TW201347788A - Novel dosage and formulation - Google Patents

Abstract

A pharmaceutical composition for inhalation comprising aclidinium in the form of a dry powder of a pharmaceutically acceptable salt in admixture with a pharmaceutically acceptable dry powder carrier, providing a delivered dose of aclidinium equivalent to about 322 micrograms aclidinium free base.

Description

Novel dosage forms and formulations

The present invention relates to a novel dosage form of aclidinium and a novel method using aclidinium and for treating respiratory diseases, in particular asthma and chronic obstructive pulmonary disease (COPD), Formulation.

Aclidinium bromide is 3(R)-(2-hydroxy-2,2-dithiane-2-ylethyloxy)-1-(3-phenoxypropyl)-1- Nitrobicyclo[2.2.2]octane bromide (3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)
1-(3-phenoxypropyl)-1-azoniabicyclo [2.2.2] octane bromide), as described in WO 01/04118. A preferred process for the production of aclidinium bromide is described in WO2008/009397. Its structural formula is

Aclidinium bromide is a white powder of the formula C ₂₆ H ₃₀ NO ₄ S ₂ Br and a molecular weight of 564.56. It is very slightly soluble in water and ethanol and is insoluble in methanol. This compound is a known long-acting anticholinergic in the treatment of respiratory diseases.

It has now surprisingly been found that for the treatment of respiratory diseases in adults, especially asthma and COPD, alidinium is most effective, with a delivery dose of about 322 micrograms (μg) administered by inhalation. The dose (weight corresponds to adiponium free base, i.e., free ammonium cation), and/or the fine particle dose corresponds to about 140 micrograms of acridinium bromide. Typically, this dose is a single dose or twice daily dose, preferably twice daily.

Typically, about 322 micrograms of the delivered dose of aclidinium free base corresponds to a delivery dose of about 375 micrograms of acridinium bromide.

Accordingly, in a first embodiment the invention provides a pharmaceutical composition for inhalation comprising a aclidinium in the form of a dry powder of a pharmaceutically acceptable salt, such as alidinium bromide, Mixed with lactose powder (i.e., lactose granules), (i) providing a delivery dose equivalent to about 322 micrograms of acridinium (per inhalation) of aclidinium and/or equivalent to about 140 micrograms. A fine particle dose of aclidinium bromide (per inhalation), or (ii) in a multi-dose dry powder inhalation device adjusted to provide approximately 322 micrograms of aclidinium (per An inhalation of aclidinium delivers a dose and/or a fine particle dose equivalent to about 140 micrograms of acridinium bromide (per inhalation). This composition can be administered one or more times a day. It is preferably once or twice a day.

In a second embodiment, the invention provides a method of treating, for example, a respiratory tract condition selected from the group consisting of asthma and chronic obstructive pulmonary disease, in a condition to be treated, comprising administering a dose, typically aclidinium One or two doses per day, such as acridinium bromide, corresponds to about 322 micrograms of acridinium and/or fine particles of about 140 micrograms of acridinium bromide. Dosage, if included, comprises administering a pharmaceutical composition in accordance with the preceding paragraphs. The invention further provides for the use of acilidinium in the manufacture of a medicament, as described in the preceding paragraph, for use in the above process.

Aclidinium can be administered as a single treatment, or with one or more additional anti-inflammatory and/or bronchodilators, for example, corticosteroids, PDE IV inhibitors, and β2-promoters, such as Formoterol, salmeterol, budesonide, and mometasone, and the invention further provides a method as described above, comprising administering an effective amount of the above Reagents, as well as pharmaceutical compositions as described above, further include the above additional agents.

no.

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Typically, acilidinium is administered as a salt having an anion X wherein X is a pharmaceutically acceptable anion of a mono or polyvalent acid. More typically, X is an anion derived from a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, or an organic acid such as methanesulphonic acid, acetic acid, fumaric acid , succinic acid, lactic acid, citric acid or maleic acid. Aclidinium is preferably in the form of acridinium bromide.

Aclidinium is preferably administered in the form of a dry powder, mixed with a suitable carrier, for example, a powder of lactose such as lactose granules, suitable for inhalation. In a preferred embodiment, the lactose is in the form of alpha-lactose monohydrate, preferably crystalline alpha-lactose monohydrate.

For example, in one embodiment, the aclidinium is an alidinium bromide mixed with a lactose powder.

The respiratory disease or condition treated by the formulation and method of the present invention is usually asthma, acute or chronic bronchitis, emphysema, chronic obstructive pulmonary disease (COPD), bronchial hyperresponsiveness or rhinitis, especially It is asthma or chronic obstructive pulmonary disease (COPD), especially COPD.

For the avoidance of doubt, delivering a dose means that the drug can be delivered at the inhalation port (the dose is emitted from the mouthpiece of the inhalation device per consistent movement). The delivered dose can be measured using standard techniques known to those of ordinary skill in the art to which the present invention pertains. In the dosage component of the active agent, "about" as used herein means plus/minus 35% or preferably acceptable change in the normal range of acceptable changes as defined by the European and US Pharmacopoeia, as currently the most stringent requirements. As defined, the US FDA draft guidelines for inhaler addition/subtraction of 25% or acceptable changes are defined by CHMP-directed drug quality inhalation and nasal product plus/minus 15%, especially in the dispensing system. / minus 10%. Thus, the "delivery dose of about 322 micrograms of acridinium free base" refers to a target dose of 322 micrograms of acridinium body to a change in the acceptable normal range of the dispensing system, such as 209-435. Micrograms of acilidinium (plus/minus 35%, acceptable changes as defined by the European and US Pharmacopoeia) or preferably 241-403 micrograms of acridinium (plus/minus 25%, eg The most stringent requirements are currently required by the US FDA to guide the draft into acceptable changes in inhalation, or better than 273-371 micrograms of acridinium (plus/minus 15%, such as CHMP-guided drug quality inhalation and nasal products) An acceptable change as defined) or in particular 289-355 micrograms of acridinium (or in the quantitative dose accuracy of the inhaler).

