HK1079091A1 - Hfa-suspension formulations containing an anticholinergic - Google Patents

Abstract

Suspensions of crystalline tiotropium bromide monohydrate (I) in the propellant gases HFA 227 and/or HFA 134a, optionally mixed with one or more further propellant gases selected from propane, butane, pentane, dimethyl ether, difluoromonochloromethane, difluoromethane, isobutane, isopentane and/or neopentane, are new. ACTIVITY : Antiasthmatic; Antiinflammatory. MECHANISM OF ACTION : Anticholinergic.

Description

HFA-suspensions containing anticholinergics

The invention relates to a method for preparing a compound containing (1 alpha, 2 beta, 4 beta, 5 alpha, 7 beta) -7- [ (hydroxy-bis-2-thiopheneacetyl) oxygen]-9, 9-dimethyl-3-oxa-9-azonia tricyclo [3.3.1.0^2,4]Compressed gas formulations of a metered aerosol of a suspension of nonane bromide crystal monohydrate, a process for their preparation and their use in the preparation of pharmaceutical compositions, in particular with anticholinergic activity.

Background

The compound (1 alpha, 2 beta, 4 beta, 5 alpha, 7 beta) -7- [ (hydroxybis-2-thiopheneacetyl) oxy]-9, 9-dimethyl-3-oxa-9-azonia tricyclo [3.3.1.0^2,4]Nonane bromides are known from european patent application EP 418716 a1 and have the following chemical structure:

this compound has valuable pharmacological properties and is known under the name tiotropium bromide (BA 679). Tiotropium bromide is a highly potent anticholinergic and therefore has a therapeutic effect on asthma or COPD (chronic obstructive pulmonary disease).

Preferably, tiotropium bromide is administered by inhalation.

The object of the present invention is to prepare HFA-metered aerosols containing tiotropium bromide, the only active ingredient in suspension form.

Detailed Description

It has been found that tiotropium bromide occurs in various crystalline modifications, depending on the conditions used for the purification of the natural product obtained after industrial production.

It has been found that these different variants can be purposefully prepared by selecting the solvent used for the crystallization and, where appropriate, the conditions used during the crystallization. Crystalline tiotropium bromide monohydrate has proven to be particularly suitable for the preparation of the formulations of the invention.

The invention therefore relates to a suspension of crystalline tiotropium bromide monohydrate in the propellant gases HFA227 and/or HFA134a, optionally mixed with one or more other propellant gases, preferably selected from propane, butane, pentane, dimethyl ether, CHClF₂，、CH₂F₂、CF₃CH₃Isobutane, isopentane and neopentane.

According to the invention, preferred suspensions contain only HFA227, a mixture of HFA227 and HFA134a or only HFA134a itself as propellant gas. If a mixed propellant gas of HFA227 and HFA134a is used in the suspension formulation of the invention, the weight ratio of the two propellant gas components may be chosen at will. In addition to HFA227 and/or HFA134a, if one or more selected from the group consisting of propane, butane, pentane, dimethyl ether, CHClF, is used in the suspension formulations of the present invention₂，、CH₂F₂、CF₃CH₃Isobutane, isopentane and neopentane, whichThe proportion of these other propellant gases is preferably less than 50%, preferably less than 40%, more preferably less than 30%.

The suspension of the invention preferably comprises 0.001-0.8% tiotropium. The present invention preferably comprises a suspension of 0.08-0.5%, more preferably 0.2-0.4% tiotropium.

Tiotropium refers to the free ammonium cation. The propellant gas suspension of the invention is characterized in that: suspensions containing tiotropium in the form of crystalline tiotropium bromide monohydrate are particularly suitable for this application. Accordingly, the present invention preferably relates to a suspension comprising 0.0012 to 1% crystalline tiotropium bromide monohydrate. Particularly useful according to the present invention are suspensions comprising 0.1-0.62%, more preferably 0.25-0.5% crystalline tiotropium bromide monohydrate.

The percentages specified in the present invention are all mass percentages. If the parts by mass of tiotropium are given in mass percentages, the corresponding values of crystalline tiotropium bromide monohydrate, which are preferred for use in the present invention, can be obtained by multiplying the conversion factor 1.2495.

In some cases in the present invention, the term suspension formulation may be used instead of the term suspension. For the purposes of the present invention, these two terms are interchangeable.

The propellant-containing inhalation aerosol or suspension formulations of the present invention may also contain other ingredients such as surface-active agents (surfactants), adjuvants, antioxidants or flavouring agents.

