EP2480287A2

EP2480287A2 - Dry powder combination of tiotropium

Info

Publication number: EP2480287A2
Application number: EP10787588A
Authority: EP
Inventors: Mahmut Bilgic
Original assignee: Individual
Current assignee: Individual
Priority date: 2009-09-23
Filing date: 2010-09-22
Publication date: 2012-08-01
Also published as: TR200907237A2; WO2011037550A3; WO2011037550A2

Abstract

The present invention relates to a pharmaceutical composition containing tiotropium formulated with an effective amount of a cromolyn derivative used for the treatment of respiratory disease by inhalation route.

Description

DRY POWDER COMBINATION OF TIOTROPIUM

Description

The present invention relates to a medicament. composition containing tiotropium combined with an effective amount of a cromolyn derivative which is used for the treatment of respiratory disease by inhalation route.

Tiotropium (Formula I) is an anticholinergic agent with chemical name (la, 2β, 4β, 5a, 7β)-7- [(hydroxidi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1.0²'⁴] nonane.

Tiotropium is described in European patent application EP0418716 for the first time. The patent relates to processes for preparing tiotropium, pharmaceutical compositions containing tiotropium, long-acting, strong anticholinergic activity of tiotropium and use of it in the treatment of respiratory disorders. Tiotropium is a long acting, strong anticholinergic bronchodilator administered orally for the treatment of respiratory diseases. This drug is available in the market with the trademark of "Spiriva" which consists of capsules containing tiotropium in dry powder from and it is administered by using a dry powder inhalation device called as "Handyhaler". Tiotropium antagonizes the effect of acetylcholine by blocking cholinergic muscarinic receptors. Tiotropium is separated slowly from Ml and M3 receptors that cause broncho-construction and it is separated rapidly from M2 receptors that inhibit release of acetylcholine from cholinergic nerve endings. This situation occurred in lung receptors demonstrates long acting bronchodilator activity of the drug. Inhalation route is a commonly preferred treatment method for respiratory disorders especially chronic disorders such as asthma and chronic obstructive pulmonary disorder (COPD) which threaten a large portion of the society. The reason is that drug reaches directly and rapidly to target area, accordingly lower doses of drug show desired effect by comparison with doses required for use via oral or parenteral route; and drug which is used in lower doses, show less side-effect than the drug administered via oral and parenteral route. Gastrointestinal disturbances, such as low resolution, low permeability, drug irritation, production of undesired metabolites and decrease of bioavailability depending on food, are felt in minimum level because drugs administered via inhalation route are not exposed to gastrointestinal medium. Medicament composition can be administered locally by dry powder inhalers, metered dose inhalers or nebulizer inhalers. Even though each of these different types of inhalers has advantages and disadvantages, particularly dry powder inhalers come to the forefront in terms of ease of use. However, there is still need to develop different formulations for delivering effective amount of dry powder formulations to the lungs. Lactose, which is a disaccharide, is generally used as a carrier in dry powder formulations developed for use via inhalation. The amount of lactose used is usually in the range of 10 mg to 50 mg, which is approximately 500-2500 times more than the amount of active agent, for a single dose. While the active agent has a weight in the unit of microgram, lactose has a weight in the unit of milligram. However, a large amount of lactose used as a carrier in dry powder formulation causes side effects such as coughing, throat irritation, etc. Therefore, dry powder formulations containing large amount of lactose when used by patient with allergy and/or lactose intolerance, cause symptoms such as nausea, stomach cramps, overfullness of the stomach, swelling of stomach, flatus, diarrhea, hives plaque. Additionally, 15 to 25% of each dose of the drugs administered by inhalation can reach the target area, the rest is mostly swallowed. Accordingly, dry powder inhalation formulations containing tiotropium and pharmaceutically acceptable salts thereof need to be improved in terms of safety and efficacy.