The delivered dose "about 375 micrograms of acridinium bromide" refers to a target dose of 375 micrograms of the adiponium bromide body to a change in the acceptable normal range of the dispensing system, such as 242-507 micrograms of adiponium bromide (plus/minus 35%, acceptable changes as defined by the European and US Pharmacopoeia) or preferably 281-469 micrograms of adiponium bromide (plus/minus 25%, as currently the most stringent requirements, US FDA guidelines draft inhalation Acceptable changes in definition), or better than 319-431 micrograms of adiponium bromide (plus/minus 15%, as indicated by CHMP guidelines for acceptable intake of drug quality and nasal products) or especially 337-413 micrograms Aldibromolammonium (or in the quantitative dose accuracy of the inhaler).

The fine particle dose (fine particle dose = pneumatic sputum cut of micro-grams of adiponium / adiponium bromide below 5 microns in the delivery reagent) is also subject to change. Thus, the fine particle dose "about 140 micrograms of adiponium bromide" refers to a target dose of 79-206 micrograms of adiponium bromide, preferably 100-190 micrograms of adiponium bromide, more preferably 110-180 micrograms. Adibubromoammonium. Fine particle doses can also be measured using standard techniques known to those of ordinary skill in the art to which the invention pertains. Typically, a fine particle dose of 140 micrograms of adiponium bromide corresponds to a fine particle dose of about 120 micrograms of adiponium. The fine particle dose "about 120 micrograms of adiponium" means a target of 67-139 micrograms of adiponium, preferably 86-163 micrograms of adiponium, more preferably 94-155 micrograms of adiponium.

In a preferred embodiment, the invention relates to a pharmaceutical composition for inhalation, comprising adipic ammonium, in the form of a dry powder of a pharmaceutically acceptable salt, such as adiponium bromide, mixed with a lactose powder (i.e., alpha a lactose monohydrate lactose granule) providing a fine particle dose corresponding to about 120 micrograms of adiponium (adipine free ammonium cation) corresponding to about 140 micrograms of adiponium bromide per inhalation, preferably 86-163 micrograms of adiponium (adipine free ammonium cation) corresponding to 100-190 micrograms of adiponium bromide per inhalation. Typically, the dose is a single daily dose or twice daily dose, preferably twice daily.

The package of the formulation may be adapted for single or multiple dose delivery. In the case of multiple dose delivery, the formulation may be pre-metered or metered for use. Therefore, dry powder inhalation is divided into three groups: (a) single dose, (b) multiple unit dose, and (c) multiple dose devices.

Formulations typically contain a powder mix of the compounds of the invention for inhalation and a suitable powder base (carrier material) such as lactose. Each capsule or cartridge may typically contain between 2 micrograms and 400 micrograms of each effective amount of active ingredient. Alternatively, the active ingredient may be free of excipients.

For the first type of single dose inhaler, a single dose has been weighed by the manufacturer into small containers, most of which are hard gel capsules. The capsule must be removed from a separate box or container and embedded in the storage area of the inhaler. Next, the capsule must be opened or perforated with a needle or cutting blade to allow a portion of the inhaled air flow to entrain the powder through the capsule or to expel the powder from the capsule via the perforations during inhalation during inhalation. After inhalation, the empty capsule is removed again from the inhaler. In most cases, in order to embed or remove the capsule, disassembly of the inhaler is necessary, which can be difficult and cumbersome for some patients. Other disadvantages associated with hard gel capsules using inhaled powders are (a) difficulty in preventing moisture inhalation in the surrounding air, and (b) problems with openings or perforations after the capsule has been exposed to extreme relative humidity, which leads to decomposition or contraction, And (c) the possibility of inhaling capsule fragments. In addition, for some capsule inhalers, incomplete drainage has been reported.

Some capsule inhalers have a drug cartridge that can be transferred from a single capsule into a receiving chamber that undergoes perforation and evacuation as described in WO 92/03175. Other capsule inhalers have a rotating cartridge and a capsule chamber that provides a venting-to-dose air conduit (e.g., WO 91/02558 and GB 2242134). They include different multi-unit dose inhalers and bubble inhalers that have a limited number of unit doses supplied on or in the belt.

Bubble inhalers provide better moisture protection than capsule inhalers. The powder is obtained by a perforated cover such as a bubble film or by detaching the cover film. When a bubble strip is used in place of the disc, the number of doses can be increased, but it is inconvenient for the patient to replace the empty strap. Accordingly, the above devices are often disposable in combination with a dosage system, including the techniques used to transport the belt and open the bubble bag.

Multi-dose inhalers do not contain a pre-measured amount of powder formulation. They consist of a relatively large container and the principle of dose measurement that needs to be operated by the patient. This container carries a plurality of doses that are individually isolated from the bulk of the powder by volumetric displacement. Different dose measurement principles exist, including rotating membranes (eg EP0069715) or discs (eg GB2041763; EP0424790; DE4239402 and EP0674533), rotating cylinders (eg EP0166294; GB2165159 and WO92/09322) and rotating frustums (eg WO92/00771), All have chambers that must be filled with powder from the container. Other multi-dose devices have measuring slides (such as US 5201308 and WO 97/00703) or measuring partial or peripheral depressions of the plunger to remove a specific volume of powder from the container to the transfer chamber or air conduit, EP0505321, WO92/04068 and WO92/04928.

