CA2426074C - Inhalable formulation of a solution containing a tiotropium salt - Google Patents
Inhalable formulation of a solution containing a tiotropium salt Download PDFInfo
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- CA2426074C CA2426074C CA002426074A CA2426074A CA2426074C CA 2426074 C CA2426074 C CA 2426074C CA 002426074 A CA002426074 A CA 002426074A CA 2426074 A CA2426074 A CA 2426074A CA 2426074 C CA2426074 C CA 2426074C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
Abstract
The present invention relates to a propellant-free inhalable formulation of tiotropium bromide or tiotropium bromide monohydrate dissolved in water or in a mixture of water and ethanol and propellant-free inhalable aerosols resulting therefrom.
Description
Case 1/1156 FF CA 02426074 2003-04-22 Boehr-nger Inge{heim Pharma KG
' 74338fft.205 lnhalable formulation of a solution containing a tiotropium salt The present invention relates to a propellant-free inhalable formulation of a pharmaceutically acceptable salt of tiotropium dissolved in water or a mixture of water and ethanol and propellant-free inhalable aerosols resulting therefrom.
The formulation according to the invention is particularly suitable for administering the active substance by inhalation, especially for treating asthma and COPD.
Tiotropium, chemically (1a,20,40,5a,70)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane, is known as tiotropium bromide from European Patent Application EP 418 716 Al. The bromide salt of tiotropium has the following chemical structure:
Me N,Me O
H Br-S O
QJH
(I) The compound has valuable pharmacological properties and is known by the name tiotropium bromide. Tiotropium and its salts are highly effective anticholinergics and can provide therapeutic benefit in the treatment of asthma or COPD (chronic obstructive pulmonary disease). The monohydrate of tiotropium bromide is also pharmacologically valuable.
Both compounds are a preferred object of the present invention.
The present invention relates to liquid active substance formulations of these compounds which can be administered by inhalation; the liquid formulations according to the invention have to meet high quality standards.
To achieve an optimum distribution of active substances in the lung it makes sense to use a liquid formulation without propellant gases administered using suitable inhalers. Those inhalers which are capable of nebulising a small amount of a liquid Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
' 74338fft.205 lnhalable formulation of a solution containing a tiotropium salt The present invention relates to a propellant-free inhalable formulation of a pharmaceutically acceptable salt of tiotropium dissolved in water or a mixture of water and ethanol and propellant-free inhalable aerosols resulting therefrom.
The formulation according to the invention is particularly suitable for administering the active substance by inhalation, especially for treating asthma and COPD.
Tiotropium, chemically (1a,20,40,5a,70)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane, is known as tiotropium bromide from European Patent Application EP 418 716 Al. The bromide salt of tiotropium has the following chemical structure:
Me N,Me O
H Br-S O
QJH
(I) The compound has valuable pharmacological properties and is known by the name tiotropium bromide. Tiotropium and its salts are highly effective anticholinergics and can provide therapeutic benefit in the treatment of asthma or COPD (chronic obstructive pulmonary disease). The monohydrate of tiotropium bromide is also pharmacologically valuable.
Both compounds are a preferred object of the present invention.
The present invention relates to liquid active substance formulations of these compounds which can be administered by inhalation; the liquid formulations according to the invention have to meet high quality standards.
To achieve an optimum distribution of active substances in the lung it makes sense to use a liquid formulation without propellant gases administered using suitable inhalers. Those inhalers which are capable of nebulising a small amount of a liquid Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
formulation in the dosage needed for therapeutic purposes within a few seconds into an aerosol suitable for therapeutic inhalation are particularly suitable.
Within the scope of the invention, preferred nebulisers are those in which an amount of less than 100 microlitres, preferably less than 50 microlitres, most preferably less than 20 microlitres of active substance solution can be nebulised preferably in one puff to form an aerosol having an average particle size of less than 20 microns, preferably less than 10 microns, so that the inhalable part of the aerosol already corresponds to the therapeutically effective quantity.
An apparatus of this kind for the propellant-free administration of a metered amount of a liquid pharmaceutical composition for inhalation is described in detail for example in Intemational Patent Application WO 91/14468 "Atomizing Device and Methods" and also in WO 97/12687, cf. Figures 6a and 6b and the accompanying description. In a nebuliser of this kind a pharmaceutical solution is converted by means of a high pressure of up to 500 bar into an aerosol destined for the lungs, which is sprayed. Within the scope of the present specification reference is expressly made to the entire contents of the literature mentioned above.
In inhalers of this kind the formulations of solutions are stored in a reservoir. It is essential that the active substance formulations used are sufficiently stable when stored and at the same time are such that they can be administered directly, if possible without any further handling, in accordance with their medical purpose.
Moreover, they must not contain any ingredients which might interact with the inhaler in such a way as to damage the inhaler or the pharmaceutical quality of the solution or of the aerosol produced.
To nebulise the solution a special nozzle is used as described for example in WO
94/07607 or WO 99/16530. Reference is expressly made here to both these publications.
WO 98/27959 discloses formulations of solutions for the inhaler described above which contain as additive the disodium salt of editic acid (sodium edetate).
For aqueous formulations of solutions which are to be converted into inhalable aerosols using the inhaler described above, the specification favours a minimum concentration of sodium edetate of 50 mg/100 ml, in order to reduce the incidence of spray anomalies. Among the Examples disclosed there is a formulation containing tiotropium bromide. In this formulation the active substance is dissolved in water.
The proportion of sodium edetate is again 50 mg/100 ml.
Surprisingly, it has now been found that formulations of solutions of tiotropium salts in water or a water-ethanol mixture wherein the proportion of the additive sodium edetate is significantly less than 50 mg/100 ml show a reduction in the scattering of the composition delivered, compared with the formulation containing tiotropium bromide known from the prior art. In addition, the spray quality is very good. Water is preferably used as the solvent. The resulting aerosol has very good properties for administration by inhalation.
Another advantage of the formulation is that, thanks to the absence of or reduction in the additive sodium edetate in the active substance formulation, the pH of the solution formulation can be lowered. Low pH levels are necessary for the long-term stability of the formulation.
It is therefore an aim of the present invention to provide an aqueous active substance formulation containing a pharmaceutically acceptable tiotropium salt which meets the high standards needed in order to be able to achieve optimum nebulisation of a solution using the inhalers mentioned hereinbefore. The active substance formulations according to the invention must be of sufficiently high pharmaceutical quality, i.e. they should be pharmaceutically stable over a storage time of some years, preferably at least one year, more preferably two years.
3a Another aim is to provide propellant-free formulations of solutions containing tiotropium salts which are nebulised under pressure using an inhaler, the composition delivered by the aerosol produced falling reproducibly within a specified range.
According to one aspect of the present invention, there is provided a pharmaceutical composition comprising: a tiotropium salt as active substance, in a concentration based on tiotropium of between 0.0005 and 5 % by weight, a solvent comprising water or a water and ethanol mixture, acid for achieving a pH between 2.0 and 3.1, a pharmacologically acceptable preservative, and editic acid or an editic acid salt in an amount of greater than 0 up to 25 mg/100 ml.
According to another aspect of the invention, there is provided a pharmaceutical composition comprising: a tiotropium salt as active substance, in a concentration based on tiotropium of between 0.0005 and 5 % by weight, a solvent comprising water or a water and ethanol mixture, acid for achieving a pH between 2.0 and 3.1, and a pharmacologically acceptable preservative.
According to the invention, any pharmaceutically acceptable salts of tiotropium may be used for the formulation. When the term tiotropium salt is used within the scope of the present invention, this is to be taken as a reference to tiotropium. According to the invention a reference to tiotropium, which is the free ammonium cation, Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
Within the scope of the invention, preferred nebulisers are those in which an amount of less than 100 microlitres, preferably less than 50 microlitres, most preferably less than 20 microlitres of active substance solution can be nebulised preferably in one puff to form an aerosol having an average particle size of less than 20 microns, preferably less than 10 microns, so that the inhalable part of the aerosol already corresponds to the therapeutically effective quantity.
