WO2011049538A2

WO2011049538A2 - Pharmaceutical composition in dry powder form

Info

Publication number: WO2011049538A2
Application number: PCT/TR2010/000207
Authority: WO
Inventors: Bilgic Mahmut
Original assignee: Bilgic Mahmut
Priority date: 2009-10-20
Filing date: 2010-10-20
Publication date: 2011-04-28
Also published as: TR200907915A2; WO2011049538A3

Abstract

Present invention relates to pharmaceutical compositions comprising β2-agonists and anticholinergic agents in dry powder form stored in a blister for use in the treatment of respiratory diseases.

Description

PHARMACEUTICAL COMPOSITION IN DRY POWDER FORM

Present invention relates to pharmaceutical compositions comprising ₂-agonists and anticholinergic agents in dry powder form strored in a blister for use in the treatment of respiratory diseases.

The molecules which named as p₂-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 4-24 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 effects rapidly but lose its effect in a short time. The second group consists of salmeterol, formoterol, bambuterol and clenbuterol and they are characterized by their long-lasting effects compared to the first group.

The drugs named as albuterol (Ventolin, Proventil), metaproterenol (Alupent), pirbuterol (Maxair), terbutaline (Brethaire), isoetharine (Bronkosol), and Levalbuterol (Xopenex), salmeterol xinafoate (Serevent) present in the markets are the 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 β₂- agonists drugs increases growling symptom in the patients. Afterwards, 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 can be seen from this, use of ₂-agonists alone for the treatment of asthma and COPD causes dangerous results.

Another method that is often used for the treatment of asthma and COPD comprises use of molecules showing anticholinergic effect. These molecules can be divided into two groups depending on the kind of acetylcholine receptor they effect. Anticholivergic molecules used for the treatment of asthma and COPD cause relaxation of the smooth muscles and hence opening of the airway by inhibiting the M3 muscarinic receptors that is resposible from contraction of the smooth muscles in the lungs. Although there are several molecules that show anticholinergic effect, among these especially ipratropium and tiotropium are used for the treatment of pulmonary diseases mentioned before.

When these molecules that show similar effects although they have different mechanisms of action are used in combined form, it was seen that side effects arising from use of high dose of p₂-agonist are minimised and upon the synergistic effect of combination the desired therapeutic effect was seen without the side effects.

Ideally, while the dosage forms of the drugs that show therapeutic effect in the body are designed, transmission methods which enables conveying the dose to the target area in a fast way and as a result of that which shows the desired effect with lower doses and hence causes less side effects are preferred.

For treatment of pulmonary system diseases, especially for treatment of diseases like asthma and COPD which treathen a large portion of the society; inhalation theraphy which enables the drug molecules to reach the target area directly is a widely preferred treatment method. Drugs administered by the inhalation route directly reach the target area and hence do not get into systemic circulation and this way problems that change the effect of the drug such as; low solubility, low permeability, low bioavailability, formation of unwanted metabolites and gastrointestinal problems like decrease in bioavailability due to food intake are felt in minimum.

Generally, there are three different methods and inhalation devices which are suitable for these methods. These are; (a) nebulization devices, (b) inhalators comprising pressurized gas and (c) dry powder inhalators.

Among these, nebulization devices may be preferred since they enable administration of the drug to every patient and they do not require use of physical power. However, the fact that these devices are not mobile, they require electrical power supply, they contain a single dose of drug, they have high risk of infection while use and the fact that the administration time of the drug is considerably a long time like 10-15 prevents daily use this method of administration.

