Indian Patents. 235060:AN IMPROVED PHARMACEUTICAL COMPOSITION FOR ASTHMA AND RELATED DISORDERS

Title of Invention	AN IMPROVED PHARMACEUTICAL COMPOSITION FOR ASTHMA AND RELATED DISORDERS
Abstract	NIL

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) PROVISIONAL SPECIFICATION [See section 10] AN IMPROVED PHARMACEUTICAL COMPOSITION FOR ASTHMA AND RELATED DISORDERS; CIPLA LIMITED, A COMPANY INCORPORATED UNDER THE INDIAN COMPANIES ACT, 1913, WHOSE ADDRESS IS 289, BELLASIS ROAD, MUMBAI CENTRAL, MUMBAI - 400 008, MAHARASHTRA, INDIA; THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THIS INVENTION. FIELD OF INVENTION The present invention is concerned with pharmaceutical combinations of β-2 adrenoreceptor agonists and anti-cholinergic agents and the therapeutic use thereof, particularly in the prophylaxis and treatment of respiratory diseases. In particular, the present invention is concerned with pharmaceutical formulations comprising combinations of β -2 adrenoreceptor agonists and anti-cholinergic agents and the therapeutic use thereof, particularly in the prophylaxis and treatment of respiratory diseases. BACKGROUND ART: The path physiology of asthma or related disorders involves bronchoconstriction resulting from bronchial smooth muscle spasm and airway inflammation with mucosal edema. Treatment of asthma, COPD (chronic obstructive pulmonary diseases) and other related disorders have been known to be treated with β-2 adrenoreceptor agonists also known as p-2 receptor agonists. Such β-2 adrenoreceptor agonists are known to provide a bronchodilator effect to patients, resulting in relief from the symptoms of breathlessness. More particularly, β-2 adrenoreceptor agonists have been shown to increase the conductance of potassium channels in airway muscle cells, leading to membrane hyperpolarization and relaxation. It has also been seen that a subgroup of P-2 adrenoreceptor agonists can be described as short acting, whilst a further subgroup of p-2 adrenoreceptor agonists can be described as long acting. The mechanism of anti-asthmatic action of the short acting subgroup is linked to the direct relaxation of airway smooth muscles and consequent bronchodilation. Drugs belonging to this short acting subgroup have quicker onset of action (within 1-15 minutes) and produce a bronchodilation that lasts for about 2-6 hours. Such drugs act as "rescue" medication i.e. where immediate relief is required. The long acting subgroup of drugs act via a similar mechanism i.e. relaxation of airway smooth muscles and consequent bronchodilation. Drugs of this long acting subgroup may have delayed onset of action, but have a longer duration of action, so are used for long-term regular treatment of reversible airways obstruction in asthma. Short acting β-2 adrenoreceptor agonists include terbutaline, salbutamol, lev-albuterol, R, R-formoterol, metaprotemol sulfate, pirbuterol acetate, bitolterol mesylate, fenoterol, procaterol and the like. Long acting β-2 adrenoreceptor agonists include salmeterol and formoterol. For example, it has been reported that inhalation of salmeterol provides persistent bronchodilation lasting over 12 hours. The extended side chain on salmeterol renders it greatly lipophilic. This lipophilicity regulates the diffusion rate away from the receptor by determining the degree of partitioning in the lipid bilayer of the membrane. Subsequent to binding the receptor, the less lipophilic, short acting agonists are rapidly removed from the receptor environment by diffusion in aqueous phase. Unbound salmeterol, by contrast, persists in the membrane and only slowly dissociates from the receptor environment. A further component of asthma is inflammation, which is treated with steroids. Also, steroids have been known to make bronchodilators more effective. If combined with bronchodilators, lower doses of steroids have been needed to achieve the same effect. Bronchoconstriction and inflammation are also associated with bronchial plugging with secretions, which is known to be treated with anti-cholinergic agents. These agents prevent increases in intracellular concentration of cyclic GMP that are caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle. Available anti-cholinergics reported are ipratropium bromide, oxitropium bromide, tiotropium bromide and the like. An important therapeutic property of ipratropium and tiotropium is their minimal inhibitory effect on mucociliary clearance, relative to atropine. Hence, the use of these agents in patients with airway disease avoids the increased accumulation of lower airway secretions encountered with atropine. Ipratropium and oxitropium bromide have a shorter duration of action. More particularly, it has been seen that after inhalation, maximal responses usually develop over 30 to 90 minutes for ipratropium and oxitropium, with tiotropium having a slower onset. The effects of ipratropium last for 4 to 6 hours, while tiotropium's effects persist for 24 hours. Ipratropium and oxitropium can thus be classified as short acting anti-cholinergic agents, whereas tiotropium can be classified as a long acting anti-cholinergic agent, based on the above described durations of action. It has also been reported that combined treatment of anti-cholinergics with β-2 adrenoreceptor agonists results in slightly greater and more prolonged bronchodilation than with either agent alone in the treatment of baseline asthma. Such combination products provide combination treatment of airway constriction and inflammation. Furthermore, combination of anti-cholinergics, such as ipratropium bromide, and β-2 adrenoreceptor agonists, such as salbutamol, is known to provide an effective therapy to reduce constriction and to reduce bronchial secretions. All these medicaments are known to be given in different dosage forms, for example MDIs, DPIs, oral and liquid formulations. Treatment with these different categories of medication calls for the patient to comply with different doses, different frequencies of doses and the like. Despite the large numbers of known treatments of respiratory diseases as discussed above, there continues to exist a clinical need for therapies of respiratory diseases which exhibit advantageous profiles of action. To this end, it has surprisingly been found that a combination of short acting and long acting β—2 adrenoreceptor agonists, with short acting and long acting anti¬cholinergics provide an