An apparatus of this kind for the propellant-free administration of a metered amount of a liquid pharmaceutical composition for inhalation is described in detail for example in Intemational Patent Application WO 91/14468 "Atomizing Device and Methods" and also in WO 97/12687, cf. Figures 6a and 6b and the accompanying description. In a nebuliser of this kind a pharmaceutical solution is converted by means of a high pressure of up to 500 bar into an aerosol destined for the lungs, which is sprayed. Within the scope of the present specification reference is expressly made to the entire contents of the literature mentioned above.
In inhalers of this kind the formulations of solutions are stored in a reservoir. It is essential that the active substance formulations used are sufficiently stable when stored and at the same time are such that they can be administered directly, if possible without any further handling, in accordance with their medical purpose.
Moreover, they must not contain any ingredients which might interact with the inhaler in such a way as to damage the inhaler or the pharmaceutical quality of the solution or of the aerosol produced.
To nebulise the solution a special nozzle is used as described for example in WO
94/07607 or WO 99/16530. Reference is expressly made here to both these publications.
WO 98/27959 discloses formulations of solutions for the inhaler described above which contain as additive the disodium salt of editic acid (sodium edetate).
For aqueous formulations of solutions which are to be converted into inhalable aerosols using the inhaler described above, the specification favours a minimum concentration of sodium edetate of 50 mg/100 ml, in order to reduce the incidence of spray anomalies. Among the Examples disclosed there is a formulation containing tiotropium bromide. In this formulation the active substance is dissolved in water.
The proportion of sodium edetate is again 50 mg/100 ml.
Surprisingly, it has now been found that formulations of solutions of tiotropium salts in water or a water-ethanol mixture wherein the proportion of the additive sodium edetate is significantly less than 50 mg/100 ml show a reduction in the scattering of the composition delivered, compared with the formulation containing tiotropium bromide known from the prior art. In addition, the spray quality is very good. Water is preferably used as the solvent. The resulting aerosol has very good properties for administration by inhalation.
Another advantage of the formulation is that, thanks to the absence of or reduction in the additive sodium edetate in the active substance formulation, the pH of the solution formulation can be lowered. Low pH levels are necessary for the long-term stability of the formulation.
It is therefore an aim of the present invention to provide an aqueous active substance formulation containing a pharmaceutically acceptable tiotropium salt which meets the high standards needed in order to be able to achieve optimum nebulisation of a solution using the inhalers mentioned hereinbefore. The active substance formulations according to the invention must be of sufficiently high pharmaceutical quality, i.e. they should be pharmaceutically stable over a storage time of some years, preferably at least one year, more preferably two years.
3a Another aim is to provide propellant-free formulations of solutions containing tiotropium salts which are nebulised under pressure using an inhaler, the composition delivered by the aerosol produced falling reproducibly within a specified range.
According to one aspect of the present invention, there is provided a pharmaceutical composition comprising: a tiotropium salt as active substance, in a concentration based on tiotropium of between 0.0005 and 5 % by weight, a solvent comprising water or a water and ethanol mixture, acid for achieving a pH between 2.0 and 3.1, a pharmacologically acceptable preservative, and editic acid or an editic acid salt in an amount of greater than 0 up to 25 mg/100 ml.
According to another aspect of the invention, there is provided a pharmaceutical composition comprising: a tiotropium salt as active substance, in a concentration based on tiotropium of between 0.0005 and 5 % by weight, a solvent comprising water or a water and ethanol mixture, acid for achieving a pH between 2.0 and 3.1, and a pharmacologically acceptable preservative.
According to the invention, any pharmaceutically acceptable salts of tiotropium may be used for the formulation. When the term tiotropium salt is used within the scope of the present invention, this is to be taken as a reference to tiotropium. According to the invention a reference to tiotropium, which is the free ammonium cation, Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
corresponds to a reference to tiotropium in the form of a salt (tiotropium salt) which contains an anion as counter-ion. Tiotropium salts which may be used within the scope of the present invention are preferably compounds which contain, in addition to tiotropium as counter-ion (anion), chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate and/or methylsulphate.
Within the scope of the present invention tiotropium bromide is preferred as the salt.
References to tiotropium bromide within the scope of the present invention must always be taken as references to all possible amorphous and crystalline modifications of tiotropium bromide. These may for example contain molecules of solvent in their crystalline structure. Of all the crystalline modifications of tiotropium bromide those which also contain water (hydrates) are preferred according to the invention. It is particularly preferred within the scope of the present invention to use tiotropium bromide monohydrate. The formulation preferably does not contain any other active substance which is not tiotropium or a pharmaceutically acceptable salt thereof.
In the formulations according to the invention the tiotropium salts are dissolved in a solvent. The solvent may be exclusively water, or it may be a mixture of water and ethanol. The relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70 % by volume, particularly up to 60 % by volume and most preferably up to 30 % by volume. The remaining % by volume consist of water.
The preferred solvent is water without the addition of ethanol.
According to the invention, the formulation preferably contains only a single tiotropium salt . However, the formulation may also contain a mixture of different tiotropium salts and solvates. Preferably, the formulation does not contain any active substance other than tiotropium as hereinbefore defined.
The concentration of the tiotropium salt based on the proportion of tiotropium in the finished pharmaceutical preparation depends on the therapeutic effect sought.
For most of the complaints which respond to tiotropium the concentration of tiotropium is between 0.0005 and 5 % by weight, preferably between 0.001 and 3 % by weight.
In the case of tiotropium bromide or tiotropium bromide monohydrate the preferred =Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
amount based on tiotropium is 0.0005 to 0.5 % by weight, more preferably 0.0005 to 0.25 % by weight and particularly preferably 0.001 to 0.1 % by weight.
The pH of the formulation according to the invention is between 2.0 and 4.5, preferably between 2.5 and 3.5 and more preferably between 2.7 and 3.3 and particularly preferably between 2.7 and 3.2. Most preferred are pHs with an upper limit of 3.1.
The pH is adjusted by the addition of pharmacologically acceptable acids.
Examples of inorganic acids which are preferred for this purpose include:
hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid.
Examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid, etc. Preferred inorganic acids are hydrochloric acid and sulphuric acid. It is also possible to use acids which form an acid addition salt with the active substance.
Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. 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 flavourings or antioxidants, such as for example citric acid or ascorbic acid.
Hydrochloric acid deserves special mention as an inorganic acid.
If desired, pharmacologically acceptable bases may be used to titrate the pH
precisely. Suitable bases include for example alkali metal hydroxides and alkali metal carbonates. The preferred alkali ion is sodium. If bases of this kind are used, care must be taken to ensure that the resulting salts, which are then contained in the finished pharmaceutical formulation, are pharmacologically compatible with the abovementioned acid.
Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
..~ .
According to the invention, there is no need to add editic acid (EDTA) or one of the known salts thereof, sodium edetate, to the present formulation as a stabiliser or complexing agent.
Another embodiment contains editic acid and/ or the abovementioned salts thereof.
In a preferred embodiment of this kind the content based on sodium edetate is less than 10 mg / 100 ml. In this case, there is one preferred range from 5 mgl 100 ml to less than 10 mg/100 ml or another from greater than 0 to 5 mg/100m1.
In another embodiment the content of sodium edetate is 10 to 30 mg / 100 ml, preferably not more than 25 mg/ 100 ml.
In a preferred embodiment this additive is omitted entirely.
The remarks made concerning sodium edetate also apply analogously to other comparable additives which have complexing properties and can be used instead, such as for example nitrilotriacetic acid and the salts thereof.
By complexing agents is preferably meant within the scope of the present invention molecules which are capable of entering into complex bonds. Preferably, these compounds should have the effect of complexing cations, most preferably metal cations.
