FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION: "Pharmaceutical combinations"
2. APPLICANT:
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - -400 008,
Maharashtra, India
3.PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention.

Technical field:
The present invention relates to novel combinations of inhalable medicaments for simultaneous or sequential administration in the prevention or treatment of respiratory, inflammatory or obstructive airway disease.
Background and prior art:
Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking.
It is expected to be the third leading cause of death by 2020. Approximately 14 million Indians are currently suffering form COPD. Currently there are 94 million smokers in India. 10 lac Indians die in a year due to smoking related diseases
Although COPD affects the lungs, it also produces significant systemic consequences.
Various therapies are currently used for the treatment of COPD. Bronchodilators and steroids form the major classes of drugs used.
WOO 139745 talks about dry powder inhalation comprising formoterol and its salts or derivatives thereof and pharmaceutically acceptable particulate diluent.
Also combination of therapy using short acting anticholinergic ipratropium bromide and long acting |3-agonist salmeterol are described in patent number WOO 176601.
Further combination therapy using steroid along with anticholinergics and beta agonist have been described in US643298 and WO0207672.
2

WO0207672 relates to a medicinal aerosol formulation and more particularly, to a medicinal aerosol formulation containing a particulate drug, or combination of at least two particulate drugs a propellant and a stabilizing agent comprising a water addition The medicament is selected from the group consisting of albuterol, atropine, budesonide, cromolyn, epinephrine, ephedrine, fentanyl, flunisolide,formoterol, ipratropium bromide, isoproterenol, pirbuterol, prednisone, mometasone, triamcinolone acetonide, salmeterol, amiloride, fluticasone, (-) 4-amino-3,5-dichloro-a- [ [ [6 (2pyridinyl) ethoxy] hexyl] amino] methyl] benzene-methanol and pharmaceutically acceptable salts, esters, hydrates and solvates of the foregoing.
US643298 relates to pharmaceutical formulations for aerosols with atleast two or more active substances for administration by inhalation or by nasal route.
Various other combinations are known in the art. But a problem associated with these drugs is that not all are once a day formulations and also if some are they require an additional dose of a beta agonist to substantiate the combination.
Even from the patient compliance point of view, the treatment calls for the patient to comply with different dosage regimens, different frequencies of administration, etc. Also, since most of the medications are in the form of aerosols, the patient is required to carry several formulations and dispensers.
Thus there remains a need to formulate and also offer to the patient a combination that needs to be taken once a day and where the patient does not have to take another dose of beta-agonist or any other to substantiate the combination dose.
3

Objectives of the invention:
The object of the present invention is to provide novel combinations of inhalable medicaments for administration in the prevention or treatment of respiratory, inflammatory or obstructive airway disease.
It is another object of the present invention to provide novel combination of inhalation medicaments for administration once daily.
It is yet another object of the present invention to provide the method of formulating such novel combinations.
Summary of the invention:
It is provided by the present invention a pharmaceutical combination comprising atleast two active substances for once daily administration by inhalation route.
It is further provided by the present invention a method of manufacturing the pharmaceutical combination comprising atleast two active substances for once daily administration by inhalation route.
It is further provided by the present invention a pharmaceutical combination comprising atleast two active substances for once daily administration by inhalation route administration in the prevention or treatment of respiratory, inflammatory or obstructive airway disease.
Description of the invention:
As discussed above the need of the hour is to formulate a truly once daily formulation. The present invention provides novel combinations comprising two or more actives for administration once daily.
4