Salts of cromoglicic acid and nedocromil are used for the treatment of bronchospasm in pharmacology. Because of this property, it is used for the treatment of asthma, allergic rhinitis, allergic and vernal conjunctivitis diseases. Products which are marketed by the trademarks of "Intal" and "Cromohexal" provide 20 mg sodium cromoglicate per dose. It is known that cromoglicic acid derivatives are used as a solubility enhancing agent in some aerosol formulations. For instance, US6475467 relates to use of a compound selected from cromoglicic acid and nedocromil derivatives in an ineffective amount in aerosol formulation that is in the form of suspension for increasing the dispersion of active agent in this suspension. The present invention relates to use of salts of cromoglicic acid and/or nedocromil (K) for the preparation of dry powder formulations containing tiotropium and/or pharmaceutically acceptable derivatives thereof (A). Initially, for the purpose of reducing the amount of lactose and alleviation of side effects caused by lactose, B has been added to the dry powder formulation which includes A. But surprisingly, it has been found that when B is used in an effective amount in the dry powder formulation which includes A, a synergistic effect occurs for the treatment of respiratory diseases. Therefore, according to the present invention, when salts of cromoglicic acid and/or nedocromil (B) are used in dry powder formulations which include tiotropium or pharmaceutically acceptable salts thereof (B), both required amount of carrier is reduced thus the side-effects caused by carrier are alleviated, and a synergistic effect is obtained for the treatment of respiratory diseases.

The present invention provides a medicament composition containing tiotropium or pharmaceutically acceptable derivatives (pharmaceutically acceptable salts, solvates, crystals) thereof as well as salts of cromoglicic acid and/or nedocromil in an effective amount for use in the treatment of respiratory diseases. The medicament composition in accordance with invention optionally contains a carrier in addition to the substances mentioned above.

In another aspect, the invention provides use of A and B defined hereinbefore in effective amounts for the preparation of a medicament which is used for the treatment of respiratory diseases especially allergic diseases. The inventors encountered a problem of inability to deliver an effective amount of dose to the lungs which is a problem widely encountered during inhalation of dry powder formulations.. In the prior art, various methods and devices are developed in order to deal with this problem.

According to the present invention, it is found that the most suitable method for delivering effective amount of dose to target area which is lung of the patient, and for making patient bring about inhalation in a most suitable way, is to inhale said medicament composition as dry powder form and to inhale said medicament from a peelable blister strip. It is found that compared to the other methods for delivery of dry powder formulation which comprise inhalation of dry powder formulation containing A and B in effective amounts from capsule or from reservoir or from separate blister strips each of which contains a kind of active agent, the method of delivering said dry powder formulation from a peelable blister strip minimize the drawbacks caused by adhesion force of micronized dry powder, and the amount of medicament formulation which reaches the lungs increases.

In another aspect, the present invention provides a method comprising delivery of medicament composition containing A and B in effective amounts and optionally a pharmaceutically acceptable carrier from a peelable blister strip by using a dry powder inhaler for the treatment of respiratory diseases especially allergic disease.

In an embodiment of the invention, tiotropium (A) may be in the form of pharmaceutially acceptable salts and solvates thereof, preferably, tiotropium bromide is used. All of crystal and amorphous forms of tiotropium, which shows different polymorphic forms, can be used within the scope of invention. Also, tiotropium used within the scope of invention can be in the form of anhydrate and hydrate, preferably, tiotropium bromide anhydrate is used.

In an embodiment of the invention, a salt of cromoglicic acid and/or nedocromil (B) can be selected from pharmaceutically acceptable salts of cromoglicic acid and/or nedocromil. Preferably, it is either sodium cromoglicate and/or nedocromil sodium.

Dry powder formulation in accordance with the present invention administered via inhalation route optionally contains pharmaceutically acceptable carrier. The carrier can be selected from a group comprising arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran, sugar alcohols such as mannitol and saccharides.

The medicament composition in accordance with the present invention is in the form of micronized dry powder particles. The active agent present in said medicament composition has average particle size in the range of 1 to 20 μηι, preferably in the range of 1 to 5 μη . The carrier present in said medicament composition typically has average particle size of not more than 300 μπι, preferably not more than 210 μηι. A salt of cromoglicic acid and/or nedocromil present in said medicament composition both as an active agent and as an excipient, that has average particle size in the range of 1 to 20 μηι and in the range of 10 to 300 μιη. The cavity volume of each blister in said blister strip contained in the dry powder inhaler which is used for delivery of said medicament composition to the lung, is in the range of 20 to 30 mm , preferably in the range of 21 to 25 mm , most preferably in the range of 22 to 23 mm .

