KR20080110854A - New formulation - Google Patents

Abstract

The present invention provides novel pharmaceutical aerosol formulations, methods of making them, their use in therapy, metered dose inhalers containing the formulations, and / or reduces variability in content equality in such formulations. It relates to the use of biocompatible polymers in providing enhanced fine particle fraction (FPF).

Description

New formulations {NOVEL FORMULATIONS}

The present invention provides novel pharmaceutical aerosol formulations, methods of making them, their use in therapy, metered dose inhalers containing the formulations, and / or reduces variability in content equality in such formulations. It relates to the use of biocompatible polymers in providing enhanced fine particle fraction (FPF).

Delivery of a pharmaceutical formulation comprising a drug suspended or dissolved in a carrier to the lungs by inhalation is an important means of treating various diseases including common diseases such as bronchial asthma and chronic obstructive pulmonary disease. Among the drugs administered to the lung are steroids, β ₂ -adrenoreceptor agonists, and anti-cholinergic agents. Such drugs are typically administered in an aerosol formulation comprising a medicament, one or more propellants and a co-solvent such as a surfactant and / or ethanol.

WO02 / 12265 and WO02 / 12266 describe androstanic novel anti-inflammatory and anti-allergic groups for treating and / or preventing diseases such as asthma and COPD comprising a compound of formula (I) or a solvate thereof: Describe the compound. It is desirable to provide pharmaceutical aerosol formulations of compounds of formula (I).

Inhaled pharmaceutical aerosol formulations include one or more hydrofluoroalkane (HFA) propellants such as 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3, It can be formulated as a suspension containing 3-heptafluoro-n-propane (HFA 227).

It is important that the prescribed dose of aerosol drug delivered consistently from the quantitative inhaler (MDI) to the patient for commercial purposes meet the specifications required by the manufacturer and comply with the requirements of the FDA and other regulatory agencies. In other words, all doses dispensed from the can must be equal within precise tolerances. Therefore, it is important that the dosage form is substantially homogeneous throughout the vat and that the dose administered at the time of operation of the metering valve remains similar within close tolerances even after storage. Therefore, the equality of doses dispensed during the shelf life of commercially available devices is important.

The problem of aggregation of the particulate drug may appear as a decrease in the fine particle fraction (FPF) after storage. FPF is a measure of dispensing capacity with the potential to reach the therapeutic portion of the lung. Thus, a significant reduction in FPF means a reduction in the therapeutically effective amount of drug available to the patient, which may be undesirable and ultimately dangerous.

Suspension formulations that are not sufficiently stabilized often result in high levels of drug deposition. The drug may be deposited on the walls of the barrel or on valve components including components of the metered dose inhaler, such as metering chambers or seals. Deposition not only results in a decrease in the total drug content in the canister that is available to the patient by drug loss, but also has an adverse effect on the function of the device, causing valve sticking, orifice blockage, or lumping of the drug. The agglomerated drug can move freely, increasing the dose given to the patient in an unpredictable manner. Moreover, a large number of bins and / or valves may be required to handle such deposition.

One of the difficulties recognized in drug suspension formulations is the difficulty in dissolving sufficient amounts of surfactant in various hydrofluoroalkane (HFA) propellants such as HFA 134a and HFA 227. Surfactants commonly used in chlorofluorocarbon propellants, such as oleic acid, are not sufficiently soluble in HFA 134a or HFA 227.

Many medical aerosol formulations using such propellant systems are disclosed, for example, in EP0372777, WO91 / 04011, WO91 / 11173, WO91 / 11495, WO91 / 14422 and WO92 / 00061. These applications relate to the preparation of pressurized aerosols for administration of a medicament by inhalation and to solve problems associated with the use of HFA propellants in the formulation, in particular instability. The addition of one or more adjuvants such as alcohols, alkanes, dimethyl ethers, surfactants (including fluorinated surfactants, carboxylic acids and certain polyethoxylates) and even small amounts of conventional chlorofluorocarbon propellants has been proposed. .

Teachings of WO98 / 34596 relating to the use of relatively low molecular weight biocompatible, preferably biodegradable polymeric compounds, or dispersions derived from particulate drugs and hydroxy acids, mercapto acids or amino acids, for pharmaceutical drug delivery formulations Despite the teaching of WO94 / 21229 describing medicinal aerosol formulations containing adjuvants, there was a need for an adjuvant that improves content uniformity and / or FPF of aerosol formulations comprising a compound of formula (I).

Summary of the Invention

The present invention has emerged in an attempt to address the problems of the prior art. In one aspect, the present invention provides a pharmaceutical aerosol formulation comprising:

i) A therapeutically effective amount of a particulate agent of formula (I) or a solvate thereof:

(ii) propellants selected from the group consisting of 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-n-propane or mixtures thereof; And

(iii) a biocompatible polymer comprising at least one compound of formula (II)

Wherein n and m independently represent an integer of at least 1 and the independent mean values of n and m in the biocompatible polymer are 6 to 25; Each unit of the formula is independently a D or L configuration:

These and further aspects are contemplated by and included herein.

FIG. 1 shows the compound of formula (II) for the average dose delivered through the valve and% FPF (Anderson Cascade Impactor stage 3-5, approximately aerodynamic diameter 1.1-4.7 μm) for the compound of formula (I) The effects of the biocompatible polymers comprising the data are collected using the Anderson Cascade Impactor at the beginning of use.

2 and 3 show biomarkers comprising a compound of formula (II) with respect to the average dose delivered via valve and% FPF for a combination of a compound of formula (I) and a β ₂ -adrenergic receptor agonist (Compound B) The effects of suitable polymers are shown, and data were collected using the Anderson Cascade Impactor at the beginning of use.

4 and 5 show biomarkers comprising a compound of formula (II) with respect to the average dose delivered via valve and% FPF for a combination of a compound of formula (I) and a β ₂ -adrenergic agonist (compound C) The effects of suitable polymers are shown, and data were collected using the Anderson Cascade Impactor at the beginning of use.

Detailed description of the invention

In some embodiments of the invention, the independent mean values of n and m in the biocompatible polymer are 7-11.

In another aspect of the invention, the pharmaceutical aerosol formulation is

(i) a therapeutically effective amount of a particulate medicament of formula (I) or a solvate thereof;

(ii) propellants selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or mixtures thereof; And

(iii) essentially including a biocompatible polymer comprising at least one compound of formula (II).

In another aspect of the invention, the pharmaceutical aerosol formulation is

(i) a therapeutically effective amount of a particulate medicament of formula (I) or a solvate thereof;

(ii) propellants selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or mixtures thereof; And

(iii) at least one biocompatible polymer comprising at least one compound of formula (II).

As mentioned above, the pharmaceutical aerosol formulations disclosed herein may be useful for treating human or veterinary drugs, particularly human or animal subjects with inflammatory and / or allergic diseases.

Thus, a further aspect of the present invention provides pharmaceutical aerosol formulations for use in treating human or animal subjects, particularly those with inflammatory and / or allergic diseases in human or veterinary drugs.

According to another aspect of the present invention there is provided a use of a pharmaceutical aerosol formulation disclosed above for the manufacture of a medicament administered by inhalation to treat a respiratory disease, for example an inflammation and / or allergic disease such as asthma or COPD. to provide.

In a further aspect, there is provided a method of treating and / or preventing a respiratory disease, comprising administering a pharmaceutical aerosol formulation disclosed above to a human or animal subject.

Pharmaceutical formulations according to the invention can be used, for example, by other anti-inflammatory agents, anticholinergic agents (especially M ₁ , M ₂ , M ₁ / M ₂ or M ₃ receptor antagonists), β ₂ -adrenergic receptor agonists, anti-infective agents ( Eg, antibiotics, antiviral agents) or one or more other therapeutically active agents selected from antihistamines.

Thus, the present invention further provides, in another aspect, for example, another anti-inflammatory agent (eg, corticosteroid or NSAID), an anticholinergic agent, β ₂ -adrenergic receptor agonist, anti-infective agent (eg, antibiotic, antiviral agent) or Provided are the previously described pharmaceutical aerosol formulations having one or more other therapeutically active agents selected from antihistamines. Preferred formulations include β ₂ -adrenoreceptor agonists and / or anticholinergic agents, and / or PDE-4 inhibitors together with compounds of formula (I) or pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof. do. Preferred combinations are those comprising one or two different therapeutic agents.

