Patent Description:
<NPL> discloses treating patients that have acute exacerbation of chronic obstructive pulmonary disease with nebulised glycopyrrolate and nebulised albuterol.

<NPL> discloses treating patients that have chronic obstructive pulmonary disease with nebulised glycopyrrolate and nebulised metaproterenol.

In one aspect, the present invention provides the use of.

Preferably the molar ratio of (A) to (B) is from <NUM>:<NUM> to <NUM>:<NUM>, for example <NUM>:<NUM> to <NUM>:<NUM>, especially from <NUM>:<NUM> to <NUM>:<NUM>, and more especially from <NUM>:<NUM> to <NUM>:<NUM>.

(A) Glycopyrrolate is a known antimuscarinic agent. More specifically it inhibits acetyl choline binding to M3 muscarinic receptors thereby inhibiting bronchoconstriction.

Glycopyrrolate is a quaternary ammonium salt. Suitable counter ions are pharmaceutically acceptable counter ions including, for example, fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl-acetate or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, <NUM>-hydroxynaphthalene-<NUM>-carboxylate, <NUM>-hydroxynaphthalene-<NUM>-carboxylate, methanesulfonate and benzenesulfonate.

Its bromide salt, namely <NUM>-[(cyclopentyl-hydroxyphenylacetyl)oxy]-<NUM>,<NUM>-dimethylpyrrolidinium bromide, has the following structural formula
<CHM>
and can be prepared using the procedures described in <CIT>.

Glycopyrrolate has two stereogenic centres and hence exists in four isomeric forms, namely (3R,<NUM>'R)-, (<NUM>,<NUM>'R)-, (3R,<NUM>'S)- and (<NUM>,<NUM>'S)-<NUM>-[(cyclopentyl-hydroxyphenylacetyl)oxy]-<NUM>,<NUM>-dimethylpyrrolidinium bromide, as described in <CIT> and <CIT>. The present invention embraces using one or more of these isomeric forms, especially the <NUM>,<NUM>'R isomer, the 3R,<NUM>'R isomer or the <NUM>,<NUM>'R isomer, thus including single enantiomers, or racemates, especially the (<NUM>,<NUM>'R/<NUM>,<NUM>'R) racemate.

(B) is a compound of formula I as hereinbefore defined. Compounds of this formula possess beta-<NUM> adrenoceptor agonist activity. They commonly have a rapid onset of action and have a prolonged stimulating action on the β2-adrenoceptor, for example up <NUM> hours or longer.

Compounds of formula I in free or salt or solvate form may be prepared by using the procedures described in international patent applications <CIT>, <CIT>, <CIT> or <CIT>.

Compounds of formula I in free form may be converted into salt form, and vice versa, in a conventional manner. The compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystallisation. Compounds of formula can be recovered from reaction mixtures and purified in a conventional manner. Isomers, such as enantiomers, may be obtained in a conventional manner, e.g. by fractional crystallisation or asymmetric synthesis from correspondingly asymmetrically substituted, e.g. optically active, starting materials.

Pharmaceutically acceptable acid addition salts of the compounds of formula I include those of inorganic acids, for example, hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example aliphatic monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid and butyric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, aromatic carboxylic acids such as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids such as o-hydroxybenzoic acid, p-hydroxy-benzoic acid, <NUM>-hydroxynaphthalene-<NUM>-carboxylic acid or <NUM>-hydroxynaphthalene-<NUM>-carboxylic acid, and sulfonic acids such as methanesulfonic acid or benzenesulfonic acid.

These salts may be prepared by known salt-forming procedures. Pharmaceutically acceptable solvates are generally hydrates. Isomers, such as enantiomers, may be obtained in a conventional manner, e.g. by fractional crystallisation or asymmetric synthesis from correspondingly asymmetrically substituted, e.g. optically active, starting materials.

The medicament of the present invention may additionally contain one or more co-therapeutic agents such as anti-inflammatory, bronchodilatory, antihistamine, decongestant or anti-tussive drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.