As we{l as ethanol, other cosolvents and/or other adjuvants may be added to the formulation according to the invention.
Preferred cosolvents are those which contain hydroxyl groups or other polar groups, for example alcohols - especially isopropylalcohol, glycols - especially propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters, provided that these are not already being used as the solvent or suspension agent.
Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
{ 7 By adjuvants and additives are meant, in this context, any pharmacologically acceptable and therapeutically useful substance which is not an active substance, but can be formulated together with the active substance in the pharmacologically suitable solvent, in order to improve the qualities of the active substance formulation.
Preferably, these substances have no pharmacological effects or no appreciable or at least no undesirable pharmacological effects in the context of the desired therapy.
The adjuvants and additives include, for example, surfactants such as e.g.
soya lecithin, oleic acid, sorbitan esters such as sorbitan trioleate, poiyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride, for example.
The preferred excipients include antioxidants such as 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 provitamins occurring in the human body.
Preservatives can be added to protect the formulation from contamination with pathogenic bacteria. Suitable preservatives are those known from the prior art, particularly benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.
Preferred formulations contain only benzalkonium chloride and sodium edetate, in addition to the solvent water and the tiotropium salt.
In another preferred embodiment, sodium edetate is omitted.
As already mentioned a number of times, tiotropium bromide is obtained in EP
716 Al and crystalline tiotropium bromide monohydrate may be obtained using a process which is described in more detail below.
In order to prepare the crystalline monohydrate according to the present invention, the tiotropium bromide obtained by the method disclosed in EP 418 716 Al, for example, first has to be taken up in water, heated, purified with activated charcoal Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
and, after removal of the activated charcoal, the tiotropium bromide-monohydrate is slowly crystallised while cooling slowly.
The following procedure is preferably followed:
In a reaction vessel of suitable dimensions, the solvent is mixed with tiotropium bromide, which has been obtained by the method disclosed in EP 418 716 Al, for example.
For each mol of tiotropium bromide put in, 0.4 to 1.5 kg, preferably 0.6 to 1 kg, most preferably about 0.8 kg of water are used as solvent.
The mixture obtained is heated with stirring, preferably to above 50 C, most preferably to above 60 C. The maximum temperature which can be selected is determined by the boiling point of the solvent used. Preferably, the mixture is heated to a range from 80-90 C.
Activated charcoal, either dry or moistened with water, is added to this solution.
Preferably, 10 to 50 g, more preferably 15 to 35 g, most preferably about 25 g of activated charcoal are put in per mol of tiotropium bromide used. If desired the activated charcoal is suspended in water before being added to the solution containing tiotropium bromide. 70 to 200 g, preferably 100 to 160 g, more preferably about 135 g of water are used, per mol of tiotropium bromide put in, in order to suspend the activated charcoal. If the activated charcoal is suspended in water beforehand, before being added to the solution containing tiotropium bromide, it is advisable to rinse again with the same amount of water.
After the activated charcoal has been added, stirring is continued at constant temperature for between 5 and 60 minutes, preferably between 10 and 30 minutes, more preferably for about 15 minutes and the mixture obtained is filtered to remove the activated charcoal. The filter is then rinsed with water. 140 to 400 g, preferably 200 to 320 g, most preferably about 270 g of water are used for this, per mol of tiotropium bromide used.
The filtrate is then slowly cooled, preferably to a temperature of 20-25 C.
The cooling preferably takes place at a cooling rate of 1 to 10 C every 10 to 30 minutes, preferably 2 to 8 C every 10 to 30 minutes, more preferably 3 to 5 C every 10 to 20 minutes, most preferably 3 to 5 C about every 20 minutes. If desired, the cooling to 20 to 25 C may be followed by further cooling to below 20 C, more preferably to 10 to 15 C.
After cooling is complete, stirring is continued for between 20 minutes and 3 hours, preferably between 40 minutes and 2 hours, more preferably for about one hour to complete the crystallisation.
Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
~
The crystals obtained are then isolated by filtering or suction filtering to remove the solvent. If it should prove necessary to subject the crystals obtained to a further washing step, it is advisable to use water or acetone as the washing solvent.
0.1 to 1.0 L, preferably 0.2 to 0.5 L, more preferably about 0.3 L of solvent may be used per mol of tiotropium bromide put in, in order to wash the tiotropium bromide monohydrate crystals obtained. If necessary the washing step may be repeated.
The product obtained is dried in vacuo or using circulating heated air until a water content of 2.5 - 4.0 % is obtained.
According to one aspect the present invention therefore also relates to formulations of solutions of the type described above using crystalline tiotropium bromide monohydrate which may be obtained by the procedure described above.
The pharmaceutical formulations containing tiotropium salts according to the invention are preferably used in an inhaler of the kind described hereinbefore in order to produce the propellant-free aerosols according to the invention. At this point we should once again expressly mention the patent documents described hereinbefore, to which reference is hereby made.
As described at the beginning, a further developed embodiment of the preferred inhaler is disclosed in WO 97/12687 and Figure 6 thereof. This nebuliser (Respimat ) can advantageously be used to produce the inhalable aerosols according to the invention containing a tiotropium salt as active substance. Because of its cylindrical shape and handy size of less than 9 to 15 cm long and 2 to 4 cm wide, the device can be carried anywhere by the patient. The nebuliser sprays a defined volume of the pharmaceutical formulation out through small nozzles at high pressures, so as to produce inhalable aerosols.
The preferred atomiser essentially consists of an upper housing part, a pump housing, a nozzle, a locking clamp, a spring housing, a spring and a storage container, characterised by - a pump housing fixed in the upper housing part and carrying at one end a nozzle body with the nozzle or nozzle arrangement, - a hollow piston with valve body, Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
- a power take-off flange in which the hollow body is fixed and which is located in the upper housing part, - a locking clamping mechanism located in the upper housing part, - a spring housing with the spring located therein, which is rotatably mounted on the u er housing pp part by means of a rotary bearing, - a lower housing part which is fitted onto the spring housing in the axial direction.
The hollow piston with valve body corresponds to a device disclosed in WO
97/12687. It projects partially into the cylinder of the pump housing and is disposed to be axially movable in the cylinder. Reference is made particularly to Figures especially Figure 3 - and the associated parts of the description. At the moment of release of the spring the hollow piston with valve body exerts, at its high pressure end, a pressure of 5 to 60 Mpa (about 50 to 600 bar), preferably 10 to 60 Mpa (about 100 to 600 bar) on the fluid, the measured amount of active substance solution.
Volumes of 10 to 50 microlitres are preferred, volumes of 10 to 20 microlitres are more preferable, whilst a volume of 15 microlitres per actuation is particularly preferred.
The valve body is preferably mounted at the end of the hollow piston which faces the nozzle body.
The nozzle in the nozzle body is preferably microstructured, i.e. produced by micro-engineering. Microstructured nozzle bodies are disclosed for example in WO-94/07607; reference is hereby made to the contents of this specification, especially Figure 1 and the associated description.
The nozzle body consists for example of two sheets of glass and/or silicon securely fixed together, at least one of which has one or more microstructured channels which connect the nozzle inlet end to the nozzle outlet end. At the nozzle outlet end there is at least one round or non-round opening 2 to 10 microns deep and 5 to 15 microns wide, the depth preferably being 4.5 to 6.5 microns and the length being 7 to microns.
If there is a plurality of nozzle openings, preferably two, the directions of spraying of the nozzles in the nozzle body may run parallel to each other or may be inclined relative to one another in the direction of the nozzle opening. In the case of a nozzle Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
' 11 =1 .
body having at least two nozzle openings at the outlet end, the directions of spraying may be inclined relative to one another at an angle of 20 degrees to 160 degrees, preferably at an angle of 60 to 150 degrees, most preferably 80 to 100 .
The nozzle openings are preferably arranged at a spacing of 10 to 200 microns, more preferably at a spacing of 10 to 100 microns, still more preferably 30 to microns. A spacing of 50 microns is most preferred.
