ME00246B - HFA SUSPENSION FORMULATIONS OF AN ANHYDRATE - Google Patents

Abstract

The invention relates to the formulation, with propellant, of a suspension, of crystalline anhydrate (1α, 2β, 4β, 5α, 7β) -7 - [(hydroxides-2-thienylacetyl) oxy] -9,9-dimethyl-3-oxa-9 -azo-niatricyclo [3.3.1.0 2,4] nonan-bromide

Description

The invention relates to preparations under gas pressure, for dispensing aerosols with a suspension formulation, crystalline anhydrate (1α, 2β, 4β, 5α, 7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9, 9-dimethyl-3 -oxa-9-azoniatricyclo[3. 3. 1. 02, 4]nonane-bromide.

Basic data related to the invention

The compound (1α, 2β, 4β, 5α, 7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9, 9-dimethyl-3-oxa-9-azoniatricyclo[3. 3. 1. 02, 4] nonane-bromide, is known based on the European patent application EP 418 716 A1, and has the following chemical structure:

The compound has valuable pharmacological properties and is known under the name tiotropium bromide (BA679). Tiotropium bromide is a very effective anticholinergic, so it can be of therapeutic use in the treatment of asthma or COPD (chronic obstructive pulmonary disease).

Tiotropium bromide is used primarily by inhalation.

The task of this invention is to prepare HFA-sols with dosing containing tiotropium bromide as the only active substance, in suspended form.

Detailed description of the invention

It was established that tiotropium bromide, depending on the choice of conditions that can be applied, during the purification of the raw product obtained under technical conditions, occurs in different crystalline modifications.

It has been found that these various modifications can be obtained in the desired form, depending on the choice of solvent used in the crystallization, as well as the choice of the selected crystallization conditions. One of these crystalline modifications is tiotropium bromide crystalline monohydrate.

Unexpectedly, it was discovered that starting from that, based on the state of the art of the still unknown crystal monohydrate of tiotropium bromide, an anhydrous crystalline modification of tiotropium bromide (tiotropium-anhydrate) can be obtained, which is extremely suitable for the preparation of suspensions in HFA 227 pressure gases and/or HFA 134a, which can be administered by inhalation.

Therefore, this invention relates to suspensions of crystalline tiotropium bromide-anhydrate, in propellant gases HFA 227 and/or HFA 134a, in a given case, in a mixture with one or more other propellant gases, primarily selected from the group consisting of propane, butane , pentane, dimethylether, CHC1F2, CH2F2, CF3CH3, isobutane, isopentane and neopentane.

If crystalline titropium bromide anhydrate is considered within the scope of this invention, then it should be considered as a reference for that anhydrous crystalline modification of titropium bromide which can be obtained by drying crystalline titropium bromide monohydrate. This crystalline modification is also referred to in the context of this invention as crystalline tiotropium bromide in anhydrous form.

On the basis of the invention, those suspensions that contain only HFA 227, a mixture of HFA 227 and HFA 134a, or only HFA 134a are preferred. If a mixture of HFA 227 and HFA 134a propellant gases is used in the formulation of the suspension, based on the invention, then the mass ratios in which these two propellant gas components can be used can be freely changed.

If in the suspension formulations, based on the invention, in addition to the propellant gases HFA 227 and/or HFA 134a, one or more other propellant gases selected from the group consisting of propane, butane, pentane, dimethyl ether, CHC1F2, CH2F2, CF3CH3, isobutane, isopentane are introduced and neopentane, then the proportion of these further components of the propellant gases is primarily below 50%, preferably below 40%, and especially below 30%.

The suspensions according to the invention preferably contain between 0.001 to 0.8% tiotropium. Based on the invention, suspensions containing 0.08 to 0.5%, and especially preferably 0.2 to 0.4% tiotropium, are preferred.

