CA2429012A1 - New pharmaceutical compositions based on tiotropium salts and salts of salmeterol - Google Patents
New pharmaceutical compositions based on tiotropium salts and salts of salmeterol Download PDFInfo
- Publication number
- CA2429012A1 CA2429012A1 CA002429012A CA2429012A CA2429012A1 CA 2429012 A1 CA2429012 A1 CA 2429012A1 CA 002429012 A CA002429012 A CA 002429012A CA 2429012 A CA2429012 A CA 2429012A CA 2429012 A1 CA2429012 A1 CA 2429012A1
- Authority
- CA
- Canada
- Prior art keywords
- acid
- inhalable
- pharmaceutical composition
- inhalation
- salts
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- 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
-
- 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
- A61K31/13—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
- 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
- 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
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Abstract
The invention relates to novel medicament compositions based on tiotropium salts and on salmeterol salts, to a method for the production thereof, and to their use for treating respiratory tract diseases.
Description
,, Case 1/1171-foreign ' ~ BOEHRINGER INGELHEIM PHARMA KG
74511 fft.205 New pharmaceutical compositions based on tiotropium salts and salts of salmeterol The present invention relates to novel pharmaceutical compositions based on tiotropium salts and salts of salmeterol, processes 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 Patent Application EP 418 716 A1 and has the following chemical structure + Me Me-.N~
O _ ~H Br O
O
H
This compound may also be referred to by its chemical name (1a.,2a,4a,5oc,7a)-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02'4]nonane bromide and has valuable pharmacological properties. The name tiotropium is intended to refer to the free cation for the purposes of the present invention.
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) and administered using suitable powder inhalers may be used. 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.
The tiotropium salts may also be inhaled in the form of suitable solutions.
74511 fft.205 New pharmaceutical compositions based on tiotropium salts and salts of salmeterol The present invention relates to novel pharmaceutical compositions based on tiotropium salts and salts of salmeterol, processes 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 Patent Application EP 418 716 A1 and has the following chemical structure + Me Me-.N~
O _ ~H Br O
O
H
This compound may also be referred to by its chemical name (1a.,2a,4a,5oc,7a)-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02'4]nonane bromide and has valuable pharmacological properties. The name tiotropium is intended to refer to the free cation for the purposes of the present invention.
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) and administered using suitable powder inhalers may be used. 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.
The tiotropium salts may also be inhaled in the form of suitable solutions.
Detailed description of the invention Surprisingly, it has been found that an unexpectedly beneficial therapeutic effect, more particularly a synergistic effect, in the treatment of inflammatory or obstructive respiratory complaints is observed when one or more tiotropium salts (~ are used in conjunction with one or more salmeterol salts (2).
As a result, it is possible to reduce substantially the undesirable side effects which often occur, for example, in the administration of ~i-mimetics such as salmeterol to humans. Examples of the central side effects of ~i-mimetics include general malaise, excitation, sleeplessness, anxiety, trembling fingers, sweats and headaches.
The name tiotropium is intended to refer to the free cation (~ for the purposes of the present invention. References to salmeterol are intended as references to the free base (2') for the purposes of the present invention.
The combinations of active substances according to the invention are surprisingly also characterised by a rapid onset of activity and also by long-lasting effects. This is of great importance to the wellbeing of the patient as, on the one hand, they experience a rapid improvement in their condition after administration of the combination and, on the other hand, a single administration per day is sufficient, thanks to the long-lasting effect.
The abovementioned effects are observed both after the simultaneous administration within a single active substance formulation and also after the successive administration of the two active substances in separate formulations. It is preferred 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 (~ and one or more salmeterol salts (2 ), optionally in the form of the solvates or hydrates thereof. The active substances may be contained either together in a single preparation or in two separate preparations.
According to the invention, pharmaceutical compositions which contain the active substances 1 and 2 in a single preparation are preferred.
According to another aspect the present invention relates to a pharmaceutical composition which contains, in addition to therapeutically effective amounts of 1 and 2, a pharmaceutically acceptable excipient. In one aspect the present invention relates to a pharmaceutical composition which contains, in addition to therapeutically effective amounts of 1 and 2, no pharmaceutically acceptable excipient.
The present invention further relates to the use of 1 and 2 for preparing a pharmaceutical composition containing therapeutically effective amounts of 1 and 2 for the treatment of inflammatory or obstructive respiratory complaints, particularly asthma or COPD, by simultaneous or successive administration.
The present invention is also directed to the simultaneous or successive use of therapeutically effective doses of the combination of the abovementioned pharmaceutical compositions 1 and 2 for the treatment of inflammatory or obstructive respiratory complaints, particularly asthma or COPD.
The tiotropium salts 1 which may be used within the scope of the present invention include the compounds which contain, in addition to tiotropium, chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methylsulphate as counter-ion (anion). Within the scope of the present invention, of all the tiotropium salts, the methanesulphonate, chloride, bromide or iodide are preferred, the methanesulphonate or bromide being of particular importance. Tiotropium bromide is of exceptional importance according to the invention.
By salts of salmeterol 2 are meant, according to the invention, pharmaceutically acceptable salts selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, xinafonic acid or malefic acid, with the proviso that 2 cannot denote salmeterol xinafoate if 1 denotes tiotropium bromide. Mixtures of the abovementioned acids may optionally also be used to prepare the salmeterol salts.
According to the invention, the salmeterol salts 2 selected from among hydrochloride, hydrobromide, sulphate, phosphate and methanesulphonate are preferred. The salts of 2 selected from hydrochloride and sulphate are particularly preferred, especially the sulphates. Salmeterol x %2 H2S04 is of exceptional importance according to the invention.
In the combinations of active substances according to the invention consisting of 1 and 2 the ingredients 1 and 2 may be in the form of their enantiomers, mixtures of enantiomers or in the form of the racemates.
r CA 02429012 2003-04-28 The proportions in which the two active substances 1 and 2 may be used in the combinations of active substances according to the invention are variable. The active substances 1 and 2 may optionally be in the form of the solvates or hydrates thereof.
Depending on the choice of the salts 1 or 2 the weight ratios which may be used for the purposes of the present invention vary on account of the different molecular weights of the various salt forms. Consequently, the weight ratios specified hereinafter are based on the tiotropium cation 1' and the free base of salmeterol 2'.
The combinations of active substances according to the invention may contain 1' and 2' in weight ratios in the range from 1:300 to 30:1, preferably from 1:230 to 20:1, particularly preferably from 1:150 to 10:1, more preferably from 1:50 to 5:1, particularly 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, particularly preferably in the range from 1:5 to 1:2.5.
For example, without restricting the scope of the invention, 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, 1.8:1.
The pharmaceutical compositions according to the invention containing the combinations of 1 and 2 are normally used so that tiotropium 1' and salmeterol 2' are administered together in doses of 0.01 to 10000 pg, preferably 0.1 to 2000 Ng, particularly preferably from 1 to 1000 Ng, more preferably from 5 to 500 Ng, preferably, according to the invention, from 10 to 200 ug, 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 30Ng, 35Ng, 45ug, 55pg, 60Ng, 65ug, 90pg, 105Ng, 110ug, 110Ng, 140Ng or similar. In these dosage ranges the active substances 1' and 2' are present in the weight rations described hereinbefore.
For example, without restricting the scope of the invention, the combinations of 1 and 2 according to the invention may contain an amount of tiotropium 1' and salmeterol 2' such that 5Ng of 1' and 25Ng of 2', 5Ng of 1' and 50ug of 2', 5~rg of 1' and 100Ng of 2', 5Ng of 1' and 200Ng of 2', 10pg of 1' and 25Ng of 2', 10Ng of 1' and 50pg of 2', 10Ng of 1' and 100Ng of 2', 10Ng of 1' and 200pg of 2', 18pg of 1' and 25pg of 2', 18Ng of 1' and 50Ng of 2', 18Ng of 1' and 100pg of 2', 18Ng of 1' and 200Ng of 2', 20Ng of 1' and 25Ng of 2', 20Ng of 1' and 50pg of 2', 20pg of 1' and 100pg of 2', 20Ng of 1' and 200Ng of 2', 36Ng of 1' and 25Ng of 2', 36pg of 1' and 50trg of 2', 36pg of 1' and 100pg of 2', 36pg of 1' and 200pg of 2', 40~g of 1' and 25Ng of 2', 40Ng of 1' and 50pg of 2', 40ug of 1' and 100pg of 2' or 40Ng of 1' and 200Ng of 2' are administered per single dose.
If the active substance combination in which 1 denotes tiotropium bromide and denotes salmeterol x'/ZH2S04 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 specified above by way of example correspond to the following quantities of 1 and 2 administered per single dose: hug of 1 and 27.9pg of 2, 6pg of 1 and 55.9Ng of 2, 6pg of 1 and 111.8trg of 2, 6pg of 1 and 223.6Ng of 2, 12pg of 1 and 27.9pg of 2, 12Ng of 1 and 55.9Ng of 2, 12Ng of 1 and 111.8pg of 2, 12pg of 1 and 223.6Ng of 2, 21.7Ng of 1 and 27.9Ng of 2, 21.7pg of 1 and 55.9pg of 2, 21.7Ng of 1 and 111.8Ng of 2, 21.7Ng of 1 and 223.6pg of 2, 24.1 pg of 1 and 27.9pg of 2, 24.1 Ng of 1 and 55.9Ng of 2, 24.1 Ng of 1 and 111.8Ng of 2, 24.1 pg of 1 and 223.6Ng of 2, 43.3pg of 1 and 27.9Ng of 2, 43.3pg of 1 and 55.9Ng of 2, 43.3pg of 1 and 111.BNg of 2, 43.3pg of 1 and 223.6Ng of 2, 48.1 Ng of 1 and 27.9Ng of 2, 48.1 pg of 1 and 55.9pg of 2, 48.1 pg of 1 and 111.8pg of 2 or 48.1 Ng of 1 and 223.6Ng of 2.
If, in the combination of 1 and 2 preferred according to the invention, wherein 2 denotes salmeterol x'hH2S04 tiotropium bromide monohydrate is used as 1, for example, the quantities of active substances 1' and 2' administered per single dose as specified above by way of example correspond to the following quantities of 1 and 2 administered per single dose: 6.2ug of 1 and 27.9~rg of 2, 6.2pg of 1 and 55.9Ng of 2, 6.2pg of 1 and 111.8pg of 2, 6.2pg of 1 and 223.6pg of 2, 12.5pg of 1 and 27.9pg of 2, 12.5Ng of 1 and 55.9pg of 2, 12.5pg of 1 and 111.BNg of 2, 12.5ug of 1 and 223.6~rg of 2, 22.5Ng of 1 and 27.9pg of 2, 22.5pg of 1 and 55.9pg of 2, 22.5Ng of 1 and 111.8Ng of 2, 22.5pg of 1 and 223.6Ng of 2, 25Ng of 1 and 27.9Ng of 2, 25Ng of 1 and 55.9Ng of 2, 25pg of 1 and 111.BNg of 2, 25Ng of 1 and 223.6ug of 2, 45Ng of 1 and 27.9Ng of 2, 45Ng of 1 and 55.9Ng of 2, 45pg of 1 and 111.8Ng of 2, 45Ng of 1 and 223.6pg of 2, 50Ng of 1 and 27.9pg of 2, 50pg of 1 and 55.9Ng of 2, 50Ng of 1 and 111.8Ng of 2 or 50pg of 1 and 223.6pg of 2.