The actives may be selected from various classes consisting of bronchodilators and corticosteroids and mixtures thereof. The bronchodilators may be either beta-agonists or anticholinergics.
Pharmaceutically active agents useful in the present invention include one or more of drugs selected from various classes consisting of bronchodilators and corticosteroids and mixtures thereof. The bronchodilators may be beta-agonists and/or anticholinergics. The terms "beta-agonist agent" or "beta-agonist" or "anticholinergic agent" or "corticosteroids" are used in broad sense to include not only the beta-agonist or anticholinergic agent per se but also their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable enantiomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, etc.
The beta-agonists may be selected from formoterol, AR- formoterol, carmoterol, indacaterol. Formoterol may be present in an amount of about 4.5- 96 meg, AR-formoterol may be present in an amount of 1.25-96 meg, carmoterol may be present in an amount of 0.5-16 meg, and indacaterol may be present in an amount of 25-800 meg.
The anticholinergic may be tiotropium. Tiotropium may be present in an amount of 4.5-80 meg.
The corticosteroids may be ciclesonide, mometasone. Ciclesonide may be present in an amount of 40-2880 meg and mometasone present in an amount of 25-2000 meg.
In one embodiment of the present invention, the beta agonist is carmoterol, the corticosteroid is ciclesonide and the anticholinergic is tiotropium. In another embodiment of the present invention, the beta agonist is carmoterol and the corticosteroid is ciclesonide. In yet another embodiment of the present invention, anticholinergic is tiotropium and the beta agonist is carmoterol.
5

The formulations of the present invention are suitable for use in MDIs (or aerosols). MDIs are compact drug delivery systems that use a liquefied propellant to atomize a precisely metered volume of a pharmaceutical formulation into particles, which are small enough to penetrate deep into the patient's lungs. MDIs allow for targeted delivery of drug to the desired site of the therapeutic effect - the lung.
The pharmaceutical combinations according to the present invention may be formulated as aerosols or MDIs.
In case of formulations which are in the form of aerosol or MDIs, the formulations may comprise cosolvents, antioxidants, surfactants, bulking agents, lubricants in addition to the actives and propellant.
In one embodiment of the present invention the actives may be combined with one or more propellants.
The present invention includes atleast one propellant such as propellant 11 (dichlorodifluoromethane), propellant 12 (monofluorotrichloromethane), Propellant 114, 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoroethane
In one embodiment of the present invention the actives may be combined with either propellant 11 or propellant 114 or a combination thereof of and propellant 12 with surface-active agents known in the art.
The surfactants may be selected from various surfactants known in the art like oils such as corn oil, olive oil, cottonseed oil and sunflower seed oil, mineral oils like liquid paraffin ,oleic acid and also phospholipids such as lecithin, or sorbitan fatty acid esters like sorbitan trioleate, Polysorbate 20, Polysorbate 80, Myvacet 9-45, Myvacet 9-08, isopropylmyristate, oleic acid, Brij, ethyloleate, glyceryl trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monosterate, glyceryl monoricinoleate, cetylalcohol, sterylalcohol, cetylpyridinium chloride, block polymers, natural oils, polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, polyethoxylated sorbitan fatty acid esters (for example polyethoxylated sorbitan trioleate), sorbimacrogol oleate,
6

synthetic amphotensides (tritons), ethylene oxide ethers of octylphenolformaldehyde condensation products, phosphatides such as lecithin, polyethoxylated fats, polyethoxylated oleotriglycerides and polyethoxylated fatty alcohols, Tagat TO V, PVP,
citric acid, PFDA (Perfluorodecanoic acid). The use of surfactants leads to comparatively
good suspension quality. One of the prefered surfactant is lecithin. The surfactant can be used in a concentration of 0.001-100%. Preferably in a range of l%-50%. More preferably in a concentration of 5%-30%.Preferably the surfactant in the present invention is in a concentration of 10%.
In another embodiment of the present invention the actives and the surfactant can be micro-milled with propellant 11 or propellant 114 or a combination thereof to form a slurry and then the slurry can be filled in canisters. The actives can be micro-milled separately or together with the propellant. Micro-milling can be done to improve the suspension quality which inturn results in a better FPD.
There is also provided by the present invention a method for the manufacture of CFC aerosol which process comprises (a) optionally micro- milling the drugs and surfactant with either propellant 11 or propellant 114 or a combination thereof, (b) Filling the slurry in the canisters, (c) Crimping with the suitable valve and (d) charging with propellant 12 through the valve
In yet another embodiment of the present invention the aerosol composition may comprise actives and either 1,1,1,2-tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-heptafluoroethane (HFA227) or a combination thereof.
Another embodiment of the present invention may comprise actives, propellant and a cosolvent.
In such a case the cosolvent has a greater polarity than the propellant. Typically the cosolvent is present in a proportion of 0.2 to 20% by weight of the total formulation. The cosolvent used may be selected from the group consisting of glycols, particularly propylene glycol, polyethylene glycol and glycerol or ethanol and mixtures thereof. Typically die cosolvent is ethanol.
7