The directions of spraying therefore meet in the region of the nozzle openings.
As already mentioned, the liquid pharmaceutical preparation hits the nozzle body at an entry pressure of up to 600 bar, preferably 200 to 300 bar and is atomised through the nozzle openings into an inhalable aerosol. The preferred particie sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns.
The locking clamping mechanism contains a spring, preferably a cylindrical helical compression spring as a store for the mechanical energy. The spring acts on the power take-off flange as a spring member the movement of which is determined by the position of a locking member. The travel of the power take-off flange is precisely limited by an upper stop and a lower stop. The spring is preferably tensioned via a stepping-up gear, e.g. a helical sliding gear, by an external torque which is generated when the upper housing part is turned relative to the spring housing in the lower housing part. In this case, the upper housing part and the power take-off flange contain a single- or multi-speed spline gear.
The locking member with the engaging locking surfaces is arranged in an annular configuration around the power take-off flange. It consists for example of a ring of plastics or metal which is inherently radially elastically deformable. The ring is arranged in a plane perpendicular to the axis of the atomiser. After the locking of the spring, the locking surfaces of the locking member slide into the path of the power take-off flange and prevent the spring from being released. The locking member is actuated by means of a button. The actuating button is connected or coupled to the locking member. In order to actuate the locking clamping mechanism the actuating button is moved parallel to the annular plane, preferably into the atomiser, and the deformable ring is thereby deformed in the annular plane. Details of the construction of the locking clamping mechanism are described in WO 97/20590.
Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
The lower housing part is pushed axially over the spring housing and covers the bearing, the drive for the spindle and the storage container for the fluid.
When the atomiser is operated, the upper part of the housing is rotated relative to the lower part, the lower part taking the spring housing with it. The spring meanwhile is compressed and biased by means of the helical sliding gear, and the clamping mechanism engages automatically. The angle of rotation is preferably a whole-number fraction of 360 degrees, e.g. 180 degrees. At the same time as the spring is tensioned, the power take-off component in the upper housing part is moved along by a given amount, the hollow piston is pulled back inside the cylinder in the pump housing, as a result of which some of the fluid from the storage container is sucked into the high pressure chamber in front of the nozzle.
If desired, a plurality of replaceable storage containers containing the fluid to be atomised can be inserted in the atomiser one after another and then used. The storage container contains the aqueous aerosol preparation according to the invention.
The atomising process is initiated by gently pressing the actuating button.
The clamping mechanism then opens the way for the power take-off component. The biased spring pushes the piston into the cylinder in the pump housing. The fluid emerges from the nozzle of the atomiser in the form of a spray.
Further details of the construction are disclosed in PCT applications WO
and WO 97/20590, to which reference is hereby made.
The components of the atomiser (nebuliser) are made of a material suitable for their function. The housing of the atomiser and - if the function allows - other parts as well are preferably made of plastics, e.g. by injection moulding. For medical applications, physiologically acceptable materials are used.
Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
Figures la/b, which are identical to Figures 6 a/b of WO 97/12687, show the Respimat nebuliser with which the aqueous aerosol preparations according to the invention can advantageously be inhaled.
Figure 1 a shows a longitudinal section through the atomiser with the spring under tension, Figure 1 b shows a longitudinal section through the atomiser with the spring released.
The upper housing part (51) contains the pump housing (52), on the end of which is mounted the holder (53) for the atomiser nozzle. In the holder is the nozzle body (54) and a filter (55). The hollow piston (57) fixed in the power take-off flange (56) of the locking clamping mechanism projects partly into the cylinder of the pump housing. At its end the hollow piston carries the valve body (58). The hollow piston is sealed off by the gasket (59). Inside the upper housing part is the stop (60) on which the power take-off flange rests when the spring is relaxed. Located on the power take-off flange is the stop (61) on which the power take-off flange rests when the spring is under tension. After the tensioning of the spring, the locking member (62) slides between the stop (61) and a support (63) in the upper housing part. The actuating button (64) is connected to the locking member. The upper housing part ends in the mouthpiece (65) and is closed off by the removable protective cap (66).
The spring housing (67) with compression spring (68) is rotatably mounted on the upper housing part by means of the snap-fit lugs (69) and rotary bearings. The lower housing part (70) is pushed over the spring housing. Inside the spring housing is the replaceable storage container (71) for the fluid (72) which is to be atomised.
The storage container is closed off by the stopper (73), through which the hollow piston projects into the storage container and dips its end into the fluid (supply of active substance solution).
The spindle (74) for the mechanical counter is mounted on the outside of the spring housing. The drive pinion (75) is located at the end of the spindle facing the upper housing part. On the spindle is the slider (76).
Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
The nebuliser described above is suitable for nebulising the aerosol preparations according to the invention to form an aerosol suitable for inhalation.
If the formulation according to the invention is nebulised using the method described o 0 above (Respimat ), the mass expelled, in at least 97 /o, preferably at least 98% of all the actuations of the inhaler (puffs), should correspond to a defined quantity with a range of tolerance of not more than 25%, preferably 20% of this quantity.
Preferably, between 5 and 30 mg, more preferably between 5 and 20 mg of formulation are delivered as a defined mass per puff.
However, the formulation according to the invention can also be nebulised using inhalers other than those described above, for example jet-stream inhalers.
Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
Examples 1. Example of the synthesis of tiotropium bromide monohydrate 15.0 kg of tiotropium bromide are added to 25.7 kg of water in a suitable reaction vessel. The mixture is heated to 80-90 C and stirred at constant temperature until a clear solution is formed. Activated charcoal (0.8 kg), moistened with water, is suspended in 4.4 kg of water, this mixture is added to the solution containing tiotropium bromide and rinsed with 4.3 kg of water. The mixture thus obtained is stirred for at ieast 15 min. at 80-90 C and then filtered through a heated filter into an apparatus which has been preheated to an outer temperature of 70 C. The filter is rinsed with 8.6 kg of water. The contents of the apparatus are cooled to a temperature of 20-25 C at a rate of 3-5 C every 20 minutes. Using cold water the apparatus is cooled further to 10-15 C and crystallisation is completed by stirring for at least another hour. The crystals are isolated using a suction filter drier, the crystal slurry isolated is washed with 9 L of cold water (10-15 C) and cold acetone (10-15 C). The crystals obtained are dried at 25 C for 2 hours in a nitrogen current.
Yield: 13.4 kg of tiotropium bromide monohydrate (86 % of theory).
Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
11. Examples of formu~lations 100 g of pharmaceutical preparation contain:
Example Amount of Amount of Amount of Amount of pH, tiotropium tiotropium benzalkonium sodium adjusted bromide, based bromide chloride edetate with HCI
on tiotropium: monohydrate, (1N) based on tiotropium:
1 0.099 g -- 10 mg 25 mg 3.0 2 0.006 g --- 10 mg 25 mg 3.0 3 0.099 g -- 10 mg 10 mg 3.0 4 0.006g --- 10mg 10mg 3.0 --- 0.099 g 10 mg 25 mg 3.0 6 --- 0.006 g 10 mg 25 mg 3.0 7 --- 0.099 g 10 mg 10mg 3.0 8 --- 0.006 g 10 mg 10 mg 3.0 The remainder is water.
Within the scope of the present invention tiotropium bromide is preferred as the salt.
References to tiotropium bromide within the scope of the present invention must always be taken as references to all possible amorphous and crystalline modifications of tiotropium bromide. These may for example contain molecules of solvent in their crystalline structure. Of all the crystalline modifications of tiotropium bromide those which also contain water (hydrates) are preferred according to the invention. It is particularly preferred within the scope of the present invention to use tiotropium bromide monohydrate. The formulation preferably does not contain any other active substance which is not tiotropium or a pharmaceutically acceptable salt thereof.