The combinations of active substances 1 and 2 according to the invention are preferably administered by inhalation. For this purpose, the ingredients 1 and 2 have to be incorporated in inhalable preparations.
Suitable inhalable preparations include inhalable powders, metering aerosols containing propellant gases or inhalable solutions free from propellant gases.
Inhalable powders according to the invention containing the active substance combination of 1 and 2 may consist solely of the abovementioned active substances or of a mixture of the abovementioned active substances with physiologically acceptable adjuvants. Within the scope of the present invention the term propellant-free solutions for inhalation also includes concentrates or sterile, ready-to-use solutions for inhalation. The preparations according to the invention may contain the active substance combination of 1 and 2 either together in one preparation or in two separate preparations. These preparations which may be used within the scope of the present invention are described in detail in the following section of the specification.
A) Inhalable powders containing the active substance combinations of 1 and 2 according to the invention The powders for inhalation according to the invention may contain _1 and 2 either on their own or in admixture with suitable physiologically harmless adjuvants If the active substances 1 and 2 are present in admixture with physiologically harmless adjuvants, the following physiologically harmless adjuvants 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. dextranes), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these adjuvants with one another. Mono- or disaccharides are preferably used, the use of lactose or glucose, particularly but not exclusively in the form of their hydrates, being preferred.
The particularly preferred adjuvant according to the invention is lactose, most preferably lactose monohydrate.
Within the scope of the powders for inhalation according to the invention the adjuvants have a maximum mean particle size of up to 250um, preferably between and 150pm, particularly preferably between 15 and 80Nm. If desired it may be useful to add finer adjuvant fractions having a mean particle size of 1 to 9Nm to the abovementioned adjuvants. These latter finer adjuvants are also selected from the abovementioned group of adjuvants which may be used. Finally, in order to prepare the powders for inhalation according to the invention, micronised active substance _1 and 2, preferably having an average particle size of 0.5 to 10pm, particularly preferably from 1 to 6pm, is added to the adjuvant mixture. Processes for preparing the powders for inhalation according to the invention by grinding and micronising and finally mixing the ingredients together are known from the prior art. The powders for inhalation 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 can be administered using inhalers known from the prior art.
Inhalable powders according to the invention which contain a physiologically harmless adjuvant in addition to 1 and 2 may for example be administered using inhalers which meter a single dose from a reservoir by means of a measuring chamber, as described in US 4570630A, or by other devices as described in DE
25 685 A. Preferably, the inhalable powders according to the invention which contain physiologically harmless adjuvant in addition to 1 and 2 are packed into capsules (to form so-called inhalettes), which are used in inhalers such as those described, for example, in WO 94/28958.
If the inhalable powders according to the invention are to be packed into capsules (inhalettes) as in the preferred application mentioned above, fillings of 1 to 30mg, preferably from 3 to 20mg, preferably 5 to 10 mg of inhalable powder per capsule are suggested. According to the invention, these contain the dosages specified above for 1' and 2' either together or separately per single dose.
B) Inhalable aerosols containing propellant, comprising the active substance combinations of 1 and 2 according to the invention:
Inhalable aerosols containing propellant according to the invention may contain 1 and 2 dissolved in the propellent gas or in dispersed form. 1 and 2 may be present in separate preparations or in a combined preparation, with 1 and 2 either both dissolved, both dispersed or only one component dissolved while the other is present in dispersed form.
The propellent gases which can be used to prepare the inhalable aerosols according to the invention are known from the prior art. Suitable propellent gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The abovementioned propellent gases may be used on their own or in mixtures thereof. Particularly preferred propellent gases are halogenated alkane derivatives selected from among TG11, TG12, TG134a and TG227. Of the abovementioned halogenated s hydrocarbons, TG134a (1,1,1,2-tetrafluoroethane) and TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof are preferred according to the invention.
The propellant-gas-containing inhalable aerosols according to the invention may also contain other ingredients such as cosolvents, stabilisers, surface-active agents (surfactants), antioxidants, lubricants and means for adjusting the pH. All these ingredients are known in the art.
The propellant-gas-containing inhalable aerosols according to the invention may contain up to 5 % by weight of active substance 1 and/or 2. Aerosols according to the invention contain, for example, 0.002 to 5 % by weight , 0.01 to 3 % by weight , 0.015 to 2 % by weight , 0.1 to 2 % by weight , 0.5 to 2 % by weight or 0.5 to 1 % by weight of active substance 1 andlor 2.
If the active substances 1 andlor 2 are present in dispersed form the particles of active substance preferably have a mean particle size of up to 10 Nm, preferably from 0.1 to 5 pm, particularly preferably from 1 to 5 Nm.
The abovementioned propellant-gas-containing inhalable aerosols according to the invention can be administered by means of inhalers known in the art (MDIs =
metered dose inhalers). Accordingly, a further aspect of the present invention relates to pharmaceutical compositions in the form of propellant-gas-containing aerosols as described above combined with one or more inhalers suitable for administering these aerosols. Furthermore, the present invention relates to inhalers, characterised in that they contain the propellant-gas-containing aerosols according to the invention as described above.
The present invention also relates to cartridges which are fitted with a suitable valve and can be used in a suitable inhaler and which contain one of the abovementioned propellant-gas-containing inhalable aerosols according to the invention.
Suitable cartridges and methods of filling these cartridges with the propellant-gas-containing inhalable aerosols according to the invention are known from the prior art.
C) Propellant-free inhalable solutions containing the active substance combinations of 1 and 2 according to the invention:
It is particularly preferable for the active substance combination according to the invention to be administered in the form of propellant-free solutions for inhalation.
Suitable solvents for this include aqueous or alcoholic, preferably ethanolic solutions.
The solvent may be water on its own or a mixture of water and ethanol. The relative proportion of ethanol to water is not restricted, but the maximum limit is preferably up to 70 percent by volume, particularly up to 60 percent by volume and most preferably up to 30 percent by volume. The remaining percent by volume are made up with water. The preferred solvent is water without the addition of ethanol. The solutions containing 1 and 2 , separately or together, are adjusted to a pH of 2 to 7, preferably 2 to 5, particularly preferably 2.5 to 3.5, with suitable acids. Most preferably, inhalable solutions according to the invention which contain 1 and 2 together have a pH of about 2.9. This pH may be achieved using acids selected from among inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include: ascorbic acid, citric acid, malic acid, tartaric acid, malefic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid and others. Preferred inorganic acids are hydrochloric acid and sulphuric acid. It is also possible to use the acids which are forming an acid addition salt with the active substance or, in the case of combined preparations, with one of the active substances. 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 properties other than their acidifying properties, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.
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.
Other embodiments contains these compound(s).
In a preferred embodiment of this kind, the content based on sodium edetate is less than 100 mg I 100 ml, preferably less than 50 mg/100 ml, most preferably less than 20 mg/100 ml.
Inhalable solutions in which the content of sodium edetate is 0 to 10mgI100m1 are generally preferred.
Co-solvents and/or other adjuvants may be added to the propellant-free inhalable solutions according to the invention.
Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols - particularly isopropylalcohol, glycols - particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
By excipients and additives is meant, in this context, any pharmacologically acceptable substance which is not an active substance, but can be formulated together with the active substances) in the pharmacologically suitable solvent, in order to improve the qualitative properties of the active substance formulation.
Preferably, these substances do not have any appreciable pharmacological effects or at least have no undesirable effects in the context of the intended therapy. The excipients and additives include e.g. surfactants such as e.g. soya lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or extend the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art. The additives also include pharmacologically harmless salts such as sodium chloride, for example, as isotonic agents.
The preferred adjuvants include antioxidants, such as ascorbic acid, for example, unless it has 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 used to protect the formulation from contamination with pathogens. Suitable preservatives are those known from the prior art, particularly cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art. The abovementioned preservatives are preferably present in concentrations of up to 50mg/100m1, particularly between 5 and 20 mg/100m1.
Preferred formulations contain only benzalkonium chloride and sodium edetate in addition to the solvent water and the active substance combination of _1 and 2.
In another preferred embodiment, sodium edetate is omitted.
The propellant-free inhalable solutions according to the invention may be administered particularly using inhalers which are able to nebulise a small amount of a liquid formulation in the therapeutically necessary dose within a few seconds to form an aerosol suitable for therapeutic inhalation. Within the scope of the present invention, nebulisers are preferred in which a quantity of less than 100 NL, preferably less than 50 NL, particularly preferably between 20 and 30 pL of active substance solution can be nebulised, preferably in one operation, to produce an aerosol having an average particle size of less than 20 pm, preferably less than 10 Nm, in such a way that the inhalable part of the aerosol corresponds to the therapeutically effective amount.
A device 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 International Patent Application WO 91114468 and also in WO 97112687 (particularly Figures 6a and 6b). The nebulisers (devices) described therein are also known by the name Respimat~.
This nebuliser (Respimat~) can advantageously be used to produce inhalable aerosols according to the invention containing the active substance combination of _1 and 2. Because of its cylindrical shape and handy size of less than 9 to 15 cm long and 2 to 4 cm wide this device can be carried anywhere by the patient. The nebuliser sprays a defined volume of the pharmaceutical formulation under high pressure through small nozzles, 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 which is fixed in the upper housing part and carries, at one end, a nozzle member with the nozzle or nozzle arrangement, - a hollow piston with valve member, - a power take-off flange in which the hollow piston is secured, and which is located in the upper housing part, - a locking clamp which is located in the upper housing part, - a spring housing with the spring located therein, which is rotatably mounted on the upper housing 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 member corresponds to a device disclosed in WO
97/12687. It projects partially into the cylinder of the pump housing and is mounted to be axially movable in the cylinder. Reference is made particularly to Figures 1-4 -particularly Figure 3 - and the associated parts of the description. At the moment of actuation of the spring, the hollow piston with valve member exerts a pressure at its high pressure end 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 quantity of active substance solution. Volumes of 10 to 50 microlitres are preferred, volumes of 10 to 20 microlitres are particularly preferred, while a volume of 15 microlitres per spray is most particularly preferred.
The valve member is preferably mounted at the end of the hollow piston facing the nozzle member.
The nozzle in the nozzle member is preferably microstructured, i.e. produced by microtechnology. Microstructured nozzle members are disclosed, for example, in WO-94/07607; reference is hereby made to this specification, particularly Figure 1 and the description thereof.
The nozzle member consists e.g. of two sheets of glass andlor silicon firmly joined 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 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 7 to 9 microns.
In the event of a plurality of nozzle openings, two being preferred, the directions of the jets from the nozzles in the nozzle member run parallel or slope relative to one another in the direction of the nozzle opening. In the case of a nozzle member with at least two nozzle openings at the inlet end the directions of the jets may be inclined relative to one another at an angle of 20 degrees to 160 degrees, preferably 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, most preferably 30 to 70 microns.