According to the present invention, the surfactant which may be contained in the suspension is preferably selected from the group consisting of polysorbate 20, polysorbate 80, mexican 9-45(Myvacet 9-45), mexican 9-08(Myvacet 9-08), isopropyl myristate, oleic acid, propylene glycol, polyethylene glycol, polyoxyethylene higher aliphatic alcohol ether (Brij), ethyl oleate, glyceryl trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, sterols (sterylalcohol), cetylpyridinium chloride, block copolymers, natural oils, ethanol and isopropanol. Among the above suspension adjuvants, polysorbate 20, polysorbate 80, Myvacet9-45, Myvacet 9-08, and isopropyl myristate are preferably used. Particular preference is given to using Myvacet9-45 or isopropyl myristate. When the suspension of the present invention contains a surfactant, the content of the surfactant is 0.0005 to 1%, preferably 0.005 to 0.5%.

Preferably, the adjuvants optionally included in the suspension of the invention are selected from the following: alanine, albumin, ascorbic acid, aspartame, betaine, cysteine, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid, or citric acid. Among them, ascorbic acid, phosphoric acid, hydrochloric acid, and citric acid are preferable, and hydrochloric acid and citric acid are more preferable.

In the case where the suspension of the present invention contains an excipient, the content of the excipient is preferably 0.0001 to 1.0%, preferably 0.0005 to 0.1%, more preferably 0.001 to 0.01%, and the present invention is particularly preferably 0.001 to 0.005%.

The antioxidant optionally contained in the suspension of the invention is preferably selected from the following: ascorbic acid, citric acid, sodium edetate, edetic acid, vitamin E, butylated hydroxytoluene, butylated hydroxyanisole and ascorbyl palmitate, with butylated hydroxytoluene, butylated hydroxyanisole and ascorbyl palmitate being preferred.

Flavoring agents that may be included in the suspensions of the invention are preferably selected from the following: mint, saccharin, Dentomint^®Aspartylphenylalanine methyl ester, volatile oil (such as cortex Cinnamomi, fructus Anisi Stellati, menthol, and Camphora), and oleum Menthae Dementholatum or Dentomint is especially preferable^®。

For administration by inhalation, finely divided active substances have to be prepared. Crystalline tiotropium bromide monohydrate prepared according to the protocol detailed in the experimental section may be milled (micronized) or obtained in finely divided form by other technical methods essentially known in the art, such as precipitation and spray drying. Methods of micronization of active substances are well known in the art. After micronization, the mean particle size of the active substance is preferably 0.5 to 10 μm, preferably 1 to 6 μm, more preferably 1.5 to 5 μm. Preferably, at least 50%, more preferably at least 60%, most preferably at least 70% of the active substance has a particle size within the above-mentioned range. More preferably, at least 80%, most preferably at least 90%, of the active substance has a particle size within the above-mentioned range.

It has also surprisingly been found that it is also possible to prepare suspensions which, in addition to the propellant gases mentioned above, contain only the active substance without further additives. Thus, another aspect of the present invention relates to a suspension comprising the active substance alone without other additives.

The suspensions of the present invention may be prepared by methods known in the art. Wherein the ingredients of the formulation are mixed with one or more propellant gases (optionally at cryogenic temperatures) and then transferred to a suitable container.

The propellant gas-containing suspension of the present invention may be administered by inhalers well known in the art (pMDIs ═ pressurized metered dose inhalers). Thus, another aspect of the present invention relates to a pharmaceutical composition in the form of a suspension as described above, in combination with one or more inhalers suitable for administering the suspension. Further, the present invention relates to an inhaler, characterized in that: comprising a propellant gas-containing suspension according to the invention as described above. The invention also relates to a container (e.g. a cartridge) containing a suitable valve for use in a suitable inhaler, and which contains a propellant gas-containing suspension of the invention as described above. Suitable containers, such as cartridges, and methods for filling these cartridges with a propellant gas-containing suspension according to the invention are known from the prior art.

In terms of the pharmaceutical activity of tiotropium, the present invention further relates to the use of the suspension for the manufacture of a medicament for administration by inhalation or nasal passage, preferably for the manufacture of a medicament for the treatment of diseases treatable by anticholinergic agents by inhalation or nasal passage.

Most preferably, the present invention further relates to the use of a suspension according to the present invention for the preparation of a pharmaceutical composition for the treatment of a respiratory disorder, preferably asthma or COPD, by inhalation.

