SK286950B6 - A pharmaceutical composition comprising one or more tiotropium salts in combination with one or more salts of salmeterol, in the form of an inhalation powder and its use - Google Patents

Abstract

A pharmaceutical composition comprising one or more tiotropium salts 1 in combination with one or more salts of salmeterol 2, optionally in the form of their enantiomers, mixtures of enantiomers or in the form of racemates, optionally in the form of solvates or hydrates, as well as optionally together with a pharmaceutically acceptable excipient, and its use in the treatment of respiratory diseases.

Description

The present invention relates to pharmaceutical compositions in the form of an inhalable powder based on tiotropium salts and salmeterol salts and their use in the treatment of respiratory diseases.

BACKGROUND OF THE INVENTION

The compound tiotropium bromide, a tiotropium salt, is known from European patent application EP 418 716 A1 and has the following chemical formula:

This compound may also be designated by its chemical name (1α, 2β, 4β, 5α, 7β) -7 - [(hydroxy-di-2-thienylacetyl) oxy] -9,9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1.02,4] -nonane bromide and has valuable pharmacological properties. In the present invention, the term tiotropium is understood as a reference to a free cation.

This compound, as well as other tiotropium salts, is a highly effective anti-cholinergic and may therefore be therapeutically useful for the treatment of asthma or COPD (chronic obstructive pulmonary disease).

The application of tiotropium salts is preferably carried out by inhalation. It is also possible to use suitable inhalation powders which are administered filled into suitable capsules (inhalers) by means of appropriate powder inhalers. Alternatively, inhalation may also be accomplished by administration of suitable inhalation aerosols. These also include powdered inhalation aerosols which contain, for example, HFA134a, HFA227 or a mixture thereof as propellant. Inhalation administration can further be carried out with suitable tiotropium salt solutions.

SUMMARY OF THE INVENTION

Surprisingly, it has been found that an unexpected advantageous therapeutic effect, in particular a synergistic effect in the treatment of inflammatory or obstructive airways diseases, was observed when one or more salts of tiotropium (1) were used in combination with one or more salmeterol salts (2).

Thus, for example, it is possible to greatly reduce unwanted side effects in humans, which are often observed with β-mimetics such as salmeterol. The central side effect of β-mimetics is, for example, general agitation, arousal, insomnia, fear, tremors, sweating and headaches.

The term tiotropium in the present invention refers to a free cation (I '). Reference to salmeterol is to be understood in the context of the present invention as a reference to the free base (2 ').

Surprisingly, the active compound combinations according to the invention are further characterized by a rapid onset of action as well as a long duration of action. This is of great importance for the patient's satisfaction, since on the one hand, the application is rapidly improved after administration and, on the other hand, once-a-day administration is sufficient due to the long efficacy. Said effects are also observed when co-administered in one single formulation of the active substances as well as in the sequential application of both active substances in separate formulations. According to the invention, simultaneous application of both active ingredient components in a single formulation is preferred.

Accordingly, the present invention provides a pharmaceutical composition comprising one or more salts of tiotropium (1) in combination with one or more salts of salmeterol (2), optionally in the form of their enantiomers, mixtures of enantiomers or in the form of their racemates, optionally in the form of solvates or hydrates is an inhalable powder comprising Compound 1 and Compound 2 in admixture with a suitable physiologically acceptable excipient, having an average particle size of 10 to 150 µmη.

Furthermore, the present invention relates to a pharmaceutical composition comprising, in addition to therapeutically effective amounts of Compound 1 and Compound 2, a pharmaceutically acceptable excipient. One embodiment of the present invention pertains to a pharmaceutical composition which, in addition to therapeutically effective amounts of Compound 1 and Compound 2, contains no pharmaceutically acceptable excipient.

The present invention further relates to the use of Compound 1 and Compound 2 for the manufacture of a pharmaceutical composition comprising therapeutically effective amounts of Compound 1 and Compound 2 for the treatment of inflammatory or obstructive airways diseases, particularly asthma or COPD, by simultaneous or sequential administration.

The present invention is further directed to the simultaneous or sequential use of therapeutically effective doses of a combination of said pharmaceutical compositions comprising Compound 1 and Compound 2 for the treatment of inflammatory or obstructive airways diseases, particularly asthma or COPD.