A spacing of 50 microns is most preferred.
The directions of the jets accordingly meet in the vicinity of the nozzle openings.
The liquid pharmaceutical preparation meets the nozzle member at an entry pressure of up to 600 bar, preferably 200 to 300 bar, and is atomised by means of the nozzle openings to form an inhalable aerosol. The preferred particle or droplet sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns.
The locking clamp contains a spring, preferably a cylindrical helical compression spring, as a store for mechanical energy. The spring acts on the power take-off flange as 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 and lower stop. The spring is preferably tensioned by a force-transmitting gear, e.g. a helical thrust gear, by means of an external torque which is produced by rotating the upper housing part 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 multiple spline gear.
The locking member with engaging locking surfaces is annually disposed about the power take-off flange. It consists, for example, of an inherently radially elastically deformable ring made of plastics or metal. The ring is disposed in a plane at right angles to the atomiser axis. After the tensioning of the spring, the locking surfaces of the locking member move into the path of the power take-off flange and prevent the spring from being released. The locking member is actuated by a button.
The actuating button is connected or coupled to the locking member. In order to actuate the locking clamp, the actuating button is pushed parallel to the ring plane, preferably into the atomiser; at the same time the deformable ring is deformed in the ring plane.
Details of the construction of the locking clamp are described in WO 97/20590.
The lower housing part is pushed axially over the spring housing and covers the mounting, the drive of the spindle and the storage container for the fluid.
When the atomiser is actuated, the upper housing part is rotated relative to the lower housing part, the latter carrying the spring housing with it. The spring is compressed and tensioned by means of the helical thrust gear and the locking 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 is pushed a certain distance in the upper housing part, the hollow piston is pulled back within the cylinder in the pump housing, as a result of which some of the fluid is sucked out of the storage container into the high pressure chamber in front of the nozzle.
A plurality of exchangeable storage containers containing the fluid to be atomised can be pushed into the atomiser as required 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 locking mechanism then opens the way for the power take-off component. The tensioned spring pushes the piston into the cylinder of the pump housing. The fluid leaves the nozzle of the atomiser in atomised form.
Other details of construction are disclosed in PCT applications WO 97/12683 and WO 97/20590, to which reference is hereby made.
The components of the atomiser (nebuliser) are made from a material suitable for their purpose. The housing of the atomiser and - if operation permits - other components too are preferably made of plastics, e.g. by injection moulding.
For medical purposes, physiologically harmless materials are used.
Figures 1 a/b, which are identical to Figure 6 alb of WO 97/12687, illustrate the nebuliser (Respimat~) 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 2 b shows a longitudinal section through the atomiser with the spring released.
The upper housing part (51 ) contains the pump housing (52), at whose end is mounted the holder (53) for the atomiser nozzle. In the holder is the nozzle member (54) and a filter (55). The hollow piston (57) secured in the power take-off flange (56) of the locking clamp projects partially into the cylinder of the pump housing.
At its end the hollow piston carries the valve member (58). The hollow piston is sealed off by means of the gasket (59). Inside the upper housing part is the stop (60) on which the power take-off flange abuts when the spring is released. On the power take-off flange is the stop (61 ) on which the power take-off flange abuts when the spring is tensioned. After the spring has been tensioned, the locking member (62) moves 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 sealed off by means of the protective cap (66) which can be fitted thereon.
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 bearing. The lower housing part (70) is pushed over the spring housing. Inside the spring housing is the replaceable storage container (71 ) for the fluid which is to be atomised (72). The storage container is sealed off by means of the stopper (73) through which the hollow piston projects into the storage container and dips its end in the fluid (store of active substance solution).
The spindle (74) for the mechanical counter is mounted in the casing surface of the spring housing. The drive pinion (75) is located on the end of the spindle which faces the upper housing part. The slider (76) is located on the spindle.
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 by the technology described above (Respimat~), the mass delivered should correspond to a defined amount with a tolerance range of not more than 25%, preferably 20% of this amount, in at least 97%, preferably at least 98% of all actuations (sprays) of the inhaler.
Preferably, between 5 and 30 mg, particularly preferably between 5 and 20 mg of formulation, are delivered per spray as a defined mass.
However, the formulation according to the invention may also be nebulised by means of inhalers other than those described above, e.g. jet -stream inhalers.
Accordingly, in another aspect, the present invention relates to pharmaceutical compositions in the form of propellant-free inhalable solutions as described above in conjunction with a device suitable for administering these solutions, preferably in conjunction with the Respimat~. The present invention is preferably directed to propellant-free inhalable solutions characterised by the active substance combination of _1 and 2 according to the invention in conjunction with the device known by the name Respimat~. Moreover, the present invention relates to the inhalation devices mentioned above, preferably the Respimat~, characterised in that they contain the propellant-free inhalable solutions according to the invention described hereinbefore.
The propellant-free solutions for inhalation according to the invention may also be presented as concentrates or sterile ready-to-use solutions for inhalation, in addition to the abovementioned solutions intended for administration using the Respimat.
Ready-to-use solutions for inhalation may be produced from the concentrates, for example by the addition of isotonic saline solutions. Sterile ready-to-use solutions for inhalation can be administered using energy-operated free-standing or portable nebulisers which produce inhalable aerosols by ultrasound or compressed air by the venturi principle or other principles.
Accordingly, in another aspect the present invention relates to pharmaceutical compositions in the form of propellant-free inhalable solutions as described above, which take the form of concentrates or sterile ready-to-use solutions, in conjunction with a device suitable for administering these solutions, characterised in that this device is an energy-operated free-standing or portable nebuliser which produces inhalable aerosols by ultrasound or compressed air by the venturi principle or other principles.
The following Examples serve to illustrate the present invention in more detail, although without restricting the scope of the invention to the following embodiments provided by way of example.
~
, CA 02429012 2003-04-28 Starting materials Tiotropium bromide:
The tiotropium bromide used in the following examples of formulations may be obtained as described in European Patent Application EP 418 716 A1.
The inhalable powders according to the invention may also be prepared using crystalline tiotropium bromide monohydrate. This crystalline tiotropium bromide monohydrate may be obtained by the following method.
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 tiotropium bromide-containing solution and rinsed with 4.3 kg of water. The mixture thus obtained is stirred for at least 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 at 3-5°C per 20 minutes to a temperature of 20-25°C. The apparatus is further cooled to 10-15°C
using cold water and crystallisation is completed by stirring for at least one hour. The crystals are isolated using a suction drier, the isolated crystal slurry is washed with 9 litres 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) The crystalline tiotropium bromide rnonohydrate thus obtained is micronised by known methods in order to prepare the active substance in the form of the average particle size which corresponds to the specifications according to the invention.
Salmeterol x'/ZH2S04_ Where reference is made to salmeterol x %Z H2S04 in the following embodiments, this was obtained as follows:
A suspension of 2.5 g (4.15 mmol) of salmeterol xinafoate is dissolved in 6 ml of ethanol. A solution of 0.14 ml of 98% sulphuric acid is slowly added to the suspension with stirring. It is heated to 35-40 °C until fully dissolved. Then the solution is diluted with 10 ml of diethylether and inoculated with salmeterol sulphate.
The salmeterol sulphate is suction filtered after 1.5 hours and washed with 20 ml of cold ethanol, acetone and diethylether.
1.5 g (78%) of salmeterol '/2-sulphate are obtained.
Examples of formulations A) Powders for inhalation:
1) Ingredients Ng per capsule tiotropium bromide 10.8 salmeterol x'/2 H SO 27.9 lactose 4961.3 Tota I 5000 2) Ingredients pg per capsule tiotropium bromide 21.7 salmeterol x'h H SO 55.9 lactose 4922.4 Total 5000 3) Ingredients Ng per capsule tiotropium bromide x 22.5 H O
salmeterol x %2 H SO 55.9 lactose 4921.6 Total 5000 B) Inhalable aerosols containing propellants:
1 ) Suspension aerosol:
Ingredients % by weight tiotropium bromide 0.015 salmeterol X '/2 H SO 0.066 soya lecithin 0.2 TG 11 : TG12 = 2:3 ad 100 2) Suspension aerosol:
Ingredients % by weight tiotropium bromide 0.029 salmeterol x %2 H SO 0.033 absolute ethanol 0.5 isopropyl m ristate 0.1 TG 227 ad 100 3) Solution aerosol:
Ingredients % by weight tiotropium bromide 0.042 salmeterol X ~~2 H SO 0.047 absolute ethanol 30 purified water 1.5 anhydrous citric acid 0.002 TG 134a ad 100 C) Propellant-free inhalable solutions:
1 ) Solution for use in the Respimat~:
Ingredients mg1100mL
tiotropium bromide 148.5 salmeterol x %2 H SO 276.7 benzalkonium chloride 10 sodium edetate 10 hydrochloric acid (aq) ad pH 2.9 water ad 100 mL
Use of the solution in the Respimat leads to a dosage of 10 pg per dose of 1 and 25 pg/dose of 2.
2) Solution for use in the Respimat~:
_ Ingredients mg1100mL
tiotropium bromide 148.5 salmeterol X 1/2 H SO 276.7 benzalkonium chloride 10 hydrochloric acid (aq) ad pH 2.9 water ad 100mL
Use of the solution in the Respimat leads to a dosage of 10 Ng per dose of 1 and 25 pg/dose of 2.
3) Solution for use in the Respimat~:
Ingredients mg1100mL
tiotropium bromide 297.1 salmeterol X 1/2 H SO 276.7 benzalkoniurn chloride 10 sodium edetate 10 hydrochloric acid (aq) ad pH 2.9 water ad 100 mL
Use of the solution in the Respimat leads to a dosage of 20 pg per dose of 1 and 25 Ng/dose of 2.
4) Solution for use in the Respimat~:
Ingredients mg1100mL
tiotropium bromide 297.1 salmeterol x '/Z H SO 276.7 benzalkonium chloride 10 hydrochloric acid (aq) ad pH 2.9 water ad 100mL
Use of the solution in the Respimat leads to a dosage of 20 Ng per dose of 1 and 25 ug/dose of 2.
'. CA 02429012 2003-04-28 5) Solution for use in the Respimat~:
Ingredients mgI100mL
.~ tiotropium bromide 148.5 salmeterol x'/2 H SO 1106.3 benzalkonium chloride 8 sodium edetate 50 hydrochloric acid (aq) ad pH 2.5 water ad 100mL
Use of the solution in the Respimat leads to a dosage of 10 pg per dose of 1 and 100 pg/dose of 2.
As a result, it is possible to reduce substantially the undesirable side effects which often occur, for example, in the administration of ~i-mimetics such as salmeterol to humans. Examples of the central side effects of ~i-mimetics include general malaise, excitation, sleeplessness, anxiety, trembling fingers, sweats and headaches.
The name tiotropium is intended to refer to the free cation (~ for the purposes of the present invention. References to salmeterol are intended as references to the free base (2') for the purposes of the present invention.
