CA2459493C - New pharmaceutical compositions for inhalation - Google Patents
New pharmaceutical compositions for inhalation Download PDFInfo
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- CA2459493C CA2459493C CA2459493A CA2459493A CA2459493C CA 2459493 C CA2459493 C CA 2459493C CA 2459493 A CA2459493 A CA 2459493A CA 2459493 A CA2459493 A CA 2459493A CA 2459493 C CA2459493 C CA 2459493C
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- Prior art keywords
- acid
- hydroxy
- hexyl
- benzenedimethanol
- methyl
- Prior art date
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Classifications
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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
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
The invention relates to novel medicament compositions based on tiotropium salts and poorly soluble salmeterol salts. The invention also relates to a method for the production of said compositions and to the use thereof for treating diseases of the respiratory tract.
Description
New pharmaceutical compositions for inhalation The present invention relates to'new pharmaceutical compositions for inhalation based on tiotropium salts and salts of salmeterol which do not dissolve,easily, process for preparing them and their use in the treatment of respiratory complaints.
Background to the invention The compound tiotropium bromide, a salt of tiotropium, is known from European 1o Patent Application EP 418 716 Al and has the following chemical structure:
Me+ N.Me O H
O, Br S --O
-OH
S
This compound can also be known by the chemical name (1a,20,40,50t,70)-7-[(hydroxydi-2-thienylacetyl)oxy]-9, 9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02.4]
nonane-bromide and has valuable pharmacological properties. The term tiotropium should be understood within the scope of the present invention as being a reference to the free cation.
Like other salts of tiotropium, it is a highly effective anticholinergic and can therefore provide therapeutic benefit in the treatment of asthma or COPD (chronic obstructive pulmonary disease).
Tiotropium salts are preferably administered by inhalation. Suitable inhalable powders packed into appropriate capsules (inhalettes) may be used, administered by means of corresponding powder inhalers. Alternatively, they may be administered by the use of suitable inhalable aerosols. These also include powdered inhalable aerosols which contain, for example, HFA134a, HFA227 or mixtures thereof as propellant gas. They may also be administered in the form of suitable solutions of the tiotropium salt.
Background to the invention The compound tiotropium bromide, a salt of tiotropium, is known from European 1o Patent Application EP 418 716 Al and has the following chemical structure:
Me+ N.Me O H
O, Br S --O
-OH
S
This compound can also be known by the chemical name (1a,20,40,50t,70)-7-[(hydroxydi-2-thienylacetyl)oxy]-9, 9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02.4]
nonane-bromide and has valuable pharmacological properties. The term tiotropium should be understood within the scope of the present invention as being a reference to the free cation.
Like other salts of tiotropium, it is a highly effective anticholinergic and can therefore provide therapeutic benefit in the treatment of asthma or COPD (chronic obstructive pulmonary disease).
Tiotropium salts are preferably administered by inhalation. Suitable inhalable powders packed into appropriate capsules (inhalettes) may be used, administered by means of corresponding powder inhalers. Alternatively, they may be administered by the use of suitable inhalable aerosols. These also include powdered inhalable aerosols which contain, for example, HFA134a, HFA227 or mixtures thereof as propellant gas. They may also be administered in the form of suitable solutions of the tiotropium salt.
Detailed description of the invention Surprisingly, an unexpectedly beneficial therapeutic effect, particularly a synergistic effect can be observed in the treatment of inflammatory or obstructive respiratory complaints if one or more, preferably one, anticholinergic is used with one or more corticosteroids and with one or more tiotropium salts (1) are used in conjunction with one or more salmeterol salts (2) which do not readily dissolve, the salmeterol salts 2 having a solubility in water of 0.1 mg/ ml or less, preferably 0.05 mg/ml or less, most preferably 0.035 mg/ml or less. These salmeterol salts 2 used within the scope of the present invention are characterised in particular by being very well tolerated locally.
This significantly reduces undesirable side effects, for example, which are frequently observed when 13-mimetics such as salmeterol are administered to humans.
Examples of central side effects of (3-mimetics include, for example, general malaise, excitement, sleeplessness, anxiety, trembling fingers, sweating and headaches.
Accordingly, the present invention relates to combinations of pharmaceutical compositions characterised in that that contain one or more, preferably one, tiotropium salt (1) in combination with one or more, preferably one salmeterol salt (j of limited solubility, the salmeterol salt 2 having a solubility in water of 0.1 mg/ ml or less, preferably 0.05 mg/ml or less, most preferably 0.035 mg/ml or less.
The term tiotropium is intended within the scope of the present invention as a reference to the free cation (1'). Any reference to salmeterol is intended within the scope of the present invention as a reference to the free base (2'). The preparation of salmeterol was first described in British Patent GB 2140800 to the content of which reference is hereby made.
The active substance combinations according to the invention are surprisingly also characterised both by a rapid onset of activity and by their long-lasting effect. This is very important to the patient as on the one hand they will rapidly experience an improvement in their condition after taking the combination and on the other hand because of the long-lasting effect it is sufficient to take the drug once a day.
The abovementioned effects are observed both when the two active substances are taken simultaneously in a single active substance formulation and when they are administered successively in separate formulations. It is preferable according to the invention to administer the two active substance ingredients simultaneously in a single formulation.
In one aspect the present invention relates to a pharmaceutical composition which contains one or more tiotropium salts 1 and one or more salmeterol salts 2 optionally in the form of their solvates or hydrates. The active substances may either be combined in a single preparation or contained in two separate formulations.
Pharmaceutical compositions which contain the active substances 1 and 2 in a single preparation are preferred according to the invention.
In another aspect the present invention relates to a pharmaceutical composition which contains, in addition to therapeutically effective quantities of I and 2, a pharmaceutically acceptable excipient. In one aspect the present invention relates to a pharmaceutical composition which does not contain any pharmaceutically acceptable excipient in addition to therapeutically effective quantities of I
and 2.
The present invention also relates to the use of 1 and 2 for preparing a pharmaceutical composition containing therapeutically effective quantities of 1 and 2 for treating inflammatory or obstructive diseases of the respiratory tract, particularly asthma and/or COPD, by simultaneous or successive administration.
The present invention also relates to the simultaneous or successive use of therapeutically effective doses of the combination of the above pharmaceutical compositions 1 and 2 for treating inflammatory or obstructive diseases of the respiratory tract, particularly asthma or COPD.
By the tiotropium salts I which may be used within the scope of the present invention are meant the compounds which contain, in addition to tiotropium as counter-ion (anion), chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methyl sulphate. Within the scope of the present invention, the methanesulphonate, chloride, bromide and iodide are preferred of all the tiotropium salts 1, the methanesulphonate and bromide being of particular importance. Of outstanding importance according to the invention is tiotropium bromide. The tiotropium salts 1 may optionally be used in the form of their solvates and hydrates. The hydrates are particularly preferably used. Of all the hydrates of the tiotropium salts 1 which may be used according to the invention, the crystalline tiotropium bromide monohydrate described in WO 02/30928 is particularly preferred within the scope of the present invention. Reference is hereby made to the entire contents of this International Patent Application.
By salts of salmeterol 2 of limited solubility are meant, according to the invention, pharmaceutically acceptable salts of salmeterol which have a solubility in water of 0.1 mg/ ml or less, preferably 0.05 mg/ml or less, most preferably 0.035 mg/ml or less.
Salmeterol has a chiral centre. The present invention includes the salts 2 in racemic 90 or enantiomerically pure form. Both the (R)- and the (S)-enantiomer are particularly important. Moreover, within the scope of the present invention, the salts 2 may be used in the form of the non-racemic mixtures of the two enantiomers.
The salmeterol salts 2 may be prepared from the free base of salmeterol according or analogously to methods known in the art for forming acid addition salts.
These comprise reacting the free base salmeterol 2' with the corresponding carboxylic acids in suitable solvents, preferably in organic solvents. For this purpose the desired acid is preferably first taken up in an organic solvent, most preferably a solvent selected from among ethyl acetate, methanol, ethanol, isopropanol and diethylether or mixtures thereof. The abovementioned solvents may optionally also be used in admixture with tert.-butyl methyI ether or cyclohexane. The acids taken up in one of the abovementioned solvents may optionally be dissolved by heating, preferably by heating up to the boiling temperature of the solvent. Salmeterol 2' optionally dissolved in one of the abovementioned solvents, is added to this solution.