Repeated dose measurement is one of the main concerns of multi-dose inhaler devices. Since the filling of the dose measuring cup or cavity is primarily under the influence of gravity, the powder formulation must exhibit good and stable flow characteristics. For reloaded single-dose and multi-unit dose inhalers, the accuracy and repeatability of the dose measurement can be guaranteed by the manufacturer. Multi-dose inhalers, on the other hand, can contain multiple doses, while the number of loading and unloading doses is typically lower.

Since the inspiratory air flow in a multi-dose device typically passes directly through the dose measuring chamber, and since the multi-dose inhaler's large and rigid dose measuring system cannot be agitated by this inspiratory air flow, the powder mass is simply The entrainment chamber is brought in and small depolymerization is obtained during the discharge process.

Therefore, a separate disintegration device is necessary. However, in practice, they are not always part of the inhaler design. Due to the large amount of dose in the multi-dose device, the powder must adhere to the air conduit and the inner wall of the depolymerization device to minimize and/or clean the components as regularly as possible so as not to affect the remaining dose in the device. Some multi-dose inhalers have a replaceable disposable drug container after the prescribed number of doses have been taken (eg, WO 97/000703). For such semi-permanent multi-dose inhalers and disposable drug containers, preventing drug accumulation is more stringent.

In a preferred embodiment, adiponium is administered via a breath-activated, multi-dose, dry powder inhaler that provides up to 200 doses from a non-removable cartridge. A better inhalation device for this purpose is Genuair® (formerly known as Novolizer SD2FL), or the application of the application described in WO 97/00703, WO 03/000325 or WO 2006/008027 is incorporated herein by reference. Genuair® is also described in H. Chrystyn et al, Int J Clin Pract, March 2012, 66, 3, 309-317; and H. Magnussen et al, Respiratory Medicine (2009) 103, 1832-1837. Another respiratory activated, multi-dose, dry powder inhaler suitable for administration of adiponium is Novolizer®, described in C. Fenton et al, Drugs 2003; 63 (22): 2437-2445; and D. Kohler, Respiratory Medicine (2004) Supplement A, S17–S21.

In another embodiment, adiponium can also be administered by a single dose dry powder inhaler as described in WO 2005/113042 or EP 1270034. These devices are low resistance unit dose inhalers. The unit dosage form of the dry powder formulation is typically a capsule made of gelatin or a synthetic polymer, preferably hydroxypropyl methyl cellulose (HPMC), also known as hypromellose. . The hypromellose capsule is preferably packaged in air bubbles. The bubble is preferably a peeled aluminum foil blister that allows the patient to remove the stored capsule without damaging the patient and optimizing product stability.

In addition to being applied to a dry powder inhaler, the composition of the present invention can be administered by aerosol application of a gas propellant or a so-called nebulizer, and can be sprayed under high pressure via a solution or suspension of a pharmaceutically active substance to produce inhalable particles. Fog.

Drugs administered by inhalation have a controlled particle size. The optimum particle size for inhalation into the bronchial system is usually from 1 to 10 μm, preferably from 2 to 5 μm. Particles having a particle size greater than 20 μm are typically too large when inhaled to reach the small airway. In order to achieve the size of these particles, the active ingredient particles produced can be downsized by conventional methods, such as micronization or supercritical fluid technology. The desired portion can be separated by air classification or screening. Preferably, the particles are crystalline.

High dose repeatability of the micronized powder is difficult due to poor fluidity and extreme agglomeration tendencies. In order to increase the efficiency of the dry powder composition, the particles should be large in the inhaler and small when entering the respiratory tract. Therefore, excipients such as lactose are usually used. In the present invention, the particle size of the excipient is usually much larger than the inhaled drug. When the excipient is lactose, it is usually expressed as lactose particles, preferably crystalline alpha-lactose monohydrate, for example, having an average particle diameter ranging from 20 to 1000 μm, preferably from 90 to 150 μm. The median particle size corresponds approximately to the average diameter and is the diameter of the particles having a larger equivalent diameter of 50% by mass, while the remaining 50% by mass has a smaller equivalent diameter. Thus, the average particle size is generally referred to in the art as d50. The particle size distribution may affect the fluidity, bulk density, and the like. Therefore, in order to characterize the particle size diameter, other equivalent diameters can be used in addition to d50, such as d10 and d90. D10 is that 10% by mass of the particles have an equivalent diameter of a smaller diameter (thus the remaining 90% is rough). D90 is an equivalent diameter of 90% by mass of the particles having a smaller diameter. In one embodiment, the lactose particles used in the formulations of the invention have a d10 of 90-160 [mu]m, a d50 of 170-270 [mu]m, and a d90 of 290-400 [mu]m.

Suitable lactose materials for use in the present invention are commercially available, such as from DMV Internacional (Respitose GR-001, Respitose SV-001, Respitose SV-003); Meggle (Capsulac 60, Inhalac 70, Capsulac 60 INH); And Borculo Domo (Lactohale 100-200, Lactohale 200-300 and Lactohale 100-300).

The weight ratio of lactose granules and adiponium is determined by the inhalation device used, but usually, for example, from 5.1:1 to 100:1, for example from 25:1 to 75:1, preferably from 25:1 to 50:1, More preferably from 30:1 to 35:1.