enhanced, synergistic therapeutic effect in terms of treatment of respiratory diseases, such as bronchoconstriction, inflammation, mucous secretions and related disorders. Also, such combination therapy is an extremely patient-friendly combination, which results in enhanced patient compliance and better control of respiratory diseases, such as asthma, compared to known combinations. DESCRIPTION OF THE INVENTION: There is provided by the present invention, therefore, a pharmaceutical product comprising (i) at least one short acting \|3-2 adrenoreceptor agonist, (ii) at least one long acting β-2 adrenoreceptor agonist, (iii) at least one short acting anti-cholinergic agent, (iv) at least one long acting anti-cholinergic agent as a combined preparation for simultaneous, separate or sequential use in the treatment of respiratory diseases. The present invention also provides a pharmaceutical formulation comprising (i) at least one short acting β-2 adrenoreceptor agonist, (ii) at least one long acting β—2 adrenoreceptor agonist, (iii) at least one short acting anti¬cholinergic agent, (iv) at least one long acting anti-cholinergic agent, together with a pharmaceutically acceptable carrier or excipient thereof. According to this preferred embodiment of the present invention there is provided a pharmaceutical product comprising (i) at least one short acting β-2 adrenoreceptor agonist, (ii) at least one long acting (3-2 adrenoreceptor agonist, (iii) at least one short acting anti-cholinergic agent, (iv) at least one long acting anti-cholinergic agent as a combined preparation for simultaneous, separate or sequential use in the treatment of respiratory diseases. Also according to this preferred embodiment of the present invention there is provided a pharmaceutical formulation comprising (i) at least one short acting β-2 adrenoreceptor agonist, (ii) at least one long acting β-2 adrenoreceptor It will be appreciated from the above that the terms "short acting β-2 adrenoreceptor agonists", "long acting β-2 adrenoreceptor agonists", "short acting anti-cholinergic agents" and "long acting anti-cholinergic agents" are well known and well understood in the field of treatment of respiratory diseases. Most of the above mentioned medications are in the form of aerosols, with the patient generally being required to carry many MDIs (metered dose inhalers) for each of these medicaments. The following prior art patent documents describe known aerosol formulations - inhalation aerosol of terbutaline (US 5980949 and WO 98/31353), inhalation aerosol of salbutamol (WO 99/48476), aerosol formulations of formoterol (US 2002058011 and WO 98/31351), inhalation aerosol of pirbuterol acetate (EP 0717987), inhalation aerosol of fenoterol (US 6045778), aerosol formulations of procaterol (US 4616022) and aerosol formulations of salmeterol (US 6143277, WO 02/051483, WO 00/61108 and WO 99/55319). Furthermore, in order to ease patient compliance, combination products have been described in the following prior art patent documents - Combinations of tiotropium and salmeterol (WO 02/38154), combinations of formoterol and salmeterol (EP'1158970), combinations of tiotropium and mometasone (WO 01/78743), combinations of tiotropium and budesonide (WO 01/78741), combinations of tiotropium and fluticasone propionate (WO 01/78739), combinations of tiotropium and rofliponide (WO 01/78736) and combinations of tiotropium and formoterol (WO 00/47200). agonist, (iii) at least one short acting anti-cholinergic agent, (iv) at least one long acting anti-cholinergic agent together with a pharmaceutically acceptable carrier or excipient therefore. Suitably in pharmaceutical products or formulations according to the present invention, a short acting β-2 adrenoreceptor agonist is selected from the group consisting of terbutaline, salbutamol, fenoterol, lev-albuterol, R, R-formoterol, bitolterol, metaproternol, pirbuterol and procaterol, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. Preferably a short acting β-2 adrenoreceptor agonist employed according to the present invention is either salbutamol or terbutaline sulphate. Suitably in pharmaceutical products or formulations according to the present invention, a long acting β-2 adrenoreceptor agonist is selected from the group consisting of salmeterol and formoterol, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. Preferably a long acting β-2 adrenoreceptor agonist employed according to the present invention is salmeterol. Suitably in pharmaceutical products or formulations according to the present invention, a short acting anti-cholinergic agent is selected from the group consisting of ipratropium and oxitropium, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. Preferably ipratropium or oxitropium bromide are employed according to the present invention. Suitably in pharmaceutical products or formulations according to the present invention, a long acting anti-cholinergic agent is tiotropium, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. Preferably tiotropium bromide is employed according to the present invention. Preferred combinations of therapeutic agents employed in pharmaceutical products and formulations according to the present invention comprise any one of the following combinations: as a short acting β-2 adrenoreceptor agonist - salbutamol; as a long acting β-2 adrenoreceptor agonist - salmeterol; as a short acting anti-cholinergic agent - ipratropium bromide; as a long acting anti-cholinergic agent - tiotropium bromide; or as a short acting β-2 adrenoreceptor agonist - terbutaline sulphate; as a long acting β-2 adrenoreceptor agonist - salmeterol; as a short acting anti-cholinergic agent - ipratropium bromide; as a long acting anti-cholinergic agent - tiotropium bromide; or as a short acting β-2 adrenoreceptor agonist - salbutamol; as a long acting β—2 adrenoreceptor agonist - salmeterol; as a short acting anti-cholinergic agent - oxitropium bromide; as a long acting anti-cholinergic agent - tiotropium bromide; or as a short acting β-2 adrenoreceptor agonist - terbutaline sulphate; as a long acting β—2 adrenoreceptor agonist - salmeterol; as a short acting anti-cholinergic agent - oxitropium bromide; as a long acting anti-cholinergic agent - tiotropium bromide; or Preferably, the concentration of a short acting β-2 adrenoreceptor agonist present in a formulation according to the present invention is in the range of about 0.01% to 5% by weight, based on the weight of the total formulation Preferably, the concentration of a long acting β-2 adrenoreceptor agonist present in a formulation according to the present invention is in the range of about 0.01% to 5% by weight, based on the weight of the total formulation. Preferably, the concentration of a short acting anti-cholinergic agent present in a formulation according to the present invention is in the range of about 0.001% to 0.05% by weight, based on the weight of the total formulation. Preferably, the concentration of a long acting anti-cholinergic agent present in a formulation according to the present invention is in the range of about 0.01% to 5% by weight, based on the weight of the total formulation. The term "physiologically functional derivative" as used herein denotes a chemical derivative of any of the specific therapeutic agents described herein having the same or similar physiological function as the free base therapeutic agent and, for example, being convertible in the body thereto. It will of course be appreciated that the present invention encompasses the use of enantiomers of the specific therapeutic agents described herein. Suitable pharmaceutically acceptable salts for use according to the present invention include those formed with both organic and inorganic acids and are well known to one of ordinary skill in the art. There is also provided by the present invention a method for the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more anti-cholinergic agents, and / or one or more β-2 adrenoreceptor agonists is indicated, which method comprises administration of a therapeutically effective amount of a pharmaceutical product comprising (i) at least one short acting β-2 adrenoreceptor agonist, (ii) at least one long acting β-2 adrenoreceptor agonist, (iii) at least one short acting anti¬cholinergic agent, (iv) at least one long acting anti-cholinergic agent as a combined preparation for simultaneous, separate or sequential use in the treatment of such respiratory diseases. The present invention also provides a method for the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more anti-cholinergic agents, and / or one or more β-2 adrenoreceptor agonists is indicated, which method comprises administration of a therapeutically effective amount of a pharmaceutical formulation comprising (i) at least one short acting β-2 adrenoreceptor agonist, (ii) at least one long acting (3-2 adrenoreceptor agonist, (iii) at least one short acting anti¬cholinergic agent, (iv) at least one long acting anti-cholinergic agent, together with a pharmaceutically acceptable carrier or excipient thereof. Preferred therapeutic agents for use in a method according to the present invention are substantially as hereinbefore described with reference to pharmaceutical products and pharmaceutical formulations according to the present invention. The term respiratory disease as used herein denotes inflammatory and obstructive airways disease, such as asthma, COPD and other related disorders. There is also provided by the present invention for use in the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more anti-cholinergic agents, and / or one or more β-2 adrenoreceptor agonists, is indicated, a pharmaceutical product comprising (i) at least one short acting β-2 adrenoreceptor agonist, (ii) at least one long acting β-2 adrenoreceptor agonist, (iii) at least one short acting anti-cholinergic agent, (iv) at least one long acting anti-cholinergic agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of respiratory diseases. There is also provided by the present invention for use in the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more anti-cholinergic agents, and / or one or more (3-2 adrenoreceptor agonists, is indicated, a pharmaceutical formulation comprising (i) at least one short acting (3-2 adrenoreceptor agonist, (ii) at least one long acting (3-2 adrenoreceptor agonist, (iii) at least one short acting anti-cholinergic agent, (iv) at least one long acting anti-cholinergic agent, together with a pharmaceutically acceptable carrier or excipient thereof. Preferred therapeutic agents for such prophylactic or therapeutic use according to the present invention are substantially as hereinbefore described with reference to pharmaceutical products and pharmaceutical formulations according to the present invention. The term respiratory disease as used herein denotes inflammatory and obstructive airways disease, such as asthma, COPD and other related disorders. There is also provided by the present invention for use in the manufacture of a medicament for the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more anti-cholinergic agents, and / or one or more (3-2 adrenoreceptor agonists is indicated, a pharmaceutical product comprising (i) at least one short acting p-2 adrenoreceptor agonist, (ii) at least one long acting (3-2 adrenoreceptor agonist, (iii) at least one short acting anti-cholinergic agent, (iv) at least one long acting anti-cholinergic agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of respiratory diseases. There is also provided by the present invention for use in the manufacture of a medicament for the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more anti-cholinergic agents, and / or one or more p-2 adrenoreceptor agonists is indicated, a pharmaceutical formulation comprising (i) at least one short acting p-2 adrenoreceptor agonist, (ii) at least one long acting β-2 adrenoreceptor agonist, (iii) at least one short acting anti-cholinergic agent, (iv) at least one long acting anti-cholinergic agent together with a pharmaceutically acceptable carrier or excipient therefore. Preferred therapeutic agents for such use in the manufacture of a medicament according to the present invention are substantially as hereinbefore described with reference to pharmaceutical products and pharmaceutical formulations according to the present invention. The term respiratory disease as used herein denotes inflammatory and obstructive airways disease, such as asthma, COPD and other related disorders. Pharmaceutical products and formulations according to the present invention include those suitable for oral, parenteral, inhalation, rectal and topical administration, with inhalation being preferred typically employing MDIs or DPIs. The pharmaceutical products and formulations may conveniently be presented in unit dosage form and may be prepared by methods well known to one of ordinary skill in the art. The present invention also provides a pharmaceutical formulation substantially as hereinbefore described, which process comprises admixing a pharmaceutically acceptable carrier or excipient with: (i) at least one short acting (3-2 adrenoreceptor agonist; (ii) at least one long acting (3-2 adrenoreceptor agonist; (iii) at least one short acting anti-cholinergic agent; (iv) at least one long acting anti-cholinergic agent; Preferably pharmaceutical formulations according to the present invention comprise aerosol formulations to be delivered from pressurized containers with the use of a suitable propellant as the carrier or excipient. Suitable propellants include 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3,-heptafluoropropane (HFA 227), or a combination of both, or mono-fluoro trichloromethane and dichloro difluoromethane, in particular 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), with HFA 134a being preferred. A pharmaceutical aerosol formulation according to the present invention preferably further comprises a polar cosolvent such as C2-6 aliphatic alcohols and polyols, for example ethanol, isopropanol and propylene glycol, with ethanol being preferred. Preferably, the concentration of the cosolvent is in the range of about 2 to 15% by weight, of the total formulation. A formulation according to the present invention may further comprise one or more surfactants. Such surfactants can be included to stabilize the formulations and for lubrication of a valve system. Some of the most commonly used surfactants in aerosol formulations are oils derived from natural sources, such as corn oil, olive oil, cottonseed oil and sunflower seed oil, and also phospholipids such as lecithin. A preferred surfactant for use according to the present invention is oleic acid. The surfactants used in the formulations of the present invention are generally present in the range of about 0.00002% to 20% by weight of the therapeutic agents present in the formulations, and more preferably in the range of about 0.00002 to 0.01% by weight of the therapeutic agents present in the formulations. The surfactants may exceed this weight ratio in cases where therapeutic agent concentration in a formulation is very low. A preferred aerosol formulation of this invention is in the form of a suspension or a particulate suspension or a clear solution. In the case of a particulate suspension or a solution, the cosolvent used should have greater polarity than the propellant used. The most commonly used cosolvent is ethanol substantially as hereinbefore described. Generally the ratio of propellant to ethanol is 50:50 to 99:1. Preferably therapeutic agents present in aerosol formulations according to the present invention are present at a concentration in the range of about 0.001% to 5% of the total formulation. Preferably, the therapeutic agents are employed at an appropriate particle size (95% below 2.5 mm, the remainder being between 2.5 to 5mm by microscope, and 95% below 5-6 m and all particles below 10-12m by laser). Pharmaceutical aerosol formulations according to the present invention are particularly suitable for use in DPIs or MDIs substantially as hereinbefore described which utilize a liquefied propellant as referred to above to expel droplets containing the therapeutic agents employed according to the present invention. Suitably a formulation according to the present invention is filled into an aluminum can through a suitable metering device and typically the can is plastic coated, lacquer-coated or anodized. The present invention will now be further illustrated by the following Examples, which do not limit the scope of the invention in any way. EXAMPLES Example 1 Per can Tiotropium bromide 2.400 mg Salbutamol 24.000 mg Salmeterol 6.000 mg Ipratropium Bromide 4.000 mg 1,1,1,2-Tetrafluoroethane 18.200 gm Example 2 Per can Tiotropium bromide 2.400 mg Terbutaline Sulphate 60.000 mg Salmetrol 6.000 mg Ipratropium Bromide 4.000 mg 1,1,1,2-Tetrafluoroethane 18.200 gm For each of the above formulations of Examples 1 and 2, the active ingredients were first weighed in a plain aluminum can. A metering valve was then placed on the can and crimped with a vacuum crimpier. Propellant 134a was then charged through the metering valve. Example 3 Per can Tiotropium bromide 2.400 mg Salbutamol 24.000 mg Salmeterol 6.000 mg Oxitropium Bromide 20.000 mg Ethanol 2.730 gm 1,1,1,2-Tetrafluoroethane 15.470 gm For the above formulation of Example 3, the active ingredients were first weighed in a plain aluminum can. Ethanol was then added and the solution was sonicated for 5 minutes. A metering valve was then placed on the can and crimped with a vacuum crimpier. Propellant 134a was then charged through the metering valve. Example 4 Per can Tiotropium bromide 2.400 mg Salbutamol 24.000 mg Salmeterol 6.000 mg Ipratropium Bromide 4.000 mg Ethanol 2.730 gm Oleic acid (10%) 5.040 mg 1,1,1,2-Tetrafluoroethane 15.470 gm For the above formulation of Example 4, the active ingredients were first weighed in a plain aluminum can. Ethanol and the surfactant we're then added and the solution was sonicated for 5 minutes. A metering valve was then placed on the can and crimped with a vacuum crimpier. Propellant 134a was then charged through the metering valve. Example 5 Per can Tiotropium bromide 2.400 mg Terbutaline Sulphate 60.000 mg Salmeterol 6.000 mg Oxitropium bromide 20.000 mg Ethanol 0.364 gm 1,1,1,2-Tetrafluoroethane 18.200 gm For the above formulation of Example 5, the active ingredients were first weighed in a plain aluminum can. Ethanol was then added and the solution was sonicated for 5 minutes. A metering valve was then placed on the can and crimped with a vacuum crimpier. Propellant 134a was then charged through the metering valve. Example 6 Per can Tiotropium bromide 2.400 mg Terbutaline Sulphate 60.000 mg Salmeterol 6.000 mg Ipratropium Bromide 4.000 mg Ethanol 0.364 gm Oleic acid (0.02%) 0.014 mg 1,1,1,2-Tetrafluoroethane 17.830 gm For the above formulation of Example 6, the active ingredients were first weighed in a plain aluminum can. Ethanol and the surfactant were then added and the solution was sonicated for 5 minutes. A metering valve was then placed on the can and crimped with a vacuum crimpier. Propellant 134a was then charged through the metering valve.

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
PROVISIONAL SPECIFICATION
[See section 10]

AN IMPROVED PHARMACEUTICAL
COMPOSITION FOR ASTHMA AND
RELATED DISORDERS;

CIPLA LIMITED, A COMPANY
INCORPORATED UNDER THE INDIAN COMPANIES ACT, 1913, WHOSE ADDRESS IS 289, BELLASIS ROAD, MUMBAI CENTRAL, MUMBAI - 400 008, MAHARASHTRA, INDIA;

THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THIS INVENTION.

FIELD OF INVENTION
The present invention is concerned with pharmaceutical combinations of β-2 adrenoreceptor agonists and anti-cholinergic agents and the therapeutic use thereof, particularly in the prophylaxis and treatment of respiratory diseases. In particular, the present invention is concerned with pharmaceutical formulations comprising combinations of β -2 adrenoreceptor agonists and anti-cholinergic agents and the therapeutic use thereof, particularly in the prophylaxis and treatment of respiratory diseases.
BACKGROUND ART:
The path physiology of asthma or related disorders involves bronchoconstriction resulting from bronchial smooth muscle spasm and airway inflammation with mucosal edema. Treatment of asthma, COPD (chronic obstructive pulmonary diseases) and other related disorders have been known to be treated with β-2 adrenoreceptor agonists also known as p-2 receptor agonists. Such β-2 adrenoreceptor agonists are known to provide a bronchodilator effect to patients, resulting in relief from the symptoms of breathlessness. More particularly, β-2 adrenoreceptor agonists have been shown to increase the conductance of potassium channels in airway muscle cells, leading to membrane hyperpolarization and relaxation.
It has also been seen that a subgroup of P-2 adrenoreceptor agonists can be described as short acting, whilst a further subgroup of p-2 adrenoreceptor agonists can be described as long acting. The mechanism of anti-asthmatic

action of the short acting subgroup is linked to the direct relaxation of airway smooth muscles and consequent bronchodilation. Drugs belonging to this short acting subgroup have quicker onset of action (within 1-15 minutes) and produce a bronchodilation that lasts for about 2-6 hours. Such drugs act as "rescue" medication i.e. where immediate relief is required. The long acting subgroup of drugs act via a similar mechanism i.e. relaxation of airway smooth muscles and consequent bronchodilation. Drugs of this long acting subgroup may have delayed onset of action, but have a longer duration of action, so are used for long-term regular treatment of reversible airways obstruction in asthma.
Short acting β-2 adrenoreceptor agonists include terbutaline, salbutamol, lev-albuterol, R, R-formoterol, metaprotemol sulfate, pirbuterol acetate, bitolterol mesylate, fenoterol, procaterol and the like. Long acting β-2 adrenoreceptor agonists include salmeterol and formoterol. For example, it has been reported that inhalation of salmeterol provides persistent bronchodilation lasting over 12 hours. The extended side chain on salmeterol renders it greatly lipophilic. This lipophilicity regulates the diffusion rate away from the receptor by determining the degree of partitioning in the lipid bilayer of the membrane. Subsequent to binding the receptor, the less lipophilic, short acting agonists are rapidly removed from the receptor environment by diffusion in aqueous phase. Unbound salmeterol, by contrast, persists in the membrane and only slowly dissociates from the receptor environment.

A further component of asthma is inflammation, which is treated with steroids. Also, steroids have been known to make bronchodilators more effective. If combined with bronchodilators, lower doses of steroids have been needed to achieve the same effect.
Bronchoconstriction and inflammation are also associated with bronchial plugging with secretions, which is known to be treated with anti-cholinergic agents. These agents prevent increases in intracellular concentration of cyclic GMP that are caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle. Available anti-cholinergics reported are ipratropium bromide, oxitropium bromide, tiotropium bromide and the like. An important therapeutic property of ipratropium and tiotropium is their minimal inhibitory effect on mucociliary clearance, relative to atropine. Hence, the use of these agents in patients with airway disease avoids the increased accumulation of lower airway secretions encountered with atropine. Ipratropium and oxitropium bromide have a shorter duration of action. More particularly, it has been seen that after inhalation, maximal responses usually develop over 30 to 90 minutes for ipratropium and oxitropium, with tiotropium having a slower onset. The effects of ipratropium last for 4 to 6 hours, while tiotropium's effects persist for 24 hours. Ipratropium and oxitropium can thus be classified as short acting anti-cholinergic agents, whereas tiotropium can be classified as a long acting anti-cholinergic agent, based on the above described durations of action.

It has also been reported that combined treatment of anti-cholinergics with β-2 adrenoreceptor agonists results in slightly greater and more prolonged bronchodilation than with either agent alone in the treatment of baseline asthma. Such combination products provide combination treatment of airway constriction and inflammation. Furthermore, combination of anti-cholinergics, such as ipratropium bromide, and β-2 adrenoreceptor agonists, such as salbutamol, is known to provide an effective therapy to reduce constriction and to reduce bronchial secretions. All these medicaments are known to be given in different dosage forms, for example MDIs, DPIs, oral and liquid formulations. Treatment with these different categories of medication calls for the patient to comply with different doses, different frequencies of doses and the like.
Despite the large numbers of known treatments of respiratory diseases as discussed above, there continues to exist a clinical need for therapies of respiratory diseases which exhibit advantageous profiles of action. To this end, it has surprisingly been found that a combination of short acting and long acting β—2 adrenoreceptor agonists, with short acting and long acting anti¬cholinergics provide an enhanced, synergistic therapeutic effect in terms of treatment of respiratory diseases, such as bronchoconstriction, inflammation, mucous secretions and related disorders. Also, such combination therapy is an extremely patient-friendly combination, which results in enhanced patient compliance and better control of respiratory diseases, such as asthma, compared to known combinations.

DESCRIPTION OF THE INVENTION:
There is provided by the present invention, therefore, a pharmaceutical product comprising (i) at least one short acting |3-2 adrenoreceptor agonist, (ii) at least one long acting β-2 adrenoreceptor agonist, (iii) at least one short acting anti-cholinergic agent, (iv) at least one long acting anti-cholinergic agent as a combined preparation for simultaneous, separate or sequential use in the treatment of respiratory diseases.
The present invention also provides a pharmaceutical formulation comprising (i) at least one short acting β-2 adrenoreceptor agonist, (ii) at least one long acting β—2 adrenoreceptor agonist, (iii) at least one short acting anti¬cholinergic agent, (iv) at least one long acting anti-cholinergic agent, together with a pharmaceutically acceptable carrier or excipient thereof.
According to this preferred embodiment of the present invention there is provided a pharmaceutical product comprising (i) at least one short acting β-2 adrenoreceptor agonist, (ii) at least one long acting (3-2 adrenoreceptor agonist, (iii) at least one short acting anti-cholinergic agent, (iv) at least one long acting anti-cholinergic agent as a combined preparation for simultaneous, separate or sequential use in the treatment of respiratory diseases.
Also according to this preferred embodiment of the present invention there is provided a pharmaceutical formulation comprising (i) at least one short acting β-2 adrenoreceptor agonist, (ii) at least one long acting β-2 adrenoreceptor

It will be appreciated from the above that the terms "short acting β-2 adrenoreceptor agonists", "long acting β-2 adrenoreceptor agonists", "short acting anti-cholinergic agents" and "long acting anti-cholinergic agents" are well known and well understood in the field of treatment of respiratory diseases.
Most of the above mentioned medications are in the form of aerosols, with the patient generally being required to carry many MDIs (metered dose inhalers) for each of these medicaments. The following prior art patent documents describe known aerosol formulations - inhalation aerosol of terbutaline (US 5980949 and WO 98/31353), inhalation aerosol of salbutamol (WO 99/48476), aerosol formulations of formoterol (US 2002058011 and WO 98/31351), inhalation aerosol of pirbuterol acetate (EP 0717987), inhalation aerosol of fenoterol (US 6045778), aerosol formulations of procaterol (US 4616022) and aerosol formulations of salmeterol (US 6143277, WO 02/051483, WO 00/61108 and WO 99/55319).
Furthermore, in order to ease patient compliance, combination products have been described in the following prior art patent documents - Combinations of tiotropium and salmeterol (WO 02/38154), combinations of formoterol and salmeterol (EP'1158970), combinations of tiotropium and mometasone (WO 01/78743), combinations of tiotropium and budesonide (WO 01/78741), combinations of tiotropium and fluticasone propionate (WO 01/78739), combinations of tiotropium and rofliponide (WO 01/78736) and combinations of tiotropium and formoterol (WO 00/47200).

agonist, (iii) at least one short acting anti-cholinergic agent, (iv) at least one long acting anti-cholinergic agent together with a pharmaceutically acceptable carrier or excipient therefore.
Suitably in pharmaceutical products or formulations according to the present invention, a short acting β-2 adrenoreceptor agonist is selected from the group consisting of terbutaline, salbutamol, fenoterol, lev-albuterol, R, R-formoterol, bitolterol, metaproternol, pirbuterol and procaterol, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. Preferably a short acting β-2 adrenoreceptor agonist employed according to the present invention is either salbutamol or terbutaline sulphate.
Suitably in pharmaceutical products or formulations according to the present invention, a long acting β-2 adrenoreceptor agonist is selected from the group consisting of salmeterol and formoterol, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. Preferably a long acting β-2 adrenoreceptor agonist employed according to the present invention is salmeterol.
Suitably in pharmaceutical products or formulations according to the present invention, a short acting anti-cholinergic agent is selected from the group consisting of ipratropium and oxitropium, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. Preferably

ipratropium or oxitropium bromide are employed according to the present invention.
Suitably in pharmaceutical products or formulations according to the present invention, a long acting anti-cholinergic agent is tiotropium, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. Preferably tiotropium bromide is employed according to the present invention.
Preferred combinations of therapeutic agents employed in pharmaceutical products and formulations according to the present invention comprise any one of the following combinations:
as a short acting β-2 adrenoreceptor agonist - salbutamol; as a long acting β-2 adrenoreceptor agonist - salmeterol; as a short acting anti-cholinergic agent - ipratropium bromide; as a long acting anti-cholinergic agent - tiotropium bromide; or
as a short acting β-2 adrenoreceptor agonist - terbutaline sulphate; as a long acting β-2 adrenoreceptor agonist - salmeterol; as a short acting anti-cholinergic agent - ipratropium bromide; as a long acting anti-cholinergic agent - tiotropium bromide; or

as a short acting β-2 adrenoreceptor agonist - salbutamol; as a long acting β—2 adrenoreceptor agonist - salmeterol; as a short acting anti-cholinergic agent - oxitropium bromide; as a long acting anti-cholinergic agent - tiotropium bromide; or
as a short acting β-2 adrenoreceptor agonist - terbutaline sulphate; as a long acting β—2 adrenoreceptor agonist - salmeterol; as a short acting anti-cholinergic agent - oxitropium bromide; as a long acting anti-cholinergic agent - tiotropium bromide; or
Preferably, the concentration of a short acting β-2 adrenoreceptor agonist present in a formulation according to the present invention is in the range of about 0.01% to 5% by weight, based on the weight of the total formulation
Preferably, the concentration of a long acting β-2 adrenoreceptor agonist present in a formulation according to the present invention is in the range of about 0.01% to 5% by weight, based on the weight of the total formulation.
Preferably, the concentration of a short acting anti-cholinergic agent present in a formulation according to the present invention is in the range of about 0.001% to 0.05% by weight, based on the weight of the total formulation.
Preferably, the concentration of a long acting anti-cholinergic agent present in a formulation according to the present invention is in the range of about 0.01% to 5% by weight, based on the weight of the total formulation.

The term "physiologically functional derivative" as used herein denotes a chemical derivative of any of the specific therapeutic agents described herein having the same or similar physiological function as the free base therapeutic agent and, for example, being convertible in the body thereto.
It will of course be appreciated that the present invention encompasses the use of enantiomers of the specific therapeutic agents described herein.
Suitable pharmaceutically acceptable salts for use according to the present invention include those formed with both organic and inorganic acids and are well known to one of ordinary skill in the art.
There is also provided by the present invention a method for the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more anti-cholinergic agents, and / or one or more β-2 adrenoreceptor agonists is indicated, which method comprises administration of a therapeutically effective amount of a pharmaceutical product comprising (i) at least one short acting β-2 adrenoreceptor agonist, (ii) at least one long acting β-2 adrenoreceptor agonist, (iii) at least one short acting anti¬cholinergic agent, (iv) at least one long acting anti-cholinergic agent as a combined preparation for simultaneous, separate or sequential use in the treatment of such respiratory diseases.

The present invention also provides a method for the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more anti-cholinergic agents, and / or one or more β-2 adrenoreceptor agonists is indicated, which method comprises administration of a therapeutically effective amount of a pharmaceutical formulation comprising (i) at least one short acting β-2 adrenoreceptor agonist, (ii) at least one long acting (3-2 adrenoreceptor agonist, (iii) at least one short acting anti¬cholinergic agent, (iv) at least one long acting anti-cholinergic agent, together with a pharmaceutically acceptable carrier or excipient thereof.
Preferred therapeutic agents for use in a method according to the present invention are substantially as hereinbefore described with reference to pharmaceutical products and pharmaceutical formulations according to the present invention. The term respiratory disease as used herein denotes inflammatory and obstructive airways disease, such as asthma, COPD and other related disorders.
There is also provided by the present invention for use in the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more anti-cholinergic agents, and / or one or more β-2 adrenoreceptor agonists, is indicated, a pharmaceutical product comprising (i) at least one short acting β-2 adrenoreceptor agonist, (ii) at least one long acting β-2 adrenoreceptor agonist, (iii) at least one short acting anti-cholinergic agent, (iv) at least one long acting anti-cholinergic agent, as a combined preparation

for simultaneous, separate or sequential use in the treatment of respiratory diseases.
There is also provided by the present invention for use in the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more anti-cholinergic agents, and / or one or more (3-2 adrenoreceptor agonists, is indicated, a pharmaceutical formulation comprising (i) at least one short acting (3-2 adrenoreceptor agonist, (ii) at least one long acting (3-2 adrenoreceptor agonist, (iii) at least one short acting anti-cholinergic agent, (iv) at least one long acting anti-cholinergic agent, together with a pharmaceutically acceptable carrier or excipient thereof.
Preferred therapeutic agents for such prophylactic or therapeutic use according to the present invention are substantially as hereinbefore described with reference to pharmaceutical products and pharmaceutical formulations according to the present invention. The term respiratory disease as used herein denotes inflammatory and obstructive airways disease, such as asthma, COPD and other related disorders.
There is also provided by the present invention for use in the manufacture of a medicament for the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more anti-cholinergic agents, and / or one or more (3-2 adrenoreceptor agonists is indicated, a pharmaceutical product comprising (i) at least one short acting p-2 adrenoreceptor agonist, (ii) at least one long acting (3-2 adrenoreceptor

agonist, (iii) at least one short acting anti-cholinergic agent, (iv) at least one long acting anti-cholinergic agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of respiratory diseases.
There is also provided by the present invention for use in the manufacture of a medicament for the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more anti-cholinergic agents, and / or one or more p-2 adrenoreceptor agonists is indicated, a pharmaceutical formulation comprising (i) at least one short acting p-2 adrenoreceptor agonist, (ii) at least one long acting β-2 adrenoreceptor agonist, (iii) at least one short acting anti-cholinergic agent, (iv) at least one long acting anti-cholinergic agent together with a pharmaceutically acceptable carrier or excipient therefore.
Preferred therapeutic agents for such use in the manufacture of a medicament according to the present invention are substantially as hereinbefore described with reference to pharmaceutical products and pharmaceutical formulations according to the present invention. The term respiratory disease as used herein denotes inflammatory and obstructive airways disease, such as asthma, COPD and other related disorders.
Pharmaceutical products and formulations according to the present invention include those suitable for oral, parenteral, inhalation, rectal and topical administration, with inhalation being preferred typically employing MDIs or

DPIs. The pharmaceutical products and formulations may conveniently be presented in unit dosage form and may be prepared by methods well known to one of ordinary skill in the art.
The present invention also provides a pharmaceutical formulation substantially as hereinbefore described, which process comprises admixing a pharmaceutically acceptable carrier or excipient with:
(i) at least one short acting (3-2 adrenoreceptor agonist; (ii) at least one long acting (3-2 adrenoreceptor agonist; (iii) at least one short acting anti-cholinergic agent; (iv) at least one long acting anti-cholinergic agent;
Preferably pharmaceutical formulations according to the present invention comprise aerosol formulations to be delivered from pressurized containers with the use of a suitable propellant as the carrier or excipient. Suitable propellants include 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3,-heptafluoropropane (HFA 227), or a combination of both, or mono-fluoro trichloromethane and dichloro difluoromethane, in particular 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), with HFA 134a being preferred.
A pharmaceutical aerosol formulation according to the present invention preferably further comprises a polar cosolvent such as C2-6 aliphatic alcohols and polyols, for example ethanol, isopropanol and propylene glycol, with

ethanol being preferred. Preferably, the concentration of the cosolvent is in the range of about 2 to 15% by weight, of the total formulation.
A formulation according to the present invention may further comprise one or more surfactants. Such surfactants can be included to stabilize the formulations and for lubrication of a valve system. Some of the most commonly used surfactants in aerosol formulations are oils derived from natural sources, such as corn oil, olive oil, cottonseed oil and sunflower seed oil, and also phospholipids such as lecithin. A preferred surfactant for use according to the present invention is oleic acid. The surfactants used in the formulations of the present invention are generally present in the range of about 0.00002% to 20% by weight of the therapeutic agents present in the formulations, and more preferably in the range of about 0.00002 to 0.01% by weight of the therapeutic agents present in the formulations. The surfactants may exceed this weight ratio in cases where therapeutic agent concentration in a formulation is very low.
A preferred aerosol formulation of this invention is in the form of a suspension or a particulate suspension or a clear solution. In the case of a particulate suspension or a solution, the cosolvent used should have greater polarity than the propellant used. The most commonly used cosolvent is ethanol substantially as hereinbefore described. Generally the ratio of propellant to ethanol is 50:50 to 99:1.

Preferably therapeutic agents present in aerosol formulations according to the present invention are present at a concentration in the range of about 0.001% to 5% of the total formulation. Preferably, the therapeutic agents are employed at an appropriate particle size (95% below 2.5 mm, the remainder being between 2.5 to 5mm by microscope, and 95% below 5-6 m and all particles below 10-12m by laser).
Pharmaceutical aerosol formulations according to the present invention are particularly suitable for use in DPIs or MDIs substantially as hereinbefore described which utilize a liquefied propellant as referred to above to expel droplets containing the therapeutic agents employed according to the present invention. Suitably a formulation according to the present invention is filled into an aluminum can through a suitable metering device and typically the can is plastic coated, lacquer-coated or anodized.
The present invention will now be further illustrated by the following Examples, which do not limit the scope of the invention in any way.
EXAMPLES Example 1 Per can
Tiotropium bromide 2.400 mg
Salbutamol 24.000 mg
Salmeterol 6.000 mg
Ipratropium Bromide 4.000 mg
1,1,1,2-Tetrafluoroethane 18.200 gm

Example 2
Per can
Tiotropium bromide 2.400 mg
Terbutaline Sulphate 60.000 mg
Salmetrol 6.000 mg
Ipratropium Bromide 4.000 mg
1,1,1,2-Tetrafluoroethane 18.200 gm
For each of the above formulations of Examples 1 and 2, the active ingredients were first weighed in a plain aluminum can. A metering valve was then placed on the can and crimped with a vacuum crimpier. Propellant 134a was then charged through the metering valve.
Example 3
Per can
Tiotropium bromide 2.400 mg
Salbutamol 24.000 mg
Salmeterol 6.000 mg
Oxitropium Bromide 20.000 mg
Ethanol 2.730 gm
1,1,1,2-Tetrafluoroethane 15.470 gm

For the above formulation of Example 3, the active ingredients were first weighed in a plain aluminum can. Ethanol was then added and the solution was sonicated for 5 minutes. A metering valve was then placed on the can and crimped with a vacuum crimpier. Propellant 134a was then charged through the metering valve.
Example 4
Per can
Tiotropium bromide 2.400 mg
Salbutamol 24.000 mg
Salmeterol 6.000 mg
Ipratropium Bromide 4.000 mg
Ethanol 2.730 gm
Oleic acid (10%) 5.040 mg
1,1,1,2-Tetrafluoroethane 15.470 gm
For the above formulation of Example 4, the active ingredients were first weighed in a plain aluminum can. Ethanol and the surfactant we're then added and the solution was sonicated for 5 minutes. A metering valve was then placed on the can and crimped with a vacuum crimpier. Propellant 134a was then charged through the metering valve.

Example 5
Per can
Tiotropium bromide 2.400 mg
Terbutaline Sulphate 60.000 mg
Salmeterol 6.000 mg
Oxitropium bromide 20.000 mg
Ethanol 0.364 gm
1,1,1,2-Tetrafluoroethane 18.200 gm
For the above formulation of Example 5, the active ingredients were first weighed in a plain aluminum can. Ethanol was then added and the solution
was sonicated for 5 minutes. A metering valve was then placed on the can
and crimped with a vacuum crimpier. Propellant 134a was then charged
through the metering valve.
Example 6
Per can
Tiotropium bromide 2.400 mg
Terbutaline Sulphate 60.000 mg
Salmeterol 6.000 mg
Ipratropium Bromide 4.000 mg
Ethanol 0.364 gm
Oleic acid (0.02%) 0.014 mg
1,1,1,2-Tetrafluoroethane 17.830 gm

For the above formulation of Example 6, the active ingredients were first weighed in a plain aluminum can. Ethanol and the surfactant were then added and the solution was sonicated for 5 minutes. A metering valve was then placed on the can and crimped with a vacuum crimpier. Propellant 134a was then charged through the metering valve.

AN IMPROVED PHARMACEUTICAL COMPOSITION FOR ASTHMA AND RELATED DISORDERS

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