The combinations of active substances according to the invention are surprisingly also characterised by a rapid onset of activity and also by long-lasting effects. This is of great importance to the wellbeing of the patient as, on the one hand, they experience a rapid improvement in their condition after administration of the combination and, on the other hand, a single administration per day is sufficient, thanks to the long-lasting effect.
The abovementioned effects are observed both after the simultaneous administration within a single active substance formulation and also after the successive administration of the two active substances in separate formulations. It is preferred 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 (~ and one or more salmeterol salts (2 ), optionally in the form of the solvates or hydrates thereof. The active substances may be contained either together in a single preparation or in two separate preparations.
According to the invention, pharmaceutical compositions which contain the active substances 1 and 2 in a single preparation are preferred.
According to another aspect the present invention relates to a pharmaceutical composition which contains, in addition to therapeutically effective amounts of 1 and 2, a pharmaceutically acceptable excipient. In one aspect the present invention relates to a pharmaceutical composition which contains, in addition to therapeutically effective amounts of 1 and 2, no pharmaceutically acceptable excipient.
The present invention further relates to the use of 1 and 2 for preparing a pharmaceutical composition containing therapeutically effective amounts of 1 and 2 for the treatment of inflammatory or obstructive respiratory complaints, particularly asthma or COPD, by simultaneous or successive administration.
The present invention is also directed to the simultaneous or successive use of therapeutically effective doses of the combination of the abovementioned pharmaceutical compositions 1 and 2 for the treatment of inflammatory or obstructive respiratory complaints, particularly asthma or COPD.
The tiotropium salts 1 which may be used within the scope of the present invention include the compounds which contain, in addition to tiotropium, chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methylsulphate as counter-ion (anion). Within the scope of the present invention, of all the tiotropium salts, the methanesulphonate, chloride, bromide or iodide are preferred, the methanesulphonate or bromide being of particular importance. Tiotropium bromide is of exceptional importance according to the invention.
By salts of salmeterol 2 are meant, according to the invention, pharmaceutically acceptable salts selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, xinafonic acid or malefic acid, with the proviso that 2 cannot denote salmeterol xinafoate if 1 denotes tiotropium bromide. Mixtures of the abovementioned acids may optionally also be used to prepare the salmeterol salts.
According to the invention, the salmeterol salts 2 selected from among hydrochloride, hydrobromide, sulphate, phosphate and methanesulphonate are preferred. The salts of 2 selected from hydrochloride and sulphate are particularly preferred, especially the sulphates. Salmeterol x %2 H2S04 is of exceptional importance according to the invention.
In the combinations of active substances according to the invention consisting of 1 and 2 the ingredients 1 and 2 may be in the form of their enantiomers, mixtures of enantiomers or in the form of the racemates.
r CA 02429012 2003-04-28 The proportions in which the two active substances 1 and 2 may be used in the combinations of active substances according to the invention are variable. The active substances 1 and 2 may optionally be in the form of the solvates or hydrates thereof.
Depending on the choice of the salts 1 or 2 the weight ratios which may be used for the purposes of the present invention vary on account of the different molecular weights of the various salt forms. Consequently, the weight ratios specified hereinafter are based on the tiotropium cation 1' and the free base of salmeterol 2'.
The combinations of active substances according to the invention may contain 1' and 2' in weight ratios in the range from 1:300 to 30:1, preferably from 1:230 to 20:1, particularly preferably from 1:150 to 10:1, more preferably from 1:50 to 5:1, particularly 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, particularly preferably in the range from 1:5 to 1:2.5.
For example, without restricting the scope of the invention, 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, 1.8:1.
The pharmaceutical compositions according to the invention containing the combinations of 1 and 2 are normally used so that tiotropium 1' and salmeterol 2' are administered together in doses of 0.01 to 10000 pg, preferably 0.1 to 2000 Ng, particularly preferably from 1 to 1000 Ng, more preferably from 5 to 500 Ng, preferably, according to the invention, from 10 to 200 ug, 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 30Ng, 35Ng, 45ug, 55pg, 60Ng, 65ug, 90pg, 105Ng, 110ug, 110Ng, 140Ng or similar. In these dosage ranges the active substances 1' and 2' are present in the weight rations described hereinbefore.
For example, without restricting the scope of the invention, the combinations of 1 and 2 according to the invention may contain an amount of tiotropium 1' and salmeterol 2' such that 5Ng of 1' and 25Ng of 2', 5Ng of 1' and 50ug of 2', 5~rg of 1' and 100Ng of 2', 5Ng of 1' and 200Ng of 2', 10pg of 1' and 25Ng of 2', 10Ng of 1' and 50pg of 2', 10Ng of 1' and 100Ng of 2', 10Ng of 1' and 200pg of 2', 18pg of 1' and 25pg of 2', 18Ng of 1' and 50Ng of 2', 18Ng of 1' and 100pg of 2', 18Ng of 1' and 200Ng of 2', 20Ng of 1' and 25Ng of 2', 20Ng of 1' and 50pg of 2', 20pg of 1' and 100pg of 2', 20Ng of 1' and 200Ng of 2', 36Ng of 1' and 25Ng of 2', 36pg of 1' and 50trg of 2', 36pg of 1' and 100pg of 2', 36pg of 1' and 200pg of 2', 40~g of 1' and 25Ng of 2', 40Ng of 1' and 50pg of 2', 40ug of 1' and 100pg of 2' or 40Ng of 1' and 200Ng of 2' are administered per single dose.
If the active substance combination in which 1 denotes tiotropium bromide and denotes salmeterol x'/ZH2S04 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 specified above by way of example correspond to the following quantities of 1 and 2 administered per single dose: hug of 1 and 27.9pg of 2, 6pg of 1 and 55.9Ng of 2, 6pg of 1 and 111.8trg of 2, 6pg of 1 and 223.6Ng of 2, 12pg of 1 and 27.9pg of 2, 12Ng of 1 and 55.9Ng of 2, 12Ng of 1 and 111.8pg of 2, 12pg of 1 and 223.6Ng of 2, 21.7Ng of 1 and 27.9Ng of 2, 21.7pg of 1 and 55.9pg of 2, 21.7Ng of 1 and 111.8Ng of 2, 21.7Ng of 1 and 223.6pg of 2, 24.1 pg of 1 and 27.9pg of 2, 24.1 Ng of 1 and 55.9Ng of 2, 24.1 Ng of 1 and 111.8Ng of 2, 24.1 pg of 1 and 223.6Ng of 2, 43.3pg of 1 and 27.9Ng of 2, 43.3pg of 1 and 55.9Ng of 2, 43.3pg of 1 and 111.BNg of 2, 43.3pg of 1 and 223.6Ng of 2, 48.1 Ng of 1 and 27.9Ng of 2, 48.1 pg of 1 and 55.9pg of 2, 48.1 pg of 1 and 111.8pg of 2 or 48.1 Ng of 1 and 223.6Ng of 2.
If, in the combination of 1 and 2 preferred according to the invention, wherein 2 denotes salmeterol x'hH2S04 tiotropium bromide monohydrate is used as 1, for example, the quantities of active substances 1' and 2' administered per single dose as specified above by way of example correspond to the following quantities of 1 and 2 administered per single dose: 6.2ug of 1 and 27.9~rg of 2, 6.2pg of 1 and 55.9Ng of 2, 6.2pg of 1 and 111.8pg of 2, 6.2pg of 1 and 223.6pg of 2, 12.5pg of 1 and 27.9pg of 2, 12.5Ng of 1 and 55.9pg of 2, 12.5pg of 1 and 111.BNg of 2, 12.5ug of 1 and 223.6~rg of 2, 22.5Ng of 1 and 27.9pg of 2, 22.5pg of 1 and 55.9pg of 2, 22.5Ng of 1 and 111.8Ng of 2, 22.5pg of 1 and 223.6Ng of 2, 25Ng of 1 and 27.9Ng of 2, 25Ng of 1 and 55.9Ng of 2, 25pg of 1 and 111.BNg of 2, 25Ng of 1 and 223.6ug of 2, 45Ng of 1 and 27.9Ng of 2, 45Ng of 1 and 55.9Ng of 2, 45pg of 1 and 111.8Ng of 2, 45Ng of 1 and 223.6pg of 2, 50Ng of 1 and 27.9pg of 2, 50pg of 1 and 55.9Ng of 2, 50Ng of 1 and 111.8Ng of 2 or 50pg of 1 and 223.6pg of 2.
The combinations of active substances 1 and 2 according to the invention are preferably administered by inhalation. For this purpose, the ingredients 1 and 2 have to be incorporated in inhalable preparations.
Suitable inhalable preparations include inhalable powders, metering aerosols containing propellant gases or inhalable solutions free from propellant gases.
Inhalable powders according to the invention containing the active substance combination of 1 and 2 may consist solely of the abovementioned active substances or of a mixture of the abovementioned active substances with physiologically acceptable adjuvants. Within the scope of the present invention the term propellant-free solutions for inhalation also includes concentrates or sterile, ready-to-use solutions for inhalation. The preparations according to the invention may contain the active substance combination of 1 and 2 either together in one preparation or in two separate preparations. These preparations which may be used within the scope of the present invention are described in detail in the following section of the specification.
A) Inhalable powders containing the active substance combinations of 1 and 2 according to the invention The powders for inhalation according to the invention may contain _1 and 2 either on their own or in admixture with suitable physiologically harmless adjuvants If the active substances 1 and 2 are present in admixture with physiologically harmless adjuvants, the following physiologically harmless adjuvants 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. dextranes), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these adjuvants with one another. Mono- or disaccharides are preferably used, the use of lactose or glucose, particularly but not exclusively in the form of their hydrates, being preferred.
The particularly preferred adjuvant according to the invention is lactose, most preferably lactose monohydrate.
Within the scope of the powders for inhalation according to the invention the adjuvants have a maximum mean particle size of up to 250um, preferably between and 150pm, particularly preferably between 15 and 80Nm. If desired it may be useful to add finer adjuvant fractions having a mean particle size of 1 to 9Nm to the abovementioned adjuvants. These latter finer adjuvants are also selected from the abovementioned group of adjuvants which may be used. Finally, in order to prepare the powders for inhalation according to the invention, micronised active substance _1 and 2, preferably having an average particle size of 0.5 to 10pm, particularly preferably from 1 to 6pm, is added to the adjuvant mixture. Processes for preparing the powders for inhalation according to the invention by grinding and micronising and finally mixing the ingredients together are known from the prior art. The powders for inhalation 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 can be administered using inhalers known from the prior art.
Inhalable powders according to the invention which contain a physiologically harmless adjuvant in addition to 1 and 2 may for example be administered using inhalers which meter a single dose from a reservoir by means of a measuring chamber, as described in US 4570630A, or by other devices as described in DE
25 685 A. Preferably, the inhalable powders according to the invention which contain physiologically harmless adjuvant in addition to 1 and 2 are packed into capsules (to form so-called inhalettes), which are used in inhalers such as those described, for example, in WO 94/28958.
