US 20040019025A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0019025A1 Gavin (43) Pub. Date: Jan. 29, 2004

(54) MEDICAL COMPOSITIONS COMPRISING (30) Foreign Application Priority Data (R,R)-FORMOTEROLAND ROFLEPONIDE Apr. 18, 2000 (GB)...... OOO96O73 (76) Inventor: Brian Charles Gavin, Rathfarnfam (IE) Publication Classification Correspondence Address: DAVIDJ LEVY, CORPORATE (51) Int. Cl." ...... A61L 9/04; A61K 31/58; INTELLECTUAL PROPERTY A61K 31/4745 GLAXOSMITHKLINE (52) U.S. Cl...... 514/171; 424/45; 514/291 FIVE MOORE DR., PO BOX 13398 RESEARCH TRIANGLE PARK, NC 27709-3398 (US) (57) ABSTRACT (21) Appl. No.: 10/257,702 The present invention is concerned with pharmaceutical formulations comprising a combination of (R,R)-formoterol (22) PCT Filed: Apr. 11, 2001 and rofileponide and the use of Such formulations in medi cine, particularly in the prophylaxis and treatment of respi (86) PCT No.: PCT/GB01/01629 ratory diseases. US 2004/0019025 A1 Jan. 29, 2004

MEDICAL COMPOSITIONS COMPRISING 0010 AS would be appreciated by the skilled person, (R,R)-FORMOTEROLAND ROFLEPONIDE rofileponide contains Several asymmetric centres. The 0001. The present invention is concerned with combina present invention includes each isomer of rofileponide, par tions of (R,R)-formoterol and rofleponide, particularly com ticularly the (22R) and (22S) isomers, either in substantially positions containing a combination of (R,R)-formoterol and pure form or admixed in any proportions. The isomers of rofileponide and the use of Such compositions in medicine, rofileponide have been described previously in WO particularly in the prophylaxis and treatment of respiratory 92/13872. diseases. 0011. By the term “physiologically functional derivative” 0002 Formoterol, i.e. 2'-hydroxy-5'-(RS)-1-hydroxy-2- is meant a chemical derivative of (R,R)-formoterol or rof (RS)-p-methoxy-O-methylphenethylaminoethylforma leponide having the same physiological function as the free nilide, particularly its fumarate Salt is a well-known adreno compound, for example, by being convertible in the body receptor agonist which is now used clinically in the thereto. According to the present invention, examples of treatment of bronchial asthma and related disorders. For physiologically functional derivatives include esters. moterol includes two asymmetric centres and in a particular 0012 Suitable salts according to the invention include form exists as the (R,R)-isomer. The (R,R) isomer of for those formed with both organic and inorganic acids. Phar moterol has been described previously, for example, in maceutically acceptable acid addition Salts include but are WO98/21175 and U.S. Pat. No. 5,795,564. not limited to those formed from hydrochloric, hydrobromic, Sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, 0003 WO92/13872 describes rofileponide i.e. 16C.,17o trifluoroacetic, Succinic, oxalic, fumaric, maleic, oxaloace butylidenedioxy-6C,9C.-difluoro-11B,21-dihydroxypregn-4- tic, methaneSulphonic, ethaneSulphonic, p-toluenesul ene-3,20-dione, Salts and esters thereof and pharmaceutical phonic, benzeneSulphonic, isethionic, and naphthalenecar formulations thereof. Rofleponide is an antiinflammatory boxylic, Such as 1-hydroxy-2-naphthalenecarboxylic acids. corticosteroid, which is proposed for use in the treatment of bronchial asthma and related disorders. 0013 Pharmaceutically acceptable esters of (R,R)-for 0004 WO 99/00134 describes combinations of formot moterol or rofileponide may have a hydroxyl group con erol and rofileponide but is silent as to the utility of (R,R)- verted to a Calkyl, aryl, aryl C alkyl, or amino acid formoterol. eSter. 0014) As mentioned above, both (R,R)-formoterol and 0005 Although formoterol fumarate and rofileponide may rofileponide and their pharmaceutically acceptable Salts, Sol be effective therapies, there exists a clinical need for asthma Vates, and physiologically functional derivatives have been therapies having potent and Selective action and having an described for use in the treatment of respiratory diseases. advantageous profile of action. Therefore, formulations of (R,R)-formoterol and rofileponide 0006 Therefore, according to the present invention there and their pharmaceutically acceptable Salts, Solvates, and is provided a combination of (R,R)-formoterol or a phar physiologically functional derivatives have use in the pro maceutically acceptable Salt, Solvate, or physiologically phylaxis and treatment of clinical conditions for which a functional derivative thereof and rofileponide or a pharma Selective f3-adrenoreceptor agonist and/or an antiinflamma ceutically acceptable Salt, Solvate, or physiologically func tory corticosteroid is indicated. Such conditions include tional derivative thereof. diseases associated with reversible airways obstruction Such 0007. It will be appreciated that the compounds of the as asthma, chronic obstructive pulmonary diseases (COPD) combination may be administered simultaneously, either in (e.g. chronic and wheezy bronchitis, emphysema), respira the Same or different pharmaceutical formulations or tory tract infection and upper respiratory tract