Where appropriate, other therapeutic ingredient (s) are employed in the form of salts (eg, alkali metal or amine salts or acid addition salts), or as prodrugs, or esters (eg lower alkyl esters), or solvates (eg hydrates). It will be apparent to those skilled in the art that the activity and / or stability and / or physical properties (eg, solubility) of the therapeutic ingredient may be optimized. It will also be apparent that, where appropriate, the therapeutic ingredients may be used in optically pure form.

Particular preference is given to pharmaceutical aerosol formulations comprising a compound of formula (I) previously described herein together with a β ₂ -adrenergic agonist.

Examples of β ₂ -adrenergic receptor agonists include salmeterol (eg, single enantiomers such as racemates or R-enantiomers or S-enantiomers), salbutamol (eg, racemates or R-enantiomers). Single enantiomer), formoterol (e.g. single enantiomer such as racemate or R, R-enantiomer), phenoterol, caroterol, ethaneterol, naminterol, clenbuterol, pirbuterol, plabubu Terrol, reproterol, bambuterol, terbutaline salmephamol, indacaterol and salts thereof, such as cinnapoate (1-hydroxy-2-naphthalenecarboxylate) salts of salmeterol, salbuta Molar sulfate salts or fumarate salts of formoterol. Preference is given to long-acting β ₂ -adrenoreceptor agonists, for example compounds which provide effective bronchodilation for about 12 hours or longer.

Other β ₂ -adrenergic receptor agonists include WO 02/066422, WO 02/070490, WO 02/076933, WO 03/024439, WO 03/072539, WO 03/091204, WO 04/016578, WO 2004/022547, WO And those disclosed in 2004/037807, WO 2004/037773, WO 2004/037768, WO 2004/039762, WO 2004/039766, WO01 / 42193 and WO03 / 042160.

Detailed β ₂ -adrenergic receptor agonists include:

3- (4-{[6-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) hexyl] oxy} butyl) benzenesulfonamide ;

3- (3-{[7-({(2R) -2-hydroxy-2- [4-hydroxy-3-hydroxymethyl) phenyl] ethyl} -amino) heptyl] oxy} propyl) benzenesulfonamide ;

4-{(1R) -2-[(6- {2-[(2,6-dichlorobenzyl) oxy] ethoxy} hexyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol ;

4-{(1R) -2-[(6- {4- [3- (cyclopentylsulfonyl) phenyl] butoxy} hexyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol ;

N- [2-hydroxyl-5-[(1R) -1-hydroxy-2-[[2-4-[[(2R) -2-hydroxy-2-phenylethyl] amino] phenyl] ethyl] Amino] ethyl] phenyl] formamide;

N- {2- [4- (3-phenyl-4-methoxyphenyl) aminophenyl] ethyl} -2-hydroxy-2- (8-hydroxy-2 (1H) -quinolinone-5-yl ) Ethylamine, and

5-[(R) -2- (2- {4- [4- (2-Amino-2-methyl-propoxy) -phenylamino] -phenyl} -ethylamino) -1-hydroxy-ethyl]- 8-hydroxy-1H-quinolin-2-one; And pharmaceutically acceptable salts thereof.

β ₂ -adrenergic receptor agonists include sulfuric acid, hydrochloric acid, fumaric acid, hydroxynaphthoic acid (eg, 1- or 3-hydroxy-2-naphthoic acid), cinnamic acid, substituted cinnamic acid, triphenylacetic acid, sulphate It may be in the form of salts formed with pharmaceutically acceptable acids selected from palmic acid, sulfanilic acid, naphthaleneacrylic acid, benzoic acid, 4-methoxybenzoic acid, 2- or 4-hydroxybenzoic acid, 4-chlorobenzoic acid and 4-phenylbenzoic acid.

Suitable anti-inflammatory agents are corticosteroids. Suitable corticosteroids that can be used with the compounds of the present invention are oral and inhaled corticosteroids and their prodrugs with anti-inflammatory activity. Examples are methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6α, 9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5- Carbonyl) oxy] -3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3- Oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioic acid S- (2-oxo-tetrahydro-furan-3S-yl) ester, 6α, 9α-difluoro-11β- Hydroxy-16α-methyl-3-oxo-17α- (2,2,3,3-tetramethycyclopropylcarbonyl) oxy-androstar-1,4-diene-17β-carbothioic acid S-cyanomethyl Ester, 6α, 9α-difluoro-11β-hydroxy-16α-methyl-17α- (1-methycyclopropylcarbonyl) oxy-3-oxo-androsto-1,4-diene-17β-carbothioic acid S-fluoromethyl esters, beclomethasone esters (eg 17-propionate Ster or 17,21-dipropionate esters), budesonide, flunisolid, mometasone esters (such as furoate esters), triamcinolone acetonides, loflefonides, ciclesonides (16α, 17 [ [(R) -cyclohexylmethylene] bis (oxy)]-11β, 21-dihydroxy-pregna-1,4-diene-3,20-dione), butyxocort propionate, RPR-106541, And ST-126. Preferred corticosteroids are fluticasone propionate, 6α, 9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl) oxy] 3-oxo-androstar-1,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α- ( 2,2,3,3-tetramethycyclopropylcarbonyl) oxy-androsta-1,4-diene-17β-carbothioic acid S-cyanomethyl ester and 6α, 9α-difluoro-11β-hydroxy -16α-methyl-17α- (1-methycyclopropylcarbonyl) oxy-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester.

Non-steroidal compounds that possess glucocorticoid efficacy that may possess selectivity for transrepression over transactivation and may be useful in combination therapy include those contained in the following patents: WO03 / 082827, WO01 / 10143, WO98 / 54159, WO04 / 005229, WO04 / 009016, WO04 / 009017, WO04 / 018429, WO03 / 104195, WO03 / 082787, WO03 / 082280, WO03 / 059899, WO03 / 101932, WO02 / 02565, WO01 / 16128 , WO00 / 66590, WO03 / 086294, WO04 / 026248, WO03 / 061651 and WO03 / 08277.

Suitable anti-inflammatory agents are nonsteroidal anti-inflammatory drugs (NSAIDs).

Suitable NSAIDs include sodium chromoglycate, nedochromyl sodium, phosphodiesterase (PDE) inhibitors (eg, theophylline, PDE4 inhibitors or mixed PDE3 / PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis (eg montelukast), iNOS Inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (eg adenosine 2a agonists), cytokine antagonists (eg chemokine antagonists such as CCR3 antagonists) or cytokine synthesis Inhibitors, or 5-lipoxygenase inhibitors. iNOS (inducible nitric oxide synthase inhibitor) is preferred for oral administration. Suitable iNOS inhibitors are those disclosed in WO93 / 13055, WO98 / 30537, WO02 / 50021, WO95 / 34534 and WO99 / 62875. Suitable CCR3 inhibitors are those disclosed in WO02 / 26722.

Of particular interest is the use of compounds of formula (I) with phosphodiesterase 4 (PDE4) in the case of formulations applied for inhalation. PDE4-specific inhibitors useful in this aspect of the invention are known to inhibit PDE4 enzymes or have been found to act as PDE4 inhibitors and are not compounds that inhibit PDE3 and PDE5 as well as other members of PDE such as PDE4. It may be any compound that is only a PDE4 inhibitor.

Compounds of interest include cis-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid, 2-carbomethoxy-4-cyano-4- ( 3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one and cis- [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane -1-ol]. In addition, cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid (also known as cilomilast) and salts, esters thereof Prodrugs or physical forms are disclosed in US Pat. No. 5,552,438, published September 3, 1996; The patents and compounds disclosed herein are hereby incorporated by reference in their entirety.