By tiotropium is meant the free ammonium cation. For propellant gas suspensions, based on the invention, it is characteristic that they contain tiotropium in the form of tiotropium bromide-anhydrate, which is extremely suitable for that application. That being said. this invention primarily relates to suspensions containing between 0.0012 and 96% of crystalline tiotropium bromide-anhydrate. Based on the invention, of particular importance are suspensions containing 0.096 to 0.6%, and 0.24 to 0.48% of crystalline tiotropium bromide-anhydrate is particularly advantageous.

The stated percentages, within the scope of this invention, are always mass percentages. When tiotropium mass fractions are expressed as mass percentages, the corresponding values for input crystalline monotropium bromide-anhydrate, which is preferred within the scope of this invention, are obtained by multiplying by the conversion factor, 1, 2036.

In this case, within the scope of this invention, instead of the name suspension, the name suspension formulation (suspension formulation) is also used. Within the scope of this invention, both names have the same meaning.

Inhalation aerosols, or suspension formulations, which contain the propellant gas according to the invention, may also contain other ingredients, such as surface-active agents (surfactants, surfactants), adjuvants, antioxidants or flavoring agents.

Surfactants (surfactants, surfactants) which, in a given case, contain suspensions, based on the invention, are primarily selected from the group consisting of Polysorbat 20, Polysorbat 80, Myvacet 9-45, Myvacet 9-08, isopropyl myristate, oleic acid, propylene glycol, polyethylene glycol, Brij, ethyl oleate, glyceryl trioleate, glyceryl mono-laurate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, sterile alcohol, cetylpyridinium chloride, block polymers, natural oil, ethanol and isopropanol. Of the above-mentioned suspension aids, Polysorbat 20, Polysorbat 80, Myvacet 9-45, Myvacet 9-08 or isopropyl myristate are primarily suitable for use. The application of Myvacet 9-45 or isopropyl myristate is particularly advantageous.

If the suspensions, based on the invention, contain surface-active agents, they are introduced primarily in a proportion of 0.0005 - 1%, particularly preferably 0.005 - 0.5%. Adjuvants, in this case, present in suspensions based on the invention, are primarily selected from the group consisting of alanine, albumin, ascorbic acid, aspartame, betaine, cysteine, phosphoric acid, nitric acid, sonic acid, sulfuric acid and citric acid. The application of ascorbic acid, phosphoric acid, sodium acid or citric acid, especially sodium acid or citric acid, is particularly advantageous.

If the suspensions, based on the invention, contain adjuvants, they are introduced primarily in a proportion of 0.0001-1.0%, preferably 0.0005-0.1%, and especially preferably 0.001-0.01%, whereby, based on the invention, the share of 0.001-0.005% is of particular importance.

Antioxidants, which in this case are found in suspensions, based on the invention, are selected primarily from the group consisting of ascorbic acid, citric acid, sodium edetate, editic acid, tocopherols, butylhydroxytoluene, butylhydroxyanisole and ascorbyl palmitate, and are primarily suitable for use, tocopherols, butylhydroxytoluene, butylhydroxyanisole or ascorbyl palmitate.

Flavoring agents, which in the given case are found in suspensions, are primarily selected from the group consisting of mint, saccharin, Dentomint, aspartame and essential oils (for example cinnamon, anise, menthol, camphor), whereby mint or Dentomint®.

With regard to inhalation use, it is necessary to prepare the active substance in the form of fine particles. For this, as explained in the experimental part, the crystalline tiotropium bromide-anhydrate that is used is obtained in the form of fine particles, either by grinding (micronization) or by means of other technical procedures known in principle, based on the state of the art, (e.g. precipitation, spray - by drying).

Processes for micronizing are known, based on the state of the art. Primarily, after micronization, the active substance has a mean particle size of 0.5 to 10 pm, preferably from 1 to 6 pm, and particularly preferably from 1.5 to 5 pm. Primarily, at least 50%, preferably at least 60%, and especially preferably at least 70% of the particles of the active substance, have a particle size that is in the range of previously mentioned sizes. It is particularly advantageous that the size, at least 80%, and the most favorable is at least 90%, of the particles of the active substance is in the previously mentioned ranges.

Unexpectedly, it was found that it is also possible to prepare suspensions that, in addition to the mentioned propellant gases, contain only the active substance, without other additives. Therefore, a further aspect of the present invention relates to suspensions, which contain only the active substance, without other additives.

Preparation of suspensions, based on the invention, can be carried out according to procedures known from the state of the art. For this, the ingredients of the formulation are mixed with one or more propellant gases (in the given case, at lower temperatures) and suitable containers are filled.

The previously mentioned suspensions, based on the invention, which contain pressure gas, can be used using, based on the state of the art, known inhalers (pMDIs = pressurized metered dose inhalers). Therefore, a further aspect of the present invention relates to the drug, in the form of the previously described suspensions, which is in connection with one or more inhalers, suitable for using these suspensions. Furthermore, this invention relates to inhalers which are characterized by containing, based on the invention, the previously described suspensions containing propellant gas. This invention further relates to containers (eg cartridges) which, provided with a suitable valve, can be used in a suitable inhaler, and which contain the above-mentioned suspensions with a propellant gas, based on the invention. Based on the state of the art, suitable containers (e.g. cartridges) and methods for filling such cartridges with suspensions containing propellant gas are known based on the invention.

With regard to the pharmaceutical effectiveness of tiotropium, this invention also relates to the use of suspensions, based on the invention, for the preparation of a drug that is administered by inhalation or nasally, primarily for the preparation of a drug for the inhalation or nasal treatment of diseases in which anticholinergics can be of therapeutic benefit .

Particularly advantageously, this invention also relates to the use of suspensions, based on the invention, for the preparation of a medicine for

inhalational treatment of respiratory diseases, primarily asthma or COPD.

The following examples serve to exemplify, in more detail, this invention, while its content is not limited by them.

Starting materials

Crystalline tiotropium bromide monohydrate:

For the preparation of crystalline tiotropium bromide monohydrate, tiotropium bromide obtained according to EP 418 716 Al can be used. It is then treated as described below.

25.7 kg of water and 15.0 kg of tiotropium bromide were introduced into a suitable reaction vessel. The mixture was heated to 80 - 90 °C and stirred at that temperature until a clear solution was formed. Activated charcoal (0.8 kg), moistened with water, was stirred in 4.4 kg of water, this mixture was introduced into a solution containing tiotropium bromide, and 4.3 kg of water was added. The mixture thus obtained was mixed for at least 15 minutes at 80 - 90 °C, and then it was filtered through a heated filter into a preheated apparatus, the jacket of which was at a temperature of 70 °C. The filter was washed with 8.6 kg of water. The contents of the apparatus were cooled to a temperature of 20 - 25 °C, with a cooling rate of 3 - 5 °C in 20 minutes. With cold water, the apparatus was further cooled to 10 - 15 °C, and crystallization was completed after at least one hour of stirring. The crystallizate was separated through a drying oven, the separated crystal flour was washed with 9 liters. cold water (10 - 15 °C) and cold acetone (10 - 15 °C). The obtained crystals were dried at 25 °C for more than 2 hours, in a stream of nitrogen.

Prinos: 13. 4 kg thiotropijumbromide-monohydrate (86 theor. %).

Tiotropium bromide-monohydrate, which is obtained according to the previously described procedure, was examined using DSC (Differential Scanning Calorimetry). The DSC diagram shows two characteristic signals. The first, relatively broad, endothermic signal between 50-120 °C corresponds to the removal of water from tiotropium bromide monohydrate and its return to the anhydrous form. The second, relatively sharp, endothermic maximum at 230 ± 5 °C corresponds to the melting of the substance. These data were obtained using the Mettler DSC 821 device, and their value was determined using the Mettler Software Package STAR. The data were obtained at a heating rate of 10 K/min.

The characterization of tiotropium bromide monohydrate was performed using IR-spectroscopy. The data were obtained using a Nicolet FTIR spectrometer, and were recalculated

by Nicolet Software-package OMNIC, version 3. 1. Measurements were performed with 2.5 pmol tiotropium bromide monohydrate, in 300 mg KBr.

The following table contains some of the important bands of the IR spectrum.

The crystalline tiotropium bromide-monohydrate that can be obtained according to the previous procedure, based on the X-ray structural analysis of the mono-crystal, has a simple monoclinic cell with the following dimensions: a = 18.0774 Å, b = 11.9711 Å, c = 9, 9321 Å, β= 102, 691°, V = 2096, 96 Å3. These data were obtained using an AFC7R-4-circle diffractometer (Rigaku) using monochromatic copper Ka radiation. Determination of the structure and refined crystal structure was performed by direct methods (program SHELXS86) and FMLQ-refinement of the structure (program TeXsan).

Kristalni tiotropiumbromid-anhidrat:

The anhydrous form is obtained from crystalline tiotropium bromide monohydrate, obtained as described above, by careful drying at 80 - 100 °C under reduced pressure, primarily in high vacuum, for a period of at least 30 minutes. Alternatively to the drying step at 80 - 100 °C, in vacuum, the anhydrous form can also be prepared by storage in the presence of dried silica gel, at room temperature, for at least 24 hours.

The crystal structure of anhydrous tiotropium bromide was determined on the basis of high-resolution X-ray powder analysis data (synhotron radiation) using a real-space setup, via the so-called "simulated annealing" (simulated annealing). Then a Rietveld analysis was performed to improve the structural parameters. These tests showed that the crystalline tiotropium bromide-anhydrite, which is used in suspensions, based on the invention, is characterized by an elementary cell

For the preparation of suspensions, based on the invention, crystalline tiotropium bromide-anhydrate, which can be obtained by the previous process, is micronized, protected from moisture, according to a process already known based on the state of the art, in order to prepare the active substance in the form of medium particle size, which corresponds to specifications, based on the invention.

Examples of formulation

Suspensions that, in addition to the active substance and propellant gas, also contain other ingredients:

Suspensions containing only the active substance and propellant gas:

Claims (9)

1. Suspensions of crystalline tiotropium bromide-anhydrate, in HFA 227 and/or HFA 134a propellant gases, in a given case, in a mixture with one or more other propellant gases, selected from the group consisting of propane, butane, pentane, dimethylether, CHClF2, CH2F2 , CF3CH3, isobutane, isopentane and neopentane. 2. Suspensions according to claim 1, characterized in that they contain between 0.001 and 0.8% of tiotropium. 3. Suspensions, according to claim 1 or 2, characterized by the fact that as further ingredients they contain surface-active agents (surfactants, surfactants), adjuvants, antioxidants and/or flavoring agents. 4. Suspensions, according to claim 3, characterized by the fact that, as surface-active agents (surfactants, surfactants), they contain one or more compounds selected from the group consisting of Polysorbate 20, Polysorbate 80, Myvacet 9-45, Myvacet 9-08, isopropylmyristate, oleic acid, propylene glycol, polyethylene glycol, Brij, ethyl oleate, glyceryl trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricin-oleate, cetyl alcohol, sterile alcohol, cetylpyridinium chloride, block polymers, natural oil, ethanol and isopropanol. 5. Suspensions, according to claim 3, characterized by the fact that as adjuvants they contain one or more compounds selected from the group consisting of alanine, albumin, ascorbic acid, aspartame, betaine, cysteine, phosphoric acid, nitric acid, sonic acid, sulfuric acid and citric acid. 6. Suspensions, according to claim 3, characterized by the fact that as antioxidants they contain one or more compounds selected from the group consisting of ascorbic acid, citric acid, sodium um-edetate, editic acid, tocopherols, butylhydroxytoluene, butylhydroxyanisole and ascorbyl palmitate. 7. Suspensions, according to claim 1 or 2, characterized by the fact that, in addition to the active substance and one or more propellant gases, they do not contain other ingredients. 8. The use of a suspension, according to one of claims 1 to 7, for the preparation of a medicine, primarily for the preparation of a medicine for inhalation or nasal treatment of diseases, in which anticholinergics can be of therapeutic benefit. 9. Use, according to claim 8, characterized by the fact that it is about respiratory diseases, primarily asthma or COPD.