Co-therapeutic agents include steroids, A2A agonists, A2B antagonists, antihistamines, caspase inhibitors, LTB4 antagonists, LTD4 antagonists, PDE4 inhibitors, mucolytics, matrix metalloproteinase inhibitors (MMPi's), leukotrienes, antibiotics, anti neoplastics, peptides, vaccines, nicotine, elastase inhibitors and sodium cromoglycate.

Such anti-inflammatory drugs include steroids, for example glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, or steroids described in <CIT>, <CIT>, <CIT>, <CIT> (especially those of Examples <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>), <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT> and <CIT>, and non-steroidal glucocorticoid receptor agonists, such as those described in <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>. Suitable A2A agonists include those described in <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT> and <CIT>. Suitable A2B antagonists include those described in <CIT> and <CIT>. Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarates promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine as well as those disclosed in <CIT>, <CIT>, <CIT>. Suitable caspase inhibitors, including interleukin- I P converting enzyme (ICE) inhibitors, include those that are disclosed in <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT> as well as those disclosed in international patent applications <CIT>, <CIT>, <CIT> and <CIT>. Suitable LTB4 antagonists include LY293111, CGS025019C, CP-<NUM>, SC-<NUM>, BIIL <NUM>, ONO <NUM>, SB <NUM> and those described in <CIT> and <CIT>. Suitable LTD4 antagonists include montelukast and zafirlukast. Suitable PDE4 inhibitors PDE4 inhibitors such as cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden),V-11294A (Napp), BAYI <NUM>-<NUM> (Bayer), SCH-<NUM> (Schering-Plough), Arofylline (Almirall Prodesfarma), PDI <NUM> / PD168787 (Park-Davis), AWD-<NUM>-<NUM> (Asta Medica), CDC-<NUM> (Celgene), SelCID(TM) CC-<NUM> (Celgene), VM554/UM565 (Vernalis), T-<NUM> (Tanabe), KW-<NUM> (Kyowa Hakko Kogyo), GRC <NUM> (Glenmark), and those described in <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT> and <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT> and <CIT>.

While (A) glycopyrrolate is an M3 antagonist, the medicament of the present invention optionally includes one or more other M3 antagonists such as ipratropium bromide, oxitropium bromide, tiotropium salt, CHF <NUM> (Chiesi), or those described in <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT> or <CIT>.

While (B) are beta-<NUM> adrenoceptor agonists, the medicament of the present invention optionally includes one or more other beta-<NUM> adrenoceptor agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol fenoterol, procaterol, and especially, formoterol, carmoterol and pharmaceutically acceptable salts thereof, compounds (in free or salt or solvate form) of formula <NUM> of <CIT>, or those described in <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT> <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT> or <CIT>.

Administration of the medicament as hereinbefore described,
i.e. with (A) and (B) in admixture, is by inhalation, i.e. (A) and (B) are in inhalable form.

The inhalable form is a dry powder, i.e. (A) and (B) are present in a dry powder comprising finely divided (A) and (B) optionally together with at least one particulate pharmaceutically acceptable carrier, which may be one or more materials known as pharmaceutically acceptable carriers, preferably chosen from materials known as carriers in dry powder inhalation compositions, for example saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran, mannitol or sorbitol. An especially preferred carrier is lactose. The dry powder may be contained as unit doses in capsules of, for example, gelatin or plastic, or in blisters (e.g. of aluminium or plastic), for use in a dry powder inhalation device, which may be a single dose or multiple dose device, preferably in dosage units of (A) and (B) together with the carrier in amounts to bring the total weight of powder per capsule to from <NUM> to <NUM>. Alternatively, the dry powder may be contained in a reservoir in a multi-dose dry powder inhalation device adapted to deliver, for example, <NUM>-<NUM> of dry powder per actuation.

In the finely divided particulate form of the medicament, the active ingredient may have an average particle diameter of up to about <NUM>, for example <NUM> to <NUM>, preferably <NUM> to <NUM>. The particulate carrier, where present, generally has a maximum particle diameter up to <NUM>, preferably up to <NUM>, and conveniently has a mean particle diameter of <NUM> to <NUM>, e.g. <NUM> to <NUM>. The particle size of the active ingredient, and that of a particulate carrier where present in dry powder compositions, can be reduced to the desired level by conventional methods, for example by grinding in an air-jet mill, ball mill or vibrator mill, sieving, microprecipitation, spray-drying, lyophilisation or controlled crystallisation from conventional solvents or from supercritical media.