Other compounds of interest include AWD-12-281 from Elbion (Hofgen, N. et al. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P 98, CAS reference No 247584020 -9); 9-benzyladenine derivative (INSERM) named NCS-613; D-4418 from Chiroscience and Schering-Plough; Benzodiazepine PDE4 inhibitors from Pfizer identified as CI-1018 (PD-168787); Benzodioxole derivatives disclosed in Kyowa Hakko in WO 99/16766; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, LJ et al Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12 (Suppl 28) Abst P2393); Loflumilast from Byk-Gulden (CAS reference No 162401-32-3) and phthalazinone (WO99 / 47505, the disclosure of which is incorporated herein by reference); Fumapentrin, a mixed PDE3 / PDE4 inhibitor manufactured and published by Byk-Gulden, (-)-p-[(4aR ^* , 10bS ^* )-9-ethoxy-1,2,3,4,4a, 10b Hexahydro-8-methoxy-2-methylbenzo [c] [1,6] naphthyridin-6-yl] -N, N-diisopropylbenzamide, now Altana; Arophylline in development by Almirall-Prodesfarma; VM554 / UM565 from Vernalis; Or T-440 (Tanabe Seiyaku, FUJI, K et al. J Pharmacol Exp Ther, 1998, 284 (1) 162), and T2585.

Further compounds of interest are disclosed in published international patent applications WO04 / 024728 (Glaxo Group Ltd), PCT / EP2003 / 014867 (Glaxo Group Ltd) and PCT / EP2004 / 005494 (Glaxo Group Ltd).

Suitable anticholinergics are compounds which act as antagonists at the muscarinic receptor, in particular, M ₁ or M ₃ receptor antagonist, M ₁ / M ₃ or M ₂ / M ₃ receptors, dual antagonists, M ₁ / M ₂ / M of the Compound that is a pan-antagonist of _three receptors. Exemplary compounds for administration via inhalation include ipratropium (e.g., bromide, CAS 22254-24-6, sold as the name Atrovent), oxytropium (e.g., bromide, CAS 30286-75) -0) and tiotropium (eg, as bromide, CAS 136310-93-5, sold as spiribar). Also of interest are rebatromate (eg, CAS 262586-79-8 as hydrobromide) and LAS-34273 disclosed in WO01 / 04118. Exemplary oral compounds include pyrenzepine (CAS 28797-61-7), darfenacin (CAS 133099-04-4, or CAS 133099-07-7 as hydrobromide, sold under the name Enablex), Oxybutynin (CAS 5633-20-5, sold under the designation ditropan), Terodilin (CAS 15793-40-5), Tolterodine (CAS 124937-51-5, or CAS 124937-52- as tartrate 6, sold under the name detrol), otylonium (e.g., bromide, CAS 26095-59-0, sold under the name spammomen), throsium chloride (CAS 10405-02-4) and solvena Sin (CAS 242478-38-2, also known as CAS 242478-37-1, or YM-905 and sold under the name Bishcare) as succinate.

Other suitable anticholinergic agents include compounds of formula (XXI), which are disclosed in US patent application 60/487981:

Wherein the preferred orientation of the alkyl chain attached to the tropan ring is endo; R ³¹ and R ³² are preferably straight or branched chain lower alkyl groups having 1 to 6 carbon atoms, cycloalkyl groups having 5 to 6 carbon atoms, cycloalkyl-alkyl having 6 to 10 carbon atoms, 2-thienyl, 2 Independently selected from the group consisting of pyridyl, phenyl, phenyl substituted by alkyl groups having no more than four carbon atoms and phenyl substituted by alkoxy groups having no more than four carbon atoms;

X ⁻ is an anion which combines with a positive charge of N atoms, and X ⁻ may be, but is not limited to, chloride, bromide, iodide, sulfate, benzene sulfonate and toluene sulfonate, for example, includes .

(3-endo) -3- (2,2-di-2-thienylethenyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane bromide;

(3-endo) -3- (2,2-diphenylethenyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane bromide;

(3-endo) -3- (2,2-diphenylethenyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane 4-methylbenzenesulfonate;

(3-endo) -8,8-dimethyl-3- [2-phenyl-2- (2-thienyl) ethenyl] -8-azoniabicyclo [3.2.1] octane bromide; And / or

(3-endo) -8,8-dimethyl-3- [2-phenyl-2- (2-pyridinyl) ethenyl] -8-azoniabicyclo [3.2.1] octane bromide.

Further suitable anticholinergic agents include compounds of formula (XXII) or (XXIII), which are disclosed in US patent application 60/511009:

Wherein the H atom indicated is at the exo position;

R ⁴¹ is an anion which is bonded to the positive charge of the N atom, and R ⁴¹ may be, but is not limited to, chloride, bromide, iodide, sulfate, benzene sulfonate and toluene sulfonate;

R ⁴² and R ⁴³ are straight or branched chain lower alkyl groups (preferably having 1 to 6 carbon atoms), cycloalkyl groups (having 5 to 6 carbon atoms), cycloalkyl-alkyl (s 6 to 10 carbon atoms) With carbon atoms), heterocycloalkyl (with 5-6 carbon atoms) and N or O as heteroatom, heterocycloalkyl-alkyl (with 6-10 carbon atoms) and N as heteroatom Or is independently selected from the group consisting of O, aryl, substituted or unsubstituted aryl, heteroaryl, and substituted or unsubstituted heteroaryl;

R ⁴⁴ is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₁₂ ) cycloalkyl, (C ₃ -C ₇ ) heterocycloalkyl, (C ₁ -C ₆ ) alkyl (C ₃ -C ₁₂ ) cycloalkyl , (C ₁ -C ₆ ) alkyl (C ₃ -C ₇ ) heterocycloalkyl, aryl, heteroaryl, (C ₁ -C ₆ ) alkyl-aryl, (C ₁ -C ₆ ) alkyl-heteroaryl, -OR ⁴⁵ , -CH ₂ OR ⁴⁵ , -CH ₂ OH, -CN, -CF ₃ , -CH ₂ O (CO) R ⁴⁶ , -CO ₂ R ⁴⁷ , -CH ₂ NH ₂ , -CH ₂ N (R ⁴⁷ ) SO ₂ R ⁴⁵ , -SO ₂ N (R ⁴⁷ ) (R ⁴⁸ ), -CON (R ⁴⁷ ) (R ⁴⁸ ), -CH ₂ N (R ⁴⁸ ) CO (R ⁴⁶ ), -CH ₂ N (R ⁴⁸ ) SO ₂ (R ⁴⁶ ), —CH ₂ N (R ⁴⁸ ) CO ₂ (R ⁴⁵ ), —CH ₂ N (R ⁴⁸ ) CONH (R ⁴⁷ );

R ⁴⁵ is (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl (C ₃ -C ₁₂ ) cycloalkyl, (C ₁ -C ₆ ) alkyl (C ₃ -C ₇ ) heterocycloalkyl, ( C ₁ -C ₆ ) alkyl-aryl, (C ₁ -C ₆ ) alkyl-heteroaryl;

R ⁴⁶ is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₁₂ ) cycloalkyl, (C ₃ -C ₇ ) heterocycloalkyl, (C ₁ -C ₆ ) alkyl (C ₃ -C ₁₂ ) cycloalkyl , (C ₁ -C ₆₎ alkyl (C ₃ -C ₇₎ heterocycloalkyl, aryl, heteroaryl, (C ₁ - C ₆₎ alkyl-aryl, (C ₁ -C ₆₎ alkyl-heteroaryl group consisting of Is selected from;

R ⁴⁷ and R ⁴⁸ are H, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₁₂ ) cycloalkyl, (C ₃ -C ₇ ) heterocycloalkyl, (C ₁ -C ₆ ) alkyl (C _3- C ₁₂ ) cycloalkyl, (C ₁ -C ₆ ) alkyl (C ₃ -C ₇ ) heterocycloalkyl, (C ₁ -C ₆ ) alkyl-aryl and (C ₁ -C ₆ ) alkyl-heteroaryl Independently selected from and includes, for example:

(Endo) -3- (2-methoxy-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide ;

3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionitrile;

(Endo) -8-methyl-3- (2,2,2-triphenyl-ethyl) -8-aza-bicyclo [3.2.1] octane;

3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionamide;

3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionic acid;

(Endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide;

(Endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane bromide;

3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propan-1-ol;

N-benzyl-3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionamide;

(Endo) -3- (2-carbamoyl-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide;

1-benzyl-3- [3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -urea;

1-ethyl-3- [3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -urea;

N- [3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -acetamide;

N- [3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -benzamide;

3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-di-thiophen-2-yl-propionitrile;

(Endo) -3- (2-cyano-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide ;

N- [3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -benzenesulfonamide;

[3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -urea;

N- [3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -methanesulfonamide; And / or

(Endo) -3- {2,2-diphenyl-3-[(1-phenyl-methanoyl) -amino] -propyl} -8,8-dimethyl-8-azonia-bicyclo [3.2.1] Octane bromide.

