DERIVATIVE IN DRY POWDER FORM

Description

The present invention relates to a medicament formulation containing tiotropium formulated with a corticosteroid and an effective amount of a cromolyn derivative for use in the treatment of respiratory diseases by inhalation route.

Tiotropium (Formula I) is an anticholinergic agent with chemical name (la, 2β, 4β, 7β)-7-

[(hydroxidi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azo niatricyclo [3.3.1.0 ² ' ⁴ ] nonane.

Tiotropium is described in European patent application numbered in EP0418716 for the first time. The patent relates to processes for preparing tiotropium, medicament formulations containing tiotropium, long-acting, strong anticholinergic activity of tiotropium and use of it in the treatment of respiratory disorders.

Tiotropium is a strong and long-acting anticholinergic bronchodilator, which is administered orally in the treatment of respiratory diseases. The drug which is in the dry powder form stored in capsules and contains tiotropium, is available in the market under the trade name Spiriva® and this drug is administered by a dry powder inhaler which is available in the market under the trade name 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. In prior art, WO01/78743 relates to use of tiotropium combined with corticosteroid compounds. In this patent document, it is stated that the combination of tiotropium and mometasone leads to significant improvements for the treatment of respiratory diseases.

Inhalation route is a commonly preferred treatment method for respiratory disorders especially chronic disorders such as asthma and chronic obstructive pulmonary disorder (COPD) which threatens a large portion of the society. The reason is that drug reaches directly and rapidly to target area and 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. Because of the fact that the drugs administered via inhalation route, reach directly to target area and do not get into circulation of blood, gastrointestinal disturbances, such as low resolution, low permeability, drug irritation, production of undesired metabolites and decrease of bioavailability depending on food, which change the effectiveness of the drug, are felt in minimum level.

The medicament formulations are admisintered locally via inhalation route by using dry powder inhalers, metered-dose inhalers or nebulizers. Although these drug delivery methods have some advantages or disadvantages when they are compared with each other, dry powder inhalers come to the forefront in terms of ease of use. Additionally, different delivery methods still need to be developed for delivering an effective dose of the medicament formulation in dry powder form 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 25 mg in a single dose and this is approximately 500-2500 times more than the amount of active agent. While the active agent has a weight in the unit of micrograms, lactose has a weight in the unit of milligrams. However, a large amount of lactose used as a carrier in dry powder formulation causes side effects such as coughing, throat irritation, etc. Additionally, 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, over fullness of the stomach, swelling of stomach, flatus, diarrhea, hives plaque. Because, 15% to 25% of each dose of the drugs administered by inhalation can reach the target area and the rest is mostly swallowed. Therefore, dry powder formulations containing tiotropium and a corticosteroid or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, enantiomers, racemates, free base, amorphous and/or crystal forms, esters thereof as active agents, are needed to be improved in terms of efficiency and safety.

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 contain cromoglicic acid derivatives and provide sodium cromoglicate up to 20 mg per dose are available under the trademarks "Intal" and "Cromohexal" in the market.

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 a salt of cromoglicic acid and/or (B) in dry powder formulations containing tiotropium or pharmaceutically acceptable salts thereof (A) combined with mometasone as active agent (M). Initially, B has been added to the dry powder formulation which includes A and M for the purpose of reducing the amount of lactose and alleviation of side effects caused by lactose. But surprisingly, it has been found that when B is used in an effective amount in the dry powder formulation which includes A and M, a synergistic effect in the treatment of respiratory diseases such as asthma, allergic rhitinis and chronic obstructive pulmonary disease occurs. Therefore, according to the present invention, when a salt of cromoglicic acid and/or nedocromil (B) is used in dry powder formulations which include tiotropium or pharmaceutically acceptable salts thereof (A) combined with mometasone substance (M), both the required amount of carrier is reduced thus the side-effects caused by carrier are minimized, and an unexpected therapeutic effect is obtained for the treatment of respiratory diseases. The present invention provides a medicament formulation in which tiotropium and/or a pharmaceutically acceptable derivative such as salt, solvate, hydrate, polymorph, amorphous and crystal form, free base (A) thereof and mometasone and/or a pharmaceutically acceptable derivative such as salt, hydrate, solvate, polymorph, enantiomer, racemate and crystal form (M) thereof and a salt of cromoglicic acid and/or nedocromil is present in effective doses. The medicament formulation in accordance with invention optionally contains a carrier in addition to the substances mentioned above.

In one aspect, the present invention provides use of the effective amounts of A, M and B defined above for the preparation of a drug which is used for the treatment of the 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.

It is found that the most suitable method for delivering effective amount of dose to target area, which is lung of the patient, is to inhale said medicament formulation as dry powder form from a peelable blister strip. It is found that compared to the other methods for delivery of dry powder formulation comprising inhalation of dry powder formulation containing A, M, 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 for delivery of said dry powder formulation from said blister strip minimize the drawbacks caused by adhesion force of micronized dry powder and the amount of the medicament formulation which reaches the lungs increases.