In the formulations according to the invention the tiotropium salts are dissolved in a solvent. The solvent may be exclusively water, or it may be a mixture of water and ethanol. The relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70 % by volume, particularly up to 60 % by volume and most preferably up to 30 % by volume. The remaining % by volume consist of water.
The preferred solvent is water without the addition of ethanol.
According to the invention, the formulation preferably contains only a single tiotropium salt . However, the formulation may also contain a mixture of different tiotropium salts and solvates. Preferably, the formulation does not contain any active substance other than tiotropium as hereinbefore defined.
The concentration of the tiotropium salt based on the proportion of tiotropium in the finished pharmaceutical preparation depends on the therapeutic effect sought.
For most of the complaints which respond to tiotropium the concentration of tiotropium is between 0.0005 and 5 % by weight, preferably between 0.001 and 3 % by weight.
In the case of tiotropium bromide or tiotropium bromide monohydrate the preferred =Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
amount based on tiotropium is 0.0005 to 0.5 % by weight, more preferably 0.0005 to 0.25 % by weight and particularly preferably 0.001 to 0.1 % by weight.
The pH of the formulation according to the invention is between 2.0 and 4.5, preferably between 2.5 and 3.5 and more preferably between 2.7 and 3.3 and particularly preferably between 2.7 and 3.2. Most preferred are pHs with an upper limit of 3.1.
The pH is adjusted by the addition of pharmacologically acceptable acids.
Examples of inorganic acids which are preferred for this purpose include:
hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid.
Examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid, etc. Preferred inorganic acids are hydrochloric acid and sulphuric acid. It is also possible to use acids which form an acid addition salt with the active substance.
Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. 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 flavourings or antioxidants, such as for example citric acid or ascorbic acid.
Hydrochloric acid deserves special mention as an inorganic acid.
If desired, pharmacologically acceptable bases may be used to titrate the pH
precisely. Suitable bases include for example alkali metal hydroxides and alkali metal carbonates. The preferred alkali ion is sodium. If bases of this kind are used, care must be taken to ensure that the resulting salts, which are then contained in the finished pharmaceutical formulation, are pharmacologically compatible with the abovementioned acid.
Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
..~ .
According to the invention, there is no need to add editic acid (EDTA) or one of the known salts thereof, sodium edetate, to the present formulation as a stabiliser or complexing agent.
Another embodiment contains editic acid and/ or the abovementioned salts thereof.
In a preferred embodiment of this kind the content based on sodium edetate is less than 10 mg / 100 ml. In this case, there is one preferred range from 5 mgl 100 ml to less than 10 mg/100 ml or another from greater than 0 to 5 mg/100m1.
In another embodiment the content of sodium edetate is 10 to 30 mg / 100 ml, preferably not more than 25 mg/ 100 ml.
In a preferred embodiment this additive is omitted entirely.
The remarks made concerning sodium edetate also apply analogously to other comparable additives which have complexing properties and can be used instead, such as for example nitrilotriacetic acid and the salts thereof.
By complexing agents is preferably meant within the scope of the present invention molecules which are capable of entering into complex bonds. Preferably, these compounds should have the effect of complexing cations, most preferably metal cations.
As we{l as ethanol, other cosolvents and/or other adjuvants may be added to the formulation according to the invention.
Preferred cosolvents are those which contain hydroxyl groups or other polar groups, for example alcohols - especially isopropylalcohol, glycols - especially propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters, provided that these are not already being used as the solvent or suspension agent.
Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
{ 7 By adjuvants and additives are meant, in this context, any pharmacologically acceptable and therapeutically useful substance which is not an active substance, but can be formulated together with the active substance in the pharmacologically suitable solvent, in order to improve the qualities of the active substance formulation.
Preferably, these substances have no pharmacological effects or no appreciable or at least no undesirable pharmacological effects in the context of the desired therapy.
The adjuvants and additives include, for example, surfactants such as e.g.
soya lecithin, oleic acid, sorbitan esters such as sorbitan trioleate, poiyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride, for example.
The preferred excipients include antioxidants such as 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 provitamins occurring in the human body.
Preservatives can be added to protect the formulation from contamination with pathogenic bacteria. Suitable preservatives are those known from the prior art, particularly benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.
Preferred formulations contain only benzalkonium chloride and sodium edetate, in addition to the solvent water and the tiotropium salt.
In another preferred embodiment, sodium edetate is omitted.
As already mentioned a number of times, tiotropium bromide is obtained in EP
716 Al and crystalline tiotropium bromide monohydrate may be obtained using a process which is described in more detail below.
In order to prepare the crystalline monohydrate according to the present invention, the tiotropium bromide obtained by the method disclosed in EP 418 716 Al, for example, first has to be taken up in water, heated, purified with activated charcoal Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
and, after removal of the activated charcoal, the tiotropium bromide-monohydrate is slowly crystallised while cooling slowly.
The following procedure is preferably followed:
In a reaction vessel of suitable dimensions, the solvent is mixed with tiotropium bromide, which has been obtained by the method disclosed in EP 418 716 Al, for example.
For each mol of tiotropium bromide put in, 0.4 to 1.5 kg, preferably 0.6 to 1 kg, most preferably about 0.8 kg of water are used as solvent.
The mixture obtained is heated with stirring, preferably to above 50 C, most preferably to above 60 C. The maximum temperature which can be selected is determined by the boiling point of the solvent used. Preferably, the mixture is heated to a range from 80-90 C.
Activated charcoal, either dry or moistened with water, is added to this solution.
Preferably, 10 to 50 g, more preferably 15 to 35 g, most preferably about 25 g of activated charcoal are put in per mol of tiotropium bromide used. If desired the activated charcoal is suspended in water before being added to the solution containing tiotropium bromide. 70 to 200 g, preferably 100 to 160 g, more preferably about 135 g of water are used, per mol of tiotropium bromide put in, in order to suspend the activated charcoal. If the activated charcoal is suspended in water beforehand, before being added to the solution containing tiotropium bromide, it is advisable to rinse again with the same amount of water.
After the activated charcoal has been added, stirring is continued at constant temperature for between 5 and 60 minutes, preferably between 10 and 30 minutes, more preferably for about 15 minutes and the mixture obtained is filtered to remove the activated charcoal. The filter is then rinsed with water. 140 to 400 g, preferably 200 to 320 g, most preferably about 270 g of water are used for this, per mol of tiotropium bromide used.
The filtrate is then slowly cooled, preferably to a temperature of 20-25 C.
The cooling preferably takes place at a cooling rate of 1 to 10 C every 10 to 30 minutes, preferably 2 to 8 C every 10 to 30 minutes, more preferably 3 to 5 C every 10 to 20 minutes, most preferably 3 to 5 C about every 20 minutes. If desired, the cooling to 20 to 25 C may be followed by further cooling to below 20 C, more preferably to 10 to 15 C.
After cooling is complete, stirring is continued for between 20 minutes and 3 hours, preferably between 40 minutes and 2 hours, more preferably for about one hour to complete the crystallisation.
Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
~
The crystals obtained are then isolated by filtering or suction filtering to remove the solvent. If it should prove necessary to subject the crystals obtained to a further washing step, it is advisable to use water or acetone as the washing solvent.
0.1 to 1.0 L, preferably 0.2 to 0.5 L, more preferably about 0.3 L of solvent may be used per mol of tiotropium bromide put in, in order to wash the tiotropium bromide monohydrate crystals obtained. If necessary the washing step may be repeated.
The product obtained is dried in vacuo or using circulating heated air until a water content of 2.5 - 4.0 % is obtained.
According to one aspect the present invention therefore also relates to formulations of solutions of the type described above using crystalline tiotropium bromide monohydrate which may be obtained by the procedure described above.
The pharmaceutical formulations containing tiotropium salts according to the invention are preferably used in an inhaler of the kind described hereinbefore in order to produce the propellant-free aerosols according to the invention. At this point we should once again expressly mention the patent documents described hereinbefore, to which reference is hereby made.