More preferred compounds useful in the present invention are

(Endo) -3- (2-methoxy-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide ;

(Endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide;

(Endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane bromide;

(Endo) -3- (2-carbamoyl-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide;

(Endo) -3- (2-cyano-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide ; And / or

(Endo) -3- {2,2-diphenyl-3-[(1-phenyl-methanoyl) -amino] -propyl} -8,8-dimethyl-8-azonia-bicyclo [3.2.1] Octane bromide.

Suitable antihistamines (also referred to as H ₁ -receptor antagonists) are known to inhibit H ₁ -receptors and include any one or more of numerous antagonists that are safe for human use. First generation antagonists include ethanolamine, ethylenediamine, and derivatives of alkylamines, for example diphenylhydramine, pyrylamine, clemastine, chloropheniramine. Second-generation antagonists that are non-sedating include loratidine, desloratidine, terfenadine, astemisol, acribastine, azelastine, levocetirizine fexofenadine, and cetirizine.

Examples of preferred antihistamines are loratidine, desloratidine, fexofenadine and cetirizine.

In the formulations of the invention, it is contemplated that biocompatible polymers comprising at least one compound of formula (II) have good surfactant properties. This surfactant property reduces the deposition on the inner surface of the can, thereby increasing the amount of drug that reaches the valve, stabilizing, enhancing and reducing the variability of the fine particle fraction (FPF), and the change in delivered dose uniformity. Reducing the surplus to provide good content equality performance and to reduce product oversupply required to achieve the delivered capacity. Biocompatible polymers comprising at least one compound of formula (II) in the formulation of the present invention are considered to be advantageous in terms of improving the stability of the aerosol formulation by reducing drug deposition, improving shelf life, and the like.

In one aspect of the invention, a pharmaceutical aerosol formulation is provided wherein the particulate medicament of formula (I) is 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β-hydroxy -16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester.

In some embodiments of the present invention, pharmaceutical aerosol formulations are provided wherein the particulate medicament of formula (I) is in unsolvated form.

In some embodiments of the invention, there is provided a pharmaceutical aerosol formulation wherein the particulate medicament of formula (I) is Form 1 polymorph.

WO02 / 12265 and WO02 / 12266 describe compounds of formula (I), including solvates, unsolvated forms and polymorph 1, these applications are incorporated herein by reference.

In one aspect of the invention, 3- (4-{[6-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) hexyl] There is provided a pharmaceutical aerosol formulation disclosed above further comprising oxy} butyl) benzenesulfonamide.

In another aspect of the invention, 3- (3-{[7-({(2R) -2-hydroxy-2- [4-hydroxy-3-hydroxymethyl) phenyl] ethyl} -amino) heptyl ] Oxy} propyl) benzenesulfonamide is provided in the pharmaceutical aerosol formulations disclosed above.

In another aspect of the invention, 4-{(1R) -2-[(6- {2-[(2,6-dichlorobenzyl) oxy] ethoxy} hexyl) amino] -1-hydroxyethyl}- There is provided a pharmaceutical aerosol formulation disclosed above further comprising 2- (hydroxymethyl) phenol.

In another aspect of the invention, 4-{(1R) -2-[(6- {4- [3- (cyclopentylsulfonyl) phenyl] butoxy} hexyl) amino] -1-hydroxyethyl}- Provided are the pharmaceutical aerosol formulations disclosed above further comprising 2- (hydroxymethyl) phenol.

In another aspect of the invention, N- [2-hydroxyl-5-[(1R) -1-hydroxy-2-[[2-4- [[(2R) -2-hydroxy-2-phenyl There is provided a pharmaceutical aerosol formulation disclosed above further comprising ethyl] amino] phenyl] ethyl] amino] ethyl] phenyl] formamide.

In another aspect of the invention, N- {2- [4- (3-phenyl-4-methoxyphenyl) aminophenyl] ethyl} -2-hydroxy-2- (8-hydroxy-2 (1H) Provided above is a pharmaceutical aerosol formulation disclosed further comprising -quinolinone-5-yl) ethylamine.

In a further aspect of the invention, 5-[(R) -2- (2- {4- [4- (2-amino-2-methyl-propoxy) -phenylamino] -phenyl} -ethylamino)- There is provided a pharmaceutical aerosol formulation disclosed above further comprising 1-hydroxy-ethyl] -8-hydroxy-1H-quinolin-2-one.

Biocompatible polymers comprising one or more compounds of formula (II) can be prepared by a number of reaction methods, such as those disclosed in WO94 / 21229 and WO98 / 34596. In one embodiment, lactic acid can be polymerized by condensation followed by capping the hydroxyl end of the polymer with an acetyl capping agent. The ethylenediamine can then be coupled to the oligolactic acid through condensation and formation of amides.

This reaction can proceed in solution and, if applicable, the solvent can also function as a propellant in the formulation. Preferred solvents that can also function as propellants are HFA 134a and HFA 227. Examples of suitable synthetic methods for polymerizing and capping polymers are described in United States Patent Application Nos 60/533172 ("Medicinal Compositions and Methods for the Preparation Thereof, Capecchi et al) and 60/613063 (" Medicinal Aerosol Formulations and Methods of Synthesizing)). Ingredients Therefor ", Bechtold et al.), The descriptions of which are incorporated herein by reference.

It is contemplated that the polymer condensation process described in US patent application 60/533172 will provide significant advantages. In addition to the unpredictable excellence of the product, it is also contemplated to provide advantages over other polymerization processes using metal-based catalysts that are more expensive, provide environmental losses and cause health problems due to residual contaminants. It also provides an improved degree of acylation or acetylation of the OH end groups and the degree of derivatization of the improved acid functional groups with capping or bridging groups such as ethylenediamine. In one aspect, the reaction method comprises less than 10%, less than 5%, or less than the amount of N, N'-ethylenebis (acetyloligolactyl) amide prepared with the unreacted oligolactic acid and oligolactic derivative having free hydroxyl Provide completeness to be less than 1%. In one aspect, the reaction process comprises a molar ratio of unreacted oligolactic acid and oligolactic acid derivatives with free carboxylic acid less than 10%, less than 5% of the amount of N, N'-ethylenebis (acetyloligolactyl) amide prepared, Or completeness to be less than 1%. The relative amounts of unreacted oligolactic acid and oligolactic acid derivatives with free carboxylic acids can be determined by conventional analytical methods such as, for example, nuclear magnetic resonance (NMR) or liquid chromatography-mass spectrometer (LC-MS). have.

The use of such biocompatible polymers for preparing formulations according to the invention is believed to result in effective suspension stabilization and reduced drug deposition. Thus, the amount of biocompatible polymer applied is preferably in the range of 0.0025% to 3% w / w, specifically 0.01% to 0.5% w / w, more specifically 0.05% to 0.2% w / w relative to the propellant. Do.

The particle size of the particulate (eg micronized) medicament will be less than 100 microns, preferably less than 20 microns, for example 1-10 microns, such as 1-, since it should be possible to optimize the amount of medicament that is inhaled into the lungs, for example, when administering an aerosol formulation. It would be desirable to have a MMAD (mass median aerodynamic diameter) in the 5 micron range.

The final aerosol formulation contains 0.005-10% w / w, preferably 0.005-5% w / w, in particular 0.01-1.0% w / w, based on the total weight of the formulation.

Administration of the medicament may be indicated for the treatment or prophylactic treatment of mild, moderate or severe acute or chronic signs. The exact dose administered will depend on the age and condition of the patient, the particular particulate agent used and the frequency of administration and ultimately will be at the discretion of the attending physician. When applied in combination with a medicament, the dose of each component of the combination will generally be the dose applied for each component used alone. Typically, administration will be one or more times per day, for example once to eight times, and may provide, for example, one, two, three or four puffs each time.

Suitable daily doses may range from 25 to 800 micrograms for compounds of formula (I), 5 to 20 micrograms for Compound B, and 10 to 50 micrograms for Compound C, depending on, for example, the severity of the disease. have.

Each commonly filled canister used as a metered dose inhaler contains 100, 160 or 240 doses or puffs of the medicament.

In some embodiments, a single propellant is applied, for example 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-n-propane, Suitably 1,1,1,2-tetrafluoroethane.

