Field of invention

The present invention relates to a new crystalline form of an active agent, the processes for preparing this crystalline form, the pharmaceutical compositions comprising this crystalline form and the use of these compositions in the treatment of respiratory system diseases.

Background of the Invention

The present invention relates to a new crystalline form of the active agent tiotropium bromide, the processes for preparing this crystalline form, the pharmaceutical compositions comprising this crystalline form and the use of these compositions in the treatment of respiratory system diseases.

Tiotropium (Formula I) is an anticholinergic agent with the chemical name (1a, 2β, 4β, 5a, 7β)- 7-[(Hydroxidi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azon iatricyclo[3.3.1.0 ^{2 4} ] nonane.

(I)

Tiotropium was disclosed in the patent application EP0418716 A1 (patents numbered USRE39820 E1 , US5610163 A and W09104252 A1 exist in the patent family) for the first time. The application includes processes for the preparation of tiotropium, pharmaceutical compositions comprising tiotropium, long acting, highly effective anticholinergic activity of tiotropium and its use in the treatment of respiratory system diseases.

Tiotropium is a long acting highly effective anticholinergic bronchodilator orally administered via dry powder inhalation for the treatment of respiratory system diseases. Tiotropium antagonizes the effect of acetylcholine by blocking cholinergic muscarinic receptors. Tiotropium is released slowly from Mi and M ₃ receptors mediated by bronchoconstriction, and rapidly from M2 receptors that inhibit acetylcholine release from cholinergic nerve endings. This situation occurring in the receptors in the lungs explains the long acting bronchodilator activity of the drug. Inhalation therapy is a widely preferred treatment for the treatment of respiratory system diseases, particularly chronic diseases that threaten a widespread segment in the society, such as asthma and chronic obstructive pulmonary disease (COPD). The reason is that the drug reaches the site of effect directly and rapidly, provides the desired effect with lower doses compared to oral and parenteral administration as the drug reaches the target area directly, and the drug used at low doses exhibits less side effects than the drug administered via oral or parenteral route. Since drugs administered by inhalation are not exposed to the gastrointestinal tract, gastrointestinal problems such as low solubility, low permeability, drug irritation, formation of undesired metabolites and reduced food-dependent bioavailability are felt at a minimum.

In addition to the aforementioned advantages of the inhalation therapy, it also has various difficulties that should be considered when converting the active ingredient to a suitable form for use by the inhalation route. For example, the active agent particles to be administered by the inhalation route, ideally has to meet the essential requirements such as appropriate aerodynamic particle size, appropriate particle shape, uniformity of particle size distribution, low aerodynamic dispersion forces, low density, high physical and chemical stability. In the aforementioned characteristics, the concepts of appropriate particle size, uniformity of particle size distribution and high physical and chemical stability are closely related to structural properties of the active ingredient.

Stability is generally understood to mean the stability of the active agent exhibited when exposed to environmental conditions, as well as the stability exhibited by the formulation during its production, and the stability it exhibits after being converted to the final product. The reason for the concept of stability to come to the forefront is that the requirement that the content of active agent reaching the target area is not less than the desired amount becomes more important, based on the fact that the administered dose is low. For example, moisture absorption, one of the factors affecting physical stability, will cause the content of active agent to be lower than the desired amount. To give another example, the tendency to change the polymorphic structure, one of the factors affecting chemical stability, is undesirable. The preservation of the crystalline form of the active agent under mechanical effect, heat effect etc. is required, and there should be no change in its polymorphic structure.

On the other hand, it is important that the active agent in pharmaceutical compositions is in a form that can be processed and stored in a proper manner. The chemical stability and the shelf life of the active agent are the two important criteria in this respect. The active ingredient and the pharmaceutical compositions containing it must have the ability to be stored during its shelf life without causing any significant changes in the physicochemical characteristics of the active ingredient.

From a chemical standpoint, these important criteria often can not be provided with amorphous active agents. The amorphous active agents generally are forms without appropriate solubility, that are unstable and chemically impure and therefore it is more difficult to produce, formulate in a pharmaceutical composition and store the amorphous active agents.

Suitable particle size and uniformity of particle size distribution are also closely related to the structural properties of the active agent. Since only particles of a particular size (1-1 Ομπι, preferably <5 m) can be administered to the lungs via inhalation route, a powder mixture of particles of different sizes will not be able to reach the target area with the desired amount. As large particles accumulate in areas outside the target area, desired small particles reach the target area and are absorbed there. In order to achieve the desired efficiency, the homogenization of the particle size distribution, in other words in order to achieve uniformity, the particle size must be reduced to the desired size. For this purpose, the powder mixture containing the active agent is subjected to challenging steps such as micronization. At this time, the active agent must have a stable structure that will enable micronization, and it is necessary to preserve its crystalline shape under the aforementioned mechanical effect.