The salts 2 are crystallised out of the resulting solution, optionally with cooling, and isolated.
According to the invention the salmeterol salts 2 of limited solubility HO
HO I O
OH F
x Saure 2 selected from among:
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-bi phenyl-4-carboxylate salt;
4-hydroxy-a' -[[[6-(4-phenylbutoxy)-hexyl]-am ino]-m ethyl]-1, 3-benzened im ethano 1-4-chlorosalicylate salt;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5 2,4-dihydroxybenzoate salt;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1, 3-benzenedimethanol-2-hydroxy-3-naphthoate salt;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-hydroxy-2-naphthoate salt;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1,3-benzenedimethanol-salicylate salt;
are preferred.
Other salmeterol salts 2 of limited solubility according to the invention which may be used in the pharmaceutical combinations according to the invention are those salts which are obtained by reacting the free base of salmeterol 2' with one or more, preferably one of the acids mentioned below:
acid solvent melting point 2 in (for salt formation) C (according to DSC) 2-hydroxy-1 -naphthoic acid ethyl acetate 122 3,5-dichlorosalicylic acid diethyl ether 108 furan-2-carboxylic acid diethyl ether 80 0,5 x 2,5-dihydroxy-terephthalic ethyl acetate 102 acid cinnamic acid ethyl acetate 89 triphenylacetic acid diethyl ether 116 4-phenylcinnamic acid ethyl acetate 109 biphenyl-2-carboxylic acid ethyl acetate 127 4-trifluoromethylcinnamic acid ethyl acetate 125 9-fluorenylideneacetic acid ethyl acetate 88 3-(2-naphthyl)acrylic acid ethyl acetate 97 3-(1 -naphthyl)acrylic acid ethyl acetate 77 1-naphthoic acid ethyl acetate 120 2,6-dichlorobenzoic acid ethyl acetate 103 3,4-dichlorobenzoic acid ethyl acetate 115 3,5-dichlorobenzoic acid ethyl acetate 110 4-bromobenzoic acid ethyl acetate 115 4-trifluoromethylbenzoic acid ethyl acetate 125 4-isopropylbenzoic acid ethyl acetate 85-90 4-tert.-butylbenzoic acid ethyl acetate 95 3-(3-indolyl)acrylic acid ethyl acetate 113 2,4-dichlorocinnamic acid ethyl acetate 138 2,6-dichlorocinnamic acid ethyl acetate 82 2,5-dimethoxy-cinnamic acid ethyl acetate 88 2-trifluoromethylcinnamic acid ethyl acetate 94 3-trifluoromethylcinnamic acid ethyl acetate 92 3-chlorocinnamic acid ethyl acetate 90 3,4-dichlorocinnamic acid ethyl acetate 116 4-bromocinnamic acid ethyl acetate 127 4-chlorocinnamic acid ethyl acetate 123 4-methoxycinnamic acid ethyl acetate 98 4-fluorocinnamic acid ethyl acetate 113 4-isopropylcinnamic acid ethyl acetate 82 4-tert.-butylcinnamic acid ethyl acetate 93 2,6-difluorocinnamic acid ethyl acetate 77 2,4-difluorocinnamic acid ethyl acetate 121 3,4-difluorocinnamic acid ethyl acetate 102 2,4,5-trifluorocinnamic acid ethyl acetate 120 3,4,5-trifluorocinnamic acid ethyl acetate 107 3-methoxysalicylic acid ethyl acetate 118 4-methoxysalicylic acid ethyl acetate 113 5-methoxysalicylic acid ethyl acetate 114 4-methylsalicylic acid ethyl acetate 116 5-aminosalicylic acid ethyl acetate/ 146 isopropanol 3-chlorosalicylic acid ethyl acetate 108 5-sulphosalicylic acid ethyl acetate/ 129 isopropanol 5-acetylsalicylic acid ethyl acetate 80 3,5-diiodosalicylic acid ethyl acetate 133 isoquinoline-1 -carboxylic acid ethyl acetate 105 9-fluorenecarboxylic acid ethyl acetate 90 9-fluorenone-1 -carboxylic acid ethyl acetate 136 3,5-diisopropyl-salicylic acid ethyl acetate 115 diflunisal ethyl acetate 104 Of particular importance according to the invention are pharmaceutical combinations of the salmeterol salts 2 of limited solubility within the scope of the invention, selected from among:
4-hydroxy-a'-[[[6-(44-phenylbutoxy)-hexyl]-am ino]-methyl]-1,3-benzenedimethanol-4-phenylcinnamate salt 2.1:
HO
HO \ I N O
OH H H
"OOC
1.35 g (6 mmol) of 4-phenylcinnamic acid is dissolved by refluxing in 75 mL of ethyl acetate. To this solution is added a warm solution of 2.5 g (6 mmol) of salmeterol in 25 mL of ethyl acetate. The solution is left to cool and stirred for 16 h at ambient temperature. The suspension is filtered, the precipitate is washed with ethyl acetate and tert.-butylmethylether and dried in vacuo at 25-30 C. 3.47 g of the title compound are obtained as a colourless solid. Melting point: 109 C;
The following compounds were prepared analogously:
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-trifluorom ethyl-cinnamate salt 2.2;
Melting point: 125 C;
This significantly reduces undesirable side effects, for example, which are frequently observed when 13-mimetics such as salmeterol are administered to humans.
Examples of central side effects of (3-mimetics include, for example, general malaise, excitement, sleeplessness, anxiety, trembling fingers, sweating and headaches.
Accordingly, the present invention relates to combinations of pharmaceutical compositions characterised in that that contain one or more, preferably one, tiotropium salt (1) in combination with one or more, preferably one salmeterol salt (j of limited solubility, the salmeterol salt 2 having a solubility in water of 0.1 mg/ ml or less, preferably 0.05 mg/ml or less, most preferably 0.035 mg/ml or less.
The term tiotropium is intended within the scope of the present invention as a reference to the free cation (1'). Any reference to salmeterol is intended within the scope of the present invention as a reference to the free base (2'). The preparation of salmeterol was first described in British Patent GB 2140800 to the content of which reference is hereby made.
The active substance combinations according to the invention are surprisingly also characterised both by a rapid onset of activity and by their long-lasting effect. This is very important to the patient as on the one hand they will rapidly experience an improvement in their condition after taking the combination and on the other hand because of the long-lasting effect it is sufficient to take the drug once a day.
The abovementioned effects are observed both when the two active substances are taken simultaneously in a single active substance formulation and when they are administered successively in separate formulations. It is preferable according to the invention to administer the two active substance ingredients simultaneously in a single formulation.
In one aspect the present invention relates to a pharmaceutical composition which contains one or more tiotropium salts 1 and one or more salmeterol salts 2 optionally in the form of their solvates or hydrates. The active substances may either be combined in a single preparation or contained in two separate formulations.
Pharmaceutical compositions which contain the active substances 1 and 2 in a single preparation are preferred according to the invention.
In another aspect the present invention relates to a pharmaceutical composition which contains, in addition to therapeutically effective quantities of I and 2, a pharmaceutically acceptable excipient. In one aspect the present invention relates to a pharmaceutical composition which does not contain any pharmaceutically acceptable excipient in addition to therapeutically effective quantities of I
and 2.
The present invention also relates to the use of 1 and 2 for preparing a pharmaceutical composition containing therapeutically effective quantities of 1 and 2 for treating inflammatory or obstructive diseases of the respiratory tract, particularly asthma and/or COPD, by simultaneous or successive administration.
The present invention also relates to the simultaneous or successive use of therapeutically effective doses of the combination of the above pharmaceutical compositions 1 and 2 for treating inflammatory or obstructive diseases of the respiratory tract, particularly asthma or COPD.
