WO2011049539A1

WO2011049539A1 - Compositions comprising a corticosteroid, a beta2 agonist as well as cromoglicic acid or ndeocromil

Info

Publication number: WO2011049539A1
Application number: PCT/TR2010/000208
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2009-10-20
Filing date: 2010-10-20
Publication date: 2011-04-28
Also published as: TR200907914A2

Abstract

The present invention relates to a pharmaceutical composition for use in the treatment of respiratory diseases, characterized in that said composition comprises a pharmaceutically effective amount of cromoglicic acid and/or nedocromil salts besides β2-agonists and corticosteroid drugs.

Description

COMPOSITIONS COMPRISING A CORTICOSTEROID, A BETA2 AGONIST AS WELL AS CROMOGLICIC ACID OR NDEOCROMIL

Description

The present invention relates to pharmaceutical compositions in dry powder form comprising a pharmaceutically effective amount of cromoglicic acid and/or nedocromil salts in addition to p₂-agonists and corticosteroid drugs for the use in the treatment of the respiratory diseases.

These molecules named as ₂-agonists in general, are categorized into two grups such as long- acting and short-acting and they lead to opening of bronchs by causing relaxation of smooth muscles around air vessels. With the help of this property, these drugs are effective in the treatment of asthma and chronic obstructive pulmonary disorder (COPD).

These drugs indicate effects in a very short time, for instance a few minutes after their inhalation and their effects can continue for up to 4 hours. They should be taken often during the day due to their short-lasting remedial effects.

The drugs included in this group are categorized into two main groups as mentioned before. The first of them is p₂-agonists comprising salbutamol, levosalbutamol, prosaterol, fenoterol, terbutaline, pirbuterol, metoproterenol, bitolterol mesilate which affects rapidly but lose its effect in a short time. The second group consists of salmeterol, formoterol, bambuterol and clenbuterol and they affect slowly compared to the other group and are characterized by their long-lasting effects. The drugs named as Albuterol (Ventolin, Proventil), metaproterenol (Alupent), pirbuterol (Maxair), terbutaline (Brethaire), isoetharine (Bronkosol), and Levalbuterol (Xopenex), salmeterol xinafoate (Serevent) in the markets can be examples of the pharmaceutical compositions comprising the molecules included in this group.

In 2005, US Food and Drug Administration (FDA) claimed that a lot of long-acting ₂-agpnists drugs increases growling symptom in the patients. Moreover, in a study carried out by Cornell and Stanford Universities, it has been found that usage for a long time and/or taking β-agonists in a high dosage in the COPD treatment increases health problems resulting from respiratory tract. As it is seen from this, different methods should be applied for the use of p₂-agonists in the treatment of asthma and COPD.

Another drug group that is often used for the treatment of asthma and COPD is corticosteroids. The molecules included in this group are used since approximately 1950s. These molecules lead to opening of the air vessels by controlling inflammation and hence decreasing mucus that forms the basis of asthma and makes the problems of asthma patients disappear for this reason. When the drugs included in this group are taken systemically, they cause serious side effects such as osteoporosis, high cholesterol, oedema, headache, sleep problems, some skin problems and growth retardation in children. Therefore, transmission methods in which lowest possible amount of these drugs enters to systemic circulation should be preferred. In asthma treatment, transmission of these kinds of molecules is applied by inhalation route in order to decrease the side-effect and to transport the highest possible maximum dose to the pulmonary system.

As it is mentioned above, β-agonist drugs trigger respiratory diseases, for preventing the side effects of these substances which are essential for use in the treatment of asthma, the combination of them with the other substances effective on the same disease is beneficial for both decreasing the amount of p₂-agonists to be taken and for the benefits of the synergic effects for the patients arising from the combination of two different drugs. For that reason, it is found that using p₂-agonists and corticosteroids together provides; decrease in the amount of p₂-agonists used, opening bronchus with the positive effect of this drug, and preventing the inflammation resulting from asthma by usingcorticosteroid.

Ideally, while the dosage forms of the drugs indicated for the remedial effects in the body, transmission methods providing delivery of the drug directly and rapidly to the target area and as a result providing the desired effect with lower doses and hence causes led side effects are preferred. Especially, when the serious side effects of corticosteroids in the systemic intake are considered, it is seen that it is very important to transmit this combination which is thought to be transmitted by respiratory route in an effective way. In the prior art, one of the problems mostly emphasized is the ones related to the transmission methods of the drugs and development of the devices.