As a result, it is necessary to produce new forms (e.g. new crystalline forms) of the active agent with better structural properties that can meet the mentioned requirements. Since each different form of the same molecule will exhibit different characteristics, the more alternatives there are to choose from the most appropriate one for inhalation therapy, the higher the possibility to reach the best result is.

A variety of documents are available, including the state of the art, regarding the different forms (such as salts, hydrates, anhydrides, crystalline and amorphous forms) of the tiotropium active agent.

For instance, while the crystalline monohydrate form of tiotropium bromide is disclosed in the patent numbered WO 0230928 A1 , its crystalline anhydride form is described in patent numbered WO 2005/042527 A1.

European patent EP 1869035 discloses the crystalline form of tiotropium bromide characterized by 20.2, 26.5, 28.0, and 31.2 XRD 2-theta values, and the method of producing such a crystalline form. In the patent numbered WO 2006/117300 A2, the crystalline anhydride form; crystalline methanol solvate; crystalline ethanol solvate; crystalline isopropanol solvate; crystalline tetrahydrofuran solvate; crystalline 1 , 4-dioxane solvate; crystalline dimethyl formamide solvate; crystalline mixed methylene chloride / methyl ethyl ketone solvate and crystalline 1- butanol solvate of tiotropium bromide is disclosed.

However, in pharmaceutical technology, the solvates are less preferred than other forms, based on their mechanical effect due to their chemical structure and their degradation tendency under heat effect.

In addition to the crystalline forms, studies on the amorphous forms of the active agent have been carried out. For instance, patent WO2013107434 discloses amorphous and crystalline forms for tiotropium iodide. However, amorphous forms are also not preferred due to the disadvantages described above.

As a result, various crystalline and amorphous forms of tiotropium have been produced in the state of the art. However, there is still a need for new crystalline forms having better structural features that meet the requirements for administrating via inhalation, which may be alternative to these forms.

Summary of the Invention

The present invention relates to a new crystalline form of tiotropium bromide, the processes for preparing this crystalline form, the pharmaceutical compositions comprising this crystalline form and the use of these compositions in the treatment of respiratory system diseases.

The tiotropium bromide crystalline form subject to the present invention is characterized by having peaks in the X-ray powder diffraction pattern (XRPD) measurement of 9.7, 10.8, 13.8 and 21.4 (± 0.2) (copper Ka radiation)) 2Θ angles.

In other words, the present invention discloses the crystalline form of tiotropium bromide characterized by the values 9.7, 10.8, 13.8 and 21.4 (± 0.2) 2Θ in the X-ray powder diffraction pattern (XRPD) measurement.

The crystalline form of tiotropium bromide according to the present invention, on the other hand, is characterized by having an endothermic peak of 230-233 ⁰ C in the DSC thermogram.

The present invention, on the other hand, describes processes for the preparation of the tiotropium bromide crystalline form according to the invention. The present invention, on the other hand, describes the pharmaceutical compositions comprising these new crystalline forms according to the invention and the preparation methods of these.

The present invention on the other hand describes the use of pharmaceutical compositions containing novel crystalline forms of the tiotropium bromide according to the invention in the treatment of respiratory diseases, in particular asthma and COPD.

Detailed Description of the Invention

The present invention relates to a novel crystalline form of the active agent tiotropium bromide.

The crystalline form subject to the present invention is characterized by having peaks in the X- ray powder diffraction pattern (XRPD) measurement of 9.7, 10.8, 13.8 and 21.4 (± 0.2) (copper Ka radiation)) 2Θ angles. The crystalline form according to the invention can also preferably be characterized by the XRPD spectrum according to drawing 1.

The tiotropium bromide crystalline form, according to the present invention is characterized by having an endothermic peak in the range of 230-233 ⁰ C in the DSC thermogram.

Preferably, the tiotropium bromide crystalline form, according to the present invention is characterized by having an endothermic peak of 232 ⁰ C in the DSC thermogram.

According to the present invention, the tiotropium bromide crystalline, is basically obtained by the evaporation of a tiotropium bromide solvate under reduced pressure at 90-107 ° C in an evaporator.

The tiotropium bromide solvate referred to herein may be any solvate in the prior art, as well as may have been obtained by any of the methods known in the art.