disease. Sequentially. If there is Sequential administration, the delay 0015 Accordingly, the present invention provides a in administering the Second compound should not be Such as method for the prophylaxis or treatment of a clinical con to lose the beneficial therapeutic effect of the combination. dition in a mammal, Such as a human, for which a Selective 0008 According to a further aspect of the present inven f-adrenoreceptor agonist and/or antiinflammatory corticos tion, there is provided a pharmaceutical formulation com teroid is indicated, which comprises administration of a prising (R,R)-formoterol or a pharmaceutically acceptable therapeutically effective amount of a combination of (R,R)- Salt, Solvate, or physiologically functional derivative thereof formoterol or a pharmaceutically acceptable Salt, Solvate, or and rofileponide or a pharmaceutically acceptable Salt, Sol physiologically functional derivative thereof and rofile Vate, or physiologically functional derivative thereof, and a ponide or a pharmaceutically acceptable Salt, Solvate, or pharmaceutically acceptable carrier or excipient, and option physiologically functional derivative thereof. The present ally one or more other therapeutic ingredients. According to invention further provides a method for the prophylaxis or treatment of a clinical condition in a mammal, Such as a a preferred aspect of the present invention, there is provided human, for which a Selective B-adrenoreceptor agonist a pharmaceutical formulation comprising (R,R)-formoterol and/or antiinflammatory corticosteroid is indicated, which fumarate and rofleponide palmitate, and a pharmaceutically comprises administration of a therapeutically effective acceptable carrier or excipient, and optionally one or more amount of a pharmaceutical formulation comprising (R,R)- other therapeutic ingredients. In the most preferred aspect, formoterol or a pharmaceutically acceptable Salt, Solvate, or the above pharmaceutical formulations are Suitable for physiologically functional derivative thereof and rofile administration by inhalation. ponide or a pharmaceutically acceptable Salt, Solvate, or 0009. It is to be understood that the present invention physiologically functional derivative thereof, and a pharma coverS all combinations of particular and preferred aspects ceutically acceptable carrier or excipient. In a preferred of the invention described herein. aspect, there is provided Such a method which comprises US 2004/0019025 A1 Jan. 29, 2004

administration of a therapeutically effective amount of a more Successful treatment. It will be understood that the pharmaceutical formulation comprising (R,R)-formoterol administration of the combination of the invention by means fumarate and rofleponide palmitate, and a pharmaceutically of a single patient pack, or patient packs of each component acceptable carrier or excipient. In particular, the present compound, and containing a package insert instructing the invention provides Such methods for the prophylaxis or patient to the correct use of the invention is a desirable treatment of a disease associated with reversible airways additional feature of the invention. obstruction Such as asthma, chronic obstructive pulmonary 0020 Hereinafter, the term “active ingredients' means disease (COPD), respiratory tract infection or upper respi (R,R)-formoterol or a pharmaceutically acceptable Salt, Sol ratory tract disease. Vate, or physiologically functional derivative thereof, pref 0016. In the alternative, there is provided a combination erably (R,R)-formoterol fumarate, and rofleponide, or a of (R,R)-formoterol or a pharmaceutically acceptable Salt, pharmaceutically acceptable Salt, Solvate, or physiologically Solvate, or physiologically functional derivative thereof and functional derivative thereof, preferably rofileponide palmi rofileponide or a pharmaceutically acceptable Salt, Solvate, or tate. physiologically functional derivative thereof, for use in 0021 Suitably, the pharmaceutical formulations which therapy, particularly for use in the prophylaxis or treatment are Suitable for inhalation according to the invention com of a clinical condition for which a Selective f32-adrenore prise the active ingredients in amounts Such that each ceptor agonist and/or antiinflammatory corticosteroid is actuation provides therapeutically effective dose, for indicated. In particular, there is provided a pharmaceutical example, a dose of (R,R)-formoterol of 10 mcg to 150 mcg, formulation comprising (R,R)-formoterol or a pharmaceu preferably 24 mcg and a dose of rofileponide of 10 mcg to 1.6 tically acceptable Salt, Solvate, or physiologically functional mg, preferably 20 mcg to 250 mcg. derivative thereof (suitably, (R,R)-formoterol fumarate) and rofileponide or a pharmaceutically acceptable Salt, Solvate, or 0022. The pharmaceutical formulations according to the physiologically functional derivative thereof (Suitably, rof invention may further include other therapeutic agents for leponide palmitate), and a pharmaceutically acceptable car example anti-inflammatory agents Such as other corticoster rier or excipient for use in therapy, particularly