It is preferred that the formulations of the invention do not contain compounds that can cause the decomposition of stratospheric ozone. Specifically, it is preferable that chlorofluorocarbons such as CCl ₃ F, CCl ₂ F ₂ and CF ₃ CCl ₃ are not actually present in the formulation.

If desired, the propellant may further contain volatile adjuvant such as saturated hydrocarbons such as propane, n-butane, isobutane, pentane and isopentane or dialkyl ethers such as dimethyl ether. Generally, up to 50% w / w of propellant may comprise, for example, 1 to 30% w / w of volatile hydrocarbons. However, formulations that are free of volatile adjuvant may be desirable. In certain cases, it may be desirable to include a suitable amount of water, which may be beneficial to modify the dielectric properties of the propellant.

Polar adjuvants that can be incorporated into the formulations of the invention when desired are, for example, C _2-6 aliphatic alcohols and polyols such as ethanol, isopropanol and propylene glycol and mixtures thereof. Typically ethanol will be applied. In general, only small amounts (eg, 0.05 to 3.0% w / w) of the polar adjuvant are required, and using an amount greater than 5% w / w may adversely tend to dissolve the drug. The formulation preferably contains less than 1% w / w polar adjuvant, for example about 0.1% w / w. Most preferably, no polar adjuvant is actually present in the formulations according to the invention. Polarity can be measured, for example, by the method disclosed in European Patent Application Publication No. 0327777.

In various optional embodiments, the formulation actually comprises (1) a volatile adjuvant such as, but not limited to, a saturated hydrocarbon such as propane, n-butane, isobutane, pentane, isopentane or dialkyl ether such as dimethyl Ether, (2) conventional surfactants such as oleic acid, lecithin and sorbitan trioleate, and / or (3) high polar components such as alcohols such as ethanol. For the purposes of the present invention, the term “substantially free” refers to the presence of said component (s) in an amount below a detectable limit.

The formulations according to the invention may optionally contain one or more additional ingredients conventionally used in the field of pharmaceutical aerosol formulations. Such optional ingredients include, but are not limited to, taste masking agents, sugars, buffers, antioxidants, water and chemical stabilizers.

The invention extends to the already described formulations consisting of these elements rather than including them.

A further embodiment of the present invention is a sealed container capable of withstanding the pressure required to maintain the propellant as a liquid, such as a metered dose inhaler, containing the aerosol formulation disclosed above.

"Metered inhaler" or MDI means a unit comprising a can, a safety cap covering the can and a formulation metering valve located in the cap. The MDI system includes a suitable channeling device. Suitable channeling devices include, for example, valve actuators and cylindrical or cone-like passages, such as mouthpiece actuators, through which drugs can be delivered from the filled container to the nose or mouth of the patient through the metering valve.

The MDI may generally comprise a container capable of withstanding the vapor pressure of the propellant used, for example plastic or plastic-coated glass bottles or preferably metal cans, for example stainless steel, optionally anodized and lacquer -Coated and / or plastic coated (e.g., in WO96 / 32099, incorporated herein by reference, some or all of its inner surface is optionally coated with one or more fluorocarbon polymers together with one or more non-fluorocarbon polymers) Aluminum or an alloy thereof, and the container is sealed with a metering valve. The cap may be secured on the can through ultrasonic melting, screw assembly or crimping. MDIs taught herein can be prepared by methods in the art (eg, see Byron, supra and WO96 / 32099). Preferably, the canister is assembled with the cap assembly where the drug metering valve is located in the cap and the cap is crimped in place.

In one embodiment of the invention, the metal inner surface of the can is coated with a fluoropolymer, most preferably blended with a non-fluoropolymer. In another embodiment, the metal inner surface of the can is coated with a polymer blend of polytetrafluoroethylene (PTFE) and polyethersulfone (PES). In a further embodiment of the invention, the entire metal inner surface of the can is coated with a polymer blend of polytetrafluoroethylene (PTFE) and polyethersulfone (PES).

The formulations according to the invention can obviate the need for further processing of the keg and / or components, for example by coating, which can result in cost savings, especially when producing bulks.

The metering valve is designed to deliver a dosage of formulation for one operation and may include a gasket to prevent leakage of propellant through the valve. The gasket can include any suitable elastomeric material such as, for example, low density polyethylene, chlorobutyl, bromobutyl, EPDM, black and white butadiene-acrylonitrile rubber, butyl rubber and neoprene. Suitable valves are well known in the aerosol industry, for example Valois, France (e.g. DF10, DF30, DF60), Bespak plc, UK (e.g. BK300, BK357) and 3M. Commercially available from Neotechnic Ltd, UK (eg Spraymiser ^™ ).

In various embodiments, MDI is disclosed in U.S. Pat.Nos. 6,119,853, 6,179,118, 6,315,112, 6,352,152, 6,390,291, 6,679,374, including but not limited to overlap packages for storing and containing MDI, as well as but not limited to U.S. Patents 6,360,739 and 6,431,168. It may also be used with other structures such as capacity counter units such as those disclosed.

Formulations of the present invention may be prepared by dispersing the medicament of formula (I) and the biocompatible polymer of formula (II) in a suitable container in a propellant, for example with the aid of an ultrasonic or high-shear mixer. . This method is preferably carried out under controlled humidity conditions.

A further aspect of the invention involves a method of filling the formulation with MDI.

Conventional bulk production methods and machines well known to those skilled in the art of pharmaceutical aerosol production can be applied to the production of large scale ash for the commercial production of filled vats. Thus, for example, in one bulk manufacturing method, the metering valve is crimped into an aluminum can to form an empty bin. The particulate medicament is added to the filling vessel and the liquefied propellant is pressurized with the liquefied propellant containing the surfactant through the filling vessel into the production vessel. The drug suspension is mixed and then recycled to the filling machine and an aliquot of the drug suspension is filled into the vat via a metering valve.

In an alternative method, an aliquot of the liquefied formulation is applied to an open canister under sufficiently cold conditions to prevent the formulation from vaporizing and then crimp the metering valve over the canister.

Typically, in batches prepared for pharmaceutical use, each filled canister is checked-weighed, the batch number is coded and then packed into a tray for storage prior to release test.

Each filled canister is conveniently assembled into a suitable channeling device prior to use to form a metered dose inhaler system for administering medication to the patient's lungs or nasal cavity.

The chemical and physical stability and pharmaceutical solubility of the aerosol formulations according to the invention can be measured by techniques well known to those skilled in the art. Thus, for example, the chemical stability of the components can be determined, for example, by HPLC assay after long term storage of the product. Physical stability data is derived from other conventional analytical techniques such as, for example, leak tests, valve delivery assays (average weight injected for one run), volume reproducibility assays (active ingredient for one run), and spray dispense analysis. You can get it.

The fine particle fraction of the aerosol formulations according to the invention can be measured by conventional techniques, for example by cascade adhesion, which measures the particle size distribution. Cascade impactors are designed to mimic a person's oral cavity and bronchus, and the cascade impactor test is designed to show the amount of drug inhaled at various stages. As used herein, the expression "cascade adhesion" assay means measuring the deposition of doses released by pressurized inhalation as defined in the European Pharmacopoeia, Section 2.9.18, 5 ^th edition "Preparations for inhalation, Apparatus D". do. This technique allows the "breathable fraction" of the aerosol formulation to be calculated. One method used to calculate the "breathable fraction" is based on the "fine particle fraction" which is the amount of active ingredient (aerodynamic diameter 1.1-4.7 μm) collected in steps 3 to 5, which is the casing disclosed above. Lung, for one operation, is expressed as a percentage of the total amount of active ingredient delivered in one operation using the Cade Impactor method. The early stage represents the upper range of the aerosol device itself, the throat and the bronchus, and the later stage represents potential systemic absorption through the lung walls which can cause serious side effects.

Metered dose inhalers are designed to deliver a fixed unit dose of a medicament, eg, 10 to 5000 micrograms per puff, per operation or "puff."

Administration of the medicament may be indicated for the treatment or prophylactic treatment of mild, moderate or severe acute or chronic signs. The exact dose administered will depend on the age and condition of the patient, the particular particulate agent used and the frequency of administration and ultimately will be at the discretion of the attending physician. When applied in combination with a medicament, the dose of each component of the combination will generally be the dose applied for each component used alone. Typically, administration will be one or more times per day, for example once to eight times, for example, one, two, three or four puffs may be provided each time.