As described at the beginning, a further developed embodiment of the preferred inhaler is disclosed in WO 97/12687 and Figure 6 thereof. This nebuliser (Respimat ) can advantageously be used to produce the inhalable aerosols according to the invention containing a tiotropium salt as active substance. Because of its cylindrical shape and handy size of less than 9 to 15 cm long and 2 to 4 cm wide, the device can be carried anywhere by the patient. The nebuliser sprays a defined volume of the pharmaceutical formulation out through small nozzles at high pressures, so as to produce inhalable aerosols.
The preferred atomiser essentially consists of an upper housing part, a pump housing, a nozzle, a locking clamp, a spring housing, a spring and a storage container, characterised by - a pump housing fixed in the upper housing part and carrying at one end a nozzle body with the nozzle or nozzle arrangement, - a hollow piston with valve body, Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
- a power take-off flange in which the hollow body is fixed and which is located in the upper housing part, - a locking clamping mechanism located in the upper housing part, - a spring housing with the spring located therein, which is rotatably mounted on the u er housing pp part by means of a rotary bearing, - a lower housing part which is fitted onto the spring housing in the axial direction.
The hollow piston with valve body corresponds to a device disclosed in WO
97/12687. It projects partially into the cylinder of the pump housing and is disposed to be axially movable in the cylinder. Reference is made particularly to Figures especially Figure 3 - and the associated parts of the description. At the moment of release of the spring the hollow piston with valve body exerts, at its high pressure end, a pressure of 5 to 60 Mpa (about 50 to 600 bar), preferably 10 to 60 Mpa (about 100 to 600 bar) on the fluid, the measured amount of active substance solution.
Volumes of 10 to 50 microlitres are preferred, volumes of 10 to 20 microlitres are more preferable, whilst a volume of 15 microlitres per actuation is particularly preferred.
The valve body is preferably mounted at the end of the hollow piston which faces the nozzle body.
The nozzle in the nozzle body is preferably microstructured, i.e. produced by micro-engineering. Microstructured nozzle bodies are disclosed for example in WO-94/07607; reference is hereby made to the contents of this specification, especially Figure 1 and the associated description.
The nozzle body consists for example of two sheets of glass and/or silicon securely fixed together, at least one of which has one or more microstructured channels which connect the nozzle inlet end to the nozzle outlet end. At the nozzle outlet end there is at least one round or non-round opening 2 to 10 microns deep and 5 to 15 microns wide, the depth preferably being 4.5 to 6.5 microns and the length being 7 to microns.
If there is a plurality of nozzle openings, preferably two, the directions of spraying of the nozzles in the nozzle body may run parallel to each other or may be inclined relative to one another in the direction of the nozzle opening. In the case of a nozzle Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
' 11 =1 .
body having at least two nozzle openings at the outlet end, the directions of spraying may be inclined relative to one another at an angle of 20 degrees to 160 degrees, preferably at an angle of 60 to 150 degrees, most preferably 80 to 100 .
The nozzle openings are preferably arranged at a spacing of 10 to 200 microns, more preferably at a spacing of 10 to 100 microns, still more preferably 30 to microns. A spacing of 50 microns is most preferred.
The directions of spraying therefore meet in the region of the nozzle openings.
As already mentioned, the liquid pharmaceutical preparation hits the nozzle body at an entry pressure of up to 600 bar, preferably 200 to 300 bar and is atomised through the nozzle openings into an inhalable aerosol. The preferred particie sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns.
The locking clamping mechanism contains a spring, preferably a cylindrical helical compression spring as a store for the mechanical energy. The spring acts on the power take-off flange as a spring member the movement of which is determined by the position of a locking member. The travel of the power take-off flange is precisely limited by an upper stop and a lower stop. The spring is preferably tensioned via a stepping-up gear, e.g. a helical sliding gear, by an external torque which is generated when the upper housing part is turned relative to the spring housing in the lower housing part. In this case, the upper housing part and the power take-off flange contain a single- or multi-speed spline gear.
The locking member with the engaging locking surfaces is arranged in an annular configuration around the power take-off flange. It consists for example of a ring of plastics or metal which is inherently radially elastically deformable. The ring is arranged in a plane perpendicular to the axis of the atomiser. After the locking of the spring, the locking surfaces of the locking member slide into the path of the power take-off flange and prevent the spring from being released. The locking member is actuated by means of a button. The actuating button is connected or coupled to the locking member. In order to actuate the locking clamping mechanism the actuating button is moved parallel to the annular plane, preferably into the atomiser, and the deformable ring is thereby deformed in the annular plane. Details of the construction of the locking clamping mechanism are described in WO 97/20590.
Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
The lower housing part is pushed axially over the spring housing and covers the bearing, the drive for the spindle and the storage container for the fluid.
When the atomiser is operated, the upper part of the housing is rotated relative to the lower part, the lower part taking the spring housing with it. The spring meanwhile is compressed and biased by means of the helical sliding gear, and the clamping mechanism engages automatically. The angle of rotation is preferably a whole-number fraction of 360 degrees, e.g. 180 degrees. At the same time as the spring is tensioned, the power take-off component in the upper housing part is moved along by a given amount, the hollow piston is pulled back inside the cylinder in the pump housing, as a result of which some of the fluid from the storage container is sucked into the high pressure chamber in front of the nozzle.
If desired, a plurality of replaceable storage containers containing the fluid to be atomised can be inserted in the atomiser one after another and then used. The storage container contains the aqueous aerosol preparation according to the invention.
The atomising process is initiated by gently pressing the actuating button.
The clamping mechanism then opens the way for the power take-off component. The biased spring pushes the piston into the cylinder in the pump housing. The fluid emerges from the nozzle of the atomiser in the form of a spray.
Further details of the construction are disclosed in PCT applications WO
and WO 97/20590, to which reference is hereby made.
The components of the atomiser (nebuliser) are made of a material suitable for their function. The housing of the atomiser and - if the function allows - other parts as well are preferably made of plastics, e.g. by injection moulding. For medical applications, physiologically acceptable materials are used.
Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
Figures la/b, which are identical to Figures 6 a/b of WO 97/12687, show the Respimat nebuliser with which the aqueous aerosol preparations according to the invention can advantageously be inhaled.
Figure 1 a shows a longitudinal section through the atomiser with the spring under tension, Figure 1 b shows a longitudinal section through the atomiser with the spring released.
The upper housing part (51) contains the pump housing (52), on the end of which is mounted the holder (53) for the atomiser nozzle. In the holder is the nozzle body (54) and a filter (55). The hollow piston (57) fixed in the power take-off flange (56) of the locking clamping mechanism projects partly into the cylinder of the pump housing. At its end the hollow piston carries the valve body (58). The hollow piston is sealed off by the gasket (59). Inside the upper housing part is the stop (60) on which the power take-off flange rests when the spring is relaxed. Located on the power take-off flange is the stop (61) on which the power take-off flange rests when the spring is under tension. After the tensioning of the spring, the locking member (62) slides between the stop (61) and a support (63) in the upper housing part. The actuating button (64) is connected to the locking member. The upper housing part ends in the mouthpiece (65) and is closed off by the removable protective cap (66).
The spring housing (67) with compression spring (68) is rotatably mounted on the upper housing part by means of the snap-fit lugs (69) and rotary bearings. The lower housing part (70) is pushed over the spring housing. Inside the spring housing is the replaceable storage container (71) for the fluid (72) which is to be atomised.
The storage container is closed off by the stopper (73), through which the hollow piston projects into the storage container and dips its end into the fluid (supply of active substance solution).
The spindle (74) for the mechanical counter is mounted on the outside of the spring housing. The drive pinion (75) is located at the end of the spindle facing the upper housing part. On the spindle is the slider (76).
Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
The nebuliser described above is suitable for nebulising the aerosol preparations according to the invention to form an aerosol suitable for inhalation.