for use in the oids (e.g. fluticasone propionate, beclomethasone dipropi prophylaxis or treatment of a clinical condition for which a onate, mometaSone furoate, triamcinolone acetonide or Selective B-adrenoreceptor agonist and/or antiinflammatory budesonide) or NSAIDs (e.g. Sodium cromoglycate, corticosteroid is indicated. In a preferred aspect, the inven nedocromil sodium, PDE-4 inhibitors, leukotriene antago tion is concerned with the prophylaxis or treatment of a nists, iNOS inhibitors, tryptase and elastase inhibitors, disease associated with reversible airways obstruction Such beta-2 integrin antagonists and adenosine 2a agonists), or as asthma, chronic obstructive pulmonary disease (COPD), other f32-adrenoreceptor agonists (Such as Salbutamol, Sal respiratory tract infection or upper respiratory tract disease. meterol, fenoterol or terbutaline and Salts thereof), or anti cholinergic agents (Such as ipratropium, or tiotropium). 0017. The amount of (R,R)-formoterol and rofileponide, or a pharmaceutically acceptable Salt, Solvate or physiologi 0023 The formulations include those suitable for oral, cally functional derivative thereof which is required to parenteral (including Subcutaneous, intradermal, intramus achieve a therapeutic effect will, of course, vary with the cular, intravenous and intraarticular), intranasal, inhalation particular compound, the route of administration, the Subject (including fine particle dusts or mists which may be gener under treatment, and the particular disorder or disease being ated by means of various types of metered dose pressurised treated. As a monotherapy, (R,R)-formoterol fumarate is aerosols, nebulisers or insufflators), rectal and topical generally administered to adult humans by aerosol inhala (including dermal, buccal, Sublingual and intraocular) tion at a dose of 12 mcg or 24 mcg twice daily. AS a administration although the most Suitable route may depend monotherapy, rofileponide is described in WO92/13872 as upon for example the condition and disorder of the recipient. being administered to adult humans by aerosol inhalation at The formulations may conveniently be presented in unit a dose of from 10 mcg to 1000 mcg, preferably 20 mcg to dosage form and may be prepared by any of the methods 250 mcg. well known in the art of pharmacy. All methods include the Step of bringing the active ingredients into association with 0.018 While it is possible for the active ingredients of the the carrier which constitutes one or more accessory ingre combination to be administered as the raw chemical, it is dients. In general the formulations are prepared by uni preferable to present them as a pharmaceutical formulation. formly and intimately bringing into association the active When the individual compounds of the combination are ingredients with liquid carriers or finely divided Solid car administered Separately, they are generally each presented as riers or both and then, if necessary, Shaping the product into a pharmaceutical formulation as described previously in the the desired formulation. art. 0024. Formulations for inhalation include powder com 0.019 Pharmaceutical formulations are often prescribed positions which will preferably contain lactose, and Spray to the patient in “patient packs' containing the whole course compositions which may be formulated, for example, as of treatment in a Single package. Patient packs have an aqueous Solutions or Suspensions or as aerosols delivered advantage over traditional prescriptions, where a pharmacist from pressurised packs, with the use of a Suitable propellant, divides a patient's Supply of a pharmaceutical from a bulk e.g. dichlorodifluoromethane, trichlorofluoromethane, Supply, in that the patient always has access to the package dichlorotetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, insert contained in the patient pack, normally missing in 1,1,1,2-tetrafluoroethane, carbon dioxide or other Suitable traditional prescriptions. The inclusion of a package insert gas. Suitable aerosol formulations include those described in has been shown to improve patient compliance with the EP 0372777 and WO93/11743. For suspension aerosols, the physicians instructions and, therefore, lead generally to active ingredients should be micronised So as to permit US 2004/0019025 A1 Jan. 29, 2004 inhalation of Substantially all of the active ingredients into 0033 Similar methods may be used for the formulation the lungs upon administration of the aerosol formulation, of Example 2: thus the active ingredients will have a particle size of leSS than 100 microns, desirably less than 20 microns, and Example 2 preferably in the range 1 to 10 microns, for example, 1 to 5 microns. 