By the tiotropium salts I which may be used within the scope of the present invention are meant the compounds which contain, in addition to tiotropium as counter-ion (anion), chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methyl sulphate. Within the scope of the present invention, the methanesulphonate, chloride, bromide and iodide are preferred of all the tiotropium salts 1, the methanesulphonate and bromide being of particular importance. Of outstanding importance according to the invention is tiotropium bromide. The tiotropium salts 1 may optionally be used in the form of their solvates and hydrates. The hydrates are particularly preferably used. Of all the hydrates of the tiotropium salts 1 which may be used according to the invention, the crystalline tiotropium bromide monohydrate described in WO 02/30928 is particularly preferred within the scope of the present invention. Reference is hereby made to the entire contents of this International Patent Application.
By salts of salmeterol 2 of limited solubility are meant, according to the invention, pharmaceutically acceptable salts of salmeterol which have a solubility in water of 0.1 mg/ ml or less, preferably 0.05 mg/ml or less, most preferably 0.035 mg/ml or less.
Salmeterol has a chiral centre. The present invention includes the salts 2 in racemic 90 or enantiomerically pure form. Both the (R)- and the (S)-enantiomer are particularly important. Moreover, within the scope of the present invention, the salts 2 may be used in the form of the non-racemic mixtures of the two enantiomers.
The salmeterol salts 2 may be prepared from the free base of salmeterol according or analogously to methods known in the art for forming acid addition salts.
These comprise reacting the free base salmeterol 2' with the corresponding carboxylic acids in suitable solvents, preferably in organic solvents. For this purpose the desired acid is preferably first taken up in an organic solvent, most preferably a solvent selected from among ethyl acetate, methanol, ethanol, isopropanol and diethylether or mixtures thereof. The abovementioned solvents may optionally also be used in admixture with tert.-butyl methyI ether or cyclohexane. The acids taken up in one of the abovementioned solvents may optionally be dissolved by heating, preferably by heating up to the boiling temperature of the solvent. Salmeterol 2' optionally dissolved in one of the abovementioned solvents, is added to this solution.
The salts 2 are crystallised out of the resulting solution, optionally with cooling, and isolated.
According to the invention the salmeterol salts 2 of limited solubility HO
HO I O
OH F
x Saure 2 selected from among:
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-bi phenyl-4-carboxylate salt;
4-hydroxy-a' -[[[6-(4-phenylbutoxy)-hexyl]-am ino]-m ethyl]-1, 3-benzened im ethano 1-4-chlorosalicylate salt;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5 2,4-dihydroxybenzoate salt;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1, 3-benzenedimethanol-2-hydroxy-3-naphthoate salt;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-hydroxy-2-naphthoate salt;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1,3-benzenedimethanol-salicylate salt;
are preferred.
Other salmeterol salts 2 of limited solubility according to the invention which may be used in the pharmaceutical combinations according to the invention are those salts which are obtained by reacting the free base of salmeterol 2' with one or more, preferably one of the acids mentioned below:
acid solvent melting point 2 in (for salt formation) C (according to DSC) 2-hydroxy-1 -naphthoic acid ethyl acetate 122 3,5-dichlorosalicylic acid diethyl ether 108 furan-2-carboxylic acid diethyl ether 80 0,5 x 2,5-dihydroxy-terephthalic ethyl acetate 102 acid cinnamic acid ethyl acetate 89 triphenylacetic acid diethyl ether 116 4-phenylcinnamic acid ethyl acetate 109 biphenyl-2-carboxylic acid ethyl acetate 127 4-trifluoromethylcinnamic acid ethyl acetate 125 9-fluorenylideneacetic acid ethyl acetate 88 3-(2-naphthyl)acrylic acid ethyl acetate 97 3-(1 -naphthyl)acrylic acid ethyl acetate 77 1-naphthoic acid ethyl acetate 120 2,6-dichlorobenzoic acid ethyl acetate 103 3,4-dichlorobenzoic acid ethyl acetate 115 3,5-dichlorobenzoic acid ethyl acetate 110 4-bromobenzoic acid ethyl acetate 115 4-trifluoromethylbenzoic acid ethyl acetate 125 4-isopropylbenzoic acid ethyl acetate 85-90 4-tert.-butylbenzoic acid ethyl acetate 95 3-(3-indolyl)acrylic acid ethyl acetate 113 2,4-dichlorocinnamic acid ethyl acetate 138 2,6-dichlorocinnamic acid ethyl acetate 82 2,5-dimethoxy-cinnamic acid ethyl acetate 88 2-trifluoromethylcinnamic acid ethyl acetate 94 3-trifluoromethylcinnamic acid ethyl acetate 92 3-chlorocinnamic acid ethyl acetate 90 3,4-dichlorocinnamic acid ethyl acetate 116 4-bromocinnamic acid ethyl acetate 127 4-chlorocinnamic acid ethyl acetate 123 4-methoxycinnamic acid ethyl acetate 98 4-fluorocinnamic acid ethyl acetate 113 4-isopropylcinnamic acid ethyl acetate 82 4-tert.-butylcinnamic acid ethyl acetate 93 2,6-difluorocinnamic acid ethyl acetate 77 2,4-difluorocinnamic acid ethyl acetate 121 3,4-difluorocinnamic acid ethyl acetate 102 2,4,5-trifluorocinnamic acid ethyl acetate 120 3,4,5-trifluorocinnamic acid ethyl acetate 107 3-methoxysalicylic acid ethyl acetate 118 4-methoxysalicylic acid ethyl acetate 113 5-methoxysalicylic acid ethyl acetate 114 4-methylsalicylic acid ethyl acetate 116 5-aminosalicylic acid ethyl acetate/ 146 isopropanol 3-chlorosalicylic acid ethyl acetate 108 5-sulphosalicylic acid ethyl acetate/ 129 isopropanol 5-acetylsalicylic acid ethyl acetate 80 3,5-diiodosalicylic acid ethyl acetate 133 isoquinoline-1 -carboxylic acid ethyl acetate 105 9-fluorenecarboxylic acid ethyl acetate 90 9-fluorenone-1 -carboxylic acid ethyl acetate 136 3,5-diisopropyl-salicylic acid ethyl acetate 115 diflunisal ethyl acetate 104 Of particular importance according to the invention are pharmaceutical combinations of the salmeterol salts 2 of limited solubility within the scope of the invention, selected from among:
4-hydroxy-a'-[[[6-(44-phenylbutoxy)-hexyl]-am ino]-methyl]-1,3-benzenedimethanol-4-phenylcinnamate salt 2.1:
HO
HO \ I N O
OH H H
"OOC
1.35 g (6 mmol) of 4-phenylcinnamic acid is dissolved by refluxing in 75 mL of ethyl acetate. To this solution is added a warm solution of 2.5 g (6 mmol) of salmeterol in 25 mL of ethyl acetate. The solution is left to cool and stirred for 16 h at ambient temperature. The suspension is filtered, the precipitate is washed with ethyl acetate and tert.-butylmethylether and dried in vacuo at 25-30 C. 3.47 g of the title compound are obtained as a colourless solid. Melting point: 109 C;
The following compounds were prepared analogously:
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-trifluorom ethyl-cinnamate salt 2.2;
Melting point: 125 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1,3-benzenedimethanol-3,4-dichloro-cinnam ate salt 2.3;
Melting point: 116 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl] -1,3-benzenedimethanol-2,4-dichloro-cinnamate salt 2.4;
Melting point: 183 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-cinnamate salt 2.5;
Melting point: 89 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1, 3-benzenedimethanol-3-(2-naphthyl)acrylate salt 2.6;
Melting point: 97 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-(1-naphthyl)acry late salt 2.7;
Melting point: 77 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,6-dichloro-cinnamate salt 2.8;
Melting point: 82 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl ]-1,3-benzenedimethanol-2,5-dimethoxy-cinnamate salt 2.9;
Melting point: 88 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1, 3-benzenedimethanol-2-trifluoromethyl-cinnamate salt 2.10;
Melting point: 94 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1, 3-benzenedimethanol-3-trifluoromethyl-cinnamate salt 2.11;
Melting point: 92 C;
Melting point: 116 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl] -1,3-benzenedimethanol-2,4-dichloro-cinnamate salt 2.4;
Melting point: 183 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-cinnamate salt 2.5;
Melting point: 89 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1, 3-benzenedimethanol-3-(2-naphthyl)acrylate salt 2.6;
Melting point: 97 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-(1-naphthyl)acry late salt 2.7;
Melting point: 77 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,6-dichloro-cinnamate salt 2.8;
Melting point: 82 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl ]-1,3-benzenedimethanol-2,5-dimethoxy-cinnamate salt 2.9;
Melting point: 88 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1, 3-benzenedimethanol-2-trifluoromethyl-cinnamate salt 2.10;
Melting point: 94 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1, 3-benzenedimethanol-3-trifluoromethyl-cinnamate salt 2.11;
Melting point: 92 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-chloro-cinnamate salt 2.12;
Melting point: 90 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-bromo-cinnamate salt 2.13;
Melting point: 127 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-chloro-cinnamate salt 2.14;
Melting point: 123 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-m ethyl]-1, 3-benzenedimethanol-4-methoxy-cinnamate salt 2.15;
Melting point: 98 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-fluoro-cinnamate salt 2.16;
Melting point: 113 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-isopropyl-cinnamate salt 2.17;
Melting point: 82 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-tert-butyl-cinnamate salt 2.18;
Melting point: 93 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1, 3-benzenedimethanol-2,4-difluoro-cinnamate salt 2.19;
Melting point: 121 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1, 3-benzenedimethanol-3,4-difluoro-cinnamate salt 2.20;
Melting point: 102 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,4,5-trifluoro-cinnamate salt 2.21;
Melting point: 120 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,4, 5-trifluoro-cinnamate salt 2.22;
5 Melting point: 107 C;
Of equal importance according to the invention are pharmaceutical combinations of the salmeterol salts 2 of limited solubility within the scope of the invention, selected from among:
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1, 3-benzenedimethanol-5-(2,4-difluorophenyl)salicylate salt 2.23:
HO
HO \ I N O
OH H H
OOC
HO F
F
30 g salmeterol is dissolved by refluxing in 300 mL of ethyl acetate. To this solution are added 18.3 g of 5-(2,4-difluorophenyl)salicylic acid (Diflunisal). The solution is left to cool to ambient temperature. The suspension is filtered off, the precipitate is washed with ethyl acetate and dried at 35 C in vacuo. 46 g of the title salt are obtained as a colourless solid melting point: 104 C
The following compounds were prepared analogously:
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,5-diisopropyl-salicylate salt 2.24;
melting point: 115 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-chloro-salicylate salt 2.25;
melting point: 123 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,5-dichloro-salicylate salt 2.26;
melting point: 108 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,5-dihydroxyterephthalate salt 2.27; (base : acid = 1:2).