A lid sheet and a base sheet of said blister strip are closed very tightly to provide impermeability by using suitable method.

According to the present invention, the lid sheet or the base sheet of the peelable blister strip consists of three layers. Two of these layers are polymeric layers and the other one is aluminium foil. Aliminium foil is used in both the lid sheet and the base sheet of the peelable blister strip to provide high humidity and gas protection because of that aluminium foil is conventionally used in both the lid sheet and the base sheet of the blister strip for high humidty and gas protection. These layers must have the sufficient thickness which provides the protection for the stability of humidity sensitive dry powder formulation which is stored in the blister cavity. Because of this reason, the thickness of aluminium foil that is used in the lid sheet and the base sheet of the peelable blister strip is in the range of 10 to 40 μηι, preferably of 15 to 30 μπι.

Two of the layers contained by the lid sheet and the base sheet of the peelable blister strip according to the present invention, are polymeric layers. These polymeric layers may be made from either same or different polymers. The thickness of these polymeric layers depends on the type of polymeric substance used and its properties. Therefore, the thickness of each polymeric layer which is used in the lid sheet and the base sheet of said blister strip is in the range of 15 to 60 μηι, preferably of 20 to 35 μιη depending on the type of polymer used.

The inside layer of blister cavity of said blister strip which is in contact with dry powder formulation is polymeric layer because of the fact that aluminium foil causes adhesion of a part of dry powder formulation to inside layer of the cavity due to electrostatic forces, and hence cause uncontrolled dosing.

According to the present invention, the polymers used for forming the polymeric layers are preferably selected from a group comprising thermo-plastic polymers such as polyethylene, polypropylene, polystyrene, polyolefin, polyamide, polyvinyl chloride, polyurethane.

The layers which are used for making up the lid sheet and the base sheet of said blister strip in accordance with present invention, are preferably same for each sheet, however the polymeric substances used for forming polymeric layers are preferably different from each other. Moreover, each of the blister cavities of the peelable blister strip can be different in shape as long as it has properties defined above.

Devices used to inhale the dry powder formulation in accordance with the present invention may be multi dose inhalers present in the prior art. For this reason, the invention provides a medicament composition as it is mentioned before. In another aspect, the invention provides a method for delivery of said medicament composition to patient's lungs effectively as it is mentioned before.

The medicament composition in accordance with the present invention containing active agents, which is preferably in dry powder form is stored in the peelable blister strip and during inhalation 2 to 50 milligram of said medicament composition is delivered to patients by using a multi dose inhaler, after each movement of the device.

In the medicament composition A is present in the amount of 1 to 50 μg, B is present in the amount of 5 to 50 mg. Accordingly, the ratio of the weight of A to the weight of B in said medicament composition is in the range of 1:400 to 1:6000. Additionally, in medicament composition, pharmaceutically acceptable carrier can be used for the purpose of adjusting the weight of each dose of medicament composition to the range of 2 to 50 mg which is in dry powder form.

The medicament composition in accordance with present invention can be used for the treatment of many respiratory diseases such as asthma, chronic obstructive pulmonary disorder (COPD) and allergic rhinitis. Accordingly, the respiratory diseases include but are not restricted to allergic or non-allergic asthma in various phases, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), exacerbation of airways hyperactivity, bronchiectasis, chronic obstructive pulmonary, airways or lung diseases (COPD, COAD or COLD) including emphysema and chronic bronchitis, pneumoconiosis, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis. The treatment of said diseases may be prophylactic or symptomatic. In addition to this, the medicament composition in accordance with the present invention is used especially for the symptomatic treatment of asthma, allergic rhinitis and COPD.