As the solvates disclosed in the patent numbered WO 2006/117300 A2, such as the crystalline methanol solvate; crystalline ethanol solvate; crystalline isopropanol solvate; crystalline tetrahydrofuran solvate; crystalline 1 ,4-dioxane solvate; crystalline dimethyl formamide solvate; crystalline mixed methylene chloride / methyl ethyl ketone solvate and crystalline 1- butanol solvate of tiotropium bromide can be given as an example to the said solvates, the mentioned solvates are not limited to these solvates.

The analysis methods used for the characterization of the crystalline structure according to the invention analysis method of the X-ray powder diffraction X-ray powder diffraction patterns were obtained using the Rigaku D/Max-2200/PC model device equipped with a copper Ka source. The relevant device has a power capacity of 200 Vac 3q 20 A/50 Hz, high temperature furnace units and a Cu-targeted x-ray tube.

Scanning parameters:

Range: 2-55 degrees 2Θ,

Step size 2θ=0.02 ^ο , continuous scanning,

Speed: 2 degrees/minute,

Step duration: 0,6 seconds.

DSC analysis method The scanning parameters related to the analysis are as follows: Device: DSC 6000, Perkin Elmer Sample weight:4-8 mg. N ₂ flow rate: 19,8 ml/min Heating rate: 10°C /min

Method: kept at 30 °C for 1 min., heated to 30-250 °C.

Short description of the figures

Figure 1 : X-ray powder diffraction pattern of the tiotropium bromide crystalline form

- X-ray powder diffraction analysis results

The X-ray powder diffraction pattern of the tiotropium bromide crystalline form according to the invention is shown in Figure 1.

According to the analysis results, the crystalline form subject to the present invention is characterized by having peaks in the X-ray powder diffraction pattern (XRPD) measurement of 9.7, 10.8, 13.8 and 21.4 (± 0.2) (copper Ka radiation)) 2Θ angles.

The process of preparing the crystalline form according to the invention

The tiotropium bromide crystalline according to the invention is basically obtained in 3 steps: 1) Obtaining Tiotropium Bromide

Tiotropium bromide, as disclosed in the patent numbered EP418716 (B1) owned by the firm Boehringer Ingelheim International GmbH is prepared from the starting material, scopine di (2- thienyl) glycolate.

For this, in the first step, scopine di(2-thienyl)glycolate is mixed with acetonitrile and dichloromethane and methylated with bromomethane.

2) Obtaining Tiotropium Bromide Solvate

In the second step, the intermediate product obtained in the first step, is crystallized in the methanol: acetone mixture to form the tiotropium bromide methanol solvate.

3) Obtaining the New Tiotropium Bromide Crystalline

In the last step, tiotropium bromide methanol solvate is evaporated under reduced pressure at 90-107 ° C in order to form tiotropium bromide.

Crystalline form according to the invention of the tiotropium bromide is a crystalline form with better structural features to meet the requirements for administration via inhalation route.

The term "Crystalline form according to the invention of the tiotropium bromide" refers to the crystalline form of tiotropium bromide with having peaks at 9.7, 10.8, 13.8 and 21.4 (± 0.2) 2Θ angles in the X-ray powder diffraction pattern.

The aforementioned crystalline form is required to be formulated for use in the treatment of inhalation. Pharmaceutical compositions and methods of preparation comprising a pharmaceutically acceptable, non-toxic, and therapeutically effective amount of the novel crystalline form of the tiotropium bromide according to the invention are also a feature of the invention.

The present invention, in other words, discloses pharmaceutical compositions comprising the new crystalline of tiotropium bromide with peaks at 9.7, 10.8, 13.8 and 21.4 (± 0.2) 2Θ angles in the X-ray powder diffraction pattern as an active agent.

The pharmaceutical compositions according to the invention contain at least one pharmaceutically acceptable excipient in addition to the active agent.

As an active agent, pharmaceutical compositions containing the crystalline form of tiotropium bromide according to the invention are in the form of dry powder or pressurized metered-dose inhalation composition and preferably in dry powder inhalation composition form. During the preparation process of dry powder inhalation compositions, two methods are commonly implemented in order to administer effective amount of the drug to the targeted area. One of these is based on controlled agglomeration of the undiluted drug, the other one is based on adhesion of the micronized drug particles to the surface of an inert carrier having large particle size. The pharmaceutical compositions according to the invention are preferably prepared by implementing the second method. When the second method is implemented, the pharmaceutical composition comprises at least one pharmaceutically acceptable inert carrier and optionally at least one pharmaceutically acceptable excipient different from the carrier(s), along with the active agent.

