CROMOGLICIC ACID DERIVATIVE

Description

The present invention relates to a pharmaceutical composition that is used by inhalation route, containing tiotropium combined with corticosteroid, and effective amount of cromolyn derivatives used for the treatment of respiratory disorder by inhalation route.

Tiotropium (Formula I) is an anticholinergic agent with chemical name (la, 2β, 4β, 7β)-7- [(hydroxidi-2-thienylacetyI)oxy]-9,9-dimethyl-3-oxa-9-azonia tricyclo [3.3.1.0 ² ' 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 anthichlolinergic bronchodilator used orally in the treatment of respiratory system diseases. Tiotropium is marketed under the trade name "Spiriva" as a dry powder form in capsules and used via inhalation device under the trade name "Handyhaler". Tiotropium is separated slowly from M _\ and M ₃ receptors that cause broncho-construction, and it is separated rapidly from M ₂ receptors that inhibit release of acetylcholine from cholinergic nerve endings. This situation that takes place in lung receptors demonstrates long acting bronchodilator activity of the drug. An example of using Tiotropium with corticosteroid substances is disclosed in patent application US2004/0266869. In this application using combination of ciclesonide with tiotropium is especially mentioned and it is indicated that when using ciclesonide in combination with one or more anticholinergic agents, there is a decreasing in side effects, especially the ones caused by use of corticosteroids.

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.

When inhaled medications reach the target area, they do not enter blood circulation. Thus, problems that change the activity of drug, such as; low solubility, low permeability, irritation, formation of unwanted metabolites and gastrointestinal problems, such as; decrease in bioavailability due to food are experienced in the lowest possible level.

Medicine formulations used in locally via inhalation can be used in dry powder inhaler, inhaler with pressured gases or nebulization devices. Although each of these different devices have positive and negative aspects, especially dry powder inhalers come into prominence with its ease of use. However, for dry powder formulations, there is still need to develop different transmission methods to convey the effective doses to the lung.

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, which is approximately 500-2500 times more than the amount of active agent, for a single dose. Lactose is milligram in weight when the active agent is in microgram. However, a large amount of lactose used as a carrier in dry powder formulation caused side effects such as coughing, throat irritation, etc. Also, dry powder formulations containing large amount of lactose when used by patient with allergy and/or lactose intolerance (sensitivity to lactose taking high doses), causes symptoms such as nausea, stomach cramps, overfullness of the stomach, swelling of stomach, flatus, diarrhea, hives plaque. Then, 15 to 25% of each dose of the drugs administered by inhalation can reach the target area, the rest is mostly swallowed. Because of these drawbacks, dry powder formulations containing tiotropium and corticosteroid or pharmaceutically acceptable salts, need to be developed 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 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 (B) in dry powder formulations containing tiotropium or pharmaceutically acceptable salts thereof (A) combined with ciclesonide or pharmaceutically acceptable salts thereof (S) administered by inhalation for the treatment of respiratory diseases. 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 and S. But surprisingly, it has been found that the combination has a synergistic effect and provides an unexpected benefit for treatment of respiratory disease like asthma, chronic obstructive lung disease, when the amount of (B) was increased and used in an effective amount in the prepared dry powder formulation which include (A) and (S). 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 derivatives thereof (A) combined with ciclesonide or pharmaceutically acceptable derivatives thereof (S), 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 such as salts, solvates, hydrates, polymorphs, amorph and/or crystal forms, free base (A) thereof with ciclesonide or pharmaceutically acceptable derivatives such as; salts, solvates, hydrates, polymorphs, enantiomers, racemates, amorph and/or crystal forms (S) thereof as well as salt of cromoglicic acid and/or nedocromil (B) 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, S 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 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, S, 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 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 which reaches lungs increases.