If the inhalable powders according to the invention are to be packed into capsules (inhalettes) as in the preferred application mentioned above, fillings of 1 to 30mg, preferably from 3 to 20mg, preferably 5 to 10 mg of inhalable powder per capsule are suggested. According to the invention, these contain the dosages specified above for 1' and 2' either together or separately per single dose.
B) Inhalable aerosols containing propellant, comprising the active substance combinations of 1 and 2 according to the invention:
Inhalable aerosols containing propellant according to the invention may contain 1 and 2 dissolved in the propellent gas or in dispersed form. 1 and 2 may be present in separate preparations or in a combined preparation, with 1 and 2 either both dissolved, both dispersed or only one component dissolved while the other is present in dispersed form.
The propellent gases which can be used to prepare the inhalable aerosols according to the invention are known from the prior art. Suitable propellent gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The abovementioned propellent gases may be used on their own or in mixtures thereof. Particularly preferred propellent gases are halogenated alkane derivatives selected from among TG11, TG12, TG134a and TG227. Of the abovementioned halogenated s hydrocarbons, TG134a (1,1,1,2-tetrafluoroethane) and TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof are preferred according to the invention.
The propellant-gas-containing inhalable aerosols according to the invention may also contain other ingredients such as cosolvents, stabilisers, surface-active agents (surfactants), antioxidants, lubricants and means for adjusting the pH. All these ingredients are known in the art.
The propellant-gas-containing inhalable aerosols according to the invention may contain up to 5 % by weight of active substance 1 and/or 2. Aerosols according to the invention contain, for example, 0.002 to 5 % by weight , 0.01 to 3 % by weight , 0.015 to 2 % by weight , 0.1 to 2 % by weight , 0.5 to 2 % by weight or 0.5 to 1 % by weight of active substance 1 andlor 2.
If the active substances 1 andlor 2 are present in dispersed form the particles of active substance preferably have a mean particle size of up to 10 Nm, preferably from 0.1 to 5 pm, particularly preferably from 1 to 5 Nm.
The abovementioned propellant-gas-containing inhalable aerosols according to the invention can be administered by means of inhalers known in the art (MDIs =
metered dose inhalers). Accordingly, a further aspect of the present invention relates to pharmaceutical compositions in the form of propellant-gas-containing aerosols as described above combined with one or more inhalers suitable for administering these aerosols. Furthermore, the present invention relates to inhalers, characterised in that they contain the propellant-gas-containing aerosols according to the invention as described above.
The present invention also relates to cartridges which are fitted with a suitable valve and can be used in a suitable inhaler and which contain one of the abovementioned propellant-gas-containing inhalable aerosols according to the invention.
Suitable cartridges and methods of filling these cartridges with the propellant-gas-containing inhalable aerosols according to the invention are known from the prior art.
C) Propellant-free inhalable solutions containing the active substance combinations of 1 and 2 according to the invention:
It is particularly preferable for the active substance combination according to the invention to be administered in the form of propellant-free solutions for inhalation.
Suitable solvents for this include aqueous or alcoholic, preferably ethanolic solutions.
The solvent may be water on its own or a mixture of water and ethanol. The relative proportion of ethanol to water is not restricted, but the maximum limit is preferably up to 70 percent by volume, particularly up to 60 percent by volume and most preferably up to 30 percent by volume. The remaining percent by volume are made up with water. The preferred solvent is water without the addition of ethanol. The solutions containing 1 and 2 , separately or together, are adjusted to a pH of 2 to 7, preferably 2 to 5, particularly preferably 2.5 to 3.5, with suitable acids. Most preferably, inhalable solutions according to the invention which contain 1 and 2 together have a pH of about 2.9. This pH may be achieved using acids selected from among inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include: ascorbic acid, citric acid, malic acid, tartaric acid, malefic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid and others. Preferred inorganic acids are hydrochloric acid and sulphuric acid. It is also possible to use the acids which are forming an acid addition salt with the active substance or, in the case of combined preparations, with one of the active substances. 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 properties other than their acidifying properties, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.
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.
Other embodiments contains these compound(s).
In a preferred embodiment of this kind, the content based on sodium edetate is less than 100 mg I 100 ml, preferably less than 50 mg/100 ml, most preferably less than 20 mg/100 ml.
Inhalable solutions in which the content of sodium edetate is 0 to 10mgI100m1 are generally preferred.
Co-solvents and/or other adjuvants may be added to the propellant-free inhalable solutions according to the invention.
Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols - particularly isopropylalcohol, glycols - particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
By excipients and additives is meant, in this context, any pharmacologically acceptable substance which is not an active substance, but can be formulated together with the active substances) in the pharmacologically suitable solvent, in order to improve the qualitative properties of the active substance formulation.
Preferably, these substances do not have any appreciable pharmacological effects or at least have no undesirable effects in the context of the intended therapy. The excipients and additives include e.g. surfactants such as e.g. soya lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or extend the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art. The additives also include pharmacologically harmless salts such as sodium chloride, for example, as isotonic agents.
The preferred adjuvants include antioxidants, such as ascorbic acid, for example, unless it has 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 used to protect the formulation from contamination with pathogens. Suitable preservatives are those known from the prior art, particularly cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art. The abovementioned preservatives are preferably present in concentrations of up to 50mg/100m1, particularly between 5 and 20 mg/100m1.
Preferred formulations contain only benzalkonium chloride and sodium edetate in addition to the solvent water and the active substance combination of _1 and 2.
In another preferred embodiment, sodium edetate is omitted.
The propellant-free inhalable solutions according to the invention may be administered particularly using inhalers which are able to nebulise a small amount of a liquid formulation in the therapeutically necessary dose within a few seconds to form an aerosol suitable for therapeutic inhalation. Within the scope of the present invention, nebulisers are preferred in which a quantity of less than 100 NL, preferably less than 50 NL, particularly preferably between 20 and 30 pL of active substance solution can be nebulised, preferably in one operation, to produce an aerosol having an average particle size of less than 20 pm, preferably less than 10 Nm, in such a way that the inhalable part of the aerosol corresponds to the therapeutically effective amount.
A device 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 International Patent Application WO 91114468 and also in WO 97112687 (particularly Figures 6a and 6b). The nebulisers (devices) described therein are also known by the name Respimat~.
This nebuliser (Respimat~) can advantageously be used to produce inhalable aerosols according to the invention containing the active substance combination of _1 and 2. Because of its cylindrical shape and handy size of less than 9 to 15 cm long and 2 to 4 cm wide this device can be carried anywhere by the patient. The nebuliser sprays a defined volume of the pharmaceutical formulation under high pressure through small nozzles, 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 which is fixed in the upper housing part and carries, at one end, a nozzle member with the nozzle or nozzle arrangement, - a hollow piston with valve member, - a power take-off flange in which the hollow piston is secured, and which is located in the upper housing part, - a locking clamp which is located in the upper housing part, - a spring housing with the spring located therein, which is rotatably mounted on the upper housing 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 member corresponds to a device disclosed in WO
97/12687. It projects partially into the cylinder of the pump housing and is mounted to be axially movable in the cylinder. Reference is made particularly to Figures 1-4 -particularly Figure 3 - and the associated parts of the description. At the moment of actuation of the spring, the hollow piston with valve member exerts a pressure at its high pressure end 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 quantity of active substance solution. Volumes of 10 to 50 microlitres are preferred, volumes of 10 to 20 microlitres are particularly preferred, while a volume of 15 microlitres per spray is most particularly preferred.
The valve member is preferably mounted at the end of the hollow piston facing the nozzle member.
The nozzle in the nozzle member is preferably microstructured, i.e. produced by microtechnology. Microstructured nozzle members are disclosed, for example, in WO-94/07607; reference is hereby made to this specification, particularly Figure 1 and the description thereof.
The nozzle member consists e.g. of two sheets of glass andlor silicon firmly joined 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 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 7 to 9 microns.
In the event of a plurality of nozzle openings, two being preferred, the directions of the jets from the nozzles in the nozzle member run parallel or slope relative to one another in the direction of the nozzle opening. In the case of a nozzle member with at least two nozzle openings at the inlet end the directions of the jets may be inclined relative to one another at an angle of 20 degrees to 160 degrees, preferably 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, most preferably 30 to 70 microns.
A spacing of 50 microns is most preferred.
The directions of the jets accordingly meet in the vicinity of the nozzle openings.
The liquid pharmaceutical preparation meets the nozzle member at an entry pressure of up to 600 bar, preferably 200 to 300 bar, and is atomised by means of the nozzle openings to form an inhalable aerosol. The preferred particle or droplet sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns.
The locking clamp contains a spring, preferably a cylindrical helical compression spring, as a store for mechanical energy. The spring acts on the power take-off flange as 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 and lower stop. The spring is preferably tensioned by a force-transmitting gear, e.g. a helical thrust gear, by means of an external torque which is produced by rotating the upper housing part 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 multiple spline gear.
The locking member with engaging locking surfaces is annually disposed about the power take-off flange. It consists, for example, of an inherently radially elastically deformable ring made of plastics or metal. The ring is disposed in a plane at right angles to the atomiser axis. After the tensioning of the spring, the locking surfaces of the locking member move into the path of the power take-off flange and prevent the spring from being released. The locking member is actuated by a button.
The actuating button is connected or coupled to the locking member. In order to actuate the locking clamp, the actuating button is pushed parallel to the ring plane, preferably into the atomiser; at the same time the deformable ring is deformed in the ring plane.
Details of the construction of the locking clamp are described in WO 97/20590.
The lower housing part is pushed axially over the spring housing and covers the mounting, the drive of the spindle and the storage container for the fluid.
When the atomiser is actuated, the upper housing part is rotated relative to the lower housing part, the latter carrying the spring housing with it. The spring is compressed and tensioned by means of the helical thrust gear and the locking 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 is pushed a certain distance in the upper housing part, the hollow piston is pulled back within the cylinder in the pump housing, as a result of which some of the fluid is sucked out of the storage container into the high pressure chamber in front of the nozzle.
A plurality of exchangeable storage containers containing the fluid to be atomised can be pushed into the atomiser as required 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 locking mechanism then opens the way for the power take-off component. The tensioned spring pushes the piston into the cylinder of the pump housing. The fluid leaves the nozzle of the atomiser in atomised form.
Other details of construction are disclosed in PCT applications WO 97/12683 and WO 97/20590, to which reference is hereby made.
The components of the atomiser (nebuliser) are made from a material suitable for their purpose. The housing of the atomiser and - if operation permits - other components too are preferably made of plastics, e.g. by injection moulding.
For medical purposes, physiologically harmless materials are used.
Figures 1 a/b, which are identical to Figure 6 alb of WO 97/12687, illustrate the nebuliser (Respimat~) 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 2 b shows a longitudinal section through the atomiser with the spring released.
The upper housing part (51 ) contains the pump housing (52), at whose end is mounted the holder (53) for the atomiser nozzle. In the holder is the nozzle member (54) and a filter (55). The hollow piston (57) secured in the power take-off flange (56) of the locking clamp projects partially into the cylinder of the pump housing.