melting point: 102 C;
4-hydroxy-a0-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1,3-benzenedimethanol-3-methoxysalicylate salt 2.28;
melting point: 118 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl ]-1, 3-benzenedimethanol-4-methoxysalicylate salt 2.29;
melting point: 113 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-methoxysalicylate salt 2.30;
melting point: 114 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-methylsalicylate salt 2.31;
melting point: 116 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-aminosalicylate salt 2.32;
melting point: 146 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-m ethyl] -1, 3-benzened imethanol-3-chlorosalicylate salt 2.33;
melting point: 108 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-sulpho-salicylate salt 2.34;
melting point: 129 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1, 3-benzenedimethanol-5-acetylsalicylate salt 2.35;
melting point: 80 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1, 3-benzenedimethanol-3, 5-diiodosalicylate salt 2.36;
melting point: 133 C;
In the abovementioned salts according to the invention the base salmeterol and the 1o acid used in each case are present in a molar ratio of salmeterol : acid of 1:1, unless otherwise stated.
The identity of the abovementioned compounds was confirmed by 1 H-NMR-spectroscopy and ESI mass spectrometry.
In the active substance combinations of 1 and 2 according to the invention, ingredients 1 and 2 may be present in the form of their enantiomers, mixtures of enantiomers or in the form of racemates.
The proportions in which the active substances 1 and 2 may be used in the active substance combinations according to the invention are variable. Active substances 1 and 2 may possibly be present in the form of their solvates or hydrates.
Depending on the choice of the compounds 1 and 2, the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various salt forms The weight ratios given below were therefore based on the tiotropium cation 1' and the free base of salmeterol 2'. The active substance combinations according to the invention may contain 1' and 2' in ratios by weight ranging from 1:300 to 30:1, preferably from 1:230 to 20:1, more preferably from 1:150 to 10:1, more preferably from 1:50 to 5:1, most preferably from 1:35 to 2:1. Of particular interest according to the invention are pharmaceutical compositions containing the combination of 1' and 2' in a weight ratio in the range from 1:25 to 1:1. preferably in the range from 1:10 to 1:2, most preferably in the range from 1:5 to 1:2.5.
For example and without restricting the scope of the invention thereto, preferred combinations of 1 and 2 according to the invention may contain tiotropium 1' and salmeterol 2' in the following weight ratios: 1:40; 1:20; 1:11.1;
1:10; 1:5.6; 1:5; 1:2.8; 1:2.5; 1:1.4; 1:1.25; 1.44:1, 1.6:1.
The pharmaceutical compositions according to the invention containing the combinations of 1 and 2 are preferably prepared by administering tiotropium 1' and salmeterol 2' together in doses of 0.01 to 10000 pg, preferably from 0.1 to 2000 pg, more preferably from 1 to 1000 pg, preferably also from 5 to 500pg, preferably according to the invention from 10 to 200pg, preferably from 20 to 100pg, most preferably from 30 to 70 pg per single dose.
For example, combinations of 1 and 2 according to the invention contain an amount of tiotropium 1' and salmeterol 2' such that the total dosage per single dose is 30pg, 35pg, 45pg, 55pg, 60pg, 65pg, 90pg, 105pg, 11 Opg, 140pg or similar. In these dosage ranges the active substances 1' and 2' are present in the weight ratios described hereinbefore.
For example and without restricting the scope of the invention thereto, the combinations of 1 and 2 according to the invention may contain an amount of tiotropium 1' and salmeterol 2' such that in each individual dose 5 pg of 1' and 25 pg of2',5pgof1'and50pgof2',5pgof1'and100pgof2',5pgof1'and200pgof 2', 10 pg of 1' and 25 pg of 2', 10 pg of 1' and 50 pg of 2, 10 pg of 1' and 100 pg of 2', 10 pg of 1' and 200 pg of 2', 18 pg of 1' and 25 pg of 2', 18 pg of 1' and 50 pg of 2', 18 pg of 1' and 100 pg of 2, 18 pg of 1' and 200 pg of 2', 20 pg of 1' and 25 pg of 2', 20 pg of 1' and 50 pg of 2', 20 pg of 1' and 100 pg of 2', 20 pg of 1' and 200 pg of 2', 36 pg of 1' and 25 pg of 2', 36 pg of 1' and 50 pg of 2', 36 pg of 1' and 100 pg of 2', 36 pg of 1' and 200 pg of 2', 40 pg of 1' and 25 pg of 2', 40 pg of 1' and 50 pg of 2', 40 pg of 1' and 100 pg of 2' or 40 pg of 1' and 200 pg of 2' are administered.
If the active substance combination wherein 1 denotes tiotropium bromide and 2 denotes one of the particularly preferred salts 2, salmeterol-4-phenylcinnamate (2.1), is used as the preferred combination of 1 and 2 according to the invention, the quantities of active substances 1' and 2' administered per single dose as mentioned above by way of example correspond to the following quantities of 1 and 2 administered per single dose: 6 pg of 1 and 38.49 pg of 2, 6 pg of 1 and 76.98 pg of 2, 6 pg of 1 and 153.96 pg of 2, 6 pg of 1 and 307.92 pg of 2, 12 pg of 1 and 38.49 pg of 2, 12 pg of 1 and 76.98 pg of 2, 12 pg of 1 and 153.96 pg of 2, 12 pg of 1 and 307.92 pg of 2, 21.7 pg of 1 and 38.49 pg of 2, 21.7 pg of 1 and 76.98 pg of 2, 21.7 pg of 1 and 153.96 pg of 2, 21.7 pg of 1 and 307.92 pg of 2, 24.1 pg of 1 and 38.49 pg of 2, 24.1 pg of 1 and 76.98 pg of 2, 24.1 pg of 1 and 153.96 pg of 2, 24.1 pg of 1 and 307.92 pg of 2, 43.3 pg of 1 and 38.49 pg of 2, 43.3 pg of 1 and 76.98 pg of 2, 43.3 pg of 1 and 153.96 pg of 2, 43.3 pg of 1 and 307.92 pg of 2, 48.1 pg of 1 and 38.49 pg of 2, 48.1 pg of 1 and 76.98 pg of 2, 48.1 pg of 1 and 153.96 pg of 2 or 48.1 pg of 1 and 307.92 pg of 2.