Generally, there are three different methods and inhalation devices which are suitable for use in the transmission of drug by inhalation route. These are; (a) nebulization devices, (b) inhalators including pressurized gas and (c) dry powder inhalators. The nebulization devices are often not preferred due to their large sizes and due to the fact that they sometimes cause infection. The inhalators including pressurized gas which is the other method are more advantageous than nebulizers since they can be easily carried, but in these devices the largest part of the dose accumulates in different points of the respiratory tract and enters the systemic circulation before it reaches the lungs and under the best circumstances only 10-20% of the drug taken reaches to the target area, in other words, in the case where the drug is taken by the patient with 100% efficiency. Anjmportant factor causing this situation is that the carrier gas used in these devices cause cold freon effect and as a consequence of this phenomenon the respiration of the patient stops for a short period while using the drug and the drug accumulates in the mouth instead of reaching to the target area by breathing of the drug. Considering the side effect of the corticosteroid that is mentioned before, it is seen that using the inhalators including pressurized gas in transmission of these group of drugs is not a correct choice for the patients.

The inhalators including dry powder come into prominence due to their ease of use. These devices can be moved to everywhere due to the fact that they have small size and they do not cause the cold freon effect since they do not comprise a carrier gas. Moreover, contrary to the inhalators including pressurized gas, simultaneous pressing and breathing are not required and this plays an important role on effective inhalation of the drug by the patients.

It is possible to categorize inhalators comprising dry powder in three groups, one of them is the inhalators comprising disposable capsule. These are not mostly preferred because of the fact that a new capsule should be placed before each use. Another inhalator including dry powder is the inhalators having reservoir comprising the dry powder. These are beneficial since they provide multiple dosing but these devices are not sufficient for providing the dose uniformity.

Another type of dry powder inhalator is the devices in which the drug is placed in the blister. The devices including blister; (a) are more advantageous than the devices comprising reservoir since it provides intake of the right dose amounts via filling each dose into different blister cavities in the factory.

Moreover, improvement of different formulations are still required for transporting the effective dose to the lungs. Lactose, which is a disaccharide, is generally used as a carrier in dry powder formulations. 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 the amount of active agent used. However, lactose used as a carrier in dry powder formulation, when used in large amounts cause 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, causes symptoms such as nausea, stomach cramps, overfullness of the stomach, swelling of stomach, flatus, diarrhea, hives plaque. Only some part of the drugs administered by inhalation can reach the target area, the rest is mostly swallowed. Therefore, it is required to develop the compositions comprising p₂-agonists and corticosteroid within the scope of the present invention.

Salts of cromoglicic acid and nedocromil are used for the treatment of bronchospasm in pharmacology. Because of this property of it, it is used for the treatment of asthma, allergic rhinitis, allergic and vernal conjunctivitis diseases.

Products comprising acid derivatives and providing up to 20 mg sodium cromoglicate per dose, are marketed by the trademarks of "Intal" and "Cromohexal".

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 inventors found that the use of cromoglicic acid and nedocromil derivatives optionally alone or combined with lactose as a carrier increases the remedial effect of the pharmaceutical compositions and also decreases the side effects arising from use of lactose in high amounts.

The present invention is related to the use of cromoglicic acid and/or nedocromil salts in the dry powder formulations comprising ₂-agonists and corticosteroids or their pharmaceutically acceptable derivatives. Initially, in the dry powder formulations comprising ₂-agonists and corticosteroids, cromoglicic acid and/or nedocromil salts are added to the formulation for decreasing lactose amount and hence the side effects resulting from lactose. However surprisingly, when the amounts of cromoglicic acid and/or nedocromil salts which are present within the combination of

and corticosteroid in the prepared dry powder formulation are increased and cromoglicic acid and/or nedocromil are used in effective amounts, it has been found that a synergistic effect between these effective substances and an unexpected benefit in the treatment of the respiratory diseases takes place. Therefore, in the present invention, cromoglicic acid and/or nedocromil salts are used in the inhalation formulations in dry powder form comprising the combination of p₂-agonist and corticosteroid, this way the carrier amount has decreased and thus the side effects arising from the carrier has been minimized and also an unexpected therapeutical benefit in the treatment of respiratory diseases has been observed. The present invention is related to the pharmaceutical composition for use for the treatment of respiratory diseases in which the combination of p₂-agonist and corticosteroid and cromoglicic acid and/or nedocromil salts are combined together in effective doses.

The inventors have faced with the usually experienced problem of not being able to provide the effective amount of dose in the inhalation formulations in dry powder form comprising the combination of p₂-agonist and corticosteroid and cromoglicic acid and/or nedocromil salts. In order to solve this problem, several methods and devices were tried.

For the purpose of providing multiple dosing and thus providing ease of use to the patients, the use of blister strip package which is reliable in terms of hygiene and also which discards the possibility of moistening of the dry powder and additionally helps the dosage to be adjusted has been preferred.