In a preferred embodiment, the adipic ammonium is administered as a dry powder formulation of adiponium bromide in the form of a mixture of lactose, preferably alpha-lactose monohydrate, and suitably administered via a dry powder inhaler. The lactose weight ratio is from 1:25 to 1:50, preferably from 1:30 to 1:35, wherein the adipic ammonium particles have an average particle size of from 2 to 5 μm in diameter, for example, a diameter of less than 3 μm, and the lactose particles have 90 D10 of -160 μm, d50 of 170-270 μm, and d90 of 290-400 μm.

Additional active agents such as β2-promoters, PDE IV inhibitors, corticosteroids, leukotriene D4 antagonists, epidermal growth factor receptor kinase inhibitors (inhibitors of egfr-kinase), p38 kinase Inhibitors (p38 kinase inhibitors) or NK1 receptor enhancers can be used in the methods and formulations of the present invention. For example, the invention as described herein provides that the adiponium formulation further comprises an effective amount of one or more of the above additional active agents, for example, further comprising an effective amount of a β2-promoting agent and/or a PDE IV inhibitor and/or Or corticosteroid. The invention also provides a method, as previously described herein, for treating a state of the respiratory tract, such as asthma or COPD, comprising administering an adiponectin formulation as described herein and further comprising simultaneously administering an effective amount of the above additional agent, such as more effective A quantity of a β2-promoting agent and/or a PDE IV inhibitor and/or a corticosteroid.

The β2-promoter suitable for use with the adipine of the present invention comprises, for example, its racemates, enantiomers, diastereomers, and mixtures thereof. Arformoterol, bambuterol, bitolterol, buzetro in the form of, and optionally in the form of its pharmaceutically compatible acid addition salts Broxaterol), carbuterol, clenbuterol, dopexamine, fenoterol, formoterol, hexoprenaline , ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meludrine, mesodarazine Metaprotenerol), nolomirole, orciprenaline, pirbuterol, procaterol, reproterol, ritodrine, Rimoterol, salbutamol, salmefamol, salmetero (salmetero) l), sibenadet, sotenerot, sulfonterol, terbutaline, tiaramide, tulobuterol ), GSK-597901, milveterol, GSK-678007, GSK-642444, GSK-159802, HOKU-81, abediterol (LAS100977), KUL-1248, Camotrow ( Carmoterol), indacaterol and 5-[2-(5,6-diethyl-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one (5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]
-8-hydroxy-1H-quinolin-2-one), 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl] Amino}ethyl]-2(3H)-benzothiazolone (4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl} ethyl]amino}ethyl]-2 (3H)-benzothiazolone), 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol (1- (2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)
-2-methyl-2-butylamino]ethanol), 1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2 -methyl-2-butylamino]ethanol (1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]
-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol), 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazine-8- 2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol (1-[2H-5-hydroxy-3-oxo-4H- 1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol), 1-[2H-5-hydroxy-3-oxo -4H-1,4-benzoxazine-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol (1-[2H- 5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-
[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol), 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl]- 2-[3-(4-n-butoxyphenyl)-2-methyl-2-propylamino]ethanol (1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin -8-yl]-2-
[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol), 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl ]-2-{4-[3-(4-Methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol (1-[ 2H-5-hydroxy-3-oxo-4H-1,4
-benzoxazin-8-yl]-2-
{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl
-2-butylamino}ethanol), 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazine-3(4H)-one (5-hydroxy) -8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4
-benzoxazin-3-(4H)-one), 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino)ethanol (1-(4-amino-3) -chloro-5-trifluoromethylphenyl)
-2-tert-butylamino)ethanol) and 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol (1-(4-ethoxycarbonylamino-3) -cyano-5-fluorophenyl)
-2-(tert-butylamino)ethanol).

The β2-promoting agent used in the composition of the present invention is preferably: selectively a racemate thereof, an enantiomers, diastereomers, and a mixture thereof. Arformoterol, bambuterol, bitolterol, buzetro in the form of, and optionally in the form of its pharmaceutically compatible acid addition salts Broxaterol), carbuterol, clenbuterol, dopexamine, fenoterol, formoterol, hexoprenaline , ibuterol, isoprenaline, levosalbutamol, mabuterol, meluadrine, nolomirole, orcinalin (orciprenaline), pirbuterol, procaterol, (R,R)-formoterol ((R,R)-formoterol), reproterol, ritodrine (ritodrine), rimoterol, salbutamol, salmefamol, sibenadet, sulphonate Sulfonterol), terbutaline, tulobuterol, GSK-597901, milveterol, abediterol (LAS100977), KUL-1248, Cammotello (carmoterol), indacaterol.

Since adiponium has a long acting time, it is preferably combined with a long-acting β2-promoter (also called LABAs). Therefore, the combined drug can be administered once or twice daily.

More preferably, the LABAs are in the form of their racemates, enantiomers, diastereomerics, and mixtures thereof, and are selectively pharmaceutically acceptable. Formoterol, salmeterol and GSK-597901, milveterol, LAS100977, 5-(2-{[6-(2) in the form of compatible acid addition salts ,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8-hydroxyquinoline-2(1H)-one (5-(2-{[6 -(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)
-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one), KUL-1248, carmoterol and indacaterol. More preferred are salmeterol, formoterol, abediterol (LAS100977) and indacaterol. Particularly preferred are salmeterol, formoterol and LAS100977 (5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}- 1(R)-hydroxyethyl)-8-hydroxyquinoline-2(1H)-one (5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}
-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one)), especially salmeterol xinafoate, formoterol fumarate and LAS100977(5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8-hydroxyquinoline-2 ( 1H)-ketone (5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)
-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one)).