Crystalline form according to the present invention of the tiotropium bromide is characterized by having an average particle size in the range of 1-10 μιτι, preferably in the range of 1-5 μητι. The pharmaceutical compositions according to the present invention are characterized in that they comprise crystalline form of tiotropium bromide in the range of 0.001-50%, preferably in the range of 0.01-10%.

The term "inert carrier" refers to a carrier that is preferably lactose, more preferably lactose monohydrate, for dry powder inhalation compositions according to the invention. The pharmaceutical compositions according to the present invention can comprise at least one inert carrier having large particle size or small particle size and optionally at least one excipient together. The inert carrier having large particle size according to the invention is characterized by having an average particle size in the range of 10-250 μιτι, preferably in the range of 10- 150 μιτι, more preferably of 150 μιτι; the inert carrier having small particle size, on the other hand, is characterized by having an average particle size (dso) in the range of 1-10 μητι, preferably of 10 μητι. The inert carrier having large particle size and small particle size can be the same agent having different particle size as well as a different agent.

At least one pharmaceutically acceptable excipient can be selected from carbohydrates such as lactose, glucose, fructose, galactose, sucrose, maltose, trehalose, maltodextrins, dextrans, cyclodextrins, starch and cellulose; polyalcohols such as sorbitol, mannitol and xylitol; amino acids such as glycine, arginine, lysine, aspartic acid and glutamic acid; peptides such as human serum albumin; gelatine; various salts and taste masking agents. The said at least one excipient is not limited to these substances.

In preparation process of pressurized metered-dose inhalation compositions, two formulation strategies are implemented depending on physicochemical characteristics of the active agent and propellant gas system. One of these formulation strategies is a solution formulation and the other one is a suspension formulation. The preferred pharmaceutical composition along with the active agent comprises propellant gases, surfactants and at least one basic excipient selected from the group of co-solvents and optionally at least one other pharmaceutically acceptable excipient.

The term "active agent" refers to the crystalline form characterized by peaks at 9.7, 10.8, 13.8 and 21.4 (± 0.2) 2Θ angles in the tiotropium bromide X-ray powder diffraction pattern.

The crystalline form of tiotropium bromide according the invention has an average particle size in the range of 1-1 Ομιτι, preferably in the range of 1-5μιτι. The pharmaceutical compositions according to the invention are characterized in that they comprise the tiotropium bromide crystalline form in the range of 0.001-50%, preferably in the range of 0.01-10%.

Depending on the formulation strategy, at least one pharmaceutically acceptable excipient can be selected from propellant gases (propellants) such as chlorofluorocarbons, hydrofluoroalkanes and hydrocarbons; surface active agents (surfactants) such as oleic acid, polysorbates, propylene glycol, polyethylene glycol, cetyl alcohol, stearyl alcohol, sorbitan fatty acid esters, sugar esters of fatty acids, glycerides of fatty acids, isopropyl myristate and lecithin; cosolvents such as ethanol, water and diethyl ether; antioxidants and sweeteners such as butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulphide, gallates (such as propyl gallate), tocopherol, citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithin, ascorbyl palmitate, ethylenediaminetetraacetate. The said at least one excipient is not limited to these substances.

The pharmaceutical compositions comprising the crystalline form according to the invention of tiotropium bromide can additionally comprise at least one active agent to be used separately, sequentially or simultaneously selected from drugs such as other anticholinergic agents, adrenergic agonists, anti-allergic agents, anti-inflammatory agents, antihistaminics, steroids, leukotriene receptor antagonists, antimuscarinic agents, PDE inhibitors and EGFR inhibitors.

Another feature of the invention is that the pharmaceutical compositions comprising the crystalline form according to the invention of tiotropium bromide are used in the treatment of respiratory tract diseases, particularly in the treatment of asthma and COPD.

Example 1.

After mixing 240 g (0.635 mol) of scopine di(2-thienyl)glycollate 1.4 1 acetonitrile and 0.970 ml of dichloromethane, a solution of 424.4 g (4.45 mole) of acetonitrile containing 50% of methyl- bromide is added thereto and stirred at room temperature for 36 hours, than filtered and washed with dichloromethane and dried. The dried product is crystallized with methanol : acetone mixture.

The obtained solid matter is evaporated in an evaporator under reduced pressure at a temperature of 90-107 ° C to give 220 g of Tiotropium Bromide crystalline (yield 73%).