If in the preferred combination of 1 and 2 according to the invention wherein denotes one of the particularly preferred salts 2, salmeterol-4-phenylcinnamate (2_1), tiotropium bromide monohydrate is used as component 1, for example, the quantities of active substances 1' and 2' administered per single dose as mentioned above by way of example correspond to the following quantities of 1 and 2 administered per single dose: 6.2 pg of 1 and 38.49 pg of 2, 6.2 pg of 1 and 76.98 pg of 2, 6.2 pg of 1 and 153.96 pg of 2, 6.2 pg of 1 and 307.92 pg of 2, 12.5 pg of 1 and 38.49 pg of 2, 12.5 pg of 1 and 76.98 pg of 2, 12.5 pg of 1 and 153.96 pg of 2, 12.5 pg of 1 and 307.92 pg of 2, 22.5 pg of 1 and 38.49 pg of 2, 22.5 pg of 1 and 76.98 pg of 2, 22.5 pg of 1 and 153.96 pg of 2, 22.5 pg of I and 307.92 pg of 2, 25 pg of I and 38.49 pg of 2, 25 pg of I and 76.98 pg of 2, 25 pg of 1 and 153.96 pg of 2, 25 pg of 1 and 307.92 pg of 2, 45 pg of 1 and 38.49 pg of 2, 45 pg of 1 and 76.98 pg of 2, 45 pg of 1 and 153.96 pg of 2, 45 pg of 1 and 307.92 pg of 2, 50 pg of 1 and 38.49 pg of 2, 50 pg of 1 and 76.98 pg of 2, 50 pg of 1 and 153.96 pg of 2 or 50 pg of 1 and 307.92 pg of 2.
The active substance combinations of 1 and 2 according to the invention are preferably administered by inhalation. For this purpose, ingredients 1 and 2 have to be made available in forms suitable for inhalation. Inhalable preparations include inhalable powders, in particular. Inhalable powders according to the invention containing the combination of active substances 1 and 2 may consist of the active substances on their own or of a mixture of the active substances with physiologically acceptable excipients. The preparations according to the invention may contain the combination of active substances 1 and 2 either together in one formulation or in two separate formulations. These formulations which may be used within the scope of the present invention are described in more detail in the next part of the specification.
Inhalable powder containing the combinations of active substances 1 and 2 according to the invention:
The inhalable powders according to the invention may contain 1 and 2 either on their own or in admixture with suitable physiologically acceptable excipients.
If the active substances 1 and 2 are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare these inhalable powders according to the invention:
monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g.
sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures 5 of these excipients. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.
Within the scope of the inhalable powders according to the invention the excipients 1o have a maximum average particle size of up to 250 pm, preferably between 10 and 150 pm, most preferably between 15 and 80 pm. It may sometimes seem appropriate to add finer excipient fractions with an average particle size of I to 9 pm to the excipient mentioned above. These finer excipients are also selected from the group of possible excipients listed hereinbefore. Finally, in order to prepare the 15 inhalable powders according to the invention, micronised active substance 1 and 2, preferably with an average particle size of 0.5 to 10 m, more preferably from 1 to 6 pm, is added to the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronising and by finally mixing the ingredients together are known from the prior art. The inhalable powders according to the invention may be prepared and administered either in the form of a single powder mixture which contains both 1 and 2 or in the form of separate inhalable powders which contain only 1 and 2.
The inhalable powders according to the invention may be administered using inhalers known from the prior art. Inhalable powders according to the invention which contain a physiologically acceptable excipient in addition to 1 and 2 may be administered, for example, by means of inhalers which deliver a single dose from a supply using a measuring chamber as described in US 4570630A, or by other means as described in DE 36 25 685 A. Preferably, the inhalable powders according to the invention which contain physiologically acceptable excipients in addition to .1 3o and 2 are packed into capsules (to produce so-called inhalettes) which are used in inhalers as described, for example, in WO 94/28958.
A particularly preferred inhaler for using the pharmaceutical combination according to the invention in inhalettes is shown in Figure 1.
TM
This inhaler (Handyhaler) for inhaling powdered pharmaceutical compositions from capsules is characterised by a housing 1 containing two windows 2, a deck 3 in which there are air inlet ports and which is provided with a screen 5 secured via a screen housing 4, an inhalation chamber 6 connected to the deck 3 on which there is a push button 9 provided with two sharpened pins 7 and movable counter to a spring 8, and a mouthpiece 12 which is connected to the housing 1, the deck 3 and a cover 11 via a spindle 10 to enable it to be flipped open or shut.
If the inhalable powders according to the invention are packed into capsules (inhalettes) for the preferred use described above, the quantities packed into each 1o capsule should be 1 to 30 mg, preferably 3 to 20 mg, more particularly 5 to 10 mg of inhalable powder per capsule. These capsules contain, according to the invention, either together or separately, the doses of 1 and 2 mentioned hereinbefore for each single dose.
The following Examples serve to illustrate the present invention further without restricting the scope of the invention to the following embodiments provided by way of example.
Formulation Examples A) Powder for inhalation:
1) Ingredients pg per capsule tiotropium bromide monohydrate 10.8 salmeterol salt (2_1) 35 lactose 4954.2 Total 5000 2) Ingredients pg per capsule tiotropium bromide monohydrate 21.7 salmeterol salt (2.23) 75 lactose 4903.3 Total 5000 3) Ingredients pg per capsule tiotropium bromide monohydrate 22.5 salmeterol salt (2`1) 80.5 lactose 4897 Total 5000 4) Ingredients pg per capsule tiotropium bromide x H2O 22.5 salmeterol salt (2.23) 95.5 lactose 4828 Total 5000
Melting point: 90 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-bromo-cinnamate salt 2.13;
Melting point: 127 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-chloro-cinnamate salt 2.14;
Melting point: 123 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-m ethyl]-1, 3-benzenedimethanol-4-methoxy-cinnamate salt 2.15;
Melting point: 98 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-fluoro-cinnamate salt 2.16;
Melting point: 113 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-isopropyl-cinnamate salt 2.17;
Melting point: 82 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-tert-butyl-cinnamate salt 2.18;
Melting point: 93 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1, 3-benzenedimethanol-2,4-difluoro-cinnamate salt 2.19;
Melting point: 121 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1, 3-benzenedimethanol-3,4-difluoro-cinnamate salt 2.20;
Melting point: 102 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,4,5-trifluoro-cinnamate salt 2.21;
Melting point: 120 C;
4-Hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,4, 5-trifluoro-cinnamate salt 2.22;
5 Melting point: 107 C;
Of equal importance according to the invention are pharmaceutical combinations of the salmeterol salts 2 of limited solubility within the scope of the invention, selected from among:
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1, 3-benzenedimethanol-5-(2,4-difluorophenyl)salicylate salt 2.23:
HO
HO \ I N O
OH H H
OOC
HO F
F
30 g salmeterol is dissolved by refluxing in 300 mL of ethyl acetate. To this solution are added 18.3 g of 5-(2,4-difluorophenyl)salicylic acid (Diflunisal). The solution is left to cool to ambient temperature. The suspension is filtered off, the precipitate is washed with ethyl acetate and dried at 35 C in vacuo. 46 g of the title salt are obtained as a colourless solid melting point: 104 C
The following compounds were prepared analogously:
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,5-diisopropyl-salicylate salt 2.24;
melting point: 115 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-chloro-salicylate salt 2.25;
melting point: 123 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,5-dichloro-salicylate salt 2.26;
melting point: 108 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,5-dihydroxyterephthalate salt 2.27; (base : acid = 1:2).
melting point: 102 C;
4-hydroxy-a0-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1,3-benzenedimethanol-3-methoxysalicylate salt 2.28;
melting point: 118 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl ]-1, 3-benzenedimethanol-4-methoxysalicylate salt 2.29;
melting point: 113 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-methoxysalicylate salt 2.30;
melting point: 114 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-methylsalicylate salt 2.31;
melting point: 116 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-aminosalicylate salt 2.32;
melting point: 146 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-m ethyl] -1, 3-benzened imethanol-3-chlorosalicylate salt 2.33;
melting point: 108 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-sulpho-salicylate salt 2.34;
melting point: 129 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1, 3-benzenedimethanol-5-acetylsalicylate salt 2.35;
melting point: 80 C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1, 3-benzenedimethanol-3, 5-diiodosalicylate salt 2.36;
melting point: 133 C;
In the abovementioned salts according to the invention the base salmeterol and the 1o acid used in each case are present in a molar ratio of salmeterol : acid of 1:1, unless otherwise stated.