At its end the hollow piston carries the valve member (58). The hollow piston is sealed off by means of the gasket (59). Inside the upper housing part is the stop (60) on which the power take-off flange abuts when the spring is released. On the power take-off flange is the stop (61 ) on which the power take-off flange abuts when the spring is tensioned. After the spring has been tensioned, the locking member (62) moves 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 sealed off by means of the protective cap (66) which can be fitted thereon.
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 bearing. The lower housing part (70) is pushed over the spring housing. Inside the spring housing is the replaceable storage container (71 ) for the fluid which is to be atomised (72). The storage container is sealed off by means of the stopper (73) through which the hollow piston projects into the storage container and dips its end in the fluid (store of active substance solution).
The spindle (74) for the mechanical counter is mounted in the casing surface of the spring housing. The drive pinion (75) is located on the end of the spindle which faces the upper housing part. The slider (76) is located on the spindle.
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 by the technology described above (Respimat~), the mass delivered should correspond to a defined amount with a tolerance range of not more than 25%, preferably 20% of this amount, in at least 97%, preferably at least 98% of all actuations (sprays) of the inhaler.
Preferably, between 5 and 30 mg, particularly preferably between 5 and 20 mg of formulation, are delivered per spray as a defined mass.
However, the formulation according to the invention may also be nebulised by means of inhalers other than those described above, e.g. jet -stream inhalers.
Accordingly, in another aspect, the present invention relates to pharmaceutical compositions in the form of propellant-free inhalable solutions as described above in conjunction with a device suitable for administering these solutions, preferably in conjunction with the Respimat~. The present invention is preferably directed to propellant-free inhalable solutions characterised by the active substance combination of _1 and 2 according to the invention in conjunction with the device known by the name Respimat~. Moreover, the present invention relates to the inhalation devices mentioned above, preferably the Respimat~, characterised in that they contain the propellant-free inhalable solutions according to the invention described hereinbefore.
The propellant-free solutions for inhalation according to the invention may also be presented as concentrates or sterile ready-to-use solutions for inhalation, in addition to the abovementioned solutions intended for administration using the Respimat.
Ready-to-use solutions for inhalation may be produced from the concentrates, for example by the addition of isotonic saline solutions. Sterile ready-to-use solutions for inhalation can be administered using energy-operated free-standing or portable nebulisers which produce inhalable aerosols by ultrasound or compressed air by the venturi principle or other principles.
Accordingly, in another aspect the present invention relates to pharmaceutical compositions in the form of propellant-free inhalable solutions as described above, which take the form of concentrates or sterile ready-to-use solutions, in conjunction with a device suitable for administering these solutions, characterised in that this device is an energy-operated free-standing or portable nebuliser which produces inhalable aerosols by ultrasound or compressed air by the venturi principle or other principles.
The following Examples serve to illustrate the present invention in more detail, although without restricting the scope of the invention to the following embodiments provided by way of example.
~
, CA 02429012 2003-04-28 Starting materials Tiotropium bromide:
The tiotropium bromide used in the following examples of formulations may be obtained as described in European Patent Application EP 418 716 A1.
The inhalable powders according to the invention may also be prepared using crystalline tiotropium bromide monohydrate. This crystalline tiotropium bromide monohydrate may be obtained by the following method.
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 tiotropium bromide-containing solution and rinsed with 4.3 kg of water. The mixture thus obtained is stirred for at least 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 at 3-5°C per 20 minutes to a temperature of 20-25°C. The apparatus is further cooled to 10-15°C
using cold water and crystallisation is completed by stirring for at least one hour. The crystals are isolated using a suction drier, the isolated crystal slurry is washed with 9 litres 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) The crystalline tiotropium bromide rnonohydrate thus obtained is micronised by known methods in order to prepare the active substance in the form of the average particle size which corresponds to the specifications according to the invention.
Salmeterol x'/ZH2S04_ Where reference is made to salmeterol x %Z H2S04 in the following embodiments, this was obtained as follows:
A suspension of 2.5 g (4.15 mmol) of salmeterol xinafoate is dissolved in 6 ml of ethanol. A solution of 0.14 ml of 98% sulphuric acid is slowly added to the suspension with stirring. It is heated to 35-40 °C until fully dissolved. Then the solution is diluted with 10 ml of diethylether and inoculated with salmeterol sulphate.
The salmeterol sulphate is suction filtered after 1.5 hours and washed with 20 ml of cold ethanol, acetone and diethylether.
1.5 g (78%) of salmeterol '/2-sulphate are obtained.
Examples of formulations A) Powders for inhalation:
1) Ingredients Ng per capsule tiotropium bromide 10.8 salmeterol x'/2 H SO 27.9 lactose 4961.3 Tota I 5000 2) Ingredients pg per capsule tiotropium bromide 21.7 salmeterol x'h H SO 55.9 lactose 4922.4 Total 5000 3) Ingredients Ng per capsule tiotropium bromide x 22.5 H O
salmeterol x %2 H SO 55.9 lactose 4921.6 Total 5000 B) Inhalable aerosols containing propellants:
1 ) Suspension aerosol:
Ingredients % by weight tiotropium bromide 0.015 salmeterol X '/2 H SO 0.066 soya lecithin 0.2 TG 11 : TG12 = 2:3 ad 100 2) Suspension aerosol:
Ingredients % by weight tiotropium bromide 0.029 salmeterol x %2 H SO 0.033 absolute ethanol 0.5 isopropyl m ristate 0.1 TG 227 ad 100 3) Solution aerosol:
Ingredients % by weight tiotropium bromide 0.042 salmeterol X ~~2 H SO 0.047 absolute ethanol 30 purified water 1.5 anhydrous citric acid 0.002 TG 134a ad 100 C) Propellant-free inhalable solutions:
1 ) Solution for use in the Respimat~:
Ingredients mg1100mL
tiotropium bromide 148.5 salmeterol x %2 H SO 276.7 benzalkonium chloride 10 sodium edetate 10 hydrochloric acid (aq) ad pH 2.9 water ad 100 mL
Use of the solution in the Respimat leads to a dosage of 10 pg per dose of 1 and 25 pg/dose of 2.
2) Solution for use in the Respimat~:
_ Ingredients mg1100mL
tiotropium bromide 148.5 salmeterol X 1/2 H SO 276.7 benzalkonium chloride 10 hydrochloric acid (aq) ad pH 2.9 water ad 100mL
Use of the solution in the Respimat leads to a dosage of 10 Ng per dose of 1 and 25 pg/dose of 2.
3) Solution for use in the Respimat~:
Ingredients mg1100mL
tiotropium bromide 297.1 salmeterol X 1/2 H SO 276.7 benzalkoniurn chloride 10 sodium edetate 10 hydrochloric acid (aq) ad pH 2.9 water ad 100 mL
Use of the solution in the Respimat leads to a dosage of 20 pg per dose of 1 and 25 Ng/dose of 2.
4) Solution for use in the Respimat~:
Ingredients mg1100mL
tiotropium bromide 297.1 salmeterol x '/Z H SO 276.7 benzalkonium chloride 10 hydrochloric acid (aq) ad pH 2.9 water ad 100mL
Use of the solution in the Respimat leads to a dosage of 20 Ng per dose of 1 and 25 ug/dose of 2.
'. CA 02429012 2003-04-28 5) Solution for use in the Respimat~:
Ingredients mgI100mL
.~ tiotropium bromide 148.5 salmeterol x'/2 H SO 1106.3 benzalkonium chloride 8 sodium edetate 50 hydrochloric acid (aq) ad pH 2.5 water ad 100mL
Use of the solution in the Respimat leads to a dosage of 10 pg per dose of 1 and 100 pg/dose of 2.
6) Solution for use in the Respimat~:
Ingredients mg/100mL
tiotropium bromide 1.5 salmeterol x'/2 H SO 276.7 benzalkonium chloride 8 sodium edetate 10 hydrochloric acid (aq) ad pH 2.5 water ad 100mL
Use of the solution in the Respimat leads to a dosage of 0.1 pg per dose of 1 and 25 pg/dose of 2.
Ingredients mg/100mL
tiotropium bromide 1.5 salmeterol x'/2 H SO 276.7 benzalkonium chloride 8 sodium edetate 10 hydrochloric acid (aq) ad pH 2.5 water ad 100mL
Use of the solution in the Respimat leads to a dosage of 0.1 pg per dose of 1 and 25 pg/dose of 2.
7) Solution for use in the Respimat~:
Ingredients mg1100mL
_ 14.9 tiotropium bromide salmeterol x'h H SO 1106.32 benzalkonium chloride 10 sodium edetate 50 hydrochloric acid (aq) ad pH 3.5 water ad 100mL
~ , . CA 02429012 2003-04-28 Use of the solution in the Respimat leads to a dosage of 1 pg per dose of 1 and 100 Ng/dose of 2.
Ingredients mg1100mL
_ 14.9 tiotropium bromide salmeterol x'h H SO 1106.32 benzalkonium chloride 10 sodium edetate 50 hydrochloric acid (aq) ad pH 3.5 water ad 100mL
~ , . CA 02429012 2003-04-28 Use of the solution in the Respimat leads to a dosage of 1 pg per dose of 1 and 100 Ng/dose of 2.
8) Solution for use in the Respimat~:
Ingredients mgI100mL
tiotropium bromide 1486.1 salmeterol X ~~2 H SO 1106.32 benzalkonium chloride 10 sodium edetate 10 hydrochloric acid (aq) ad pH 3.5 water ad 100mL
Use of the solution in the Respimat leads to a dosage of 100 pg per dose of 1 and 100 Ngldose of 2.
Ingredients mgI100mL
tiotropium bromide 1486.1 salmeterol X ~~2 H SO 1106.32 benzalkonium chloride 10 sodium edetate 10 hydrochloric acid (aq) ad pH 3.5 water ad 100mL
Use of the solution in the Respimat leads to a dosage of 100 pg per dose of 1 and 100 Ngldose of 2.
9) Concentrated solution:
Ingredients mg1100mL
tiotropium bromide 1486.1 salmeterol X ~~2 H SO 11063.2 benzalkonium chloride 20 sodium edetate 100 hydrochloric acid (aq) ad pH 3.5 water ad 100mL
Ingredients mg1100mL
tiotropium bromide 1486.1 salmeterol X ~~2 H SO 11063.2 benzalkonium chloride 20 sodium edetate 100 hydrochloric acid (aq) ad pH 3.5 water ad 100mL
Claims (34)
1) Pharmaceutical composition, characterised in that it contains one or more tiotropium salts (1) combined with one or more salmeterol salts (2), optionally in the form of the enantiomers, mixtures of enantiomers or in the form of the racemates thereof, optionally in the form of the solvates or hydrates and optionally together with a pharmaceutically acceptable excipient.
2) Pharmaceutical composition according to claim 1, characterised in that the active substances 1 and 2 are contained either together in a single preparation or in two separate preparations.
3) Pharmaceutical composition according to one of claims 1 or 2, characterised in that 1 is contained in the form of the chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methylsulphate, preferably in the form of the bromide.
4) Pharmaceutical composition according to one of claims 1 to 3, characterised in that 2 is selected from the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, xinafonic acid or maleic acid, with the proviso that 2 cannot denote salmeterol xinafoate if 1 denotes tiotropium bromide.