For example, the present invention provides a pharmaceutical composition for inhalation comprising a pharmaceutically acceptable salt such as bromine in the form of a dry powder of aclidinium and lactose powder and formoterol fumaric acid. The ester (formoterol fumarate) is mixed, (i) providing a dose of aclidinium equivalent to about 322 micrograms of aclidinium free base and/or equivalent to about 140 micrograms of aclidinium bromide. Fine particle dose and a single quantitative nominal dose of about 5-25 micrograms (such as 6, 8.5, 12, 18 or 24 micrograms, such as 6 or 12 micrograms) formoterol fumarate Or (ii) a multi-dose dry powder inhalation device adjusted to provide an adilidinium delivery dose equivalent to about 322 micrograms of aclidinium free base and/or an albromo bromide equivalent to about 140 micrograms. A fine particle dose of ammonium (aclidinium bromide) and a single quantitative nominal dose of about 5-25 micrograms (eg 6, 8.5, 12, 18 or 24 micrograms, such as 6 or 12 micrograms) of formoterol fumarate (formoterol fumarate). A formal dose of about 6 micrograms of formoterol fumarate typically corresponds to a delivery dose of about 4.5 micrograms of formoterol fumarate and a nominal dose of about 12 micrograms. Formoterol fumarate generally corresponds to a delivery dose of about 9 micrograms of formoterol fumarate.

"The delivery dose of about 4.5 micrograms of formoterol fumarate" refers to the target dose of 4.5 micrograms of formoterol fumarate body pair in the distribution system. Acceptable changes in the normal range, such as 2.9-6.1 micrograms of formoterol fumarate (addition / subtraction of 35%, acceptable changes as defined by the European and US Pharmacopoeia) or better 3.3-5.6 micrograms of formoterol fumarate (plus/minus 25%, as currently the most stringent requirements, acceptable changes as defined by the US FDA guidelines draft), or better 3.8-5.2 micrograms of formoterol fumarate (plus/minus 15%, such as CHMP-guided drug quality inhalation and acceptable changes as defined by nasal products) or especially 4.0-5.0 micrograms Formoterol fumarate (or quantitative dose accuracy in an inhaler).

"Approximately 9 micrograms of formoterol fumarate" delivered dose refers to the target dose of 9 micrograms of formoterol fumarate body pair in the distribution system Acceptable changes in the normal range, such as 5.8-12.2 micrograms of formoterol fumarate (addition / subtraction of 35%, acceptable changes as defined by the European and US Pharmacopoeia) or better For 6.7-11.3 micrograms of formoterol fumarate (plus/minus 25%, as currently the most stringent requirements, acceptable changes as defined by the US FDA guidelines draft), or better 7.6-10.3 micrograms of formoterol fumarate (plus/minus 15%, such as CHMP-guided drug quality inhalation and acceptable changes as defined by nasal products) or especially 8.1-9.9 micrograms Formoterol fumarate (or quantitative dose accuracy in an inhaler).

In a particular embodiment, a nominal dose of about 6 micrograms of formoterol fumarate typically corresponds to a dose of about 5.8 micrograms of formoterol fumarate. (formoterol fumarate).

"The delivery dose of about 5.8 micrograms of formoterol fumarate" refers to the target dose of 5.8 micrograms of formoterol fumarate to the distribution system. Acceptable changes in the normal range, such as 3.7-7.8 micrograms of formoterol fumarate (addition / subtraction of 35%, acceptable changes as defined by the European and US Pharmacopoeia) or better For 4.3-7.3 micrograms of formoterol fumarate (plus/minus 25%, as currently the most stringent requirements, acceptable changes as defined by the US FDA guidelines draft inhalation), or better 4.9-6.6 micrograms of formoterol fumarate (plus/minus 15%, such as CHMP-guided drug quality inhalation and acceptable changes as defined by nasal products) or especially 5.2-6.4 micrograms Formoterol fumarate (or quantitative dose accuracy in an inhaler).

In another particular embodiment, a nominal dose of about 12 micrograms of formoterol fumarate typically corresponds to a delivery dose of about 11.8 micrograms of formoterol fumarate. Ester (formoterol fumarate).

"The delivery dose of about 11.8 micrograms of formoterol fumarate" refers to the target dose of 11.8 micrograms of formoterol fumarate body pair in the distribution system. Acceptable changes in the normal range, such as 7.6-15.9 micrograms of formoterol fumarate (addition / subtraction of 35%, acceptable changes as defined by the European and US Pharmacopoeia) or better 8.8-14.8 micrograms of formoterol fumarate (plus/minus 25%, as currently the most stringent requirements, acceptable changes as defined by the US FDA guidelines draft inhalation), or better 10.0-13.6 micrograms of formoterol fumarate (plus/minus 15%, such as CHMP-guided drug quality inhalation and acceptable changes as defined by nasal products) or especially 10.6-13.0 micrograms Formoterol fumarate (or quantitative dose accuracy in an inhaler).

In another particular embodiment, a nominal dose of about 12 micrograms of formoterol fumarate typically corresponds to a delivery dose of about 12 micrograms of formoterol fumarate. Ester (formoterol fumarate).

"The delivery dose of about 12 micrograms of formoterol fumarate" refers to the target dose of 12 micrograms of formoterol fumarate body pair in the distribution system. Acceptable changes in the normal range, such as 7.8-16.2 micrograms of formoterol fumarate (addition / subtraction of 35%, acceptable changes as defined by the European and US Pharmacopoeia) or better It is 9.0-15.0 micrograms of formoterol fumarate (plus/minus 25%, as currently the most stringent requirements, acceptable changes as defined by the US FDA guidelines draft), or better 10.2-13.8 micrograms of formoterol fumarate (plus/minus 15%, such as CHMP-guided drug quality inhalation and acceptable changes as defined by nasal products) or especially 10.8-13.2 micrograms Formoterol fumarate (or quantitative dose accuracy in an inhaler).