0034) 0.025 Intranasal sprays may be formulated with aqueous or non-aqueous vehicles with the addition of agents Such as thickening agents, buffer Salts or acid or alkali to adjust the Per actuation pH, isotonicity adjusting agents or anti-oxidants. (R,R)-formoterol fumarate 12 microgram Rofleponide 100 microgram 0026 Capsules and cartridges or for example gelatin, or 1,1,1,2-Tetrafluoroethane to 75.0 mg blisters of for example laminated aluminium foil, for use in an inhaler or insuflator may be formulated containing a powder mix of the active ingredients and a Suitable powder base Such as lactose or Starch. In this aspect, the active B: Dry Powder Inhalers ingredients are Suitably micronised So as to permit inhalation Example 3 of Substantially all of the active ingredients into the lungs upon administration of the dry powder formulation, thus the 0035) active ingredients will have a particle size of less than 100 microns, desirably less than 20 microns, and preferably in the range 1 to 10 microns. Per cartridge or blister 0.027 Solutions for inhalation by nebulation may be (R,R)-formoterol fumarate 24 microgram formulated with an aqueous vehicle with the addition of Rofleponide 200 microgram agents Such as acid or alkali, buffer Salts, isotonicity adjust Lactose Ph. Eur. to 12.5 mg ing agents or antimicrobials. They may be Sterilised by or to 25.0 mg filtration or heating in an autoclave, or presented as a non-Sterile product. 0036) The active ingredients are micronised and bulk 0028 Preferred unit dosage formulations are those con blended with the lactose in the proportions given above. The taining a pharmaceutically effective dose, as hereinbefore blend is filled into hard gelatin capsules or cartridges or in recited, or an appropriate fraction thereof, of the active ingredient. Thus, in the case of formulations designed for specifically constructed double foil blister packs to be delivery by metered dose pressurised aerosols, one actuation administered by an inhaler Such as a Rotahaler, Diskhaler, or of the aerosol may deliver half of the therapeutically effec Diskus inhaler (each of these being a Trademark of Glaxo tive amount Such that two actuations are necessary to deliver Group Limited). the therapeutically effective dose. 0037 Similar methods may be used for the formulations of Example 4: 0029. It should be understood that in addition to the ingredients particularly mentioned above, the formulations Example 4 of this invention may include other agents conventional in the art having regard to the type of formulation in question. 0038 Furthermore, the claimed formulations include bioeduiva lents as defined by the US Food and Drugs Agency. 0.030. For a better understanding of the invention, the Per cartridge or blister following Examples are given by way of illustration. (R,R)-Formoterol fumarate 12 microgram EXAMPLES Rofleponide 100 microgram Lactose Ph. Eur. to 12.5 mg A: Metered Dose Inhalers or to 25.0 mg Example 1 0031) 1. A pharmaceutical formulation comprising (R,R)-for Per actuation moterol or a pharmaceutically acceptable Salt, Solvate, or physiologically functional derivative thereof and rofile (R,R)-formoterol fumarate 24 microgram ponide or a pharmaceutically acceptable Salt, Solvate, or Rofleponide 200 microgram physiologically functional derivative thereof, and a pharma 1,1,1,2-Tetrafluoroethane to 75.0 mg ceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients. 0.032 The micronised active ingredients are weighed into 2. A pharmaceutical formulation comprising (R,R)-for an aluminium can, 1,1,1,2-tetrafluoroethane is then added moterol fumarate and rofileponide palmitate, and a pharma from a vacuum flask and a metering Valve is crimped into ceutically acceptable carrier or excipient, and optionally one place. or more other therapeutic ingredients. US 2004/0019025 A1 Jan. 29, 2004

3. A pharmaceutical formulation according to claim 1 or physiologically functional derivative thereof, and optionally claim 2 which comprises another corticosteroid, another one or more other therapeutic ingredients, and 1,1,1,2- f2-adrenoreceptor agonist or an anticholinergic agent. tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane or mix 4. A pharmaceutical formulation according to claim 3, tures thereof as propellant. wherein the other B-adrenoreceptor agonist is Salbutamol, Salmeterol, fenoterol, terbutaline, or a Salt thereof. 9. A method for the prophylaxis or treatment of a clinical 5. A pharmaceutical formulation according to claim 3 condition in a mammal, Such as a human, for which a wherein the anticholinergic agent is ipratropium or tiotro Selective B-adrenoreceptor agonist and/or an antiinflamma pium. tory corticosteroid is indicated, which comprises adminis 6. A pharmaceutical formulation according to any one of tration of a therapeutically effective amount of a pharma claims 1 to 6 which is suitable for administration by inha ceutical formulation according to any one of claims 1 to 9. lation. 10. A method according to claim 11 wherein the clinical 7. A pharmaceutical formulation according to any one of condition is a disease associated with reversible airways claims 1 to 6 which is Suitable for intranasal administration. obstruction Such as asthma, chronic obstructive pulmonary 8. A pharmaceutical formulation consisting of (R,R)- disease (COPD), respiratory tract infection or upper respi formoterol or a pharmaceutically acceptable Salt, Solvate, or ratory tract disease. physiologically functional derivative thereof and rofile ponide or a pharmaceutically acceptable Salt, Solvate, or