Inhalators comprising pressurized gas are more advantageous compared to the nebulization devices due to the fact that they are mobile and they have a small size. However, these cause accumulation of the drug in the mouth due to large particle size of the mlecules. Under the best circumstances, in other words, when the patient has used the device with 100% efficacy, at most 10-20 % of the drug reaches to the target area. Furthermore, when the drug is sprayed, the particles move very fast (100 km/h) and the temperature of the drug decreases rapidly and in some patients breathing stops as a result of the collision of the cold drug particles with the palate, this is called the cold freon effect. Both the cold freon effect and the carrier gas used in the transmittal of the drug triggers coughing reflex and prevents the delivery of the drug to the lungs. When all of these are taken into account, despite the fact that inhalators comprising pressurized gas have some advantages, they are unable to provide ease of use and the desired therapeutic effect. The inhalators including dry powder came 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 mostly not 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. These enable administration of multiple doses of the drug just like the inhalators with a reservoir. The devices including blister; 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 is still required for delivery of the effective dose to the lungs. Inventors have surprisingly found that use of compositions comprising p₂-agonists and anticholinergic agents in dry powder form stored in aluminium blister pack and used in multiple dose dry powder inhalers provides effective and accurate dose amount and this way side effects of said therapeutic agents are felt in minimum and hence the therepeutic effect is felt in maximum due to the synergistic effect of the combination and to the efficacy of the delivery method of the medication.

Present invention relates to; pharmaceutical composition comprising combination of β₂- agonists and anticholinergic agents in dry powder form, storing said pharmaceutical composition in a peelable blister pack and administration of said composition via a dry powder inhaler.

The inventors have faced with the usually experienced problem of not being able to provide the effective amount of dose in the inhalation. 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 lid sheet 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.

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

In present invention it was seen that the method that is most suitable for administration of effective dose amount to the target area is one wherein the pharmaceutical composition is in dry powder form and stored in blister pack. Method of invention, compared to the methods wherein the pharmaceutical composition comprising at least one p₂-agonist and at least one anticholinergic agent is stored in a capsule or wherein two active agents are stored in two blisters separately is effected from the adhesive power of the micronized powder in minimum amount and an increase in the delivery rate of the pharmaceutial composition was observed. In another aspect present invention provides a method for treatment of patients having pulmonary disease, especially asthma and COPD, wherein said method comprises administration of effective amounts of at least one p₂-agonist and at least one anticholinergic agent and optionally a carrier stored in a peelable blister pack via a dry powder inhaler.

Moreover, in order to obtain maximum benefit from the dry powder formulation that will be administered to the lungs via inhalation, the blister cavity wherein the dry powder is stored must have the maximum discharge capacity.

Additionally, the patents numbered WO-A-2007/012871, WOA-2004/11067, WO-A- 2007/068900, WO- A-2005/0114089 disclose dry powder inhaler wherein the two active agents that are to be combined are stored separately in blister strips to provide multi-active combination. In these devices, both of the blisters comprising different active agents are opened prior to inhalation and during the inhalation these two active agents are mixed in the manifold of the device. However, since two blisters will be used, after the inhalation there will be uninhaled active agent remained in each of the blister and this way it will not be possible to deliver required dose of dry powder formulation. Whereas, when the dry powder inhaler comprising single blister strip containing the combination is used, medication in dry powder form will be inhaled as a result of opening a single blister and this way amount of drypowder remained uninhaled after the inhalation will decrease and this will provide effective dosing.

Surprisingly, the inventors have found that the efficient method of inhaling a medicament comprising combination of ₂-agonist and anticholinergic agent is provided by inhaling said composition in dry powder form, at the same time from a single aluminium blister through a inhalation device that provides multiple inhalation.

Furthermore, inventors have found that delivery of the formulation comprising combination of ₂-agonist and anticholinergic to the lungs was provided in a controlled manner when said combination is in dry powder form

In another aspect present invention provides a medication comprising combination of β₂- agonist and anticholinergic in dry powder form which is inhaled effectively.

In another aspect present invention provides a combination of 2-agonist and anticholinergic combination is dry powder form and inhaled with maximum discharge capacity. In another aspect present invention provides a combination of p2-agonist and anticholinergic combination is dry powder form inhaled by a dry powder inhaler comprising peelable single blister pack.