The medicament may be a controlled release formulation comprising finely divided particles of (A) and (B) within a hydrophobic matrix material, e.g. comprising magnesium stearate, for example as described in international patent application <CIT>.

The inhalable medicament may be administered using an inhalation device suitable for the inhalable form, such devices being well known in the art. Accordingly, the invention also provides a pharmaceutical product comprising a medicament or pharmaceutical composition as hereinbefore described in inhalable form as hereinbefore described in association with one or more inhalation devices. In a further aspect, the invention provides an inhalation device, or a pack of two or more inhalation devices, containing a medicament or pharmaceutical composition as hereinbefore described in inhalable form as hereinbefore described.

Where the inhalable form of the active ingredient is the finely divided particulate form, the inhalation device may be, for example, a dry powder inhalation device adapted to deliver dry powder from a capsule or blister containing a dry powder comprising a dosage unit of (A) and (B) or a multidose dry powder inhalation (MDPI) device adapted to deliver, for example, <NUM>-<NUM> of dry powder comprising a dosage unit of (A) and (B) per actuation. The dry powder formulation preferably contains the active ingredients optionally together with a diluent or carrier, such as lactose, of the desired particle size distribution and a compound that helps to protect against product performance deterioration due to moisture e.g. magnesium stearate. Suitable such dry powder inhalation devices are well known. For example, a suitable device for delivery of dry powder in encapsulated form is that described in <CIT>, while a suitable MDPI device is that described in <CIT>.

The molar ratio of (A) to (B) may be, in general, from <NUM>:<NUM> to <NUM>:<NUM>, for example from <NUM>:<NUM> to <NUM>:<NUM> or from <NUM>:<NUM> to <NUM>:<NUM>, preferably from <NUM>:<NUM> to <NUM>:<NUM>, more preferably from to <NUM>:<NUM>, from <NUM>:<NUM> to <NUM>:<NUM> or from <NUM>:<NUM> to <NUM>:<NUM>.

A suitable daily dose of the compound (A), particularly as the bromide salt, for inhalation may be from <NUM> to <NUM>µg, preferably from <NUM> to <NUM>µg, and especially from <NUM> to <NUM>µg, e.g. from <NUM> to <NUM>µg.

A suitable daily dose of compound (B) for inhalation may be from <NUM>µg to <NUM>µg, for example from <NUM> to <NUM>µg, from <NUM> to <NUM>µg, preferably from <NUM> to <NUM>µg, e.g. from <NUM> to <NUM>µg or from <NUM> to <NUM>µg.

A suitable unit dose of compound (A), particularly as the bromide salt, may be from <NUM>µg to <NUM>µg, preferably from <NUM> to <NUM>µg, especially from <NUM> to <NUM>µg, e.g. from <NUM> to <NUM>µg.

A suitable unit dose of compound (B) may be from <NUM>µg to <NUM>µg, for example from <NUM> to <NUM>µg, from <NUM> to <NUM>µg, preferably from <NUM> to <NUM>µg, e.g. from <NUM> to <NUM>µg or from <NUM> to <NUM>µg.

These unit doses may be administered once or twice daily in accordance with the daily doses mentioned hereinbefore. A single dose is preferred. The precise unit and daily dose used will of course depend on the condition to be treated, the patient and the efficiency of the inhalation device.

In one preferred embodiment of the invention, the medicament of the invention is a pharmaceutical composition which is a dry powder in a capsule containing a unit dose of (A) and (B), for example for inhalation from a single capsule inhaler, the capsule suitably containing a unit dose of (A) e.g. as hereinbefore described; and a unit dose of (B), e.g. as hereinbefore described, together with a pharmaceutically acceptable carrier as hereinbefore described in an amount to bring the total weight of dry powder per capsule to between <NUM> and <NUM>, for example <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM>.