If the formulation according to the invention is nebulised using the method described o 0 above (Respimat ), the mass expelled, in at least 97 /o, preferably at least 98% of all the actuations of the inhaler (puffs), should correspond to a defined quantity with a range of tolerance of not more than 25%, preferably 20% of this quantity.
Preferably, between 5 and 30 mg, more preferably between 5 and 20 mg of formulation are delivered as a defined mass per puff.
However, the formulation according to the invention can also be nebulised using inhalers other than those described above, for example jet-stream inhalers.
Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
Examples 1. Example of the synthesis of tiotropium bromide monohydrate 15.0 kg of tiotropium bromide are added to 25.7 kg of water in a suitable reaction vessel. The mixture is heated to 80-90 C and stirred at constant temperature until a clear solution is formed. Activated charcoal (0.8 kg), moistened with water, is suspended in 4.4 kg of water, this mixture is added to the solution containing tiotropium bromide and rinsed with 4.3 kg of water. The mixture thus obtained is stirred for at ieast 15 min. at 80-90 C and then filtered through a heated filter into an apparatus which has been preheated to an outer temperature of 70 C. The filter is rinsed with 8.6 kg of water. The contents of the apparatus are cooled to a temperature of 20-25 C at a rate of 3-5 C every 20 minutes. Using cold water the apparatus is cooled further to 10-15 C and crystallisation is completed by stirring for at least another hour. The crystals are isolated using a suction filter drier, the crystal slurry isolated is washed with 9 L of cold water (10-15 C) and cold acetone (10-15 C). The crystals obtained are dried at 25 C for 2 hours in a nitrogen current.
Yield: 13.4 kg of tiotropium bromide monohydrate (86 % of theory).
Case 1/1156 FF CA 02426074 2003-04-22 Boehringer Ingelheim Pharma KG
11. Examples of formu~lations 100 g of pharmaceutical preparation contain:
Example Amount of Amount of Amount of Amount of pH, tiotropium tiotropium benzalkonium sodium adjusted bromide, based bromide chloride edetate with HCI
on tiotropium: monohydrate, (1N) based on tiotropium:
1 0.099 g -- 10 mg 25 mg 3.0 2 0.006 g --- 10 mg 25 mg 3.0 3 0.099 g -- 10 mg 10 mg 3.0 4 0.006g --- 10mg 10mg 3.0 --- 0.099 g 10 mg 25 mg 3.0 6 --- 0.006 g 10 mg 25 mg 3.0 7 --- 0.099 g 10 mg 10mg 3.0 8 --- 0.006 g 10 mg 10 mg 3.0 The remainder is water.
Claims (31)
1. A pharmaceutical composition comprising:
a tiotropium salt as active substance, in a concentration based on tiotropium of between 0.0005 and 5 by weight, a solvent comprising water or a water and ethanol mixture, acid for achieving a pH between 2.0 and 3.1, and a pharmacologically acceptable preservative.
a tiotropium salt as active substance, in a concentration based on tiotropium of between 0.0005 and 5 by weight, a solvent comprising water or a water and ethanol mixture, acid for achieving a pH between 2.0 and 3.1, and a pharmacologically acceptable preservative.
2. A pharmaceutical composition according to claim 1, wherein the tiotropium salt is a chloride, bromide, iodide, methanesulphonate, para-toluene-sulphonate or methylsulphate salt.
3. A pharmaceutical composition according to claim 1, wherein the tiotropium salt is tiotropium bromide.
4. A pharmaceutical composition according to claim 1, wherein the tiotropium salt is tiotropium bromide monohydrate.
5. A pharmaceutical composition according to any one of claims 1 to 4, wherein the solvent is the water.
6. A pharmaceutical composition according to any one of claims 1 to 4, wherein the solvent is the water-ethanol mixture.
7. A pharmaceutical composition according to claim 6, wherein the water-ethanol mixture comprises up to 70 volume % ethanol.
8. A pharmaceutical composition according to claim 6, wherein the water-ethanol mixture comprises up to 60 volume % ethanol.
9. A pharmaceutical composition according to claim 6, wherein the water-ethanol mixture comprises up to 30 volume % ethanol.
10. A pharmaceutical composition according to any one of claims 1 to 9, further comprising a complexing agent.
11. A pharmaceutical composition according to any one of claims 1 to 10, further comprising a stabiliser.
12. A pharmaceutical composition according to any one of claims 1 to 11, further comprising a pharmaceutically acceptable adjuvant in addition to the preservative.
13. A pharmaceutical composition according to claim 12, wherein the pharmaceutically acceptable adjuvant is an antioxidant.
14. A pharmaceutical composition according to any one of claims 1 to 11, further comprising a pharmaceutically acceptable additive in addition to the preservative.
15. A pharmaceutical composition according to any one of claims 1 to 14, further comprising editic acid or an editic acid salt in an amount of greater than zero to 25 mg/100 ml.
16. A pharmaceutical composition according to claim 15, wherein the editic acid salt is present in an amount of from 5 to less than 10 mg/100 ml.
17. A pharmaceutical composition according to claim 15, wherein the editic acid salt is present in an amount of from 10 to 25 mg/100 ml.
18. A pharmaceutical composition according to claim 16 or 17, wherein the editic acid salt is sodium edetate.
19. A pharmaceutical composition according to any one of claims 1 to 18, wherein the pH is between 2.5 and 3.1.
20. A pharmaceutical composition according to any one of claims 1 to 18, wherein the pH is between 2.7 and 3.1.
21. A pharmaceutical composition according to any one of claims 1 to 18, wherein the pH is between 2.7 and 3Ø
22. A pharmaceutical composition according to any one of claims 1 to 21, wherein the concentration of tiotropium is between 0.001 and 3 % by weight, based on weight of the composition.
23. A pharmaceutical composition according to any one of claims 1 to 21, wherein the concentration of tiotropium is between 0.0005 to 0.5 % by weight, based on weight of the composition.
24. A pharmaceutical composition according to any one of claims 1 to 21, wherein the concentration of tiotropium is between 0.0005 to 0.25 % by weight, based on weight of the composition.
25. A pharmaceutical composition according to any one of claims 1 to 21, wherein the concentration of tiotropium is between 0.001 to 0.1 % by weight, based on weight of the composition.
26. A pharmaceutical composition according to any one of claims 1 to 25, wherein the preservative is benzalkonium chloride.
27. A pharmaceutical composition according to any one of claims 1 to 26, wherein the solvent is water or the water and ethanol mixture without a co-solvent.
28. A pharmaceutical composition according to any one of claims 1 to 27 for treatment of one or both of asthma and chronic obstructive pulmonary disorder.
29. Use of a composition as defined in any one of claims 1 to 27 in treatment of one or both of asthma and chronic obstructive pulmonary disorder.
30. Use of a composition as defined in any one of claims 1 to 27 in preparation of a medicament for treatment of one or both of asthma and chronic obstructive pulmonary disorder.