In the prior art, one of the problems emphasized mostly is the transmission of the dry powder formulations used in the respiratory diseases to the lungs in an effective way. Each blister in said blister strip package is pierced with a piercing device or it is opened by peeling the top layer and this way the dry powder formulation becomes ready for inhalation to the lungs. The dry powder inhaler comprising blisters that are opened by piercing or peeling requires additional mechanic components and this situation makes the use of the device difficult by increasing the size, volume and complexity of the dry powder inhaler. Moreover, in the blisters opened by tearing, the amount of the dry powder remained in the blister after inhalation increases due to the roughness formed resulting from tearing and hence the rate of utilization from the dry powder formulation decreases. Moreover, it may lead to inhalation of small particles formed during tearing to the respiratory tract.

Accordingly, an aspect of the present invention; comprises that the dry powder composition comprising ₂-agonist and corticosteroid and cromoglicic acid and/or nedocromil salts is stored in the blister strip package opened by peeling off and is applied to the patient by the dry powder inhaler device.

The blister strip package which is preferred to be used in the present invention opened by peeling consists of two layers. At the bottom layer, the blister cavities comprising the dry powder formulations are present. The top layer acts as a lid and peeling said top layer results in opening blisters in order to make the dry powder formulation ready for inhalation.

In another aspect, the present invention provides a method comprising delivery of the pharmaceutical composition comprising effective amounts of the combination of p₂-agonist and corticosteroid and cromoglicic acid and/or nedocromil salts and optionally a pharmaceutically acceptable carrier stored in blister strip package by a dry powder inhalation device for the treatment of the patients having respiratory diseases, especially for the patients having allergic diseases. p₂-agonists that can be used in said invention can be chosen from but not limited by a group comprising salbutamol, levosalbutamol, prosaterol, fenoterol, terbutaline, pirbuterol, metoproterenol, bitolterol mesilate, salmeterol, formoterol, bambuterol and clenbuterol and their pharmaceutically acceptable salts, esters, solvates thereof.

Corticosteroid that can be used in said invention can be chosen from but not limited by triamcinolone, beclomethazone, mometasone, ciclesonid, budesonide and flutikasone or their pharmaceutically acceptable salts, solvates, derivatives thereof. Cromoglicic acid and/or nedocromil salts that can be used in said invention can be chosen from its pharmaceutically acceptable salts. It can be preferably selected from sodium chromoglycate and/or nedocromile sodium.

The dry powder composition that can be inhaled by inhalation route can optionally comprise another carrier. These carriers can be chosen from sugar alcohols such as arabinose, glycose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran or mannitol or from saccharides .

The pharmaceutical composition in accordance with the present invention is in the form of micronized dry powder particles. The active agents present in said composition have average particle size of 1 to 20 μη , preferably 1 to 5 μηι. The carrier present in said composition typically has average particle size of not more than 300 μη , preferably not more than 210 μηι. Salt of cromoglicic acid and/or nedocromil present in said composition both as an active agent and as an excipient, has average particle size in the range of 1 to 20 μιη and in the range of 10 to 300 μηι.

The cavity volume of each blister in blister strip package contained in the dry powder inhaler which is used for delivery of said composition to the lungs, is in the range of 20 to 30 mm³, preferably in the range of 21 to 25 mm³, most preferably in the range of 22 to 23 mm³.

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

The lid and base sheet comprising the blister strip package in accordance with the present invention consists of three- layers. Two of these layers are polymeric layers and the other one is aluminium foil. Aluminium foil is used in both lid sheet and base sheet of the blister strip to provide high humidity and gas protection due to the fact that aluminium foil is conventionally used in both lid sheet and base sheet of blister strip package for high humidity and gas protection. These layers must have the sufficient thickness which provides the protection for the stability of hygroscopic dry powder formulation which is stored in blister cavity. Because of this reason, the thickness of aluminium foil that is used in lid sheet and base sheet of the blister strip package is in the range of 10 to 40 μηι, preferably in the range of 15 to 40 μη . Two of the layers contained by lid sheet and base sheet of the 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 lid sheet and base sheet of said blister strip is in the range of 15 to 60 μηι, preferably of 20 to 35 μηι depending on the type of used polymer.

When the inside layer of the cavity is made up of aluminium foil a part of the dry powder formulation remains in the cavity uninhaled due to electrostatic forces, therefore the layer covering the inside of the cavity is the polymeric layer to prevent the formation of this adhesive force. 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, polyolefm, polyamide, polyvinyl chloride, polyurethane.