The present invention, is explained with examples given below, but it is not restricted to these examples. Parts given in examples represent the weights of ingredients. Example 1

The medicament composition in dry powder form which is stored in a blister strip to be delivered by using multi-dose inhaler described in GB2242163 or a similar one to this and is prepared by mixing 18 parts of tiotropium bromide anhydrate and 12000 parts of sodium cromoglicate, having average particle size of 1 to 5 μπι, and 12000 parts of sodium cromoglicate having average particle size of not more than 300 μπι, which are micronized in an air jet mill, and 2000 parts of a carrier such as lactose as second carrier.

Tiotropium bromide anhydrate (A) given in this example may be extended pharmaceutically acceptable salts and polymorphous forms thereof, sodium cromoglicate (B) given in this example may be extended pharmaceutically acceptable salts cromoglicic acid and nedocromil, more or less amount of pharmaceutically acceptable carrier may optionally be added and thus example number 1 is repeated as following:

Amount of tiotropium Amount of cromoglicic acid (part) (part)

Example 2 9 12000

Example 3 9 20000

Example 4 9 30000

Example 5 9 50000

Example 6 12 12000

Example 7 12 20000

Example 8 12 30000

Example 9 12 50000

Example 10 15 12000

Example 1 1 15 20000

Example 12 15 30000

Example 13 15 50000 Example 14 18 12000

Example 15 18 20000

Example 16 18 30000

Example 17 18 50000

Example 18 21 12000

Example 19 21 20000

Example 20 21 30000

Example 21 21 50000

Example 22 24 12000

Example 23 24 20000

Example 24 24 30000

Example 25 24 50000

Example 26 27 12000

Example 27 27 20000

Example 28 27 30000

Example 29 27 50000

Example 30 30 12000

Example 31 30 20000

Example 32 30 30000

Example 33 30 50000

Claims

1. A medicament composition containing tiotropium (A) for use in the treatment of respiratory disorder by inhalation route characterized in that said medicament composition contains an effective amount of pharmaceutically acceptable salt of cromoglicic acid and/or nedocromil (B).

2. A medicament composition according to claim 2, wherein tiotropium (A) is preferably tiotropium bromide.

3. A medicament composition according to claim 1, wherein tiotropium (A) is preferably tiotropium bromide anhydrate.

4. A medicament composition according to any one of preceding claims, wherein the salt of cromoglicic acid (B) is sodium cromoglicate.

5. A medicament composition according to any one of claims 1 to 3, wherein the salt of nedocromil (B) is nedocromil sodium.

6. A medicament composition according to claim 1, wherein said medicament composition is used locally for the treatment of respiratory diseases by inhalation route contains micronized dry powder.

7. A medicament composition in dry powder form according to claim 6, wherein said medicament composition is administered directly to airways by using inhalation device.

8. A medicament composition in dry powder according to claim 6, wherein the active agent have average particle size of 1 to 20 μιη, preferably 1 to 5 μηι.

9. A medicament composition in dry powder form according to any one of the preceding claims, wherein tiotropium (A) is present in the amount of 1 to 50 μg for each dose, and a salt of cromoglicic acid and/or nedocromil (B) is present in the amount of 1 to 50 mg for each dose and a pharmaceutically acceptable carrier is in any amount for adjusting each dose of medicament composition, which is in dry powder form, to the range of 2 to 50 mg

10. A medicament composition in dry powder form according to claim 9, wherein the ratio of the weight of tiotropium to the weight of a salt of cromoglicic acid (B) is in the range of 1 :400 to 1 :6000.

11. A medicament composition in dry powder form according to claim 6, wherein said medicament composition optionally contains a pharmaceutically acceptable carrier.

12. A medicament composition according to claim 11, wherein said medicament composition contains a carrier selected from a group comprising monosaccharide, disaccharide, polysaccharide and oligosaccharide.

13. Use of a medicament composition containing tiotropium or a pharmaceutically acceptable salt thereof (A) and a salt of cromoglicic acid and/or nedocromil (B) and optionally a pharmaceutically acceptable carrier by a dry powder inhaler in which said medicament composition is stored in a peelable blister strip for the treatment of respiratory diseases.

14. Use of tiotropium (A) and a salt of cromoglicic acid and/or nedocromil (B) for the preparation of a medicament according to the preceding claims for use in the treatment of inflammatory or obstructive respiratory diseases.