The identity of the abovementioned compounds was confirmed by 1 H-NMR-spectroscopy and ESI mass spectrometry.
In the active substance combinations of 1 and 2 according to the invention, ingredients 1 and 2 may be present in the form of their enantiomers, mixtures of enantiomers or in the form of racemates.
The proportions in which the active substances 1 and 2 may be used in the active substance combinations according to the invention are variable. Active substances 1 and 2 may possibly be present in the form of their solvates or hydrates.
Depending on the choice of the compounds 1 and 2, the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various salt forms The weight ratios given below were therefore based on the tiotropium cation 1' and the free base of salmeterol 2'. The active substance combinations according to the invention may contain 1' and 2' in ratios by weight ranging from 1:300 to 30:1, preferably from 1:230 to 20:1, more preferably from 1:150 to 10:1, more preferably from 1:50 to 5:1, most preferably from 1:35 to 2:1. Of particular interest according to the invention are pharmaceutical compositions containing the combination of 1' and 2' in a weight ratio in the range from 1:25 to 1:1. preferably in the range from 1:10 to 1:2, most preferably in the range from 1:5 to 1:2.5.
For example and without restricting the scope of the invention thereto, preferred combinations of 1 and 2 according to the invention may contain tiotropium 1' and salmeterol 2' in the following weight ratios: 1:40; 1:20; 1:11.1;
1:10; 1:5.6; 1:5; 1:2.8; 1:2.5; 1:1.4; 1:1.25; 1.44:1, 1.6:1.
The pharmaceutical compositions according to the invention containing the combinations of 1 and 2 are preferably prepared by administering tiotropium 1' and salmeterol 2' together in doses of 0.01 to 10000 pg, preferably from 0.1 to 2000 pg, more preferably from 1 to 1000 pg, preferably also from 5 to 500pg, preferably according to the invention from 10 to 200pg, preferably from 20 to 100pg, most preferably from 30 to 70 pg per single dose.
For example, combinations of 1 and 2 according to the invention contain an amount of tiotropium 1' and salmeterol 2' such that the total dosage per single dose is 30pg, 35pg, 45pg, 55pg, 60pg, 65pg, 90pg, 105pg, 11 Opg, 140pg or similar. In these dosage ranges the active substances 1' and 2' are present in the weight ratios described hereinbefore.
For example and without restricting the scope of the invention thereto, the combinations of 1 and 2 according to the invention may contain an amount of tiotropium 1' and salmeterol 2' such that in each individual dose 5 pg of 1' and 25 pg of2',5pgof1'and50pgof2',5pgof1'and100pgof2',5pgof1'and200pgof 2', 10 pg of 1' and 25 pg of 2', 10 pg of 1' and 50 pg of 2, 10 pg of 1' and 100 pg of 2', 10 pg of 1' and 200 pg of 2', 18 pg of 1' and 25 pg of 2', 18 pg of 1' and 50 pg of 2', 18 pg of 1' and 100 pg of 2, 18 pg of 1' and 200 pg of 2', 20 pg of 1' and 25 pg of 2', 20 pg of 1' and 50 pg of 2', 20 pg of 1' and 100 pg of 2', 20 pg of 1' and 200 pg of 2', 36 pg of 1' and 25 pg of 2', 36 pg of 1' and 50 pg of 2', 36 pg of 1' and 100 pg of 2', 36 pg of 1' and 200 pg of 2', 40 pg of 1' and 25 pg of 2', 40 pg of 1' and 50 pg of 2', 40 pg of 1' and 100 pg of 2' or 40 pg of 1' and 200 pg of 2' are administered.
If the active substance combination wherein 1 denotes tiotropium bromide and 2 denotes one of the particularly preferred salts 2, salmeterol-4-phenylcinnamate (2.1), is used as the preferred combination of 1 and 2 according to the invention, the quantities of active substances 1' and 2' administered per single dose as mentioned above by way of example correspond to the following quantities of 1 and 2 administered per single dose: 6 pg of 1 and 38.49 pg of 2, 6 pg of 1 and 76.98 pg of 2, 6 pg of 1 and 153.96 pg of 2, 6 pg of 1 and 307.92 pg of 2, 12 pg of 1 and 38.49 pg of 2, 12 pg of 1 and 76.98 pg of 2, 12 pg of 1 and 153.96 pg of 2, 12 pg of 1 and 307.92 pg of 2, 21.7 pg of 1 and 38.49 pg of 2, 21.7 pg of 1 and 76.98 pg of 2, 21.7 pg of 1 and 153.96 pg of 2, 21.7 pg of 1 and 307.92 pg of 2, 24.1 pg of 1 and 38.49 pg of 2, 24.1 pg of 1 and 76.98 pg of 2, 24.1 pg of 1 and 153.96 pg of 2, 24.1 pg of 1 and 307.92 pg of 2, 43.3 pg of 1 and 38.49 pg of 2, 43.3 pg of 1 and 76.98 pg of 2, 43.3 pg of 1 and 153.96 pg of 2, 43.3 pg of 1 and 307.92 pg of 2, 48.1 pg of 1 and 38.49 pg of 2, 48.1 pg of 1 and 76.98 pg of 2, 48.1 pg of 1 and 153.96 pg of 2 or 48.1 pg of 1 and 307.92 pg of 2.
If in the preferred combination of 1 and 2 according to the invention wherein denotes one of the particularly preferred salts 2, salmeterol-4-phenylcinnamate (2_1), tiotropium bromide monohydrate is used as component 1, for example, the quantities of active substances 1' and 2' administered per single dose as mentioned above by way of example correspond to the following quantities of 1 and 2 administered per single dose: 6.2 pg of 1 and 38.49 pg of 2, 6.2 pg of 1 and 76.98 pg of 2, 6.2 pg of 1 and 153.96 pg of 2, 6.2 pg of 1 and 307.92 pg of 2, 12.5 pg of 1 and 38.49 pg of 2, 12.5 pg of 1 and 76.98 pg of 2, 12.5 pg of 1 and 153.96 pg of 2, 12.5 pg of 1 and 307.92 pg of 2, 22.5 pg of 1 and 38.49 pg of 2, 22.5 pg of 1 and 76.98 pg of 2, 22.5 pg of 1 and 153.96 pg of 2, 22.5 pg of I and 307.92 pg of 2, 25 pg of I and 38.49 pg of 2, 25 pg of I and 76.98 pg of 2, 25 pg of 1 and 153.96 pg of 2, 25 pg of 1 and 307.92 pg of 2, 45 pg of 1 and 38.49 pg of 2, 45 pg of 1 and 76.98 pg of 2, 45 pg of 1 and 153.96 pg of 2, 45 pg of 1 and 307.92 pg of 2, 50 pg of 1 and 38.49 pg of 2, 50 pg of 1 and 76.98 pg of 2, 50 pg of 1 and 153.96 pg of 2 or 50 pg of 1 and 307.92 pg of 2.
The active substance combinations of 1 and 2 according to the invention are preferably administered by inhalation. For this purpose, ingredients 1 and 2 have to be made available in forms suitable for inhalation. Inhalable preparations include inhalable powders, in particular. Inhalable powders according to the invention containing the combination of active substances 1 and 2 may consist of the active substances on their own or of a mixture of the active substances with physiologically acceptable excipients. The preparations according to the invention may contain the combination of active substances 1 and 2 either together in one formulation or in two separate formulations. These formulations which may be used within the scope of the present invention are described in more detail in the next part of the specification.