In another aspect, the present invention provides a method comprising delivery of the medicament formulation which contains A, M 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 diseases.

In an embodiment of the invention, tiotropium (A) can be in the form of its pharmaceutially acceptable salts, solvates, esters, free base, or polymorphs 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 or hydrate, preferably, tiotropium bromide anhydrate is used.

In an embodiment of the invention, the corticosteroid is preferably mometazone (M) can be selected from pharmaceutially acceptable salts, solvates, hydrates, esters, free base, enantiomers, racemates, polymorphs, amorphous or crystal forms thereof.. In an embodiment of the invention, a salt of cromoglicic acid and/or nedocromil (B) comprises the forms of pharmaceutically acceptable salts thereof. It is preferably selected from sodium chromoglycate and/or nedocromil sodium.

The medicament formulation in dry powder form in accordance with the present invention administered via inhalation route optionally contains pharmaceutically acceptable carrier. The carrier is 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 formulation in accordance with the present invention is in the form of micronized dry powder particles. The active agents present in said medicament formulation have average particle size of 1 to 20 μπι, preferably in the range of 1 to 6 μπι. The carrier present in said medicament formulation typically has average particle size of not more than 300 μηι, preferably not more than 210 μιη. A salt of cromoglicic acid and/or nedocromil present in said medicament formulation both as an active agent and as an excipient, that has average particle size in the range of 1 to 20 μπι and in the range of 10 to 300 μπι.

The cavity volume of each blister in said blister strip contained in the dry powder inhaler which is used for delivery of said medicament formulation to the lung, is in the range of 20 to 30 mm ³ , 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 μηι. 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 μιη, preferably of 20 to 35 μπι 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 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 formulation as it is mentioned before. In another aspect, the invention provides a method for delivery of said medicament formulation to patient's lungs effectively as it is mentioned before.

The medicament formulation 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 formulation which contains one for each dose of A, M and B, is delivered to patients by using a multi dose inhaler, after each movement of the device.

In the medicament formulation of present invention, A is present in the amount of 1 to 50 μg, preferably 5 to 30 μg, M is present in the amount of 5 to 750 μg, preferably 5 to 550 μg, B is present in the amount of 1 to 50 mg, preferably 1 to 25 mg. Accordingly, the ratio of the total weight of A and M to the weight of B in said medicament formulation is generally in the range of 1:5 to 1:1500. Additionally, in said medicament formulation, any of the pharmaceutically acceptable carriers can be used for the purpose of adjusting weight of each dose of said medicament formulation which is in dry powder form to the range of 2 to 50 mg. The medicament formulation 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 formulation 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 formulation in dry powder form which is stored in a peelable blister strip to be delivered by using multi-dose inhalation device and is prepared by mixing 18 parts of tiotropium bromide anhydrate, 200 parts of mometasone and 8000 parts of sodium cromoglicate, having average particle size of 1 to 5 μπι, and 10000 parts of sodium cromoglicate having average particle size of lower than 300 μηι, which are micronized in an air jet mill, and 5000 parts of a pharmaceutically acceptable carrier like lactose.

As given in this example, tiotropium bromide anhydrate (A) can be extended to pharmaceutically acceptable salts, hydrates, anhydrates, and polymorphs, mometasone (M) can be extended to its pharmaceutically acceptable salts, enantiomers, racemates, polymorphs, solvates, hydrates, crystal and amorphous forms thereof and sodium chromoglycate can be also extended to its pharmaceutically acceptable salts of cromoglicic acid and nedocromil, more or less amount of pharmaceutically acceptable carrier may optionally be added, and, thus example 1 is repeated as following: Cromoglicic Acic

Tiotropium Amount Mometasone Amount

Amount (part) (part)

(part)

Examp 2 9 110 12000

Examp 3 9 110 20000

Examp 4 9 330 30000

Examp 5 9 220 10000

Examp 6 12 330 12000

Examp 7 12 440 20000

Examp 8 12 110 30000

Examp 9 12 110 10000

Examp 10 15 440 12000

Examp 11 15 330 20000

Examp 12 15 440 30000

Examp 13 15 . 220 10000

Examp 14 18 220 12000

Examp 15 18 220 20000

Examp 16 18 330 30000

Examp 17 18 440 10000

Examp 18 21 440 12000

Examp 19 21 220 20000

Examp 20 21 220 30000

Examp 21 21 110 10000

Examp 22 24 220 12000

Examp 23 24 110 20000

Examp 24 24 440 30000

Examp 25 24 330 10000

Examp 26 27 330 12000

Examp 27 27 440 20000 Examp 28 220 30000

Examp 29 27 330 15000

Examp 30 30 330 12000

Examp 31 30 110 20000

Examp 32 30 440 30000

Examp 33 30 550 50000