31. A process for preparing a pharmaceutical composition according to any one of claims 1 to 27 comprising admixing the components recited in any one of claims 1 to 27.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10054036 | 2000-10-31 | ||
| DE10054036.8 | 2000-10-31 | ||
| PCT/EP2001/012292 WO2002036104A2 (en) | 2000-10-31 | 2001-10-24 | Inhalative solution formulation containing a tiotropium salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2426074A1 CA2426074A1 (en) | 2002-05-10 |
| CA2426074C true CA2426074C (en) | 2008-12-23 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002426074A Expired - Fee Related CA2426074C (en) | 2000-10-31 | 2001-10-24 | Inhalable formulation of a solution containing a tiotropium salt |
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| EP (2) | EP1837021A3 (en) |
| JP (1) | JP4344135B2 (en) |
| KR (1) | KR100853107B1 (en) |
| CN (2) | CN100396285C (en) |
| AR (1) | AR038764A1 (en) |
| AT (1) | ATE373473T1 (en) |
| AU (2) | AU2002221738B2 (en) |
| BG (1) | BG66315B1 (en) |
| BR (1) | BRPI0115076B8 (en) |
| CA (1) | CA2426074C (en) |
| CY (1) | CY1107825T1 (en) |
| CZ (1) | CZ300794B6 (en) |
| DE (2) | DE10152521A1 (en) |
| DK (1) | DK1333819T3 (en) |
| EA (1) | EA007604B1 (en) |
| EC (1) | ECSP034541A (en) |
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| ES (1) | ES2294045T3 (en) |
| HK (1) | HK1060524A1 (en) |
| HR (1) | HRP20030338B1 (en) |
| HU (1) | HU229411B1 (en) |
| IL (2) | IL155538A0 (en) |
| ME (1) | ME00244B (en) |
| MX (1) | MXPA03003742A (en) |
| MY (1) | MY138940A (en) |
| NO (1) | NO332519B1 (en) |
| NZ (1) | NZ526023A (en) |
| PE (1) | PE20030092A1 (en) |
| PL (1) | PL203316B1 (en) |
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| SA (1) | SA01220482B1 (en) |
| SI (1) | SI1333819T1 (en) |
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| UA (1) | UA78690C2 (en) |
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| WO (1) | WO2002036104A2 (en) |
| ZA (1) | ZA200302922B (en) |
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|---|---|---|---|---|
| DE10216036A1 (en) * | 2002-04-11 | 2003-10-23 | Boehringer Ingelheim Pharma | Aerosol formulation for inhalation containing a tiotropium salt |
| CN1292748C (en) * | 2003-03-05 | 2007-01-03 | 南昌弘益科技有限公司 | Timepidium bromide inhalant powders and their preparing process |
| DK2083007T3 (en) * | 2003-11-03 | 2013-07-29 | Boehringer Ingelheim Int | Tiotropium salts, processes for their preparation, and drug formulations containing them |
| DK1682541T3 (en) * | 2003-11-03 | 2010-06-28 | Boehringer Ingelheim Int | Process for the preparation of tiotropium salts |
| SI1881980T1 (en) | 2005-05-02 | 2012-12-31 | Boehringer Ingelheim International Gmbh | Novel crystalline forms of tiotropium bromide |
| EP2044967A1 (en) * | 2007-10-01 | 2009-04-08 | Boehringer Ingelheim Pharma GmbH & Co. KG | Atomiser |
| CN104306361A (en) * | 2014-09-24 | 2015-01-28 | 万特制药(海南)有限公司 | Tiotropium bromide-containing inhalable solution |
| CN111374963A (en) * | 2018-12-31 | 2020-07-07 | 天津药业研究院有限公司 | Tiotropium solution for inhalation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3931041C2 (en) * | 1989-09-16 | 2000-04-06 | Boehringer Ingelheim Kg | Esters of thienyl carboxylic acids with amino alcohols, their quaternization products, processes for their preparation and medicaments containing them |
| SG45171A1 (en) * | 1990-03-21 | 1998-01-16 | Boehringer Ingelheim Int | Atomising devices and methods |
| DE19536902A1 (en) * | 1995-10-04 | 1997-04-10 | Boehringer Ingelheim Int | Miniature fluid pressure generating device |
| DE19653969A1 (en) * | 1996-12-20 | 1998-06-25 | Boehringer Ingelheim Kg | New aqueous pharmaceutical preparation for the production of propellant-free aerosols |
| DE19847968A1 (en) * | 1998-10-17 | 2000-04-20 | Boehringer Ingelheim Pharma | Separate storage of an active material and a solvent comprises a closure cap and a container, with a chamber attached to the unit. |
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2001
- 2001-10-24 NZ NZ526023A patent/NZ526023A/en not_active IP Right Cessation
- 2001-10-24 BR BRPI0115076A patent/BRPI0115076B8/en not_active IP Right Cessation
- 2001-10-24 AT AT01992567T patent/ATE373473T1/en active
- 2001-10-24 ES ES01992567T patent/ES2294045T3/en not_active Expired - Lifetime
- 2001-10-24 EP EP07111499A patent/EP1837021A3/en not_active Withdrawn
- 2001-10-24 RS YUP-330/03A patent/RS50859B/en unknown
- 2001-10-24 EA EA200300482A patent/EA007604B1/en not_active IP Right Cessation
- 2001-10-24 SI SI200130774T patent/SI1333819T1/en unknown
- 2001-10-24 IL IL15553801A patent/IL155538A0/en active IP Right Grant
- 2001-10-24 AU AU2002221738A patent/AU2002221738B2/en not_active Expired
- 2001-10-24 EE EEP200300203A patent/EE05314B1/en unknown
- 2001-10-24 PT PT01992567T patent/PT1333819E/en unknown
- 2001-10-24 WO PCT/EP2001/012292 patent/WO2002036104A2/en active IP Right Grant
- 2001-10-24 CA CA002426074A patent/CA2426074C/en not_active Expired - Fee Related
- 2001-10-24 JP JP2002538916A patent/JP4344135B2/en not_active Expired - Lifetime
- 2001-10-24 CN CNB018183158A patent/CN100396285C/en not_active Expired - Lifetime
- 2001-10-24 DK DK01992567T patent/DK1333819T3/en active
- 2001-10-24 KR KR1020037006013A patent/KR100853107B1/en active IP Right Grant
- 2001-10-24 ME MEP-2008-404A patent/ME00244B/en unknown
- 2001-10-24 UA UA2003054959A patent/UA78690C2/en unknown
- 2001-10-24 EP EP01992567A patent/EP1333819B1/en not_active Expired - Lifetime
- 2001-10-24 DE DE10152521A patent/DE10152521A1/en not_active Withdrawn
- 2001-10-24 CZ CZ20031486A patent/CZ300794B6/en unknown
- 2001-10-24 DE DE50113037T patent/DE50113037D1/en not_active Expired - Lifetime
- 2001-10-24 PL PL360405A patent/PL203316B1/en unknown
- 2001-10-24 CN CNA2008100985489A patent/CN101292964A/en active Pending
- 2001-10-24 SK SK527-2003A patent/SK286027B6/en not_active IP Right Cessation
- 2001-10-24 HU HU0301378A patent/HU229411B1/en unknown
- 2001-10-24 MX MXPA03003742A patent/MXPA03003742A/en active IP Right Grant
- 2001-10-24 AU AU2173802A patent/AU2173802A/en active Pending
- 2001-10-28 SA SA01220482A patent/SA01220482B1/en unknown
- 2001-10-29 UY UY26989A patent/UY26989A1/en not_active Application Discontinuation
- 2001-10-29 MY MYPI20015000A patent/MY138940A/en unknown
- 2001-10-29 TW TW090126764A patent/TWI293885B/en active
- 2001-10-31 AR ARP010105087A patent/AR038764A1/en not_active Ceased/Invalidation/Refusal/Rejection/Nullification
- 2001-10-31 PE PE2001001086A patent/PE20030092A1/en not_active Application Discontinuation
-
2003
- 2003-04-07 EC EC2003004541A patent/ECSP034541A/en unknown
- 2003-04-14 ZA ZA200302922A patent/ZA200302922B/en unknown
- 2003-04-16 BG BG107727A patent/BG66315B1/en active Active
- 2003-04-21 IL IL155538A patent/IL155538A/en unknown
- 2003-04-28 HR HR20030338A patent/HRP20030338B1/en not_active IP Right Cessation
- 2003-04-29 NO NO20031911A patent/NO332519B1/en not_active IP Right Cessation
-
2004
- 2004-05-20 HK HK04103586A patent/HK1060524A1/en not_active IP Right Cessation
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2007
- 2007-12-07 CY CY20071101562T patent/CY1107825T1/en unknown
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Effective date: 20201026 |