Inhalable powder containing the combinations of active substances 1 and 2 according to the invention:
The inhalable powders according to the invention may contain 1 and 2 either on their own or in admixture with suitable physiologically acceptable excipients.
If the active substances 1 and 2 are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare these inhalable powders according to the invention:
monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g.
sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures 5 of these excipients. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.
Within the scope of the inhalable powders according to the invention the excipients 1o have a maximum average particle size of up to 250 pm, preferably between 10 and 150 pm, most preferably between 15 and 80 pm. It may sometimes seem appropriate to add finer excipient fractions with an average particle size of I to 9 pm to the excipient mentioned above. These finer excipients are also selected from the group of possible excipients listed hereinbefore. Finally, in order to prepare the 15 inhalable powders according to the invention, micronised active substance 1 and 2, preferably with an average particle size of 0.5 to 10 m, more preferably from 1 to 6 pm, is added to the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronising and by finally mixing the ingredients together are known from the prior art. The inhalable powders according to the invention may be prepared and administered either in the form of a single powder mixture which contains both 1 and 2 or in the form of separate inhalable powders which contain only 1 and 2.
The inhalable powders according to the invention may be administered using inhalers known from the prior art. Inhalable powders according to the invention which contain a physiologically acceptable excipient in addition to 1 and 2 may be administered, for example, by means of inhalers which deliver a single dose from a supply using a measuring chamber as described in US 4570630A, or by other means as described in DE 36 25 685 A. Preferably, the inhalable powders according to the invention which contain physiologically acceptable excipients in addition to .1 3o and 2 are packed into capsules (to produce so-called inhalettes) which are used in inhalers as described, for example, in WO 94/28958.
A particularly preferred inhaler for using the pharmaceutical combination according to the invention in inhalettes is shown in Figure 1.
TM
This inhaler (Handyhaler) for inhaling powdered pharmaceutical compositions from capsules is characterised by a housing 1 containing two windows 2, a deck 3 in which there are air inlet ports and which is provided with a screen 5 secured via a screen housing 4, an inhalation chamber 6 connected to the deck 3 on which there is a push button 9 provided with two sharpened pins 7 and movable counter to a spring 8, and a mouthpiece 12 which is connected to the housing 1, the deck 3 and a cover 11 via a spindle 10 to enable it to be flipped open or shut.
If the inhalable powders according to the invention are packed into capsules (inhalettes) for the preferred use described above, the quantities packed into each 1o capsule should be 1 to 30 mg, preferably 3 to 20 mg, more particularly 5 to 10 mg of inhalable powder per capsule. These capsules contain, according to the invention, either together or separately, the doses of 1 and 2 mentioned hereinbefore for each single dose.
The following Examples serve to illustrate the present invention further without restricting the scope of the invention to the following embodiments provided by way of example.
Formulation Examples A) Powder for inhalation:
1) Ingredients pg per capsule tiotropium bromide monohydrate 10.8 salmeterol salt (2_1) 35 lactose 4954.2 Total 5000 2) Ingredients pg per capsule tiotropium bromide monohydrate 21.7 salmeterol salt (2.23) 75 lactose 4903.3 Total 5000 3) Ingredients pg per capsule tiotropium bromide monohydrate 22.5 salmeterol salt (2`1) 80.5 lactose 4897 Total 5000 4) Ingredients pg per capsule tiotropium bromide x H2O 22.5 salmeterol salt (2.23) 95.5 lactose 4828 Total 5000
Claims (25)
1. Pharmaceutical composition containing one or more tiotropium salts (1) for use in combination with one or more salmeterol salts (2) of limited solubility, the salmeterol salts 2 having a solubility in water of 0.05 mg/ml or less.
2. Pharmaceutical composition according to claim 1, wherein the active substances 1 and 2 are present together in a single preparation.
3. Pharmaceutical composition according to claim 1, wherein the active substances 1 and 2 are present in two separate preparations.
4. Pharmaceutical composition according to any one of claims 1 to 3, wherein 1 is present in the form of the chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methylsulphate.
5. Pharmaceutical composition according to any one of claims 1 to 3, wherein 1 is present in the form of the bromide.
6. Pharmaceutical composition according to any one of claims 1 to 5, wherein 2 is an acid addition salt of salmeterol free base (2') with one of the following acids: 2-hydroxy-1-naphthoic acid, 3,5-dichlorosalicylic acid, furan-2-carboxylic acid, 2,5-dihydroxy-terephthalic acid, cinnamic acid, triphenylacetic acid, 4-phenylcinnamic acid, biphenyl-2-carboxylic acid, 4-trifluoromethylcinnamic acid, 9-fluorenylideneacetic acid, 3-(2-naphthyl)acrylic acid, 3-(1-naphthyl)acrylic acid, 1-naphthoic acid, 2,6-dichlorobenzoic acid, 3,4-dichlorobenzoic acid, 3,5-dichlorobenzoic acid, 4-bromobenzoic acid, 4-trifluoromethylbenzoic acid, 4-isopropylbenzoic acid, 4-tert.-butylbenzoic acid, 3-(3-indolyl)acrylic acid, 2,4-dichlorocinnamic acid, 2,6-dichlorocinnamic acid, 2,5-dimethoxy-cinnamic acid, 2-trifluoromethylcinnamic acid, 3-trifluoromethylcinnamic acid, 3-chlorocinnamic acid, 3,4-dichlorocinnamic acid, 4-bromocinnamic acid, 4-chlorocinnamic acid, 4-methoxycinnamic acid, 4-fluorocinnamic acid, 4-isopropylcinnamic acid, 4-tert.-butylcinnamic acid, 2,6-difluorocinnamic acid, 2,4-difluorocinnamic acid, 3,4-difluorocinnamic acid, 2,4,5-trifluorocinnamic acid, 3,4,5-trifluorocinnamic acid, 3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-methoxysalicylic acid, 4-methylsalicylic acid, 5-aminosalicylic acid, 3-chlorosalicylic acid, 5-sulphosalicylic acid, 5-acetylsalicylic acid, 3,5-diiodosalicylic acid, isoquinoline-1-carboxylic acid, 9-fluorenecarboxylic acid, 9-fluorenone-1-carboxylic acid, 3,5-diisopropyl-salicylic acid or diflunisal.
7. Pharmaceutical composition according to any one of claims 1 to 5, wherein 2 is:
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-phenylcinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-trifluoromethyl-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,4-dichloro-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,4-dichloro-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-(2-naphthyl)acrylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-(1-naphthyl)acrylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,6-dichloro-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,5-dimethoxy-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2-trifluoromethyl-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-trifluoromethyl-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-chloro-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-bromo-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-chloro-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-methoxy-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1, 3-benzenedimethanol-4-fluoro-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-isopropyl-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-tert-butyl-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenyl butoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,4-difluoro-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,4-difluoro-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,4,5-trifluoro-cinnamate salt; or 4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,4,5-trifluoro-cinnamate salt.
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-phenylcinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-trifluoromethyl-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,4-dichloro-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,4-dichloro-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-(2-naphthyl)acrylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-(1-naphthyl)acrylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,6-dichloro-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,5-dimethoxy-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2-trifluoromethyl-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-trifluoromethyl-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-chloro-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-bromo-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-chloro-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-methoxy-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1, 3-benzenedimethanol-4-fluoro-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-isopropyl-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-tert-butyl-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenyl butoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,4-difluoro-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,4-difluoro-cinnamate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,4,5-trifluoro-cinnamate salt; or 4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,4,5-trifluoro-cinnamate salt.
8. Pharmaceutical composition according to any one of claims 1 to 5, wherein 2 is:
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5-(2,4-difluorophenyl)salicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,5-diisopropyl-salicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-chloro-salicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,5-dichloro-salicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,5-dihydroxyterephthalate salt (base:acid = 1:2);
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-methoxysalicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-methoxysalicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5-methoxysalicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-methylsalicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5-aminosalicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-chlorosalicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5-sulpho-salicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5-acetylsalicylate salt; or 4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,5-diiodosalicylate salt.