The salts of tiotropium 1 useful in the present invention are compounds which contain, in addition to tiotropium, chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate or methylsulfate as counterion (anion). Within the scope of the present invention, of all tiotropium salts, methanesulfonate, chloride, bromide or iodide are preferred, with methanesulfonate or bromide being of particular importance. According to the invention, tiotropium bromide is of particular importance.

Salmeterol 2 salts according to the invention are pharmaceutically acceptable salts selected from salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, filmaric acid, succinic acid, lactic acid, citric acid, tartaric acid, xinafonic acid or with maleic acid, provided that compound 2 cannot be salmeterol xinafonan when compound 1 is tiotropium bromide. Optionally, mixtures of the acids mentioned may also be used to produce salts of salmeterol.

Salmeterol 2 salts according to the invention are preferably selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate and methanesulfonate. Particularly preferred are salts of compound 2 selected from hydrochloride and sulfate, of which sulfates are most preferred. According to the invention, salmeterol x V2H2SO4 is of particular importance.

In the active compound combinations according to the invention of compound 1 and compound 2, the components, compound 1 and compound 2, may be present in the form of their enantiomers, mixtures of enantiomers or in the form of racemates.

The ratios in which both the active compounds Compound 1 and the compound 2 can be used in the active compound combinations according to the invention are variable. The active compounds compound 1 and compound 2 may optionally exist in the form of their solvates or hydrates. Depending on the choice of salt of compound 1 or compound 2, the weight ratios applicable in the present invention vary based on different molecular weights of different salt forms. The following weight ratios therefore based on tiotropium cation 1 'as well as salmeterol 2' free base. The active compound combinations according to the invention may contain compound l 'and compound 2' in weight ratios from 1: 300 to 30: 1, more preferably from 1: 230 to 20: 1, particularly preferably from: 150 to 10: 1, particularly preferably from 1: 300 to 20: 1. 1: 50 to 5: 1, most preferably from 1:35 to 2: 1. According to the invention, pharmaceutical compositions comprising a combination of compound 1 'and compound 2' in a weight ratio of from 1: 25 to 1: 1, more preferably from 1: 10 to 1: 2, most preferably from 1: 5 to 1: 2.5.

By way of example and without limiting the scope of the invention, preferred combinations of compound 1 and a compound of the invention may contain tiotropium 1 'and salmeterol 2' in the following weight ratios: 1:40;

: 20; 1: 11.1; 1: 10; 1: 5.6; 1: 5; 1: 2.8; 1: 2.5 ;, 1: 1.4; 1: 1.25; 1.44: 1; 1.6: 1st

Administration of a pharmaceutical composition of the invention comprising a combination of compound 1 and compound is usually carried out by dosing tiotropium 1 'and salmeterol 2' in a combined dose of 0.01 to 10,000 pg, more preferably 0.1 to 2000 pg, particularly preferably 1 to 2 pg. 1000 pg, particularly preferably from 5 to 500 pg, even more preferably according to the invention from 10 to 200 pg, even more preferably from 20 to 100 pg, most preferably from 30 to 70 pg.

For example, the combinations of Compound 1 and Compound 2 of the invention contain an amount of tiotropium 1 'and salmeterol 2' such that the single dose is 30 pg, 35 pg, 45 pg, 55 pg, 60 pg, 65 pg, 90 pg, 105 pg in a single dose. 110 pg, 140 pg or the like. In these dosage ranges, the active substances 1 'and 2' are contained in the stated weight ratios.

By way of example and without limiting the scope of the invention, the combinations of Compound 1 and Compound 2 of the invention may contain such amounts of tiotropium 1 'and salmeterol 2' that 5 µg of Compound 1 'and 25 µg of Compound 2', 5 µg are administered in a single dose. Compound I 'and 50 µg Compound 2', 5 µg Compound I 'and 100 µg Compound 2', 5 µg Compound I 'and 200 µg Compound I', 10 µg Compound I 'and 25 µg Compound I', 10 µg Compound I 'and 50 µg Compound 2 ', 10 µg of compound 1', 100 µg of compound 2 ', 10 µg of compound 1' and 200 µg of compound 2 ', 18 µg of compound 1' and 25 µg of compound 1 ', 18 µg of compound 1' and 50 µg of compound 2 ' and 100 pg of 2 ', 18 pg of 1' and 200 pg of 2 ', 20 pg of 1' and 25 pg of 2 ', 20 pg of 1' and 50 pg of 2 ', 20 pg of 1' and 100 pg of 2 ' , 20 pg of Compound 1 'and 200 pg of Compound 2', 36 pg of Compound 1 'and 25 pg of Compound 2', 36 pg china 1 'and 50 pg of 2', 36 pg of 1 'and 100 pg of 2', 36 pg of 1 'and 200 pg of 2', 40 pg of 1 'and 25 pg of 2', 40 pg of 1 'and 50 pg of 2 2 ', 40 µg of 1' and 100 µg of 2 'or 40 µg of 1' and 200 µg of 2 '.