Suitable dosage regimens for other agents will be known or readily available to those skilled in the art.

Another aspect of the invention provides the use of a biocompatible polymer of formula (II) to improve FPF or reduce variability in content equality, for example by reducing the relative standard error (RDS) of the individual release dose. Include.

Unless otherwise specified in the context of the specification and the claims below, the terms "comprises" and "comprising" and the like include variations of the specified integer or step without excluding any other integer or step or group of integers or steps. Or it will be understood to include groups of integers.

The following non-limiting examples are intended to illustrate the present invention.

Capacity Passing Unit (DTU) Method Procedure

The dose aggregation device (500 ml separating funnel with cotton plug) was sampled and the flow rate was set to 20 L / min. The test unit was stored at ambient temperature for 2 weeks before the DUT test after manufacture. For the initial testing of the unit, the MDI was primed twice with a priming actuator, primed four times with the test actuator and discarded, shaking the unit between each run. Twice test agonists were collected in a volume collection device while shaking the unit between each run. The collection device was washed with a suitable volume of diluent and the wash with the collected volume was analyzed by conventional HPLC analysis. At the end of the unit test, the MDI was run and discarded for an additional 48 hours and shaken between each run. The MDI was then run four times with a new test actuator and discarded. Two test agonists were then collected in the dose collection device and the unit was shaken between each run. The collection device was rinsed with a suitable volume of diluent and the washes with the collected volume were analyzed by conventional HPLC analysis.

The reported result is the average of 10 units at both the beginning and end of unit use.

Anderson Cascade Impactor (ACI) Method Procedure

Anderson Cascade Impactor Mark II (ACI) was assembled and the flow rate was set to 28.3 L / min. The unit was primed four times with the test actuator with shaking between runs prior to dose collection. Five to 20 agonists were collected in the ACI assembly. The ACI was dismantled and the components washed with a suitable amount of solvent to ensure dissolution of all formulation components. Washes were collected for analysis by conventional HPLC analysis.

Test compound

The test compound was as follows :

Compound A-6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxo-androstar-1,4-diene-17β-car Bothioic acid S-fluoromethyl ester.

Compound B-N- [2-hydroxy-5-[(1R) -1-hydroxy-2-[[2-4-[[(2R) -2-hydroxy-2-phenylethyl] amino] phenyl ] Ethyl] amino] ethyl] phenyl] formamide.

Compound C-3- (4-{[6-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) -phenyl] ethyl} amino) hexyl] oxy} butyl Benzenesulfonamide.

Compound D-4-{(1R) -2-[(6- {2-[(2,6-dichlorobenzyl) oxy] ethoxy} hexyl) amino] -1-hydroxyethyl} -2- (hydroxy Methyl) phenol.

Compound E-N- {2- [4- (3-phenyl-4-methoxyphenyl) aminophenyl] ethyl} -2-hydroxy-2- (8-hydroxy-2 (1H) -quinolinone- 5-yl) ethylamine.

Example 1: Compound A. MDI. 25 μg / act. 60 operations

The cold-charge device comprising the stainless steel ash container with the air-induced mixer and the filling valve was assembled. The propellant was cooled to about -60 ° C. The batch vessel was cooled to at least −30 ° C. and approximately half of the total propellant cooled was added. The propellant was allowed to reach at least -50 ° C. While operating the blender, 1.3013 g of the biocompatible polymer comprising the compound of formula (II) was added at a concentration of 0.1% w / w relative to the propellant and 0.4294 g of 6α, 9α-difluoro-17α-[( 2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester powder was added. The remaining cold propellant was added up to the total weight of 1299 g of HFA 134a and the container was rinsed to ensure the addition of all powders. The suspension was mixed at about 3000 rpm for about 15 minutes. Before filling the MDI unit, it was confirmed that the formulation temperature was about -60 ° C. The fill valve was adjusted to deliver a suitable fill weight. The fluoropolymer coated aluminum canister was filled with 7.3 g of HFA 134a with a specific fill weight target. The Valois DF60 Mark 66 valve was immediately placed in a vat and crimped. Each unit was formulated to deliver a total of about 100 operations. The formulation was then allowed to warm to room temperature and spray tested twice and discarded to verify that the unit is operating correctly.

Comparative surfactant-free formulations were generally prepared as described above except that no biocompatible polymer of formula (II) was added to the formulation.

Dose Uniformity-Compound A. MDI. HFA 134a. 25 μg / act. 60 operations

Table 1 shows the total average dose of medicament delivered through the actuator, combined at the beginning and end of the dose used. The target output of the drug is 22.5 μg / act (assuming 10% effector deposition).

Table 1

Surfactant-free 0.1% w / w polymer of formula (II) Early 66% 98% 12 weeks at 40 ° C / 75% relative humidity 72% 98%

Table 2 shows the variability of the individual doses by adding the beginning and end of the doses used (% relative standard error, n = 20).

TABLE 2

Surfactant-free 0.1% w / w polymer of formula (II) Early 7.5% 4.4% 12 weeks at 40 ° C / 75% relative humidity 8.1% 4.3%

Fine Particle Fraction-Compound A, MDI, HFA 134a, 25 μg / act, 60 Runs

Table 3 shows the fine particle fraction (FPF) expressed as a percentage of 25 μg total dose target.

TABLE 3

Surfactant-free 0.1% w / w polymer of formula (II) Early 17% 24% 12 weeks at 40 ° C / 75% relative humidity 16% 22%

Additional formulations with varying concentrations of the biocompatible polymers of the invention were prepared by similar methods.

Example 2 Compound A in Combination with Compound B. MDI. 25/10 μg / act. 60 operations

The cold-charge device comprising the stainless steel ash container with the air-induced mixer and the filling valve was assembled. The propellant was cooled to about -60 ° C. The batch vessel was cooled to at least −30 ° C. and approximately half of the total propellant cooled was added. The propellant was allowed to reach at least -50 ° C. While operating the blender, 1.0379 g of a biocompatible polymer comprising the compound of formula (II) was added at a concentration of 0.1% w / w relative to the propellant and 0.3564 g of 6α, 9α-difluoro-17α- [ (2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxo-androsto-1,4-diene-17β-carbothioic acid S-fluoromethyl ester powder and 0.1539 g of N -[2-hydroxy-5-[(1R) -1-hydroxy-2-[[2-4-[[(2R) -2-hydroxy-2-phenylethyl] amino] phenyl] ethyl] amino ] Ethyl] phenyl] formamide powder was added. The remaining cold propellant was added below the total weight of 1033 g of HFA 134a and the container was rinsed to ensure the addition of all powders. The suspension was mixed at about 3000 rpm for about 15 minutes. Before filling the MDI unit, it was confirmed that the formulation temperature was about -60 ° C. The fill valve was adjusted to deliver a suitable fill weight. The fluoropolymer coated aluminum canister was filled with 7.3 g of HFA 134a with a specific fill weight target. The Valois DF60 Mark 66 valve was immediately placed in a vat and crimped. Each unit was formulated to deliver a total of about 100 operations. The formulation was then allowed to warm to room temperature and spray tested twice and discarded to verify that the unit is operating correctly.

Comparative surfactant-free formulations were generally prepared as described above except that no biocompatible polymer of formula (II) was added to the formulation.

Dose Uniformity—Compound A in combination with Compound B. MDI. HFA 134a. 25/10 μg / act. 60 operations

Table 4 shows the total average dose of medicament delivered through the actuator, combined at the beginning and end of the dose used.

Target output of Compound B is 8.5 μg (assuming 15% effector deposition).

Target output of Compound A is 22.5 μg (assuming 10% effector deposition).

Table 4

Compound B Component Compound A component Surfactant-free 0.1% w / w polymer of formula (II) Surfactant-free 0.1% w / w polymer of formula (II) Early 71% 98% 63% 107% 12 weeks at 40 ° C / 75% relative humidity 73% 99% 62% 110%

Table 5 shows the variability of the individual doses by adding the beginning and end of the doses used (% relative standard error, n = 20).