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5-(2,4-difluorophenyl)salicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,5-diisopropyl-salicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-chloro-salicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,5-dichloro-salicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,5-dihydroxyterephthalate salt (base:acid = 1:2);
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-methoxysalicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-methoxysalicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5-methoxysalicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-methylsalicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5-aminosalicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-chlorosalicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5-sulpho-salicylate salt;
4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5-acetylsalicylate salt; or 4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,5-diiodosalicylate salt.
9. Pharmaceutical composition according to any one of claims 1 to 8, wherein the weight ratios of tiotropium free cation (1') to salmeterol free base (2') are in the range from 1:300 to 30:1.
10. Pharmaceutical composition according to any one of claims 1 to 8, wherein the weight ratios of tiotropium free cation (1') to salmeterol free base are in the range from 1:230 to 20:1.
11. Pharmaceutical composition according to any one of claims 1 to 10, comprising a dosage of the combination of tiotropium free cation (1') and salmeterol free base (2') of 0.01 to 1000 µg.
12. Pharmaceutical composition according to any one of claims 1 to 10, comprising a dosage of the combination of tiotropium free cation (1') and salmeterol free base (2') of 0.1 to 200 µg.
13. Pharmaceutical composition according to any one of claims 1 to 12, which is in the form of a powder suitable for inhalation.
14. Pharmaceutical composition according to claim 13, which is an inhalable powder which contains 1 and 2 in admixture with one or more suitable physiologically acceptable excipients selected from among the monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, salts, and mixtures of these excipients with one another.
15. Pharmaceutical composition according to claim 14, wherein the excipient has a maximum mean particle size of up to 250 µm.
16. Pharmaceutical composition according to claim 14, wherein the excipient has a maximum mean particle size of between 10 and 150 µm.
17. Pharmaceutical composition according to claim 13, which is an inhalable powder which contains only the active substances 1 and 2 as its sole ingredients.
18. A capsule containing the pharmaceutical composition as defined in claim 14, 15, 16 or 17.
19. Use of a composition as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, or the capsule as defined in claim 18, for preparing a medicament for the treatment of asthma.
20. Use of a composition as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, or the capsule as defined in claim 18, for preparing a medicament for the treatment of COPD.
21. Use of a tiotropium salt (1) in combination with a salmeterol salt (2) for the treatment of asthma or COPD, wherein the salmeterol (2) has a solubility in water of 0.05 mg/ml or less.
22. Use according to claim 21, wherein the tiotropium salt (1) is as defined in claim 4 or 5.
23. Use according to claim 21 or 22, wherein the salmeterol salt (2) is as defined in claim 6, 7 or 8.
24. Use according to any one of claims 21 to 23, for the treatment of asthma.
25. Use according to any one of claims 21 to 23, for the treatment of COPD.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10145438.4 | 2001-09-14 | ||
| DE2001145438 DE10145438A1 (en) | 2001-09-14 | 2001-09-14 | New salts of salmeterol with substituted salicylic acid, useful as well tolerated beta-mimetic agents for treating asthma or chronic obstructive pulmonary disease |
| DE10209243.5 | 2002-03-04 | ||
| DE2002109243 DE10209243A1 (en) | 2002-03-04 | 2002-03-04 | Synergistic, well tolerated medicament combination of tiotropium salt and sparingly water-soluble salmeterol salt, useful for treating asthma or chronic obstructive pulmonary disease |
| PCT/EP2002/009974 WO2003024452A1 (en) | 2001-09-14 | 2002-09-06 | Novel medicaments for inhalation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2459493A1 CA2459493A1 (en) | 2003-03-27 |
| CA2459493C true CA2459493C (en) | 2011-08-02 |
Family
ID=26010149
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2459493A Expired - Fee Related CA2459493C (en) | 2001-09-14 | 2002-09-06 | New pharmaceutical compositions for inhalation |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1429768B1 (en) |
| JP (1) | JP2005504076A (en) |
| AR (1) | AR036518A1 (en) |
| CA (1) | CA2459493C (en) |
| MX (1) | MXPA04002401A (en) |
| PE (1) | PE20030646A1 (en) |
| UY (1) | UY27445A1 (en) |
| WO (1) | WO2003024452A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8513279B2 (en) | 1999-07-14 | 2013-08-20 | Almirall, S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
| US9254262B2 (en) | 2008-03-13 | 2016-02-09 | Almirall, S.A. | Dosage and formulation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10351663A1 (en) * | 2002-12-20 | 2004-07-01 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Stable, accurately dosable inhalable powder medicament for treating asthma or chronic obstructive pulmonary disease, containing tiotropium, specific form of salmeterol xinafoate and auxiliary |
| EP1651270B1 (en) * | 2003-07-29 | 2007-03-21 | Boehringer Ingelheim International GmbH | Medicaments for inhalation comprising betamimetics and an anticholinergic |
| JP2009504603A (en) * | 2005-08-06 | 2009-02-05 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Method of treating dyspnea by administering a combination of tiotropium salt and salmeterol salt |
| WO2008020032A1 (en) * | 2006-08-16 | 2008-02-21 | Action Medicines, S.L. | Use of 2,5-dihydroxybenzene derivatives for the treatment of ocular diseases |
| EP2100599A1 (en) | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease |
| EP2510928A1 (en) | 2011-04-15 | 2012-10-17 | Almirall, S.A. | Aclidinium for use in improving the quality of sleep in respiratory patients |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1172663B (en) * | 1961-04-28 | 1964-06-25 | Maggioni & C Spa | Process for the production of bismuth tri- (p-phenylcinnamate) |
| GB8310477D0 (en) * | 1983-04-18 | 1983-05-25 | Glaxo Group Ltd | Chemical compounds |
| DE19726871C1 (en) * | 1997-06-24 | 1999-03-04 | Werner Kreutz | Synergistic compositions for the selective control of tumor tissue |
| DE19921693A1 (en) * | 1999-05-12 | 2000-11-16 | Boehringer Ingelheim Pharma | Pharmaceutical composition for treating respiratory disorders, e.g. asthma, comprises combination of anticholinergic and beta-mimetic agents having synergistic bronchospasmolytic activity and reduced side-effects |
| DK1169019T3 (en) * | 1999-04-14 | 2003-06-02 | Glaxo Group Ltd | Pharmaceutical aerosol formulation |
| DE10056104A1 (en) * | 2000-11-13 | 2002-05-23 | Boehringer Ingelheim Pharma | Drug compositions useful for treatment of respiratory diseases, especially asthma and chronic obstructive pulmonary disease comprises tiotropium salts and salmeterol salts |
-
2002
- 2002-09-06 EP EP02777013.0A patent/EP1429768B1/en not_active Expired - Lifetime
- 2002-09-06 MX MXPA04002401A patent/MXPA04002401A/en active IP Right Grant
- 2002-09-06 JP JP2003528548A patent/JP2005504076A/en active Pending
- 2002-09-06 CA CA2459493A patent/CA2459493C/en not_active Expired - Fee Related
- 2002-09-06 WO PCT/EP2002/009974 patent/WO2003024452A1/en active Application Filing
- 2002-09-12 PE PE2002000899A patent/PE20030646A1/en not_active Application Discontinuation
- 2002-09-12 UY UY27445A patent/UY27445A1/en not_active Application Discontinuation
- 2002-09-13 AR ARP020103470A patent/AR036518A1/en not_active Withdrawn
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8513279B2 (en) | 1999-07-14 | 2013-08-20 | Almirall, S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
| US8802699B2 (en) | 1999-07-14 | 2014-08-12 | Almirall, S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
| US9056100B2 (en) | 1999-07-14 | 2015-06-16 | Almirall, S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
| US9333195B2 (en) | 1999-07-14 | 2016-05-10 | Almirall, S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
| US9254262B2 (en) | 2008-03-13 | 2016-02-09 | Almirall, S.A. | Dosage and formulation |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2003024452A1 (en) | 2003-03-27 |
| UY27445A1 (en) | 2003-04-30 |
| EP1429768B1 (en) | 2016-11-16 |
| MXPA04002401A (en) | 2004-05-31 |
| CA2459493A1 (en) | 2003-03-27 |
| PE20030646A1 (en) | 2003-07-23 |
| AR036518A1 (en) | 2004-09-15 |
| JP2005504076A (en) | 2005-02-10 |
| EP1429768A1 (en) | 2004-06-23 |
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| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20180906 |