The layers making up lid sheet and 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 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 pharmaceutical composition as it is mentioned before. In another aspect, the invention provides a method for delivery of pharmaceutical composition to patient's lungs effectively as mentioned before.

The pharmaceutical composition containing active agents which is in dry powder form is stored in a blister strip and during dosing with a multi dose inhalator, with each movement of the device it can deliver 5 to 50 milligram of the dry powder wherein one each dose comprises the combination of p₂-agonist and corticosteroid and cromoglicic acid and/or nedocromil salts .

In the pharmaceutical composition of present invention, the combination of p₂-agonist and corticosteroid can be present in the amount of 1 to 1000 μg, cromoglicic acid and/or nedocromil salt can be present in the amount of 5 to 50 mg. Accordingly, the ratio of the total weight of the combination of p₂-agonist and corticosteroid to the weight of cromoglicic acid and/or nedocromil salt in said pharmaceutical composition is in the range of 1 :5 to 1 : 10000. Additionally, in pharmaceutical composition any pharmaceutically acceptable carrier can be used for the purpose of adjusting each dose of pharmaceutical composition which is in dry powder form to the range of 5 mg to 50 mg.

Pharmaceutical composition in accordance with the 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 pharmaceutical composition in accordance with the present invention is used especially for the symptomatic treatment of asthma, allergic rhinitis and COPD.

Claims

1. A pharmaceutical composition containing combination of p₂-agonist and corticosteroid or its pharmaceutically acceptable salt for the use in the treatment of respiratory diseases by inhalation route characterized in that said pharmaceutical composition contains an effective amount of cromoglicic acid and/or nedocromil.

2. A pharmaceutical composition according to claim 1, characterized in that corticosteroid used in said composition can be chosen from a group comprising but not limited with triamcinolone, beclomethazone, mometasone, ciclesonid, budesonide and flutikasone or their pharmaceutically acceptable salts, solvates, derivatives thereof.

3. A pharmaceutical composition according to claim 1, characterized in that in said composition p₂-agonists used can be chosen from a group comprising but not limited with salbutamol, levosalbutamol, prosaterol, fenoterol, terbutaline, pirbuterol, metoproterenol, bitolterol mesilate, salmeterol, formoterol, bambuterol and clenbuterol and their pharmaceutically acceptable salts, esters, solvates thereof.

4. A pharmaceutical composition according to any of the previous claims, characterized in that said pharmaceutical composition comprise sodium cromoglycate as cromoglicic acid salt

5. A pharmaceutical composition according to any of the previous claims, characterized in that said pharmaceutical composition comprise nedocromil sodium salt as nedocromil salt.

6. A pharmaceutical composition according to claim 1 used for respiratory diseases locally by inhalation route, characterized in that its content is in the form of micronized dry powder.

7. A pharmaceutical composition in the dry powder form according to claim 6, characterized in that said composition is directly administered to the respiratory tract by a dry powder inhalation device.

8. A pharmaceutical composition in the dry powder form according to claim 6, characterized in that the content of the active agent has an average particle size of 1 to 20 μηι, preferably 1 to 5 μηι.

9. A pharmaceutical composition in the dry powder form according to one of the previous claims, characterized in that the amount of ₂-agonist and corticosteroid in each dose is in the range of 1-1000 μg, the amount of cromoglicic acid and/or nedocromil salt in each dose is in the range of 1-50 mg and any amount of pharmaceutically suitable carrier can be used in order to adjust each powder of the dry powder pharmaceutical composition to the amount of 5 mg to 50 mg.

10. A pharmaceutical composition in the dry powder form according to claim 9, characterized in that the ratio of the weight of the combination of p₂-agonist and corticosteroid to the weight of cromoglicic acid and/or nedocromil salt is in the range of 1 :5 to 1 :10000.

11. A pharmaceutical composition in the dry powder form according to claim 1, characterized in that said composition comprises optionally a pharmaceutically acceptable carrier.

12. A carrier that is found in a pharmaceutical composition according to claim 1 1, characterized in that said carrier is chosen from a group comprising monosaccharide, disaccharide, polysaccharide and oligosaccharide.

13. Use of a pharmaceutical composition in the dry powder form, comprising the combination of p₂-agonist and corticosteroid and cromoglicic acid and/or nedocromile salts and optionally a pharmaceutically acceptable carrier, by a dry powder inhalation device wherein said composition is stored in a blister strip package, for the treatment of pulmonary diseases.

14. Use of the combination of p₂-agonist and corticosteroid and cromoglicic acid and/or nedocromil salts described in any of the previous claims, for the manufacture of a drug for the treatment of an inflammatory or obstructive respiratory disease.