In another aspect, the present invention provides a method comprising delivery of medicament composition containing A, S and B in effective amounts and optionally a pharmaceutically acceptable carrier from a blister strip by using 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 pharmaceutically acceptable salts, hydrates, solvates, esters, polymorphs, free base, crystal and/or amorphous forms 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, corticosteroid can be selected from preferably ciclesonide (S) or its pharmaceutically acceptable salts, hydrates, solvates, esters, polymorphs, enantiomers, rasemates, free base, crystal and amorph forms.

In an embodiment of the invention, salt of cromoglicic acid and/or nedocromil (B) can be selected from pharmaceutically acceptable salts thereof. Preferably, it can be 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 agents present in said medicament composition have average particle size in the range of 1 to 20 μπι, preferably in the range of 1 to 6 μηι. The carrier present in said medicament composition typically has average particle size of not more than 300 μπι, preferably not more than 210 μπι. 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 μπι and in the range of 10 to 300 μπι.

The cavity volume of each blister in the peelable 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 ³ , preferably in the range of 21 to 25 mm ³ , most preferably in the range of 22 to 23 mm ³ .

A lid sheet and a base sheet which constitutes 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 both in the lid sheet and in 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 peelable 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 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 μπι, preferably of 20 to 35 μηι 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 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 which constitute the peelable blister strip can be different in shape as long as it has the 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 mentioned before. In another aspect, the invention provides a method for delivery of medicament composition to patient's lungs effectively as 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 including one for each dose of A,S and B is delivered to patients by using a multi dose inhaler, after each movement of the device.

In the medicament composition of present invention A is present in the amount of 1 to 50 μg, preferably 1 to 30 μg, S is present in the amount of 5 to 750 μg, preferably 5 to 550 μ£, 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 S to the weight of B in said medicament composition is in the range of 1:5 to 1:1500. Additionally, in medicament composition pharmaceutically acceptable carrier can be used for the purpose of adjusting each dose of medicament composition, which is in dry powder form, to the range of 2 to 50 mg.

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.

This 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 the peelable blister strip to be delivered by using multi-dose inhaler and is prepared by mixing 18 parts of tiotropium bromide anhydrate, 200 parts of ciclesonide and 8000 parts of sodium cromoglicate, having average particle size of 1 to 5 μιη, and 10000 parts of sodium cromoglicate having average particle size of not more than 300 μπι, which are micronized in an air jet mill, and 5000 parts of carrier which is suitable as a pharmaceutical such as lactose. As given in the following example, tiotropium bromide anhydrate may be extended tiotropium or pharmaceutically acceptable salts and polymorphs(A) thereof; ciclesonide may be extended pharmaceutically acceptable salts, enantiomers, racemates, polymorphs, solvates, hydrates, amorph and/or crystal forms (S) thereof, sodium cromoglicate (B) may be extended salts of cromoglicic acid and pharmaceutically acceptable salts of nedocromil, more or less amount of pharmaceutically acceptable carrier may optionally be added, and, thus example 1 is repeated as following:

Amount of Tiotropiu Amount of Ciclocinii Amount of

Bromide Cromoglicic acid

parts parts parts

Example 2 9 100 12000

Example 3 9 100 20000

Example 4 9 100 30000

Example 5 9 100 10000

Example 6 12 200 12000

Example 7 12 200 20000

Example 8 12 400 30000

Example 9 12 400 10000

Example 10 15 400 12000

Example 11 15 400 20000

Example 12 15 400 30000

Example 13 15 400 10000

Example 14 18 200 12000

Example 15 18 200 20000

Example 16 18 400 30000

Example 17 18 400 10000

Example 18 21 500 12000 Example 19 21 500 20000 Example 20 21 500 30000 Example 21 21 500 10000 Example 22 24 600 12000 Example 23 24 600 20000 Example 24 24 600 30000 Example 25 24 750 10000 Example 26 27 400 18000 Example 27 27 400 20000 Example 28 27 400 30000 Example 29 27 400 15000 Example 30 30 200 17000 Example 31 30 200 20000 Example 32 30 600 30000 Example 33 30 600 50000