizer.
     


    Ansprüche

    1. Behälter umfassend eine pharmazeutische Zusammensetzung, die eine Lösung ist und für die Verabreichung mit einem Vernebler geeignet ist, umfassend

    (i) 0,0005 % bis 0,008 % w/w Tiotropium oder eines pharmazeutisch verträglichen Salzes davon;

    (ii) Wasser;

    (iii) einen Komplexbildner, wobei der Komplexbildner Dinatrium-EDTA ist und in einer Konzentration von 0,01 Gew.-% vorliegt; und

    (iv) 0,9 Gew.-% Natriumchlorid,

    wobei der pH der Zusammensetzung von 2,2 bis 2,9 reicht und die Zusammensetzung frei von quaternären Ammoniumkonservierungsmitteln ist.
     
    2. Behälter nach Anspruch 1, wobei der pH der Zusammensetzung von 2,7 bis 2,9 reicht.
     
    3. Behälter nach Anspruch 1 oder Anspruch 2, wobei der Behälter ein Behälter aus Polyethylen niedriger Dichte ist.
     
    4. Behälter nach Anspruch 1-3, wobei die Zusammensetzung mehr als 95 % der Anfangsmenge an Tiotropium oder eines pharmazeutisch verträglichen Salzes davon nach Lagerung für 3 Monate bei 25 °C in dem Behälter umfasst.
     
    5. Behälter nach Anspruch 1-4, wobei die Zusammensetzung eine Lösung ist.
     
    6. Pharmazeutische Lösung, geeignet für die Verabreichung mit einem Vernebler, im Wesentlichen bestehend aus

    (i) 0,0005 % bis 0,008 % w/w Tiotropium oder eines pharmazeutisch verträglichen Salzes davon,

    (ii) einem Komplexbildner, wobei der Komplexbildner Dinatrium-EDTA ist; und

    (iii) 0,9 % Natriumchlorid; und

    (iv) Wasser,

    wobei der pH der pharmazeutischen Lösung von 2,2 bis 2,9 reicht, die pharmazeutische Lösung frei von quaternären Ammoniumkonservierungsmitteln ist und die Konzentration des Komplexbildners in einer Konzentration von 0,01 Gew.-% vorliegt.
     
    7. Pharmazeutische Lösung nach Anspruch 6, wobei der pH der Zusammensetzung oder Lösung von 2,7 bis 2,9 reicht.
     
    8. Behälter nach Anspruch 5 oder pharmazeutische Lösung nach Anspruch 6 oder Anspruch 7, wobei Tiotropium in der Zusammensetzung in einer Menge von 0,001 mg bis 0,3 mg vorliegt.
     
    9. Behälter oder pharmazeutische Lösung nach Anspruch 5 bis 8, wobei der pH der Zusammensetzung oder Lösung 2,7 beträgt.
     
    10. Behälter oder pharmazeutische Lösung nach einem der Ansprüche 5-9, wobei die Osmolalität der Zusammensetzung zwischen etwa 275 mOsm/kg bis etwa 325 mOsm/kg beträgt.
     
    11. Behälter oder pharmazeutische Lösung nach einem der Ansprüche 7-10, wobei die Zusammensetzung keine Mischung oder Verdünnung vor Verabreichung erfordert.
     
    12. Behälter oder pharmazeutische Lösung nach einem der Ansprüche 5-11 zur Verwendung bei der Linderung von Bronchospasmus im Zusammenhang mit chronisch obstruktiver Lungenerkrankung.
     
    13. Behälter oder pharmazeutische Lösung nach Anspruch 12, wobei die Zusammensetzung in vernebelter Form verabreicht wird.
     
    14. Verfahren zur Herstellung eines Behälters oder einer pharmazeutischen Lösung nach einem der Ansprüche 1-13, wobei das Verfahren die folgenden Schritte umfasst:

    (a) Lösen von Tiotropium oder seines Salzes in Wasser;

    (b) Zugabe eines Komplexbildners und von Natriumchlorid zu der Lösung von Schritt (a);

    (c) Einstellen des pH der Lösung auf 2,7 bis 2,9;

    (d) Filtern der Lösung (zum Beispiel mit einem 0,2-Mikron-Filter); und

    (e) Füllen eines geeigneten Behälters mit der Lösung.


     
    15. Verfahren nach Anspruch 14, wobei Schritt (b) das Zugeben von Natriumchlorid und Dinatrium-EDTA als Komplexbildner in der wässrigen Lösung von Tiotropiumbromid umfasst.
     
    16. Kit umfassend einen Vernebler, Anweisungen zur Verwendung des Verneblers und eine Einheitsdosis-Ampulle, wobei die Einheitsdosis-Ampulle ein Behälter ist oder eine pharmazeutische Lösung nach einem der Ansprüche 1-15 umfasst; wahlweise, wobei der Vernebler ausgewählt ist aus einem Strahlvernebler, Ultraschallvernebler, Vibrating-Mesh-Vernebler und einem atmungsbetätigten Vernebler.
     