5) Pharmaceutical composition according to claim 4, characterised in that 2 is selected from the salts hydrochloride, hydrobromide, sulphate, phosphate and methanesulphonate, preferably from hydrochloride and sulphate.
6) Pharmaceutical composition according to one of claims 1 to 5, characterised in that the ratios by weight of tiotropium 1' to salmeterol 2' are in a range from 1:300 to 30:1, preferably from 1:230 to 20:1.
7) Pharmaceutical composition according to one of claims 1 to 6, characterised in that a single administration corresponds to a dosage of the active substance combination 1' and 2' of from 0.01 to 1000 µg, preferably from 0.1 to 200 µg.
8) Pharmaceutical composition according to one of claims 1 to 7, characterised in that it is in the form of a preparation suitable for inhalation.
9) Pharmaceutical composition according to claim 8, characterised in that it is a preparation selected from among the inhalable powders, metering aerosols containing propellant and propellant-free solutions for inhalation.
10) Pharmaceutical composition according to claim 9, characterised in that it is an inhalable powder which contains 1 and 2 in admixture with suitable physiologically harmless adjuvants selected from among monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, salts, or mixtures of these adjuvants with one another.
11) Inhalable powders according to claim 10, characterised in that the adjuvant has a maximum mean particle size of up to 250µm, preferably between 10 and 150µm.
12) Capsules, characterised in that they contain powders for inhalation according to claim 10 or 11.
13) Pharmaceutical composition according to claim 9, characterised in that it is an inhalable powder which contains only the active substances 1 and 2 as its ingredients.
14) Pharmaceutical composition according to claim 9, characterised in that it is an inhalable aerosol containing propellant, which contains 1 and 2 in dissolved or dispersed form.
15) Inhalable aerosol containing propellant according to claim 14, characterised in that it contains, as propellant gas, hydrocarbons such as n-propane, n-butane or isobutane or halohydrocarbons such as chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
16) Inhalable aerosol containing propellant according to claim 15, characterised in that the propellent gas is TG11, TG12, TG134a, TG227 or mixtures thereof, preferably TG134a, TG227 or a mixture thereof.
17) Inhalable aerosol containing propellant according to claim 14, 15 or 16, characterised in that it optionally contains one or more other ingredients selected from among cosolvents, stabilisers, surfactants, antioxidants, lubricants and agents for adjusting the pH.
18) Inhalable aerosol containing propellant according to one of claims 14 to 17, characterised in that it may contain up to 5 % by weight of active substance 1' and/or 2'.
19) Pharmaceutical composition according to claim 9, characterised in that it is a propellant-free inhalable solution which contains water, ethanol or a mixture of water and ethanol as solvent.
20) Inhalable solution according to claim 19, characterised in that the pH of the solution is 2 - 7, preferably 2 - 5.
21) Inhalable solution according to claim 20, characterised in that the pH is adjusted by means of an acid selected from among hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and propionic acid or mixtures thereof.
22) Inhalable solution according to one of claims 19 to 21, characterised in that it optionally contains other co-solvents and/or adjuvants.
23) Inhalable solution according to claim 22, characterised in that it contains, as co-solvents, ingredients which contain hydroxyl groups or other polar groups, e.g. alcohols - particularly isopropylalcohol, glycols - particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
24) Solution for inhalation according to one of claims 22 or 23, characterised in that they contain as adjuvants surfactants, stabilisers, complexing agents, antioxidants and/or preservatives, flavourings, pharmacologically harmless salts and/or vitamins.
25) Solutions for inhalation according to claim 24, characterised in that they contain editic acid or a salt of editic acid, preferably sodium edetate, as complexing agent.
26) Solutions for inhalation according to claim 24 or 25, characterised in that they contain as antioxidants compounds selected from among ascorbic acid, vitamin A, vitamin E and tocopherols.
27) Solutions for inhalation according to claim 24, 25 or 26, characterised in that they contain as preservatives compounds selected from among cetylpyridinium chloride, benzalkonium chloride, benzoic acid and benzoates.
28) Solutions for inhalation according to one of claims 22 to 27, characterised in that they contain only benzalkonium chloride and sodium edetate in addition to the active substances 1 and 2 and the solvent.
29) Solutions for inhalation according to one of claims 22 to 27, characterised in that they contain only benzalkonium chloride in addition to the active substances 1 and 2 and the solvent.
30) Solutions for inhalation according to one of claims 19 to 29, characterised in that they are concentrates or sterile ready-to-use solutions for inhalation.
31) Use of an inhalable solution according to one of claims 19 to 29 for nebulising in an inhaler according to WO 91/14468 or an inhaler as described in Figures 6a and 6b of WO 97/12687.
32) Use of an inhalable solution according to claim 30 for nebulising in an energy-operated free-standing or portable nebuliser which produces inhalable aerosols by means of ultrasound or compressed air according to the venturi principle or other principles.
33) Use of a composition according to one of claims 1 to 30 for preparing a medicament for the treatment of respiratory diseases.
34) Use according to claim 33 for preparing a medicament for the treatment of asthma or COPD.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10056104A DE10056104A1 (en) | 2000-11-13 | 2000-11-13 | Drug compositions useful for treatment of respiratory diseases, especially asthma and chronic obstructive pulmonary disease comprises tiotropium salts and salmeterol salts |
| DE10056104.7 | 2000-11-13 | ||
| PCT/EP2001/012962 WO2002038154A1 (en) | 2000-11-13 | 2001-11-09 | Novel medicament compositions based on tiotropium salts and on salmeterol salts |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2429012A1 true CA2429012A1 (en) | 2002-05-16 |
Family
ID=7663071
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002429012A Abandoned CA2429012A1 (en) | 2000-11-13 | 2001-11-09 | New pharmaceutical compositions based on tiotropium salts and salts of salmeterol |
Country Status (32)
| Country | Link |
|---|---|
| EP (3) | EP1808174A1 (en) |
| JP (2) | JP4282322B2 (en) |
| KR (2) | KR100940752B1 (en) |
| CN (1) | CN1678318A (en) |
| AT (2) | ATE362761T1 (en) |
| AU (3) | AU2791002A (en) |
| BG (1) | BG107781A (en) |
| BR (1) | BR0115226A (en) |
| CA (1) | CA2429012A1 (en) |
| CY (1) | CY1106774T1 (en) |
| CZ (1) | CZ20031444A3 (en) |
| DE (3) | DE10056104A1 (en) |
| DK (2) | DK1335728T3 (en) |
| EA (1) | EA007904B1 (en) |
| EC (1) | ECSP034571A (en) |
| EE (1) | EE200300228A (en) |
| ES (2) | ES2287629T3 (en) |
| HR (1) | HRP20030378A2 (en) |
| HU (1) | HUP0301447A3 (en) |
| IL (2) | IL155718A0 (en) |
| MX (1) | MXPA03004164A (en) |
| NO (1) | NO20032111L (en) |
| NZ (1) | NZ526400A (en) |
| PL (1) | PL205330B1 (en) |
| PT (2) | PT1335728E (en) |
| RS (2) | RS50286B (en) |
| SG (1) | SG167657A1 (en) |
| SI (2) | SI1335728T1 (en) |
| SK (2) | SK286950B6 (en) |
| UA (1) | UA74853C2 (en) |
| WO (1) | WO2002038154A1 (en) |
| ZA (1) | ZA200302921B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006510680A (en) * | 2002-12-16 | 2006-03-30 | ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト | HFC solution formulation containing tiotropium |
| AU2004285683B2 (en) * | 2003-11-03 | 2011-04-21 | Boehringer Ingelheim International Gmbh | Method for producing tiotropium salts, tiotropium salts and pharmaceutical formulations, containing the same |
| 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 |
| US9737520B2 (en) | 2011-04-15 | 2017-08-22 | Almirall, S.A. | Aclidinium for use in improving the quality of sleep in respiratory patients |
| US10085974B2 (en) | 2008-03-13 | 2018-10-02 | Almirall, S.A. | Dosage and formulation |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7214687B2 (en) | 1999-07-14 | 2007-05-08 | Almirall Ag | Quinuclidine derivatives and medicinal compositions containing the same |
| DE60017450T2 (en) * | 1999-11-23 | 2006-03-02 | Glaxo Group Ltd., Greenford | PHARMACEUTICAL FORMULATIONS CONTAINING SALMETEROL |
| EP1429768B1 (en) * | 2001-09-14 | 2016-11-16 | Boehringer Ingelheim Pharma GmbH & Co.KG | Novel medicaments for inhalation |
| US7244415B2 (en) | 2002-03-28 | 2007-07-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | HFA suspension formulations of an anhydrate |
| DE10214263A1 (en) * | 2002-03-28 | 2003-10-16 | Boehringer Ingelheim Pharma | HFA suspension formulations containing an anticholinergic |
| US7311894B2 (en) | 2002-03-28 | 2007-12-25 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | HFA suspension formulations containing an anticholinergic |
| DE10256080A1 (en) * | 2002-11-29 | 2004-06-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Combination medicinal product for inhalation containing tiotropium |
| US7250426B2 (en) | 2002-11-29 | 2007-07-31 | Boehringer Ingelheim Pharma Gmbh & Co Kg | Tiotropium-containing pharmaceutical combination for inhalation |
| 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 |
| DE10345065A1 (en) * | 2003-09-26 | 2005-04-14 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Aerosol formulation for inhalation containing an anticholinergic |
| ES2350981T3 (en) * | 2003-11-03 | 2011-01-28 | Boehringer Ingelheim International Gmbh | PROCEDURE FOR THE PREPARATION OF NEW SALTS OF TIOTROPY. |
| PL1905451T3 (en) * | 2004-05-31 | 2010-05-31 | Almirall Sa | Combinations comprising antimuscarinic agents and corticosteroids |
| ES2257152B1 (en) * | 2004-05-31 | 2007-07-01 | Laboratorios Almirall S.A. | COMBINATIONS THAT INCLUDE ANTIMUSCARINIC AGENTS AND BETA-ADRENERGIC AGONISTS. |
| CN101166738B (en) | 2005-05-02 | 2011-06-01 | 贝林格尔·英格海姆国际有限公司 | Novel crystalline forms of tiotropium bromide |
| 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 |