The pharmaceutical composition for inhalation comprises adipine and a beta-promoter, for example, formoterol or abediterol (LAS 100977), which may be administered once or more daily. It is preferably once or twice a day.

In the present invention, examples of suitable PDE4 inhibitors which can be combined with adipine are benafentrine dimaleate, etazolate, denbufylline, rolipram. (rolipram), cipamfylline, zardaverine, arofylline, filaminast, tipelukast, tofimilast ), piclamilast, tolafentrine, mesopram, drotaverine hydrochloride, lirimilast, roflumilast ), cilomilast, oglemilast, apremilast, 6-[2-(3,4-diethoxyphenyl)thiazol-4-yl]pyridine 2-carboxylic acid (6-[2-(3,4-Diethoxyphenyl)thiazol-4-yl]pyridine-2-carboxylic acid (tetomilast), (R)-(+)-4 -[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine ((R)-(+)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl) )
-2-phenylethyl]pyridine, CDP-840), N-(3,5-dichloro-4-pyridyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indole- 3-yl]-2-oxoethylamine (N-(3,5-Dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)
-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide, GSK-842470), 9-(2-fluorobenzyl)-N6-methyl-2-(trifluoromethyl)adenine (9 -(2-Fluorobenzyl)-N6-methyl-2-(trifluoromethyl)adenine, NCS-613), N-(3,5-dichloro-4-pyridyl)-8-methoxyquinoline-5- N-(3,5-Dichloro-4-pyridinyl-8-methoxyquinoline-5-carboxamide, D-4418), N-[9-methyl-4-oxo-1-phenyl-3, 4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepine-3(R)-yl]pyridine-4-carboxamide (N-[9 -Methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo
[3,2,1-jk][1,4]benzodiazepin-3(R)-yl]pyridine-4-carboxamide), 3-[3-(cyclopentyloxy)-4-methoxybenzyl] -6-(ethylamino)8-isopropyl-3H-indole hydrochloride (3-[3-(Cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)
-8-isopropyl-3H-purine hydrochloride, V-11294A), 6-[3-(N,N-dimethylaminecarbamimidino)phenylsulfonyl]-4-(3-methoxyphenyl) Amino)-8-methylquinoline-3-carbamoylamine hydrochloride (6-[3-(N,N-Dimethylcarbamoyl)phenylsulfonyl]-4-
(3-methoxyphenylamino)-8-methylquinoline-3-carboxamide hydrochloride, GSK-256066), 4-[6,7-diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]-1 -(2-methoxyethyl)pyridine-2(1H)-one (4-[6,7-Diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]-1-
(2-methoxyethyl)pyridin-2(1H)-one, T-440), (-)-trans-2-[3'-[3-(N-cyclopropylaminemethanyl)-4-oxo --1,4-Dihydro-1,8-naphthyridin-1-yl]-3-fluorobiphenyl-4-yl]cyclopropanecarboxylic acid ((-)-trans-2-[3'-[ 3-(N-Cyclopropylcarbamoyl)-4-oxo-1,4
-dihydro-1,8-naphthyridin-1-yl]-3-fluorobiphenyl-4-yl]
Cyclopropanecarboxylic acid, MK-0873), CDC-801, UK-500001, BLX-914, 2-methoxymethanyl-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethyl) Oxyphenyl)cyclohexan-1-one (2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-
Difluroromethoxyphenyl)-cyclohexan 1-one), cis [4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol (cis [4-cyano] -4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)
-cyclohexan-1-ol], 5(S)-[3-(cyclopentyloxy)-4-methoxyphenyl]-3(S)-(3-methylbenzyl)piperidin-2-one (5(S)-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3(S)
-(3-methylbenzyl)piperidin-2-one, IPL-455903), ONO-6126 (Eur Respir J 2003, 22 (Suppl. 45): Abst 2557) and International Patent Application No. WO03/097613, WO2004/058729, WO Compounds claimed in 2005/049581, WO 2005/123693 and WO 2005/123692.

Examples of suitable corticosteroids and glucocorticoids that can be combined with adipine are prednisolone, methylprednisolone, dexamethasone, and dexamethasone. Dexamethasone cipecilate, naflocort, deflazacort, halopredone acetate, budesonide, beclomethasone Dipropionate), hydrocortisone, triamcinolone acetonide, fluocinolone acetonide, fluocinonide, clocortolone pivalate , methylprednisolone aceponate, dexamethasone palmitoate, tipredane, hydrocortisone aceponate, prednicarbate, dipropyl Alclometasone dipropionate, butixocort propionate, RPR-106541, halometasone Methylprednisolone suleptanate, mometasone furoate, rimexolone, prednisolone farnesylate, ciclesonide, deproxone Proponate propionate, fluticasone propionate, fluticasone furoate, halobetasol propionate, loteprednol etabonate, betamethasone Betamethasone butyrate propionate, flunisolide, prednisone, dexamethasone sodium phosphate, triamcinolone, betamethasone Betamethasone 17-valerate, betamethasone, betamethasone dipropionate, 21-chloro-11β-hydroxy-17α-[2-(methylthio)ethoxycarbonyl ]-4-Chloro-11beta-hydroxy-17alpha-[2-(methylsulfanyl)acetoxy]
-4-pregnene-3,20-dione), desisobutyrylciclesonide, hydrocortisone acetate, hydrocortisone sodium succinate, NS-126 , prednisolone sodium phosphate and hydrocortisone probutate, prednisolone sodium metasulfobenzoate and clobetasol propionate, especially It is budesonide or mometasone.