In another aspect present invention provides a combination of 2-agonist and anticholinergic in dry powder form inhaled through a single blister simultaneously to obtain dose sufficiency. In another aspect present invention provides inhalation of a combination of P2-agonist and anticholinergic in dry powder form by a dry powder inhaler which is simple, safe to use, able to provide multiple dosing, have low cost of manufacture.

The dry powder drug comprising the combination of ₂-agonist and anticholinergic can

According to the invention, the carrier in the dry powder drug can be selected from a group comprising monosaccharides, disaccharides, polysaccharides and oligosaccharides. Preferably lactose is used.

According to the invention the amount of carrier in the dry powder drug is 0-50 mg

The cavity volume of the blister comprising the combination of p₂-agonist and corticosteroid combination in dry powder form and mentioned lactose content is in the range of 20 to 30 mm , preferably of 21 to 25 mm , most preferably of 22 to 23 mm Without facing the mentioned problems, the blister strip pack of the present invention is comprised of a blister which has a cavity volume in the range of 20 to 30 mm , preferably of

3 3

21 to 25 mm , most preferably of 22 to 23 mm and this kind of blister cavity has a load range of 10-100%, preferably 20-90% and most preferably 50-85%. Lid sheet and base sheet of said blister strip are closed very tightly to provide impermeability by using any suitable method.

The lid and base sheet comprising the blister strip package in accordance with the present invention consists of several layers. Polymeric layers, aluminium foil and preferably Aclar® fluoropoylmer film; are among the layers that form the lid and base sheet. Aclar® fluoropolymer film is a polymeric film which used in a blister pack and provides excellent moisture barrier. This chemically inert polymeric film does not cause any change in taste of formulation when it is in contact with dry powder formulation. It can easily form a layered structure with various other polymeric layers. It has a structure which is appropriate to the treatment of heat. To decrease the gas and humidity permeability of the layer and to protect stability of the dry powder stored in the blisters that are present on the peelable blister strip, dessicant agents are preferably added to the polymeric layers. Silica gel, zeolite, alumina, bauksite, anhydrous calcium sulphate, activated carbon and hygroscopic clays can be given as the examples of this dessicant agents. Aluminium foil is used in both lid sheet and base sheet of the blister strip to provide high humidity and gas protection because of that aluminium foil is conventionally used in both lid sheet and base sheet of blister strip package with high humidity 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 lid sheet and base sheet of the blister strip package is in the range of ID to 40 μπι, preferably of 15 to 30 μηι.

The polymeric layers contained by lid sheet and base sheet of the blister strip according to the present invention are the layers which are made from 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. Since adhesion of a part of the dry powder formulation in the inside layer of the cavity due to electrostatic forces results in the inhalation of only some part of the dose when the layer which is in contact with the dry powder formulation is aluminium foil, 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, polyolefin, polyamide, polyvinyl chloride, polyurethane or synthetic polymers

Morever, blisters which form the blister pack may be in any shape provided that the above- mentioned features. Anticholinergic drugs which are one of the group of active agents of the dry powder formulation according to the invention can be selected from ipratropium and tiotropium or their pharmaceutically acceptable salts, solvates, derivatives thereof. p₂-agonists which are one of the group of active agents of the dry powder formulation according to the invention can be selected from salbutamol, levosalbutamol, prosaterol, fenoterol, terbutaline, pirbuterol, metoproterenol, bitolterol mesilate, salmeterol, formoterol, bambuterol and clenbuterol, arformeterol ve Isoetarin and their pharmaceutically acceptable salts, esters, solvates thereof.

The dry powder formulation in blister cavity of mentioned peelable blister strip pack is produced according to the prior art. The particle size of the active agents in dry powder formulation is less than 20μηι. Lactose is used -as a pharmaceutical excipient. The different sized pharmaceutical excipient particles comprising fine or more coarse particles which are various particle size distribution, can be used to provide effective dry powder inhalation. The ratio of anticholinergic or a pharmaceutically acceptable salt thereof and p₂-agonist or a pharmaceutically acceptable salt thereof in the dry powder formulation of the invention is in- the range of 4.5: 1 and 1 :4, preferably 2: 1 and 0.3: 1 by weight.