    Revendications

    1. Récipient comprenant une composition pharmaceutique, étant une solution et étant approprié pour une administration avec un nébuliseur comprenant

    (i) de 0,0005 % à 0,008 % en poids de tiotropium ou d'un sel de celui-ci acceptable sur le plan pharmaceutique ;

    (ii) de l'eau ;

    (iii) un agent complexant, l'agent complexant étant l'EDTA disodique et présent à une concentration de 0,01 % en poids ; et

    (iv) 0,9 % en poids de chlorure de sodium

    dans lequel le pH de la composition est compris dans la plage allant de 2,2 à 2,9, et ladite composition est exempte de conservateurs à base d'ammonium quaternaire.
     
    2. Récipient selon la revendication 1, dans lequel le pH de la composition est compris dans la plage allant de 2,7 à 2,9.
     
    3. Récipient selon la revendication 1 ou la revendication 2, dans lequel le récipient est un récipient en polyéthylène de faible densité.
     
    4. Récipient selon les revendications 1 à 3, dans lequel la composition comprend plus de 95 % de la quantité initiale de tiotropium ou d'un sel de celui-ci acceptable sur le plan pharmaceutique après avoir était stocké pendant 3 mois à 25 °C dans le récipient.
     
    5. Récipient selon l'une quelconque des revendications 1 à 4, dans lequel la composition est une solution.
     
    6. Solution pharmaceutique appropriée pour une administration avec un nébuliseur constituée essentiellement de

    (i) 0,0005 % à 0,008 % en poids de tiotropium ou d'un sel de celui-ci acceptable sur le plan pharmaceutique,

    (ii) un agent complexant, l'agent complexant étant l'EDTA disodique ; et

    (iii) 0,9 % du chlorure de sodium ; et

    (iv) d'eau,

    dans lequel le pH de la solution pharmaceutique est compris dans la plage allant de 2,2 à 2,9, ladite solution pharmaceutique est exempte de conservateurs à base d'ammonium quaternaire, et la concentration de l'agent complexant est présent à une concentration de 0,01 % en poids.
     
    7. Solution pharmaceutique selon la revendication 6, dans laquelle le pH de la composition ou de la solution est compris dans la plage allant de 2,7 à 2,9.
     
    8. Récipient selon la revendication 5 ou solution pharmaceutique selon la revendication 6 ou la revendication 7, du tiotropium étant présent dans la composition en une quantité allant de 0,001 mg à 0,3 mg.
     
    9. Récipient ou solution pharmaceutique selon la revendication 5 à 8, le pH de la composition ou de la solution étant de 2,7.
     
    10. Récipient ou solution pharmaceutique selon l'une quelconque des revendications 5 à 9, l'osmolalité de la composition étant comprise entre environ 275 mOsm/kg et environ 325 mOsm/kg.
     
    11. Récipient ou solution pharmaceutique selon l'une quelconque des revendications 7 à 10, la composition ne nécessitant aucun mélange ou aucune dilution avant son administration.
     
    12. Récipient ou solution pharmaceutique selon l'une quelconque des revendications 5 à 11 destiné à être utilisé dans le soulagement du bronchospasme associé à la broncho-pneumopathie chronique obstructive.
     
    13. Récipient ou solution pharmaceutique selon la revendication 12, la composition étant administrée sous forme nébulisée.
     
    14. Procédé de préparation d'un récipient ou d'une solution pharmaceutique selon l'une quelconque des revendications 1 à 13, dans lequel le procédé comprend les étapes de :

    (a) dissolution de tiotropium ou de son sel dans l'eau ;

    (b) addition d'un agent complexant et de chlorure de sodium à la solution de l'étape (a) ;

    (c) ajustement du pH de la solution de 2,7 à 2,9 ;

    (d) filtration de la solution (par exemple, avec un filtre de 0,2 micron) ; et

    (e) remplissage d'un récipient approprié avec la solution.


     
    15. Procédé selon la revendication 14, dans lequel l'étape (b) comprend l'ajout de chlorure de sodium et d'EDTA disodique en tant qu'agent complexant dans la solution aqueuse de bromure de tiotropium.
     
    16. Kit comprenant un nébuliseur, des instructions pour l'utilisation du nébuliseur et un flacon mono-dose, dans lequel le flacon mono-dose est un récipient ou comprend une solution pharmaceutique selon l'une quelconque des revendications 1 à 15 ; dans lequel le nébuliseur est éventuellement choisi parmi un nébuliseur à jet, un nébuliseur à ultrasons, un nébuliseur à tamis vibrant et un nébuliseur actionné par la respiration.
     






    Cited references

    REFERENCES CITED IN THE DESCRIPTION



    This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

    Patent documents cited in the description




    Non-patent literature cited in the description