The following examples illustrate the present invention more fully, but the invention is not limited to just the contents thereof.

Raw materials

Crystalline tiotropium bromide monohydrate:

tiotropium obtained according to EP 418716 a1 may be used to prepare crystalline tiotropium bromide monohydrate. The preparation process is carried out as follows.

To 25.7kg of water, 15.0kg of tiotropium bromide was added in a suitable reaction vessel. The mixture was heated to 80-90 ℃ and stirred at constant temperature until a clear solution was formed. Water-moist activated carbon (0.8kg) was suspended in 4.4kg of water, and the mixture was added to a solution containing tiotropium bromide and washed with 4.3kg of water. The resulting mixture was stirred at 80-90 ℃ for at least 15 minutes and then passed through a heated filter to filter it into a device preheated to an external temperature of 70 ℃. The filter was rinsed with 8.6kg of water. The contents of the apparatus were cooled to 20-25 deg.C at a rate of 3-5 deg.C decrease every 20 minutes. The apparatus was further cooled to 10-15 ℃ by using cold water. Crystallization is completed by stirring for at least 1 hour. The crystals were separated using a suction dryer and the crystal slurry was washed with 9L of cold water (10-15 ℃ C.) and cold acetone (10-15 ℃ C.). The crystals obtained were dried at 25 ℃ for 2 hours in a stream of nitrogen.

Yield: 13.4kg of tiotropium bromide monohydrate (86% of theory)

The tiotropium bromide monohydrate obtainable by the above method was detected by DSC (differential scanning calorimetry). The DSC diagram shows two characteristic signals. First, a relatively broad endothermic signal between 50-120 ℃ is formed due to dehydration of the monohydrate of tiotropium bromide to its anhydrous form. Second, a relatively sharp endothermic peak at 230 ± 5 ℃ is formed due to melting of the substance. These data were obtained using Mettler DSC 821 and evaluated using the Mettler STAR software package. Data was recorded at a heating rate of 10K/min.

Crystalline tiotropium bromide monohydrate can be characterized by IR spectroscopy characterization data. Data were obtained using a Nicolet FTIR spectrometer and evaluated using the Nicolet OMNIC software package version 3.1. The measurement was carried out under conditions in which 2.5. mu. mol of tiotropium bromide monohydrate was contained in 300mg of KBr. The following table gives several important IR spectral bands.

Wave number (cm)-1)	Attribution	Type of vibration
			3570，3410	O-H	Telescopic vibration
3105	Aryl radical C-H	Telescopic vibration
			1730	C＝O	Telescopic vibration
1260	Epoxide C-O	Telescopic vibration
			1035	Ester C-OC	Telescopic vibration
720	Thiophene(s)	Ring vibration

Single crystal X-ray structural analysis showed: the crystalline tiotropium bromide monohydrate obtainable by the above process has a simple monoclinic unit cell of the following dimensions:

a＝18.0774Å，b＝11.9711Å，c＝9.9321Å，β＝102.691°，V＝2096.96ų。

these data were obtained by an AFC7R 4-circuit diffractometer (Rigaku) using single-frequency copper K α rays. The determination and refinement of the crystal structure is obtained by direct methods (SHELXS 86 program) and FMLQ-refinement (TeXsan program).

To prepare the suspension of the present invention, crystalline tiotropium bromide monohydrate obtainable by the above process is micronized by methods known in the art to prepare the active substance having an average particle size corresponding to that described in the present specification.

The method for measuring the average particle size of the active material will be described below.

Determination of the particle size of micronized tiotropium bromide monohydrate:

measurement equipment and settings:

the equipment was operated according to the manufacturer's protocol.

The measuring equipment comprises: HELOS laser diffraction Spectroscopy, Sympa Tec

A dispersing device: RODOS drying diffuser (dry disperser), Sympa Tec, with suction filter funnel

The content of the sample is as follows: 50mg-400mg

Product feeding: vibri Vibrating trough (Vibrating channel), messers

Frequency of vibration tank: 40 liters to 100 percent

Sample introduction duration time: 15-25 seconds (in the case of 200 mg)

Focal length (focal length): 100mm (measuring range: 0.9-175 μm)

Measuring time: about 15 seconds (at 200 mg)

Cycle time: 20 milliseconds

Start/stop position: 1% on the groove 28

Dispersing gas: compressed air

Pressure: 3 bar

Vacuum (vacuum): maximum value

The evaluation method comprises the following steps: HRLD

Preparation of the test specimens/product feed:

approximately 200mg of test substance was weighed out on a card. Another card was used to break up all the larger pieces. Then, the powder was finely scattered on the front half of the vibrating trough (starting from about 1cm from the leading edge). After the start of the measurement, the frequency of the vibrating trough is adjusted from about 40% to 100% (until the end of the measurement). The sample is introduced as continuously as possible. However, the content of the product is not so much as to ensure sufficient dispersion. The time required for feeding the entire 200mg sample is, for example, about 15 to 25 seconds.