When a preferred combination according to the invention is used as a combination of active ingredients consisting of compound and compound 2, in which compound 1 is tiotropium bromide and compound 2 is salmeterol x ΆH ₂ SO ₄ , the amounts of active ingredients I 'and 2 'applied in a single dose to the amounts of compound 1 and compound 2 administered in a single dose: 6 µg of compound 1 and

27.9 pg of compound 2, 6 pg of compound 1 and 55.9 pg of compound 2, 6 pg of compound 1 and 111.8 pg of compound 2, 6 pg of compound 1 and 223.6 pg of compound 2, 12 pg of compound 1 and 27, 9 pg of compound 2, 12 pg of compound 1 and 55.9 pg of compound 2, 12 pg of compound 1 and 111.8 pg of compound 2, 12 pg of compound 1 and 223.6 pg of compound 2, 21.7 pg of compound 1 and 27, 9 pg of compound 2, 21.7 pg of compound 1 and 55.9 pg of compound 2.21.7 pg of compound 1 and 111.8 pg of compound 2, 21.7 pg of compound 1 and 223.6 pg of compound 2, 24.1 pg of compound 1 and 27.9 pg of compound 2, 24.1 pg of compound 1 and 55.9 pg of compound 2, 24.1 pg of compound 1 and 111.8 pg of compound 2, 24.1 pg of compound 1 and

223.6 pg of compound 2, 43.3 pg of compound 1 and 27.9 pg of compound 2, 43.3 pg of compound 1 and 55.9 pg of compound 2,

43.3 pg of compound 1 and 111.8 pg of compound 2.43.3 pg of compound 1 and 223.6 pg of compound 2.48.1 pg of compound 1 and 27.9 pg of compound 2.48.1 pg of compound 1 and 55 , 9 pg of compound 2.48.1 pg of compound 1 and 111.8 pg of compound 2 or 48.1 pg of compound 1 and 223.6 pg of compound 2.

If, for example, tiotropium bromide monohydrate is used as compound 1 in the combination of compound 1 and compound 2 preferred according to the invention, in which compound 2 is salmeterol x Ά H ₂ SO ₄ , the above amounts of active ingredients I 'and 2' are given as a single dose. amounts of compound 1 and compound 2 administered in a single dose: 6.2 pg of compound 1 and 27.9 pg of compound 2, 6.2 pg of compound 1 and 55.9 pg of compound 2, 6.2 pg of compound 1 and 111.8 pg Compound 2, 6.2 pg of Compound 1 and 223.6 pg of Compound 2, 12.5 pg of Compound 1 and 27.9 pg of Compound 2, 12.5 pg of Compound 1 and 55.9 pg of Compound 2, 12.5 pg of Compound 1 and 111.8 pg of compound 2, 12.5 pg of compound 1 and 223.6 pg of compound 2, 22.5 pg of compound 1 and

27.9 pg of compound 2, 22.5 pg of compound 1 and 55.9 pg of compound 2, 22.5 pg of compound 1 and 111.8 pg of compound 2,

22.5 pg of compound 1 and 223.6 pg of compound 2, 25 pg of compound 1 and 27.9 pg of compound 2, 25 pg of compound 1, and

55.9 pg of compound 2, 25 pg of compound 1 and 111.8 pg of compound 2, 25 pg of compound 1 and 223.6 pg of compound 2, 45 pg of compound 1 and 27.9 pg of compound 2, 45 pg of compound 1 and 55.9 pg compound 2, 45 µg of compound 1 and 111.8 µg of compound 2, 45 µg of compound 1 and 223.6 µg of compound 2, 50 µg of compound 1 and 27.9 µg of compound 2, 50 µg of compound 1 and 55.9 µg of compound 2 , 50 µg of Compound 1 and 111.8 µg of Compound 2 or 50 µg of Compound 1a

223.6 pg of compound 2.