Bahsedilen §erit seklindeki ayrilabilir blister ambalajda her bir blistenn ihtiva ettigi kuru toz formunda bir ilacin antikolinerjik ya da farmasotik olarak uygun bir tuzunun icerigi 1-50 pg, P2-agonisti ya da farmasotik olarak uygun bir tuzunun icerigi 1-100 pg'dir. The medicament in dry powder form stored in each blister of mentioned peelable blister strip pack contain 1- 50pg of anticholinergic agent or a pharmaceutically acceptable salt thereof, 1-lOOpg of β₂- agonist or a pharmaceutically acceptable salt thereof.

Pharmaceutical composition in accordance with the present invention which comprisescombination of p2-agonist and anticholinergic agent in dry powder form 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 comprising a combination comprising of a

anticholinergic and a p₂-agonist characterized in that

• the components of said combination are in the dry powder form,

· two active agents contained in said pharmaceutical composition are together and they are stored in a peelable, aluminium blister strip,

• said pharmaceutical composition is suitable to be administered by a patient by a device suitable for dry powder

2. A pharmaceutical composition according to claim 1 , wherein anticholinergic used can be selected from tiotropium and ipratropium or pharmaceutically acceptable salts, solvates, derivatives thereof.

3. A pharmaceutical composition according to claim 1, wherein p₂-agonists used can be chosen from 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.

4. A pharmaceutical composition in the dry powder form according to claim 1 wherein said medicament comprises preferably one or more pharmaceutically acceptable carrier and adequate amounts of active agents comprising the mentioned combination.

5. A carrier according to claim 4 wherein said carrier can be selected from a group of a group of monosaccharides, disaccharides, polysaccharides and oligosaccharides

6. A pharmaceutical composition in the dry powder form according to claim 1 wherein said medicament comprises the carrier in an amount of 0 to 50 mg

7. A pharmaceutical composition in the dry powder form according to claim 1, wherein the average partide size of the active agents is less than 20μηι.

8. A pharmaceutical composition in the dry powder form according to any one of the previous claims, the weight ratio of anticholinergic or a pharmaceutically acceptable salt thereof to p₂-agonist or a pharmaceutically acceptable salt thereof in said pharmaceutical composition is in the range of 4.5: 1 and 1 :4, preferably in the range of 2: 1 and 0,3: 1.

9. A pharmaceutical composition in the dry powder form stored in blister wherein each blister is in a blister strip pack according to claims 1 , contains l-50μg of an anticholinergic or a pharmaceutically acceptable salt thereof, l-100μg of p₂-agonist or a pharmaceutically acceptable salt thereof

10. A peelable blister strip according to claim 1 characterized in that it consists of the lid and the base sheets which are opened by peeling away from each other before inhalation.

11. The base sheet according to claim 10 wherein said base sheet consists of more than one layers including also polymeric layer and aluminum foil.

12. The lid sheet according to claim 10 wherein said lid sheet consists of more than one layers including also polymeric layer and aluminum foil

13. A polymeric layer according to any one of the claims 10 to 12 put in the sheets of the blister strip, wherein said polymeric layer contains a desiccant.

14. A polymeric layer according to Claims 13 put in the sheets of the blister strip wherein said polymeric layer is made of a polymeric material which can be preferably selected from thermoplastics and synthetic polymers.

15. A pharmaceutical composition according to claim 1 wherein said composition is used for the treatment of chronic obstructive pulmonary disorder (COPD), allergic rhinitis, allergic or non-allergic asthma in various phases, acute lung injury (ALI), exacerbation of airways hyperactivity, bronchiectasis, emphysema, 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.

16. A pharmaceutical composition according to claim 15 wherein said compositon is preferably used for the treatment of chronic obstructive pulmonary disorder (COPD) and allergic asthma.