| ES2298049B1 (en) | 2006-07-21 | 2009-10-20 | Laboratorios Almirall S.A. | PROCEDURE FOR MANUFACTURING BROMIDE OF 3 (R) - (2-HIDROXI-2,2-DITIEN-2-ILACETOXI) -1- (3-PHENOXIPROPIL) -1-AZONIABICICLO (2.2.2) OCTANO. |
| US20120220557A1 (en) * | 2011-02-17 | 2012-08-30 | Chiesi Farmaceutici S.P.A. | Liquid propellant-free formulation comprising an antimuscarinic drug |
| JP6335798B2 (en) * | 2012-02-28 | 2018-05-30 | 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 | New propellant-containing tiotropium formulation |
| WO2015065222A1 (en) * | 2013-10-28 | 2015-05-07 | Шолекс Девелопмент Гмбх | Pharmaceutical inhaled drug with micronized tiotropium bromide as active ingredient for the treatment of bronchial asthma and chronic obstructive pulmonary disease and method for producing same |
| TW201835041A (en) | 2017-02-17 | 2018-10-01 | 印度商托仁特生技有限公司 | Compounds with Beta-Adrenergic Agonist and Antimuscarinic Activity |
| WO2019142214A1 (en) * | 2018-01-19 | 2019-07-25 | Cipla Limited | Pharmaceutical composition comprising tiotropium for inhalation |
| CN116173025A (en) * | 2018-07-26 | 2023-05-30 | 四川海思科制药有限公司 | Aerosol pharmaceutical composition containing glycopyrronium salt and indacaterol salt, and preparation method and application thereof |
| CN116196298A (en) * | 2018-07-26 | 2023-06-02 | 四川海思科制药有限公司 | Aerosol pharmaceutical composition containing glycopyrronium salt and preparation method and application thereof |
| US11826382B2 (en) | 2020-05-01 | 2023-11-28 | Tygrus, LLC | Therapeutic material with low pH and low toxicity active against at least one pathogen for addressing patients with respiratory illnesses |
| WO2022119661A1 (en) * | 2020-12-04 | 2022-06-09 | Tygrus, LLC | THERAPEUTIC MATERIAL WITH LOW pH AND LOW TOXICITY ACTIVE AGAINST AT LEAST ONE PATHOGEN FOR ADDRESSING PATIENTS WITH RESPIRATORY ILLNESSES |
| US11642372B2 (en) | 2020-05-01 | 2023-05-09 | Tygrus, LLC | Therapeutic material with low pH and low toxicity active against at least one pathogen for addressing patients with respiratory illnesses |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ509328A (en) * | 1998-07-24 | 2002-11-26 | Jago Res A | Medicinal aerosol formulations |
| DE19835346A1 (en) * | 1998-08-05 | 2000-02-10 | Boehringer Ingelheim Pharma | Two-part capsule for pharmaceutical preparations for powder inhalers |
| DE19847971A1 (en) * | 1998-10-17 | 1999-09-02 | Schiering | Filter fire occurrence prevention method |
| DE19847970A1 (en) * | 1998-10-17 | 2000-04-20 | Boehringer Ingelheim Pharma | Stable concentrated liquid formulation of inhalable drug, e.g. formoterol or salbutamol, in solution or suspension medium, used after dilution for treatment of respiratory disorders by inhalation |
| 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 |
| DE19961300A1 (en) * | 1999-12-18 | 2001-06-21 | Asta Medica Ag | Storage system for medicinal products in powder form and inhaler equipped with them |
-
2000
- 2000-11-13 DE DE10056104A patent/DE10056104A1/en not_active Withdrawn
-
2001
- 2001-09-11 UA UA2003065486A patent/UA74853C2/en unknown
- 2001-11-09 KR KR1020087020177A patent/KR100940752B1/en not_active IP Right Cessation
- 2001-11-09 AT AT04028508T patent/ATE362761T1/en active
- 2001-11-09 SI SI200130347T patent/SI1335728T1/en unknown
- 2001-11-09 JP JP2002540737A patent/JP4282322B2/en not_active Expired - Lifetime
- 2001-11-09 EP EP07104722A patent/EP1808174A1/en not_active Withdrawn
- 2001-11-09 RS YUP-355/03A patent/RS50286B/en unknown
- 2001-11-09 DE DE50105729T patent/DE50105729D1/en not_active Expired - Lifetime
- 2001-11-09 EP EP01989446A patent/EP1335728B1/en not_active Expired - Lifetime
- 2001-11-09 PL PL365989A patent/PL205330B1/en not_active IP Right Cessation
- 2001-11-09 KR KR1020037006434A patent/KR100886094B1/en not_active IP Right Cessation
- 2001-11-09 IL IL15571801A patent/IL155718A0/en unknown
- 2001-11-09 CZ CZ20031444A patent/CZ20031444A3/en unknown
- 2001-11-09 BR BR0115226-2A patent/BR0115226A/en active Pending
- 2001-11-09 AU AU2791002A patent/AU2791002A/en active Pending
- 2001-11-09 CN CNA018187773A patent/CN1678318A/en active Pending
- 2001-11-09 EP EP04028508A patent/EP1514546B1/en not_active Expired - Lifetime
- 2001-11-09 EE EEP200300228A patent/EE200300228A/en unknown
- 2001-11-09 PT PT01989446T patent/PT1335728E/en unknown
- 2001-11-09 DK DK01989446T patent/DK1335728T3/en active
- 2001-11-09 MX MXPA03004164A patent/MXPA03004164A/en active IP Right Grant
- 2001-11-09 SK SK50015-2009A patent/SK286950B6/en not_active IP Right Cessation
- 2001-11-09 SK SK741-2003A patent/SK286939B6/en not_active IP Right Cessation
- 2001-11-09 CA CA002429012A patent/CA2429012A1/en not_active Abandoned
- 2001-11-09 AT AT01989446T patent/ATE291428T1/en active
- 2001-11-09 WO PCT/EP2001/012962 patent/WO2002038154A1/en active Application Filing
- 2001-11-09 DE DE50112535T patent/DE50112535D1/en not_active Expired - Lifetime
- 2001-11-09 DK DK04028508T patent/DK1514546T3/en active
- 2001-11-09 AU AU2002227910A patent/AU2002227910B2/en not_active Ceased
- 2001-11-09 ES ES04028508T patent/ES2287629T3/en not_active Expired - Lifetime
- 2001-11-09 EA EA200300503A patent/EA007904B1/en not_active IP Right Cessation
- 2001-11-09 PT PT04028508T patent/PT1514546E/en unknown
- 2001-11-09 NZ NZ526400A patent/NZ526400A/en unknown
- 2001-11-09 SG SG200505149-5A patent/SG167657A1/en unknown
- 2001-11-09 ES ES01989446T patent/ES2240549T3/en not_active Expired - Lifetime
- 2001-11-09 SI SI200130751T patent/SI1514546T1/en unknown
- 2001-11-09 HU HU0301447A patent/HUP0301447A3/en unknown
- 2001-11-09 RS RSP-2009/0105A patent/RS20090105A/en unknown
-
2003
- 2003-04-14 ZA ZA200302921A patent/ZA200302921B/en unknown
- 2003-04-28 EC EC2003004571A patent/ECSP034571A/en unknown
- 2003-05-01 IL IL155718A patent/IL155718A/en not_active IP Right Cessation
- 2003-05-08 BG BG107781A patent/BG107781A/en active Pending
- 2003-05-12 HR HR20030378A patent/HRP20030378A2/en not_active Application Discontinuation
- 2003-05-12 NO NO20032111A patent/NO20032111L/en not_active Application Discontinuation
-
2004
- 2004-12-08 JP JP2004355226A patent/JP4282594B2/en not_active Expired - Lifetime
-
2007
- 2007-05-22 AU AU2007202303A patent/AU2007202303B2/en not_active Ceased
- 2007-07-30 CY CY20071101011T patent/CY1106774T1/en unknown
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10034867B2 (en) | 1999-07-14 | 2018-07-31 | Almirall, S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
| 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 |
| US9687478B2 (en) | 1999-07-14 | 2017-06-27 | Almirall, S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
| US10588895B2 (en) | 1999-07-14 | 2020-03-17 | Almirall, S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
| JP2006510680A (en) * | 2002-12-16 | 2006-03-30 | ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト | HFC solution formulation containing tiotropium |
| AU2004285683B2 (en) * | 2003-11-03 | 2011-04-21 | Boehringer Ingelheim International Gmbh | Method for producing tiotropium salts, tiotropium salts and pharmaceutical formulations, containing the same |
| AU2004285683C1 (en) * | 2003-11-03 | 2011-09-08 | Boehringer Ingelheim International Gmbh | Method for producing tiotropium salts, tiotropium salts and pharmaceutical formulations, containing the same |
| US9254262B2 (en) | 2008-03-13 | 2016-02-09 | Almirall, S.A. | Dosage and formulation |
| US10085974B2 (en) | 2008-03-13 | 2018-10-02 | Almirall, S.A. | Dosage and formulation |
| US11000517B2 (en) | 2008-03-13 | 2021-05-11 | Almirall, S.A. | Dosage and formulation |
| US9737520B2 (en) | 2011-04-15 | 2017-08-22 | Almirall, S.A. | Aclidinium for use in improving the quality of sleep in respiratory patients |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2002227910B2 (en) | Novel medicament compositions based on tiotropium salts and on salmeterol salts | |
| CA2431565C (en) | Pharmaceutical compositions based on anticholinergics and ciclesonide | |
| CA2440699C (en) | Compounds for treating inflammatory diseases | |
| US20070128125A1 (en) | Pharmaceutical Compositions Based on Tiotropium Salts and Salts of Salmeterol | |
| CA2455167C (en) | New pharmaceutical compositions based on anticholinergics, corticosteroids and betamimetics | |
| US6608054B2 (en) | Pharmaceutical compositions based on anticholinergics and endothelin antagonists | |
| US20120189556A1 (en) | Pharmaceutical compositions based on anticholinergics and corticosteroids | |
| CA2481468C (en) | Medicaments containing betamimetic drugs and a novel anticholinesterase drug | |
| US20030018019A1 (en) | Pharmaceutical compositions based on anticholinergics, corticosteroids and betamimetics | |
| CA2733294C (en) | Pharmaceutical combination of a tiotropium salt and ciclesonide | |
| CA2434872A1 (en) | Medicament compositions with negligible side-effects containing betamimetics | |
| US20040161386A1 (en) | Pharmaceutical compositions based on anticholinergic and dopamine agonists | |
| EP1651224B1 (en) | Medicaments for inhalation comprising an anticholinergic and a betamimetic | |
| CA2582207A1 (en) | Inhalation medicament containing an anticholinesterase drug, salmeterol and a steroid selected from the ciclesonide or mometasone furoate group | |
| EP1551405A1 (en) | Tiotropium salts for reducing respiratory mortality rate | |
| US20020193394A1 (en) | Compounds for treating inflammatory diseases | |
| ZA200406751B (en) | Medicaments containing steroids and a novel anticholinesterase drug | |
| CA2436510A1 (en) | Pharmaceutical compositions with few side effects | |
| AU2004262901B2 (en) | Combination of an anticholinergic and a steroid and its use to treat respiratory disorders by inhalation | |
| CA2441964C (en) | New pharmaceutical compositions based on anticholinergics and endothelin antagonists | |
| CA2436537C (en) | Pharmaceutical compositions comprising tiotropium salts and antihistamines | |
| CA2582153A1 (en) | Inhalation medicament containing a novel anticholinesterase drug, formoterol and a steroid | |
| CA2492026A1 (en) | New pharmaceutical compositions based on new anticholinergics and pde-iv inhibitors | |
| CA2527178A1 (en) | New long-acting drug combinations for the treatment of respiratory complaints | |
| CA2430592C (en) | New pharmaceutical compositions based on anticholinergics and dopamine agonists |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |