Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/08—Bronchodilators

Definitions

• the present invention relates to pharmaceutical compositions for inhalation which comprise one or more bronchodilators and an inhaled corticosteroid. More particularly, the present invention relates to pharmaceutical compositions comprising olodaterol, an inhaled corticosteroid and/or an anticholinergic agent. The present invention also relates to a process for preparing the pharmaceutical composition and use thereof in the treatment and/or prevention of respiratory, inflammatory or obstructive airway disease.
• BACKGROUND OF INVENTION Asthma and chronic obstructive pulmonary disease (COPD) are the common conditions or ailments which affect many people. Airflow obstruction is the main characteristic feature in each of these airway diseases and the medications utilized in the treatment are also often similar.
• Asthma is a chronic inflammatory disorder of the airways associated with airway hyper responsiveness, which leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. These episodes are associated with variable airflow obstruction within the lung which is often reversible, either spontaneously or with treatment.
• COPD chronic obstructive pulmonary disease
• COPD chronic obstructive pulmonary disease
• bronchodilators such as beta 2 -agonists, anticholinergics and steroids.
• Beta 2 -agonists can be short acting for immediate relief, or long acting for long term prevention of asthma symptoms.
• Long acting pVagonists improve lung function, reduce symptoms and protect against exercise- induced dyspnea in patients with asthma and COPD.
• Long acting p 2 -agonists induce bronchodilation by causing prolonged relaxation of airway smooth muscle.
• long acting p 2 -agonists (LABAs) exert other effects such as inhibition of airway smooth-muscle cell proliferation and inflammatory mediator release, as well as non smooth-muscle effects, such as stimulation of mucociliary transport, cytoprotection of the respiratory mucosa and attenuation of neutrophil recruitment and activation. Further, use of a long acting p 2 -agonist reduces the frequency of drug administration.
• LABAs long acting p 2 -agonists
• ICS Inhaled corticosteroids
• ICS inhaled corticosteroids
• ICS regular inhaled corticosteroids
• Corticosteroids are known to exhibit inhibitory effect on inflammatory cells as well as inflammatory mediators involved in the pathogenesis of respiratory disorders.
• ICS inhaled corticosteroids
• ICS inhaled corticosteroids
• use of these corticosteroids, especially in children, has been limited due to their potential side effects. In children and teenagers, these medicines can prohibit or slow down growth and may affect the function of adrenal glands.
• Another possible problem in children is that these corticosteroids may cause infections such as chickenpox and measles.
• corticosteroids cause suppression of the Hypothalamic-Pituitary-Adrenal (HP A) axis, produces adverse effects on the bone growth in children and on the bone density in the elderly, ocular complications (cataract formation and glaucoma) and skin atrophy.
• HP A Hypothalamic-Pituitary-Adrenal
• corticosteroids may seem to increase the risk of high blood pressure and bone diseases. Bone associated diseases by using corticosteroids are especially more likely to occur in elderly females.
• the therapeutic options in the treatment of asthma and chronic obstructive pulmonary disease (COPD) which are not adequately controlled by the use of low to moderate doses of inhaled corticosteroid (ICS) are either to increase the dose of the inhaled corticosteroid (ICS) or to combine the therapy of an inhaled corticosteroid (ICS) with bronchodilators such as ⁇ 2 - agonists and/or anticholinergics.
• COPD chronic obstructive pulmonary disease
• corticosteroids include beclomethasone, budesonide, fluticasone, mometasone, ciclesonide and triamcinolone.
• Anticholinergic agents also act as bronchodilators and are potential alternatives to beta agonists. However, anticholinergics can also be administered along with p 2 -agonists (LABAs) for the management of asthma. Anticholinergics act by competing with acetylcholine for the receptor sites at vagus nerve or nerve-muscle junctions. This prevents the transmission of reflexes that are induced by asthma stimuli.
• anticholinergic drugs is advantageous in elderly patients since, the responsiveness to ⁇ 2 - agonists declines as age increases. Further, it is also advantageous to use in patients who have developed tolerance with the continuous use of p 2 -agonist agents.
• anticholinergics can also be used in patients suffering from nocturnal asthma, chronic asthma with concurrent fixed way obstruction, intrinsic asthma and also in patients with asthma of longer duration.
• long-acting beta agonist (LABA) and inhaled corticosteroid (ICS).
• COPD chronic obstructive pulmonary disease
• Some of these approved combinations for the treatment of asthma and chronic obstructive pulmonary disease (COPD) are salmeterol/fluticasone propionate (Advair diskus ® , Advair ® HFA), and formoterol fumarate dihydrate/budesonide (Symbicort ® ).
• most of the available combinations of a long-acting beta agonist (LABA) with inhaled corticosteroid (ICS) have to be administered twice daily.
• the treatment calls for the patient to comply with different dosage regimens, different frequencies of administration, etc.
• US20080041370 discloses a propellant-free aerosol formulation comprising olodaterol and an active substance selected from budesonide, beclomethasone, fluticasone and ciclesonide or a metabolite thereof.
• US2008041369 discloses a propellant-free aerosol formulation comprising olodaterol, an active substance selected from budesonide, beclomethasone, fluticasone and ciclesonide or a metabolite thereof and an active substance selected from tiotropium salts, oxitropium salts, flutropium salts, ipratropium salts, glycopyrronium salts and trospium salts.
• US20120058980 discloses a combination of olodaterol, ciclesonide, tiotropium and butylhydroxytoluene as an antioxidant.
• EP1940409, US20070086957 and US20110135582 disclose a combination of olodaterol and tiotropium in the ratio 1 : 1 to 10: 1.
• EP1781298 and, US20050239778 disclose a combination of olodaterol and tiotropium.
• EP1781298 discloses the combination of olodaterol and ciclesonide.
• US20070088030, US20100009984 and US20110190284 disclose a combination of olodaterol and an active agent selected from tiotropium, oxitropium, flutropium, ipratropium, glycopyronium and trospium.
• combination therapy of a bronchodilator with an inhaled corticosteroid improves pulmonary efficiency, reduces inflammatory response and provides symptomatic relief as compared to higher doses of inhaled corticosteroid alone in patients affected by respiratory disorders such as asthma
• selection of a specific bronchodilator and inhaled corticosteroid plays a very important role in formulation of fixed dose combinations to control respiratory disorders. Additionally, it simplifies the therapy and reduces the cost. Reducing the dose frequency to the minimum is a main step in simplifying asthma management for improving patient adherence to the therapy.
• a combination of a long-acting ⁇ 2 - agonist (LABA) and an inhaled corticosteroid (ICS) is critical since both drugs should be capable of being administered once daily. So, a treatment method where a long-acting ⁇ 2 - agonist (LABA) is required to be administered once daily and an inhaled corticosteroid (ICS) is required to be administered twice daily,or vice versa will not be useful since the purpose of once a day treatment is defeated.
• the object of the present invention is to provide a pharmaceutical composition comprising one or more bronchodilators and an inhaled corticosteroid (ICS) for administration in the prevention or treatment of respiratory, inflammatory or obstructive airway disease.
• Another object of the present invention is to provide a pharmaceutical composition comprising p 2 -agonist and an inhaled corticosteroid (ICS) and/or anticholinergic agent for administration in the prevention or treatment of respiratory, inflammatory or obstructive airway disease.
• Another object of the present invention is to provide a pharmaceutical composition comprising one or more p 2 -agonist and an inhaled corticosteroid (ICS) and/or an anticholinergic agent for once daily administration in the prevention or treatment of respiratory, inflammatory or obstructive airway disease.
• ICS corticosteroid
• Yet another object of the present invention is to provide a process for preparing a pharmaceutical composition comprising one or more 2 -agonist and an inhaled corticosteroid (ICS) and/or an anticholinergic agent for administration in the prevention or treatment of respiratory, inflammatory or obstructive airway disease.
• ICS corticosteroid
• a further object of the present invention is to provide a method for prophylaxis or treatment of asthma, COPD or a related respiratory or nasal disorder which comprises administering a pharmaceutical composition comprising one or more 2 -agonist and an inhaled corticosteroid (ICS) and/or an anticholinergic agent.
• ICS corticosteroid
• a pharmaceutical composition comprising one or more bronchodilators and an inhaled corticosteroid (ICS).
• ICS corticosteroid
• a pharmaceutical composition comprising one or more p 2 -agonist, an inhaled corticosteroid (ICS) and an anticholinergic agent.
• ICS inhaled corticosteroid
• a pharmaceutical composition comprising one or more p 2 -agonist and an inhaled corticosteroid (ICS) and/or an anticholinergic agent for once daily administration.
• ICS inhaled corticosteroid
• a process for preparing a pharmaceutical composition comprising one or more p 2 -agonist and an inhaled corticosteroid (ICS) and/or an anticholinergic agent.
• a pharmaceutical composition comprising one or more p 2 -agonist and an inhaled corticosteroid (ICS) and/or an anticholinergic agent for use in treating disorders or conditions that respond to, or are prevented, ameliorated or eliminated by, the administration of one or more bronchodilators and an inhaled corticosteroid (ICS) and/or an anticholinergic agent.
• ICS inhaled corticosteroid
• a method for prevention or treatment of asthma, COPD or a related respiratory or nasal disorder which comprises administering to a subject in need thereof, a pharmaceutical composition comprising one or more p 2 -agonist and an inhaled corticosteroid (ICS) and/or an anticholinergic agent.
• ICS corticosteroid
• ICS inhaled corticosteroid
• the present invention thus, provides pharmaceutical compositions for inhalation comprising ⁇ 2 - agonist, an inhaled corticosteroid and/or an anticholinergic agent.
• a preferred p 2 -agonist for use in the present invention is olodaterol, which is preferably olodaterol hydrochloride. . . .
• Suitable inhaled corticosteroid (ICS) for use in the present invention includes fluticasone, mometasone, budesonide, beclomethasone and ciclesonide.
• Suitable anticholinergics agent for use in the present invention includes tiotropium, oxitropium, flutropium, ipratropium, glycopyrronium, trospium, aclidinium, umeclidinium and darotropium.
• the preferred inhaled corticosteroid is fluticasone mometasone and ciclesonide.
• the preferred anticholinergic agent is tiotropium, umeclidinium and darotropium.
• the terms "olodaterol”, “fluticasone”, “mometasone”, “budesonide”, “beclomethasone”, "ciclesonide”, “tiotropium”, “oxitropium”, “flutropium”, “ipratropium”, “glycopyrronium”, “trospium”, “aclidinium”, “umeclidinium” and “darotropium” are used in broad sense to include not only “olodaterol", “fluticasone”, “mometasone”, “budesonide”, “beclomethasone”, "ciclesonide”, “tiotropium”, “oxitropium”, “flutropium”, “ipratropium”, “glycopyrronium”, “trospium”, “aclidinium”, “umeclidinium” and “darotropium” are used in broad sense to include not only “olodaterol”, “fluticasone
• composition for inhalation comprising of: (a) olodaterol;
• an inhaled corticosteroid selected from the group consisting of: fluticasone, mometasone, budesonide, beclomethasone and ciclesonide; and/or
• an anticholinergic agent selected from the group consisting of tiotropium, oxitropium, flutropium, ipratropium, glycopyronium, trospium, aclidinium, umeclidinium and darotropium, preferably wherein (a), (b) and (c) are formulated for simultaneous, separate or sequential administration.
• a particularly preferred pharmaceutical composition of the present invention comprises: (a) olodaterol (b) mometasone and (c) tiotropium.
• a particularly preferred pharmaceutical composition of the present invention comprises: (a) olodaterol (b) mometasone furoate and (c) tiotropium bromide.
• a particularly preferred pharmaceutical composition of the present invention comprises: (a) olodaterol (b) futicasone and (c) tiotropium.
• a particularly preferred pharmaceutical composition of the present invention comprises: (a) olodaterol (b) fluticasone furoate and (c) tiotropium bromide.
• a particularly preferred pharmaceutical composition of the present invention comprises: (a) olodaterol (b) ciclesonide and (c) darotropium, preferably darotropium bromide.
• a particularly preferred pharmaceutical composition of the present invention comprises: (a) olodaterol (b) ciclesonide and (c) umeclidinium, preferably umeclidinium bromide.
• a pharmaceutical composition comprising olodaterol and an inhaled corticosteroid.
• a pharmaceutical composition comprising: (a) olodaterol and (b) an inhaled corticosteroid selected from the group consisting of fluticasone, mometasone, budesonide, beclomethasone and ciclesonide, preferably wherein (a) and (b) are formulated for simultaneous, separate or sequential administration.
• a particularly preferred pharmaceutical composition of the present invention comprises: (a) olodaterol and (b) mometasone.
• a further particularly preferred pharmaceutical composition of the present invention comprises: (a) olodaterol and (b) fluticasone furoate.
• compositions are effective for treating inflammatory and/or obstructive diseases of the respiratory tract, particularly asthma or chronic obstructive pulmonary disease (COPD).
• COPD chronic obstructive pulmonary disease
• compositions of the present invention advantageously provide a rapid onset of action, longer duration of action and improved control of obstructive or inflammatory airway diseases, or reduction in the exacerbations of the diseases.
• compositions of the present invention advantageously reduce the risk of undesirable side effects as compared to the repeated exposure of the steroid alone involved in the treatment of inflammatory or obstructive airways diseases.
• compositions of the present invention facilitates the treatment of an obstructive and inflammatory airway disease with use of a fixed dose combination in a single medicament.
• pharmaceutical compositions of the present invention provide for the administration of combination therapies by use of a single inhaler for patients who currently have to make use of multiple inhalers.
• patients may administer pharmaceutical compositions of the present invention from a single inhaler instead of administering from three different inhalers, one for corticosteroid, one for anticholinergic and one for a long acting beta 2 -agonist. This is particularly important in case of elderly patients who may get confused between the inhalers and who also suffer from several other medical conditions such as heart disease and arthritis, and are receiving multiple other medications.
• compositions of the present invention are formulated for once daily administration.
• Olodaterol is chemically known as 6-hydroxy-8-[(lR)-l-hydroxy-2-[[2-(4-methoxyphenyl)-l,l- dimethylethyl]amino]ethyl]-2H-l,4-benzoxazin-3(4H)- one.
• a particularly preferred pharmaceutically acceptable salt of olodaterol is olodaterol hydrochloride monohydrate. According to the present invention, olodaterol may be present in an amount of from about 2mcg to about 50mcg.
• compositions of the present invention may comprise an anticholinergic such as tiotropium preferably tiotropium bromide.
• Tiotropium bromide is an anticholinergic bronchodilator that antagonises muscarinic Ml, M2 and M3 receptors. Tiotropium bromide, is chemically described as (la, 2B, 4 ⁇ , 5a, 7 ⁇ )-7- [(Hydroxydi-2-thienylacetyl) oxy]-9, 9-diihethyl-3-oxa-9-azoniatricyclo [3.3.1.02,4] nonane bromide monohydrate.
• Tiotropium has a longer duration of action of up to 32 hours. Also tiotropium exhibits an improvement in dyspnea and ceases the need for rescue therapy. Tiotropium in combination with pulmonary rehabilitation (PR) associated with an increased exercise endurance time, produces clinically meaningful improvements in dyspnea and health status as compared to pulmonary rehabilitation (PR) alone in COPD patients.
• PR pulmonary rehabilitation
• tiotropium is more potent than ipratropium in the treatment of patients with COPD in terms of the effect of lung function, dyspnea, exacerbation rates and health status.
• tiotropium may be present in an amount of from about 2mcg to about 50mcg.
• the pharmaceutical compositions of the present invention may also comprise an inhaled corticosteroid, preferably selected from the group consisting of mometasone, fluticasone, budesonide, beclomethasone and ciclesonide.
• fluticasone furoate fluticasone propionate and fluticasone valerate are particularly preferred pharmaceutically acceptable esters of fluticasone.
• fluticasone furoate may be present in an amount of from about 25mcg to about 800mcg.
• Fluticasone furoate is a novel corticosteroid which substantially overcomes the potential side effects that are generally produced by the use of conventional corticosteroids. Moreover, fluticasone furoate exhibits 1.7 times higher binding affinity for the human glucocorticoid receptor as compared to that of fluticasone propionate and also provides prolonged protection up to 26 hours against airway hyper-responsiveness as compared to fluticasone propionate. Fluticasone furoate has a longer duration of action with an elimination half life of 15.1 hrs.
• Fluticasone furoate is a synthetic fluorinated corticosteroid that has been developed as an intranasal treatment for patients with symptoms of rhinitis and has an enhanced affinity towards the glucocorticoid receptor. Further, fluticasone furoate has greater potency when compared to other clinically used corticosteroids such as mometasone furoate, budesonide, fluticasone propionate, ciclesonide, for the glucocorticoid receptor and against the pro-inflammatory transcription factors nuclear factor ⁇ (NF- ⁇ ), activation protein- 1, and tumor necrosis factor— induced interleukin-8 cytokine production. Chronic inflammation which is commonly associated with asthma is also managed by fluticasone furoate.
• NF- ⁇ nuclear factor ⁇
• activation protein- 1 activation protein- 1
• tumor necrosis factor— induced interleukin-8 cytokine production chronic inflammation which is commonly associated with asthma is also managed by fluticasone furoate.
• mometasone furoate A particularly preferred pharmaceutically acceptable ester of mometasone is mometasone furoate.
• mometasone furoate may be present in an amount of from about 25mcg to about 800mcg.
• Mometasone furoate is chemically known as (11[ ⁇ ], 16[ ⁇ ])-9, 21-dichloro-17-[(2- furanylcarbonyl) oxy] - 11 -hydroxy- 16-methy lpregna- 1 ,4-diene-3 ,20-dione.
• Mometasone furoate is a synthetic 17-heterocyclic corticosteroid and exhibits a long duration of action
• the pharmaceutical compositions of the present invention typically may comprise one or more pharmaceutically acceptable excipients.
• the active ingredients may be used as separate formulations or as a single combined formulation. When combined in the same formulation, it will be appreciated that the active ingredients must be stable and compatible with each other and with the other components of the formulation.
• compositions of the present invention are formulated for inhalation and may therefore be administered by any suitable methods used for delivery of the drugs to the respiratory tract.
• the composition of the present invention may be in the form of an aerosol compositions, powders, sprays, solutions, suspensions, a nasal spray, nasal drops or an insufflation powder.
• aerosol compositions may be administered by any conventional means, for example using a metered dose inhaler (MDI), dry powder inhaler (DPI) or nebulizer.
• MDI metered dose inhaler
• DPI dry powder inhaler
• nebulizer nebulizer
• the various dosage forms according to the present invention may comprise carriers/excipients suitable for formulating the same.
• compositions of the present invention are preferably in a form suitable for administration by a MDI, for example, in the form of an aerosol composition.
• Such compositions may comprise one or more pharmaceutically acceptable excipients, in particularselected from the group of HFC/HFA ...propellants, corsolvents, bulking agents, nonvolatile . components, buffers/pH adjusting agents, surface active agents, preservatives, complexing agents, or combinations thereof.
• Suitable propellants are those which, when mixed with the cosolvent(s), form a homogeneous propellant system in which a therapeutically effective amount of the medicament can be dissolved.
• the HFC/HFA propellant must be toxicologically safe and must have a vapor pressure which is suitable to enable the medicament to be administered via a pressurized MDI.
• the HFC/HFA propellants may comprise, one or more of 1,1,1,2-tetrafluoroethane (HFA-134(a)) and 1,1,1,2,3,3,3,-heptafluoropropane (HFA-227), HFC- 32 (difluoromethane), HFC- 143(a) (1,1,1-trifluoroethane), HFC- 134 (1,1,2,2-tetrafluoroethane), and HFC- 152a (1,1-difluoroethane) or combinations thereof and such other propellants which may be known to the person having a skill in the art.
• HFA-134(a) 1,1,1,2-tetrafluoroethane
• HFA-227 1,1,1,2,3,3,3,3,-heptafluoropropane
• HFC- 32 difluoromethane
• HFC- 143(a) (1,1,1-trifluoroethane
• HFC- 134 1,1,2,3,3,3,-
• co-solvent means any solvent which is miscible in the formulation in the amount desired and which, when added provides a formulation in which the medicament can be dissolved.
• the function of the co-solvent is to increase the solubility of the medicament and the excipients in the formulation.
• the co-solvent may comprise one or more of, C2- C6 aliphatic alcohols, such as, but not limited to, ethyl alcohol and isopropyl alcohol; glycols such as but not limited to propylene glycol, polyethylene glycols, polypropylene glycols, glycol ethers, and block copolymers of oxyethylene and oxypropylene; and other substances, such as, but not limited to, glycerol, polyoxyethylene alcohols, and polyoxyethylene fatty acid esters; hydrocarbons such as, but not limited, to n-propane, n-butane, isobutane, n-pentane, iso-pentane, neo-pentane, and n-hexane; and ethers such as but not limited to diethyl ether and combinations thereof.
• C2- C6 aliphatic alcohols such as, but not limited to, ethyl alcohol and isopropyl alcohol
• Suitable surfactants which may be employed in an aerosol composition of the present invention include those which may serve to stabilize the solution formulation and improve the performance of valve systems of the metered dose inhaler.
• Preferred surfactants include one or more ionic and/or non- ionic surfactants.
• suitbale surfactants include, but are not limited to, oleic acid, sorbitan trioleate, lecithin, isopropylmyristate, tyloxapol, polyvinylpyrrolidone, polysorbates such as polysorbate 80, vitamin E-TPGS, and macrogol hydroxystearates such as macrogol- 15 -hydroxystearate and combinations thereof.
• non-volatile component refers to the suspended or dissolved constituents of the pharmaceutical composition that would remain after evaporation of the solvent(s) present.
• the non-volatile component may comprise one or more of monosaccharides such as, but not limited to, glucose, arabinose; disaccharides such as lactose, maltose; oligosaccharides and polysaccharides such as, but not limited to, dextrans; polyalcohol such as, but not limited to, glycerol, sorbitol, mannitol, xylitol; salts such as, but not limited to, potassium chloride, magnesium chloride, magnesium sulphate, sodium chloride, sodium citrate, sodium phosphate, sodium hydrogen phosphate, sodium hydrogen carbonate, potassium citrate, potassium phosphate, potassium hydrogen phosphate, potassium hydrogen carbonate, calcium carbonate and calcium chloride and combinations thereof.
• monosaccharides such as, but not limited to, glucose, arabinose
• disaccharides such as lactose, maltose
• oligosaccharides and polysaccharides such as, but not limited to, dextrans
• Suitable bulking agents may be employed in the pharmaceutical compositions of the invention, in particular aerosol compositions that are intended for administration using an MDI.
• the bulking agent may comprise one or more of saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, terhalose, lactose, maltose, starches, dextran or mannitol and combinations thereof.
• Suitable buffers or pH adjusting agents may be employed in the pharmaceutical compositions of the invention, in particular aerosol compositions that are intended for administration using an MDI.
• the buffer or the pH adjusting agent may comprise one or more of organic or inorganic acids such as, but not limited to, citric acid, ascorbic acid, hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid and combinations thereof.
• Suitable preservatives may be employed in the pharmaceutical compositions of the invention, in particular aerosol compositions that are intended for administration using an MDI, to protect the formulation from contamination with pathogenic bacteria.
• the preservative may comprise one or more of benzalkonium chloride, benzoic acid, benzoates such as sodium benzoate and such other preservatives which may be known to the person having a skill in the art and combinations thereof.
• Suitable complexing agents may be employed in the pharmaceutical compositions of the invention, in particular aerosol compositions that are intended for administration using an MDI, capable of forming complex bonds.
• the complexing agent may comprise one or more of, but not limited to, sodium EDTA or disodium EDTA and combinations thereof.
• compositions of the present invention are preferably in a form suitable for administration by a dry powder inhaler (DPI).
• DPI dry powder inhaler
• the pharmaceutically acceptable excipients suitable for dry powder inhalation according to the present invention may be selected from suitable carriers which include, but are not limited to, sugars such as glucose, saccharose, lactose and fructose, starches or starch derivatives, oligosaccharides such as dextrins, cyclodextrins and their derivatives, polyvinylpyrrolidone, alginic acid, tylose, silicic acid, cellulose, cellulose derivatives (for example cellulose ether), sugar alcohols such as mannitol or sorbitol, calcium carbonate, calcium phosphate, etc.
• suitable carriers include, but are not limited to, sugars such as glucose, saccharose, lactose and fructose, starches or starch derivatives, oligosaccharides such as dextrins, cyclodextrins and their derivatives, polyvinylpyrrolidone, alginic acid, tylose, silicic acid,
• lactose lactitol, dextrates, , dextrose, maltodextrin, saccharides including monosaccharides, disaccharides, polysaccharides; sugar alcohols such as arabinose, ribose, mannose, sucrose, trehalose, maltose, dextran, magnesium stearate, cellobiose octaacetate and combinations thereof.
• compositions of the present invention are preferably in a form suitable for administration by nebulization. Nebulization therapy has an advantage over other inhalation therapies, since it is easy to use and does not require co-ordination or much effort. It also works much more rapidly than medicines taken by mouth.
• Such compositions may comprise suitable excipients such as one or more, but not limited to, tonicity agents, pH regulators, and chelating agents in a suitable vehicle.
• Suitable isotonicity adjusting agents include sodium chloride, potassium chloride, zinc chloride, calcium chloride and mixtures thereof.
• Other isotonicity-adjusting agents may also include, but are not limited to, mannitol, glycerol, and dextrose and mixtures thereof.
• the pH of pharmaceutical compositions of the invention may be adjusted by the addition of one or more pH regulators such as pharmacologically acceptable acids.
• Pharmacologically acceptable inorganic acids or organic acids may be used for this purpose.
• preferred inorganic acids include one or more acids selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and phosphoric acid and combinations thereof.
• particularly suitable organic acids include one or more acids selected from the group consisting of ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and propionic acid and combinations thereof.
• EDTA editic acid
• sodium EDTA or disodium EDTA dihydrate sodium edetate
• the dosage form as nasal spray and nasal drops may comprise thickening agents.
• cellulose derivatives for example cellulose ether
• lower unsaturated aliphatic alcohols and/or lower unsaturated aliphatic oxyalcohols for example methyl cellulose, carboxymethyl cellulose, hydroxypropylmethylcellulose
• gelatin polyvin
• one or more anti-microbial preservative agents may also be added to the pharmaceutical compositions of the invention, in particular for multi-dose packages.
• the pharmaceutical composition according to the present invention may be included in one or more suitable containers provided with means enabling the application of the contained formulation to the respiratory tract.
• compositions of the invention are in the form of a powder for inhalation and are intended to be administered by a DPI, it may be encapsulated in capsules of gelatin or HPMC, or in blisters.
• the dry powder may be contained as a reservoir either in a single dose or multi-dose dry powder inhalation device
• the powder for inhalation may be suspended in a suitable liquid vehicle and packed in an aerosol container along with suitable propellants or mixtures thereof.
• the powder for inhalation may be dispersed in a suitable gas stream to form an aerosol composition.
• the pharmaceutical compositions of the invention may be packed in plain aluminium cans or SS (stainless steel) cans or any such cans suitable for MDI delivery.
• Some aerosol drugs tend to adhere to the inner surfaces, i.e., walls of the cans and valves, of the MDI. This can lead to the patient getting significantly less than the prescribed amount of the active agent upon each activation of the MDI.
• Such cans may be suitably treated to avoid any adherence of the active on the walls thereof using techniques known in the art, for example coating the inner surface of the container with a suitable polymer can reduce this adhesion problem.
• suitable coatings include fluorocarbon copolymers such as FEP-PES (fluorinated ethylene propylene and polyethersulphone) and PFA-PES (perfluoroalkoxyalkane and polyethersulphone), epoxy and ethylene.
• the inner surfaces of the cans may be anodized, plasma treated or plasma coated.
• compositions of the invention are in the form of nasal sprays and nasal drops for administration into the nasal passages it may be done by means of a dropper (or pipette) that includes a glass, plastic or metal dispensing tube. Fine droplets and sprays can be provided by an intranasal pump dispenser or squeeze bottle as well known in the art.
• compositions of the present invention may further comprise, in addition to those pharmaceutically active ingredients detailed above, one or more active(s) selected from the group comprising of, antihistamines, antiallergics or leukotriene antagonists, or their pharmaceutically acceptable salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof.
• active(s) selected from the group comprising of, antihistamines, antiallergics or leukotriene antagonists, or their pharmaceutically acceptable salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof.
• compositions of the present invention comprise olodaterol, an inhaled corticosteroid and/or an anticholinergic agent.
• active ingredients are formulated for simultaneous, separate or sequential administration.
• the active ingredients may be administered sequentially, either olodaterol, the inhaled corticosteroid, or where present, the anticholinergic agent may be administered first.
• the active ingredients may be administered either in the same or different pharmaceutical compositions.
• Adjunctive therapy i.e. where one active ingredient is used as the primary treatment and the other active ingredient(s) is/are used to assist that primary treatment is also an embodiment of the present invention.
• a product comprising: (a) olodaterol and (b) an inhaled corticosteroid selected from the group comprising mometasone or fluticasone; as a combined preparation for simultaneous, separate or sequential use for treatment and /or prevention of respiratory, inflammatory or obstructive airway disease.
• a product comprising (a) olodaterol; (b) an inhaled corticosteroid selected from the group comprising mometasone or fluticasone; (c) an anticholinergic agent, which is preferably tiotropium as a combined preparation for simultaneous, separate or sequential use for treatment and /or prevention of respiratory, inflammatory or obstructive airway disease.
• Compositions for use according to the present invention may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredients. These may for example, comprise metal or plastic foil, such as a blister pack. Where compositions are intended for administration as two separate compositions these may be presented in the form of a twin pack.
• compositions may also be prescribed in "patient packs" containing the whole course of treatment in a single package.
• a package insert has been shown to improve patient compliance with the prescribing physician's instructions.
• a patient pack comprising at least one active ingredient of the combination according to the invention and an information insert containing directions to use the combination of the invention.
• the present invention provides a fixed dose combination.
• compositions of the present invention may be conveniently presented in a unit dosage form and may be prepared by any of the methods well known in the art. Suitable methods include the step of bringing into association the active ingredients with a carrier which constitutes one or more pharmaceutically acceptable excipients. In general, compositions may be prepared by uniformly and intimately bringing into association the active ingredients with one or more liquid carriers or finely divided solid carriers, or both. It will be appreciated that when the active ingredients are administered independently, each may be administered by a different means.
• the present invention also provides a process for manufacturing the compositions according to the present invention.
• the present invention provides a process of preparing pharmaceutical compositions for administration by a metered dose inhaler, which process comprises admixing a pharmaceutically acceptable carrier or excipient with one or more active pharmaceutical ingredients of the invention and a propellant, and thereafter transferring the composition to a suitable container, preferably a pre-crimped can.
• the invention provides a process of preparing a pharmaceutical compositions for administration by dry powder inhalation, which process comprises admixing of a pharmaceutically acceptable carrier or excipient with one or more active pharmaceutical ingredients of the invention and providing the composition as a dry powder.
• the invention provides a process of preparing pharmaceutical compositions for administration by nebulisation, which process comprises dissolving the drugs, optionally chelating agents, osmotic/isotonicity adjusting agents and any other suitable ingredients in the vehicle and adjusting the pH using a suitable pH adjusting agent.
• the invention also provides a method for the prevention and/or treatment of a respiratory, inflammatory or obstructive airway disease, in particular chronic obstructive pulmonary disease, in a mammal, such as a human, which method comprises administration of a therapeutically effective amount of pharmaceutical compositions according to the present invention.
• the present invention also provides pharmaceutical compositions according to the present invention for use in preventing and/or treating disorders or conditions that respond to, or are prevented, ameliorated or eliminated by, the administration one or more bronchodilators and an inhaled corticosteroid (ICS), such as a respiratory, inflammatory or obstructive airway disease, in particular chronic obstructive pulmonary disease.
• ICS corticosteroid
• step 2 The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity of HFA was added.
• step 2 The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity of HFA was added. 3) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
• step 2 The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity of HFA was added.
• step 2 The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity of HFA was added.
• step 2 The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity of HFA was added.
• step 2 The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity of HFA was added.
• Ciclesonide, Darotropium Bromide and Olodaterol were homogenized with lactose and part quantity of HFA.
• step 2 The suspension obtained in step 1 and 2 was transferred to the mixing vessel where remaining quantity of FIFA was added.
• Ciclesonide 200 meg 1.
• Ciclesonide, Olodaterol and Darotropium Bromide were homogenized with part quantity of HFA and transferred to the mixing vessel.
• Ciclesonide, Olodaterol and Darotropium Bromide were homogenized with part quantity of HFA and transferred to the mixing vessel.
• Ciclesonide, Umeclidinium Bromide and Olodaterol were homogenized and part quantity of HFA.
• step 2 The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity of HFA was added.
• Ciclesonide, Umeclidinium Bromide and Olodaterol were homogenized with lactose and part quantity of HFA.
• step l The suspension obtained in step l was transferred to the mixing vessel where remaining quantity of HFA was added.
• Ciclesonide 200 meg 1.
• Ciclesonide, Olodaterol and Umeclidinium Bromide were homogenized with part quantity of HFA and transferred to the mixing vessel.
• Ciclesonide, Olodaterol and Umeclidinium Bromide were homogenized with part quantity of HFA and transferred to the mixing vessel.
• step 2 The cosift of step 1 was then sifted with the remaining quantity of lactose and blended.
• step 2 The cosift of step 1 was then sifted with the remaining quantity of lactose and blended. 3) The : blend of step 2 was then filled in capsules.
• step 2 The cosift of step 1 was then sifted with the remaining quantity of lactose and blended.
• step 2 was then filled in capsules.
• step 2 The cosift of step 1 was then sifted with the remaining quantity of lactose and blended.
• step 2 was then filled in capsules.
• step 2 The cosift of step 1 was then sifted with the remaining quantity of lactose and blended. 3) The blend of step 2 was then filled in capsules.
• step 2 The cosift of step 1 was then sifted with the remaining quantity of lactose and blended.
• step 2 was then filled in capsules. It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.

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• 2013
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