The application of the active compound combination according to the invention composed of compound 1 and compound 2 is preferably carried out by inhalation. To this end, it is necessary to prepare components 1 and 2 in a form which can be administered by inhalation. Inhalable powders are suitable as inhalation dosage forms. An inhalable powder according to the invention comprising a combination of active substances composed of compound 1 and compound 2 can exist separately from said active substances or from a mixture of said substances with physiologically acceptable excipients. Within the scope of the present invention, propellant-free inhalable solutions also include concentrates or sterile, ready-to-use inhalable solutions. The dosage forms of the invention may comprise a combination of active ingredients composed of compound 1 and compound 2 either together in one or two separate dosage forms. These dosage forms useful in the present invention will be described in detail in the following.

Inhalable powders containing the active compound combinations according to the invention composed of compound 1 and compound

The inhalable powders of the invention may contain compound 1 and compound 2 either alone or in admixture with suitable physiologically acceptable excipients.

When the active compounds Compound 1 and Compound 2 are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients can be used for the manufacture of these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose) ), oligosaccharides and polysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, xylite), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients. The use of monosaccharides or disaccharides is preferred, and the use of lactose or glucose, particularly but not exclusively, in the form of their hydrates is particularly preferred. As a particularly preferred excipient within the meaning of the invention, lactose is most preferably used as an excipient in the form of lactose monohydrate.

The excipients within the inhalable powders of the invention have a maximum mean particle size of up to 250 µm, more preferably from 10 to 150 µm, most preferably from 15 to 80 µm. Alternatively, it may be sensible to admix the finer excipient fraction with a mean particle size of from 1 to 9 µm to said excipients. The latter finer excipients are also selected from the group of useful excipients mentioned. Finally, in the manufacture of the inhalable powders according to the invention, the micronized active compounds Compound 1 and Compound 2 are admixed, preferably with a mean particle size of from 0.5 to 10 µm, particularly preferably from 1 to 6 µm. The process for producing the inhalable powders according to the invention by grinding and micronizing, as well as the subsequent mixing of the components, is known from the prior art. The inhalable powders according to the invention may exist and be administered either in the form of a single powder mixture containing both Compound 1 and Compound 2, or in the form of separate inhalable powders containing only Compound 1 and Compound 2.

The inhalable powders according to the invention can be administered using inhalers known in the art. The inhalable powders according to the invention which, in addition to compound 1 and compound 2, further comprise a physiologically acceptable excipient, can be administered, for example, by inhalers which dispense a single dose from the reservoir using a measuring chamber as described in US 4570630A or other apparatus, as described in DE 36 25 685 A. However, it is preferable to fill inhalable powders according to the invention containing, in addition to compound 1 and compound 2, physiologically acceptable excipients into capsules (so-called inhalers) which can be administered using inhalers such as described in WO 94/28958 . If the inhalable powders according to the invention are to be filled according to said preferred application into capsules (inhalers), the amount of filling may be from 1 to 30 mg, more preferably from 3 to 20 mg, most preferably from 5 to 10 mg of inhalation powder per capsule. These contain, according to the invention, either a single dose or a single dose of the compound I 'and the compound 2' mentioned above.

The following examples serve to broadly illustrate the present invention, but without limiting the scope thereof to the following exemplary embodiments.

DETAILED DESCRIPTION OF THE INVENTION

Starting materials Tiotropium bromide

The tiotropium bromide used in the following formulation examples can be obtained as described in European patent application EP 418 716 A1.

Crystalline tiotropium bromide monohydrate may also be used to produce the inhalable powder of the invention. This crystalline tiotropium bromide monohydrate can be obtained as follows.