Table 5

Compound B Component Compound A component Surfactant-free 0.1% w / w polymer of formula (II) Surfactant-free 0.1% w / w polymer of formula (II) Early 11.8% 5.8% 11.7% 2.6% 12 weeks at 40 ° C / 75% relative humidity 10.3% 6.1% 9.6% 2.1%

Fine particle fraction-Compound A in combination with Compound B, MDI, HFA 134a, 25 μg / act, 60 runs

Table 6 shows the fine particle fractions expressed as a percentage of 10 μg total dose target for Compound B and 25 μg total dose target for Compound A.

Table 6

Compound B Component Compound A component Surfactant-free 0.1% w / w polymer of formula (II) Surfactant-free 0.1% w / w polymer of formula (II) Early 20% 25% 18% 32% 12 weeks at 40 ° C / 75% relative humidity 21% 26% 18% 35%

Additional formulations with varying concentrations of the biocompatible polymers of the invention were prepared by similar methods.

Example 3: Compound A in Combination with Compound C. MDI. 25 / 12.5 μg / act. 60 operations

A cold-charge device consisting of a stainless steel ash container with an air-induced mixer and a fill valve was assembled. The propellant was cooled to about -60 ° C. The batch vessel was cooled to at least −30 ° C. and approximately half of the total propellant cooled was added. The propellant was allowed to reach at least -50 ° C. While operating the blender, 1.8037 g of a biocompatible polymer comprising the compound of formula (II) was added and 0.5944 g of 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β- Hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester powder and 0.3786 g of 3- (4-{[6-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) -phenyl] ethyl} amino) hexyl] oxy} butyl) benzenesulfonamide powder was added. The remaining cold propellant was added below the total weight of 1797 g of HFA 134a and the container was cleaned to ensure the addition of all powders. The suspension was mixed at about 3000 rpm for about 15 minutes. Before filling the MDI unit, it was confirmed that the formulation temperature was about -60 ° C. The fill valve was adjusted to deliver a suitable fill weight. The fluoropolymer coated aluminum canister was filled with 7.3 g of HFA 134a with a specific fill weight target. The Valois DF60 Mark 66 valve was immediately placed in a vat and crimped. Each unit was formulated to deliver a total of about 100 operations. The formulation was then warmed to room temperature and spray tested twice and discarded to verify that the unit was operating correctly.

Comparative surfactant-free formulations were generally prepared as described above except that no biocompatible polymer of formula (II) was added to the formulation.

Dose Uniformity—Compound A in Combination with Compound C. MDI. HFA 134a. 25 / 12.5 μg / act. 60 operations

Table 7 shows the total average dose of medicament delivered through the actuator, combined at the beginning and end of the dose used.

Target output of Compound C is 11.3 μg (assuming 10% effector deposition).

Target output of Compound A is 22.5 μg (assuming 10% effector deposition).

TABLE 7

Compound C Component Compound A component Surfactant-free 0.1% w / w polymer of formula (II) Surfactant-free 0.1% w / w polymer of formula (II) Early 80% 96% 75% 101% 12 weeks at 40 ° C / 75% relative humidity 90% 112% 76% 107%

Table 8 shows the variability of individual doses by adding the beginning and end of the dose used (% relative standard error, n = 20).

Table 8

Compound C Component Compound A component Surfactant-free 0.1% w / w polymer of formula (II) Surfactant-free 0.1% w / w polymer of formula (II) Early 6.9% 3.9% 7.2% 3.6% 12 weeks at 40 ° C / 75% relative humidity 10.0% 4.3% 9.9% 3.6%

Fine Particle Fraction-Compound A in Combination with Compound C, MDI, HFA 134a, 25 / 12.5 μg / act, 60 Runs

Table 9 shows the fine particle fraction (FPF) expressed as a percentage of 12.5 μg total dose target for Compound C and 25 μg total dose target for Compound A.

Table 9

Compound C Component Compound A component Surfactant-free 0.1% w / w polymer of formula (II) Surfactant-free 0.1% w / w polymer of formula (II) Early 14% 28% 11% 21% 12 weeks at 40 ° C / 75% relative humidity 21% 25% 16% 20%

Example 4: Compound A in Combination with Compound D. MDI. 100/100 μg / act. 60 operations

A cold-charge device consisting of a stainless steel ash container with an air-induced mixer and a fill valve was assembled. The propellant was cooled to about -60 ° C. The batch vessel was cooled to at least −30 ° C. and approximately half of the total propellant cooled was added. The propellant was allowed to reach at least -50 ° C. While operating the blender, add 4.3119 g of biocompatible polymer comprising the compound of formula (II) and 5.6562 g of 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β- Hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester powder and 9.0090 g of 4-{(1R) -2-[(6- { 2-[(2,6-dichlorobenzyl) oxy] ethoxy} hexyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol powder was added. The remaining cold propellant was added below the total weight of 4294 g of HFA 134a and the container was cleaned to ensure the addition of all powders. The suspension was mixed at about 3000 rpm for about 15 minutes. Before filling the MDI unit, it was confirmed that the formulation temperature was about -60 ° C. The fill valve was adjusted to deliver a suitable fill weight. The fluoropolymer coated aluminum canister was filled with 7.3 g of HFA 134a with a specific fill weight target. The Vespac BK357930MT valve was immediately placed in a barrel and crimped. Each unit was formulated to deliver a total of about 100 operations. The formulation was then allowed to warm to room temperature and spray tested twice and discarded to verify that the unit is operating correctly.

Dose Uniformity—Compound A in Combination with Compound D. MDI. HFA 134a. 100/100 μg / act. 60 operations

Table 10 shows the total average dose of medicament delivered through the actuator, combined at the beginning and end of the dose used.

Target output of Compound D is 90 μg (assuming 10% effector deposition).

Target output of Compound A is 90 μg (assuming 10% effector deposition).

Table 10

Compound D Component Compound A component 0.1% w / w polymer of formula (II) 0.1% w / w polymer of formula (II) Early 101% 106% 12 weeks at 40 ° C / 75% relative humidity 104% 111%

Table 11 shows the variability of individual doses by adding the beginning and end of the doses used (% relative standard error, n = 20).

Table 11

Compound D Component Compound A component 0.1% w / w polymer of formula (II) 0.1% w / w polymer of formula (II) Early 2.5% 2.6% 12 weeks at 40 ° C / 75% relative humidity 3.1% 2.3%

Fine Particle Fraction-Compound A in Combination with Compound D, MDI, HFA 134a, 100/100 μg / act, 60 Runs

Table 12 shows the fine particle fraction (FPF) expressed as a percentage of 100 μg total dose target for Compound D and 100 μg total dose target for Compound A.

Table 12

Compound D Component Compound A component 0.1% w / w polymer of formula (II) 0.1% w / w polymer of formula (II) Early 32% 21% 12 weeks at 40 ° C / 75% relative humidity 27% 19%

Example 5: Compound A in Combination with Compound E. MDI. 100/50 μg / act. 60 operations

A cold-charge device consisting of a stainless steel ash container with an air-induced mixer and a fill valve was assembled. The propellant was cooled to about -60 ° C. The batch vessel was cooled to at least −30 ° C. and approximately half of the total propellant cooled was added. The propellant was allowed to reach at least -50 ° C. While running the blender, 3.7025 g of a biocompatible polymer comprising a compound of formula (II) was added and 2.4286 g of 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β- Hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester powder and 6.9699 g of N- {2- [4- (3-phenyl-4 -Methoxyphenyl) aminophenyl] ethyl} -2-hydroxy-2- (8-hydroxy-2 (1H) -quinolinone-5-yl) ethynamine powder was added. The remaining cold propellant was added below the total weight of 3691 g of HFA 134a and the container was rinsed to ensure the addition of all powders. The suspension was mixed at about 3000 rpm for about 15 minutes. Before filling the MDI unit, it was confirmed that the formulation temperature was about -60 ° C. The fill valve was adjusted to deliver a suitable fill weight. The fluoropolymer coated aluminum canister was filled with 7.3 g of HFA 134a with a specific fill weight target. The Vespac BK357930MT valve was immediately placed in a barrel and crimped. Each unit was formulated to deliver a total of about 100 operations. The formulation was then allowed to warm to room temperature and spray tested twice and discarded to verify that the unit is operating correctly.

Dose Uniformity—Compound E in Combination with Compound A. MDI. 100/50 μg / act. 60 operations

Table 13 shows the total average dose of medicament delivered through the actuator, combined at the beginning and end of the dose used.

The target output of compound E is 90 μg (assuming 10% effector deposition).

Target output of Compound A is 45 μg (assuming 10% effector deposition).