Preparation examples

Suspensions of other ingredients, in addition to the active substance and propellant gas, are included:

a) 0.02% tiotropium^*

0.20% polysorbate 20

99.78％HFA227

b) 0.02% tiotropium^*

1.00% isopropyl myristate

98.98％HFA227

c) 0.02% tiotropium^*

0.3％Myvacet 9-45

99.68％HFA227

d) 0.04% tiotropium^*

1.00％Myvacet 9-08

98.96％HFA227

e) 0.04% tiotropium^*

0.04% polysorbate 80

99.92％HFA227

f) 0.04% tiotropium^*

0.005% oleic acid

99.955％HFA227

g) 0.02% tiotropium^*

0.1％Myvacet9-45

60.00％HFA227

39.88％HFA134a

h) 0.02% tiotropium^*

0.30% isopropyl myristate

20.00％HFA227

79.68％HFA134a

i) 0.02% tiotropium^*

0.01% oleic acid

60.00％HFA227

39.97％HFA134a

^*Tiotropium bromide monohydrate form

(conversion factor 1.2495)

Suspension containing only active substance and propellant gas:

j) 0.02% tiotropium^*

99.98％HFA227

k) 0.02% tiotropium^*

99.98％HFA134a

l) 0.04% Tiotropium^*

99.96％HFA227

m) 0.04% tiotropium^*

99.96％HFA134a

n) 0.02% tiotropium^*

20.00％HFA227

79.98％HFA134a

o) 0.02% tiotropium^*

60％HFA227

39.98％HFA134a

p) 0.04% Tiotropium^*

40.00％HFA227

59.96％HFA134a

q) 0.04% tiotropium^*

80.00％HFA227

19.96％HFA134a

^*Tiotropium bromide monohydrate form

(conversion factor 1.2495)

Claims (10)

1. Suspension of crystalline tiotropium bromide monohydrate in the propellant gases HFA227 and/or HFA134a, optionally mixed with one or more other propellant gases selected from propane, butane, pentane, dimethyl ether, CHClF₂、CH₂F₂、CF₃CH₃Isobutane, isopentane and neopentane, wherein the crystalline tiotropium bromide monohydrate has a simple monoclinic cell of the following dimensions: 18.0774 Å, 11.9711 Å, 9.9321 Å, 102.691 ° and 2096.96 Å ° V³。

2. Suspension according to claim 1, characterized in that it comprises 0.001-0.8% tiotropium.

3. Suspension according to claim 1 or 2, characterized in that it comprises as further ingredients adjuvants.

4. Suspension according to claim 1 or 2, characterized in that surface-active agents, antioxidants or flavouring agents are contained as further ingredients.

5. Suspension according to claim 4, characterized in that one or more compounds selected from the group consisting of polysorbate 20, polysorbate 80, mexican 9-45, mexican 9-08, isopropyl myristate, oleic acid, propylene glycol, polyethylene glycol, polyoxyethylene higher aliphatic alcohol ethers, ethyl oleate, glycerol trioleate, glycerol monolaurate, glycerol monooleate, glycerol monostearate, glycerol monoricinoleate, cetyl alcohol, sterols, cetylpyridinium chloride, block copolymers, natural oils, ethanol and isopropanol are contained as surface-active agents.

6. Suspension according to claim 3, characterized in that it contains as auxiliary material one or more compounds selected from the group consisting of alanine, albumin, ascorbic acid, aspartame, betaine, cysteine, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid or citric acid.

7. Suspension according to claim 4, characterized in that it contains as antioxidant one or more compounds selected from ascorbic acid, citric acid, sodium edetate, edetic acid, vitamin E, butylhydroxytoluene, butylhydroxyanisole and ascorbyl palmitate.

8. Suspension according to claim 1 or 2, characterized in that it contains only the active substance and one or more propellant gases.

9. Use of the suspension of any one of claims 1-8 for the preparation of a pharmaceutical composition for the treatment of respiratory disorders by inhalation or nasal passage.

10. Use according to claim 9, characterized in that the disease is asthma or COPD.