For example, the present invention provides a pharmaceutical composition for inhalation comprising a pharmaceutically acceptable salt, such as bromine, in the form of a dry powder of aclidinium and a pharmaceutically acceptable carrier, such as lactose granules. And a blend of formoterol fumarate, (i) providing a dose of aclidinium equivalent to about 322 micrograms of aclidinium free base and/or equivalent to about The fine particle dose of 140 micrograms of acridinium bromide and a single quantitative nominal dose of about 100-900 micrograms (eg, 100, 110, 200, 220, 300, 330, 400, 440, 800 or 880 micrograms, For example, 200-450, such as 220 or 440 micrograms) formoterol fumarate, or (ii) a multi-dose dry powder inhalation device is adjusted to provide an equivalent of about 322 micrograms of adiponium. (aclidinium) free base acridine infusion dose and / or equivalent to about 140 micrograms of aclidinium bromide fine particle dose and a single quantitative nominal dose of about 100-900 micrograms (such as 100 , 110, 200, 220, 300, 330, 400, 440, 800 or 880 micrograms, for example 200-450, such as 220 or 440 micrograms) formoterol fumarate.

The pharmaceutical composition for inhalation comprises adiponium and a corticosteroid, such as mometasone fumarate, which may be administered one or more times daily. It is preferably once or twice a day.

The invention also provides a pharmaceutical composition comprising adipic ammonium, a beta2-promoter as defined above, and a corticosteroid, as defined above. The best corticosteroid is mometasone fumarate. These three compositions are suitable for administration once or twice daily.

The following examples are provided to provide a sufficiently clear and complete description of the invention in the art to which the invention pertains, but should not be construed as limiting the basic aspects of the subject matter, as set forth in the foregoing section.
Example example 1
1.1 Inhalation pharmaceutical composition comprising adiponium bromide and lactose

A pharmaceutical composition comprising a batch size of 80 kg of adiponium bromide and an alpha-lactose monohydrate having a d50 of 90-160 micrometers, a d50 of 170-270 micrometers, and a d90 of 290-400 micrometers was prepared.

Mix the adiponium bromide (2.462 kg) and the α-lactose monohydrate (77.538 kg) Bohle blender, sieve the mixture through a sieving machine BTS (Bohle BTS), and finally, mix the mixture at Mix in the Boler Mixer.

The Genuair® (H. Chrystyn et al. (2009)) cartridge fills this composition. The cartridge is adjusted to provide 30 or 60 metered doses. Each actuation of Genuair® provides a dose of 13 mg of the above composition.
Example 1.2. Measurement of delivered dose

The measurement of the delivered dose of the pharmaceutical composition described in point 1.1 (the amount of drug available at the inhalation port) is based on the "collection tube" apparatus (CT) and based on the European Pharmacopoeia ¹ (7) , Section 2.9.18 and US Pharmacopoeia ² USP36-NF31, Chapter 601. In this regard, the Genuair® inhaler is mounted to the collection tube by a dispenser, pressed by the dose button of the Genuair® inhaler and then released, followed by 2L or 4L of air via the inhaler (the inspiratory flow rate via the inhaler is 4KPa) Drop about 65L/min) and collect the tube and inhale. Subsequently, the inhalation powder delivered to the collection tube was extracted with a solvent and analyzed using a High Performance Liquid Chromatography (HPLC).

The average dose per actuation (per inhalation) was 322 micrograms of adiponium (aldipine free ammonium cation), which corresponds to 375 micrograms of adiponium bromide. The acceptable variation defined by the quality of the drug in CHMP Guideline ^{3 for} inhalation and nasal products is 274-370 micrograms of adiponium (adipine free ammonium cation), which corresponds to 319-431 micrograms of adiponium bromide.
Example 1.3. Measurement of Fine Particle Dose (FPD)

The aerodynamic evaluation test of the fine particles (FPD < 5 μm) of the inhaled powder composition was carried out in conjunction with a Genuair® inhaler. The fine particle dose of the pharmaceutical composition described in point 1.1 is based on the principles of aerodynamic evaluation and in accordance with the European Pharmacopoeia ¹ 7th Edition (7.0, Chapter 2.9.18 and US Pharmacopoeia ² USP 36-NF31, Chapter 601 Calculations; using a modified pneumatic impactor analysis using a modified Anderson Cascade Impactor (ACI), 60 liter/min configuration, including pre-separator, stage-1,-0 and stage 1-7 (filtration stage The content of active ingredient at each stage of the impactor is determined by HPLC.

According to the European Pharmacopoeia ¹ 7th Edition (7.0), Chapter 2.9.18 and the United States Pharmacopoeia ² USP36-NF31, Chapter 601, calculate the fine particle dose (FPD < 5 μm); point-to-point interpolation per dose. Linear point-to-point interpolation is done between the stages of the corresponding effective cut-off diameter of the 5 μm mark.

In order to obtain a fine particle dose, the cumulative percentage value (y value) at the line passing through the 5 μm mark of the data plot is determined. The cumulative percentage found must be multiplied by the mass sum of the active ingredients for each dose on Stage-1 to Stage 7 (filter) to obtain a fine particle dose, <5 μm, in micrograms.
Fine particle dose (FPD) [μg] = yFPD·F/100%
FPD = Fine particle dose < 5 μm of active ingredient per dose [μg].
yFPD = y value [%] of cumulative mass percentage at a particle size of 5 μm was evaluated by point-to-point interpolation.
F = total mass [μg] of each dose in Phase-1 to Stage 7 (filter).