25.7 kg of water and 15.0 kg of tiotropium bromide were mixed in a suitable reaction vessel. The mixture was heated to 80-90 ° C and stirred at a constant temperature until a clear solution was formed. Activated carbon (0.8 kg) moistened with water was soaked in 4.4 kg of water, this mixture was added to a solution containing tiotropium bromide and rinsed with 4.3 kg of water. The mixture thus obtained was stirred for a minimum of 15 minutes at 80 to 90 ° C and then filtered through a heated filter in a preheated apparatus with a jacket temperature of 70 ° C. The filter was washed with 8.6 kg of water. The capture in the apparatus was cooled to 20-25 ° C with 3-5 ° C in 20 minutes. Using water cooling, the apparatus was further cooled to 10-15 ° C and the crystallization was completed with at least one hour of additional stirring. The crystallizate was collected by suction drying, the isolated crystal slurry was washed with 9 liters of cold water (10-15 ° C) and cold acetone (10-15 ° C). The obtained crystals were dried at 25 ° C for 2 hours under a stream of nitrogen.

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

The crystalline tiotropium bromide monohydrate so obtained was micronized by known methods to give the active ingredient in the form of medium particle sizes which correspond to the specifications of the invention.

Salmeterol x '/ILSCL

In the following examples, when referring to salmeterol x 1 / 2H 2 SO 4, this is obtained as follows.

A suspension of 2.5 g (4.15 mmol) of salmeterol xinafonane was dissolved in 6 ml in ethanol. While stirring, 0.14 ml of a 98% sulfuric acid solution was added slowly to the suspension. It was heated to 35-40 ° C until completely dissolved. Subsequently, the mixture was diluted with 10 ml of diethylether and the solution was seeded with salmeterol sulfate. The salmeterol sulfate was aspirated after 1.5 hours and washed with 20 ml of cold ethanol, acetone and diethyl ether each time. 1.5 g (78%) of salmeterol Ά-sulfate were obtained.

Examples of pharmaceutical compositions

Inhalation powder

1), ____________________________________________________________________________________________________________________________________________________________

ingredients pg in one capsule tiotropium bromide 10.8 salmeterol x 'ÄEfyStýj 27.9 lactose 4,961.3 together 5000

2)

ingredients μg per capsule tiotropium bromide 21.7 salmeterol x '/ 2H 2 SO 4 55.9 lactose 4,299.4 together 5000

3)

ingredients gg in one capsule tiotropium bromide 22.5 salmeterol x 1/1 H 2 SO 4 55.9 lactose 4,921.6 together 5000

PATENT CLAIMS

Claims (10)

PATENT CLAIMS Pharmaceutical composition, characterized in that it comprises one or more salts of tiotropium (1) in combination with one or more salts of salmeterol (2), optionally in the form of their enantiomers, mixtures of enantiomers or in the form of their racemates, optionally in the form of solvates or hydrates, and being an inhalation powder comprising Compound 1 and Compound 2 in admixture with a suitable physiologically acceptable excipient, having an average particle size of 10 to 150 gm. Pharmaceutical composition according to claim 1, characterized in that compound 1 is in the form of chloride, bromide, iodide, methanesulfonate, ara-toluenesulfonate or methylsulfate, preferably in the form of bromide. A pharmaceutical composition according to any one of claims 1 or 2 wherein compound 2 is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, filmaric acid, succinic acid. , lactic acid, citric acid, xinafonic acid and maleic acid. Pharmaceutical composition according to claim 3, characterized in that compound 2 is selected from the group consisting of hydrochloric, hydrobromic, sulfuric, phosphorous methanesulfonic acid salts, preferably hydrochloric acid and sulfuric acid salts. Pharmaceutical composition according to any one of claims 1 to 4, characterized in that the weight ratios of tiotropium 1 'to salmeterol 2' are in the range from 1: 300 to 30: 1, more preferably from 1: 230 to 20: 1. Pharmaceutical composition according to any one of claims 1 to 5, characterized in that the single administration corresponds to a dose of active ingredient combination 1 'and 2' in the range from 0.01 to 1000 µg, preferably from 0.1 to 200 gg. Pharmaceutical composition according to any one of claims 1 to 6, characterized in that it is in the form of an inhalable powder which contains, together with a mixture of compound 1 and compound 2, suitable physiologically acceptable excipients selected from the group consisting of monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, salts, or mixtures of these excipients. Capsules, characterized in that they contain inhalable powders according to any one of claims 1 to 7. Use of a pharmaceutical composition according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment of respiratory diseases. Use according to claim 9 for the preparation of a medicament for the treatment of asthma or COPD.