Table 13

Compound E Component Compound A component 0.1% w / w polymer of formula (II) 0.1% w / w polymer of formula (II) Early 104% 104% 12 weeks at 40 ° C / 75% relative humidity 106% 109%

Table 14 shows the variability of individual doses by adding the beginning and end of the dose used (% relative standard error, n = 20).

Table 14

Compound E Component Compound A component 0.1% w / w polymer of formula (II) 0.1% w / w polymer of formula (II) Early 2.6% 2.7% 12 weeks at 40 ° C / 75% relative humidity 1.8% 1.6%

Fine Particle Fraction-Compound A in Combination with Compound E, MDI, 100/50 μg / act, 60 Runs

Table 15 shows the fine particle fraction (FPF) expressed as a percentage of 100 μg total dose target for Compound E and 50 μg total dose target for Compound A.

Table 15

Compound E Component Compound A component 0.1% w / w polymer of formula (II) 0.1% w / w polymer of formula (II) Early 26% 23% 12 weeks at 40 ° C / 75% relative humidity 28% 22%

Additional formulations with varying concentrations of the biocompatible polymers of the invention were prepared by similar methods.

Since the concentration of the biocompatible polymer in the formulation has been increased to a concentration of at least 0.1% w / w for the propellant, we consider that the data and figures show an increase in the FPF and the volume delivered through the valve.

The data also appear to indicate that adding the biocompatible polymer of the present invention to the pharmaceutical aerosol formulation results in reduced variability of the individual doses.

Claims (31)

i) A therapeutically effective amount of a particulate agent of formula (I) or a solvate thereof:

(ii) propellants selected from the group consisting of 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-n-propane or mixtures thereof; And (iii) a pharmaceutical aerosol formulation comprising a biocompatible polymer comprising at least one compound of formula (II)

Wherein n and m of the biocompatible polymer independently represent an integer of at least 1 and the independent mean values of n and m are 6-25; Each unit of the formula is independently a D or L configuration:

. The pharmaceutical aerosol formulation of claim 1 wherein the independent mean values of n and m in the biocompatible polymer are 7 to 11. 11. 3. The method according to claim 1, wherein the particulate agent of formula (I) is 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3 A pharmaceutical aerosol formulation that is -oxo-androsto-1,4-diene-17β-carbothioic acid S-fluoromethyl ester. The pharmaceutical aerosol formulation according to claim 1, wherein the compound of formula (I) is in unsolvated form. 5. A pharmaceutical aerosol formulation according to claim 4 wherein the compound of formula (I) is Form 1 polymorph. The pharmaceutical aerosol formulation according to any one of claims 1 to 5, wherein the propellant is 1,1,1,2-tetrafluoroethane. The pharmaceutical aerosol formulation according to any one of claims 1 to 5, wherein the propellant is 1,1,1,2,3,3,3-heptafluoro-n-propane. The pharmaceutical aerosol formulation according to any one of claims 1 to 7, wherein the biocompatible polymer is present in the range of 0.0025% to 3% w / w relative to the propellant. The pharmaceutical aerosol formulation of claim 8, wherein the biocompatible polymer is present in the range of 0.01% to 0.5% w / w relative to the propellant. The pharmaceutical aerosol formulation of claim 9, wherein the biocompatible polymer is present in the range of 0.05% to 0.2% w / w relative to the propellant. The pharmaceutical aerosol formulation according to claim 1, further comprising one or more other therapeutically active agents. The pharmaceutical aerosol formulation of claim 11, wherein the other therapeutically active agent is a β ₂ -adrenergic receptor agonist. 13. The method of claim 12, wherein the β ₂ -adrenergic agonist is salmeterol; (R) -salmeterol; Salbutamol; (R) -salbutamol; Formoterol; (R, R) -formoterol; Phenoterol; Caroterol; Ethaneterol; Naminterol; Clenbuterol; Pirbuterol; Flarobuterol; Leproterol; Bambuterol; Terbutalin; Salmephamol; Indacaterol; 3- (4-{[6-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) hexyl] oxy} butyl) benzenesulfonamide ; 3- (3-{[7-({(2R) -2-hydroxy-2- [4-hydroxy-3-hydroxymethyl) phenyl] ethyl} -amino) heptyl] oxy} propyl) benzenesulfonamide ; 4-{(1R) -2-[(6- {2-[(2,6-dichlorobenzyl) oxy] ethoxy} hexyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol ; 4-{(1R) -2-[(6- {4- [3- (cyclopentylsulfonyl) phenyl] butoxy} hexyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol ; N- [2-hydroxyl-5-[(1R) -1-hydroxy-2-[[2-4-[[(2R) -2-hydroxy-2-phenylethyl] amino] phenyl] ethyl] Amino] ethyl] phenyl] formamide; N- {2- [4- (3-phenyl-4-methoxyphenyl) aminophenyl] ethyl} -2-hydroxy-2- (8-hydroxy-2 (1H) -quinolinone-5-yl ) Ethylamine; 5-[(R) -2- (2- {4- [4- (2-Amino-2-methyl-propoxy) -phenylamino] -phenyl} -ethylamino) -1-hydroxy-ethyl]- 8-hydroxy-1H-quinolin-2-one; And pharmaceutically acceptable salts thereof. The pharmaceutical aerosol formulation of claim 13, wherein the β ₂ -adrenergic agonist is selected from salmeterol and (R) -salmeterol. The method according to claim 12, wherein the β ₂ -adrenergic agonist is sulfuric acid, hydrochloric acid, fumaric acid, hydroxynaphthoic acid, cinnamic acid, substituted cinnamic acid, triphenylacetic acid, sulfamic acid, sulfanilic acid, A pharmaceutical aerosol formulation in the form of a salt formed with a pharmaceutically acceptable acid selected from naphthalene acrylic acid, benzoic acid, 4-methoxybenzoic acid, 2- or 4-hydroxybenzoic acid, 4-chlorobenzoic acid and 4-phenylbenzoic acid. The pharmaceutical aerosol formulation of claim 15 wherein the β ₂ -adrenoreceptor agonist is salmeterol cinapoate (1-hydroxy-2-naphthalenecarboxylate). The pharmaceutical aerosol formulation of claim 15 wherein the β ₂ -adrenergic agonist is salbutamol sulfate. The pharmaceutical aerosol formulation of claim 15 wherein the β ₂ -adrenergic agonist is formoterol fumarate. An aerosol formulation as claimed in any one of claims 1 to 18, comprising dispersing a biocompatible polymer comprising a medicament of formula (I) and at least one compound of formula (II) in a propellant in a suitable container. How to prepare. 19. A pharmaceutical aerosol formulation according to any one of claims 1 to 18 for use in veterinary medicine or human medicine. Use of a pharmaceutical aerosol formulation as claimed in claim 1 for the manufacture of a medicament administered by inhalation to treat a respiratory disease. Use according to claim 20 or 21, wherein the respiratory disease is asthma. The method of claim 20 or 21, wherein the respiratory disease is chronic obstructive pulmonary disease (COPD). A method of treating or preventing a respiratory disease, comprising administering to a human or animal subject a pharmaceutical aerosol formulation as claimed in claim 1. A metered dose inhaler containing therein the pharmaceutical aerosol formulation according to any one of claims 1 to 18. 27. The metered dose inhaler of claim 25, wherein the entire metal inner surface of the can is coated with a polymer blend of polytetrafluoroethylene and polyethersulfone. Use of a biocompatible polymer comprising at least one compound of formula (II) in a pharmaceutical formulation as claimed in any one of claims 1 to 18 to enhance the fine particle fraction of the formulation. Use of a biocompatible polymer comprising at least one compound of formula (II) in a pharmaceutical formulation as claimed in claim 1 for improving the stability of the fine particle fraction of the formulation. Use of a biocompatible polymer comprising at least one compound of formula (II) in a pharmaceutical formulation as claimed in claim 1 for reducing variability in delivery dose uniformity of the formulation. Use of a biocompatible polymer comprising at least one compound of formula (II) in a pharmaceutical formulation as claimed in claim 1 for reducing variability in the fine particle fraction of the formulation. Use of a biocompatible polymer comprising at least one compound of formula (II) in a pharmaceutical formulation as claimed in any one of claims 1 to 18 to reduce the product excess supply required to achieve the delivery dose.

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