The average fine particle dose per actuation (per inhalation) was 120 micrograms of adiponium (aldipine free ammonium cation), which corresponds to 140 micrograms of adiponium bromide. The accepted variance is 86-163 micrograms of adiponium (adipine free ammonium cation) corresponding to 100-190 micrograms of adiponium bromide.
[1] United States Pharmacopeial Convention. Chapter 601. Aerosols, metered-dose inhalers, and dry powder inhalers. In: USP36-NF31. Rockville, MD: USP; 2013:242-262
[2] European Pharmacopeia. Section 2.9.18 – Preparations for inhalation: Aerodynamic assessment of fine particles, 7th edition, European Commission, Strasbourg, 2010, pp 274-285
[3] Human Drug Group (CHMP). Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products. Doc. Ref. EMEA/CHMP/QWP/49313/2005 Corr, 2006

Modifications are included within the scope of the invention which do not affect, alter, modify or modify the basic aspects of the described pharmaceutical compositions.

Claims (26)

A pharmaceutical composition for inhalation comprising a dry powder in the form of a pharmaceutically acceptable salt, adlidinium, mixed with a lactose powder to provide an equivalent of about 322 micrograms of acinidium free base. The aclidinium delivers a dose and/or a fine particle dose equivalent to about 140 micrograms of acridinium bromide. The pharmaceutical composition according to claim 1, wherein a dose of aclidinium equivalent to about 322 micrograms of aclidinium free base is provided in the form of a single dose dry powder formulation and/or Or equivalent to a fine particle dose of about 140 micrograms of acridinium bromide. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is provided in a multi-dose dry powder inhalation device in a form for administering a multi-dose dry powder formulation to provide an equivalent of about 322 micrograms. Acridine in the free base of the alidinium free base and/or a fine particle dose corresponding to about 140 micrograms of acridinium bromide. A pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutically acceptable salt of aclidinium is aclidinium bromide. A pharmaceutical composition according to any one of the preceding claims, wherein the lactose is in the form of a-lactose monohydrate. The pharmaceutical composition according to any one of the preceding claims, wherein the weight ratio of acilidinium to lactose is from 1:25 to 1:75, preferably from 1:25 to 1:50. A pharmaceutical composition according to any one of the preceding claims, wherein the average particle size of the aclidinium is in the range of 2 to 5 microns. The pharmaceutical composition according to any one of the preceding claims, wherein the lactose particles have a d10 of 90-160 μm, a d50 of 170-270 μm, and a d90 of 290-400 μm. The pharmaceutical composition according to any one of the preceding claims, further comprising an effective amount of one or more additional active agents selected from the group consisting of β2-promotors, PDE IV inhibitors, and corticosteroids. . The pharmaceutical composition according to claim 9, wherein the additional active agent is selected from the group consisting of formoterol, salmeterol, and butylidene in the form of a free or pharmaceutically acceptable salt. Budsonide and mometasone. The pharmaceutical composition of claim 10, wherein the additional active agent is formoterol fumarate in an amount of about 5-25 micrograms per nominal dose. The pharmaceutical composition of claim 11, wherein the additional active agent is formoterol fumarate in an amount of about 6 micrograms per nominal dose. The pharmaceutical composition of claim 11, wherein the additional active agent is formoterol fumarate in an amount of about 12 micrograms per nominal dose. A method of treating a respiratory condition selected from the group consisting of asthma and chronic obstructive pulmonary disease in a condition to be treated comprising administering a celidinium equivalent to about 322 micrograms of acridinium free base once daily (aclidinium) Delivery dose and / or a fine particle dose equivalent to about 140 micrograms of acridinium bromide. A method of treating a respiratory condition selected from the group consisting of asthma and chronic obstructive pulmonary disease in a condition to be treated comprising administering adiponium equivalent to about 322 micrograms of aclidinium free base twice daily. (aclidinium) delivers a dose and/or a fine particle dose equivalent to about 140 micrograms of acridinium bromide. The method of claim 14, wherein the pharmaceutical composition according to any one of claims 1 to 13 is administered. The method of any one of claims 14-16, comprising administering an effective amount of one or more additional selected from the group consisting of a β2-promotor, a PDE IV inhibitor, and a corticosteroids. Active reagents. The method of claim 17, wherein the additional active agent is selected from the group consisting of formoterol, salmeterol, and butylene cortisol in the form of a free or pharmaceutically acceptable salt. Budesonide) and mometasone (mometasone). The method of claim 18, wherein the additional active agent is formoterol fumarate in an amount of about 5-25 micrograms per nominal dose. Use of a free or pharmaceutically acceptable salt form of aclidinium for the manufacture of a medicament for administration according to the method of any one of claims 14-19. Use of a free or pharmaceutically acceptable salt form of aclidinium for the manufacture of a pharmaceutical composition according to any one of claims 1-13. A free or pharmaceutically acceptable salt form of aclidinium for use in any of the methods described in claims 14-19. The formulation of any one of claims 1 to 13 for use in any of the methods described in claim 14-19. The formulation of any one of claims 1 to 13 for use in the treatment of a respiratory condition selected from the group consisting of asthma and chronic obstructive pulmonary disease. A dry powder inhalation device adapted to actuate to deliver a dose of aclidinium equivalent to about 322 micrograms of aclidinium free base and/or equivalent to about 140 micrograms of ardibromo Fine particle dose of ammonium (aclidinium bromide). The dry powder inhalation device of claim 25, wherein the device is a single dose and/or multiple doses.