In another preferred embodiment of the invention, the medicament of the invention is a pharmaceutical composition which is a dry powder for administration from a reservoir of a multi-dose dry powder inhaler adapted to deliver, for example, <NUM> to <NUM> of powder containing a unit dose of (A) and (B) per actuation, for example, where (A) is in the form of the maleate salt, a powder comprising, by weight, <NUM> to <NUM> parts, for example <NUM> to <NUM> parts, <NUM> to <NUM> parts, or <NUM> to <NUM> parts of (A); <NUM> to <NUM> parts, e.g. <NUM> to <NUM> parts, <NUM> to <NUM> parts, or <NUM> to <NUM> parts of (B); <NUM> to <NUM> part magnesium stearate, and <NUM> to <NUM> parts, e.g. <NUM> to <NUM> parts or <NUM> to <NUM> parts of a pharmaceutically acceptable carrier as hereinbefore described.

The medicaments of the invention are advantageous in the treatment of inflammatory or obstructive airways disease, exhibiting highly effective bronchodilatory and anti-inflammatory properties. For instance, it is possible using the combination therapy of the invention to reduce the dosages of (A) or (B) required for a given therapeutic effect compared with those required using treatment with either (A) or (B) alone, thereby minimising possibly undesirable side effects. Furthermore, using the combinations of the invention, particularly using compositions containing (A) and (B), medicaments which have a rapid onset of action and a long duration of action may be prepared. Moreover, using such combination therapy, medicaments which result in a significant improvement in lung function may be prepared. In another aspect, using the combination therapy of the invention, medicaments which provide effective control of obstructive or inflammatory airways diseases, or a reduction in exacerbations of such diseases, may be prepared. In a further aspect, using compositions of the invention containing (A) and (B), medicaments which reduce or eliminate the need for treatment with short-acting rescue medicaments such as salbutamol or terbutaline, may be prepared; thus compositions of the invention containing (A) and (B) facilitate the treatment of an obstructive or inflammatory airways disease with a single medicament.

Treatment of inflammatory or obstructive airways diseases in accordance with the invention may be symptomatic or prophylactic treatment. Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than <NUM> or <NUM> years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "wheezy infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as "wheezy-infant syndrome".

Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti-inflammatory (e.g. corticosteroid) or bronchodilatory. Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognised asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about <NUM> to <NUM> am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy.

Other inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include acute/adult lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), cystic fibrosis, chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis and emphysema, bronchiectasis and exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. Further inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tobacosis and byssinosis.

The invention is illustrated by the following Examples.

Compound A1, namely <NUM>-[(cyclopentyl-hydroxyphenylacetyl)oxy]-<NUM>,<NUM>-dimethylpyrrolidinium bromide (glycopyrrolate), is commercially available as a racemate or is prepared using the procedures described in <CIT>.

Compound B1, namely (R)-<NUM>-[<NUM>-(<NUM>,<NUM>-diethyl-indan-<NUM>-ylamino)-<NUM>-hydroxy-ethyl]-<NUM>-hydroxy-<NUM>-quinolin-<NUM>-one maleate, is prepared using the procedures described in international patent application <CIT>.

Gelatin capsules suitable for use in a capsule inhaler such as that described in <CIT> and <CIT> are prepared, each capsule containing a dry powder obtained by mixing Compound A1 and Compound B1 which have been ground to a mean particle diameter of <NUM> to <NUM> and lactose monohydrate having a particle diameter below <NUM>, the amounts being as shown in the Table <NUM> below:.

Claim 1:
The use of:
(A) glycopyrrolate; and
(B) a compound of formula I
<CHM>
in free or salt or solvate form,
wherein W is a group of formula
<CHM>
R<NUM>, R<NUM> and R<NUM> are each H, R<NUM> is OH, R<NUM> and R<NUM> are each H and
Rx and Ry are both -CH<NUM>-, and R<NUM> and R<NUM> are each H and R<NUM> and R<NUM> are each CH<NUM>CH<NUM>-;
in the preparation of a medicament for combination therapy by simultaneous administration of (A) and (B) in the treatment of an inflammatory or obstructive airways disease, wherein the administration is by inhalation,
and wherein (A) and (B) are present in admixture in inhalable form as a dry powder comprising finely divided (A) and (B) optionally together with the least one particulate pharmaceutically acceptable carrier.