The present invention also provides a method for the manufacture of the above composition which method comprises (a) Addition of the active ingredients to the canister, (b) Addition of the cosolvent optionally to (a) and sonication of the same, (c) Crimping the canister with the metered valve (d) charging the canister with the propellant.
In yet another embodiment the present invention may comprise the actives, propellant, surface-active agent and cosolvent.
The surface-active agent stabilizes the formulation and helps in the lubrication of a valve system in the inhaler. Some of the most commonly used surface active agents are those known in the art and be selected from among Polysorbate 20, Polysorbate 80, Myvacet 9-45, Myvacet 9-08, isopropylmyristate, oleic acid, Brij, ethyloleate, glyceryl trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monosterate, glyceryl monoricinoleate, cetylalcohol, sterylalcohol, cetylpyridinium chloride, block polymers, natural oils, polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, polyethoxylated sorbitan fatty acid esters (for example polyethoxylated sorbitan trioleate), sorbimacrogol oleate, synthetic amphotensides (tritons), ethylene oxide ethers of octylphenolformaldehyde condensation products, phosphatides such as lecithin, polyethoxylated fats, polyethoxylated oleotriglycerides and polyethoxylated fatty alcohols, Tagat TO V , PVP, citric acid, PFDA (Perfluorodecanoic acid).
The surface-active agents are preferably used in a concentration of 0.02-10%by weight of the active ingredients.
The present invention also provides a method for the manufacture of the above composition which method comprises (a) Addition of the active ingredients to the canister, (b) Addition of the cosolvent and the surfactant solution to (a) and sonication of the same, (c) Crimping the canister with the metered valve (d) charging the canister with the propellant.
Another embodiment of the present invention comprises active along with bulking agent and propellant.
8

The bulking agent acts as a carrier for the drug to reach the lungs. The bulking agent may be present in a concentration of 10-500% by weight of the active. More preferably in a range of 10-300% by weight of the active. The bulking agent may be selected from the class of saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, terhalose, lactose, maltose, starches, dextran or mannitol. The preferred bulking agent is Lactose.
The present invention also provides a method for the manufacture of the above aerosol composition which method comprises (a) Addition of the active ingredients to the canister, (b) Addition of the bulking agent to (a) (c) Crimping the canister with the metered valve (d) charging the canister with the propellant.
Yet another embodiment of the present invention comprises the actives along with surfactant and propellant.
The surfactant may be selected from the class of salts of stearic acids or esters such as ascorbyl palmitate, isopropyl myristate and tocopherol esters. Preferably the magnesium salt of stearic acid, isopropyl myristate. More preferably magnesium stearate. The surfactant is used in a concentration of 0.01% to 10% by weight of the active.
The present invention also provides a method for the manufacture of the above aerosol composition which method comprises (a) Addition of the active ingredients to the canister, (b) Addition of the surfactant to (a) (c) Crimping the canister with the metered valve (d) charging the canister with the propellant.
In yet another embodiment one or more actives can be spray-coated or spray-dried or co-precipitated. The spray coating, spray drying or co-precipitation may be done by mixing the active in a solution of surface active agents in a suitable non-polar solvent and further removing the solvent.
In a further aspect of the present invention there is provided a method for the treatment in a mammal, such as a human, of chronic obstructive pulmonary disease, which method
9

comprises administration of a therapeutically effective amount of a pharmaceutical composition according to the present invention.
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.
It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
It must be noted that, as used in this specification, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example,
reference to "a propellant" includes a single propellant as well as two or more different propellants, reference to a "cosolvent" refers to a single cosolvent or to combinations of two or more cosolvents, and the like.
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.
Example 1 CFC inhaler

Ingredients Qty/can
Tiotropium bromide monohydrate 1.980 mg
carmoterol 0.32 mg
ciclesonide 0.16mg
Lecithin 0.304 mg
Propellant 11 3.22 gms
Propellant 12 8.0 ems
10

Example 2 CFC inhaler

Ingredients Qty/can
Tiotropium bromide monohydrate 1.980 mg
carmoterol 0.64 mg
Lecithin 0.304 mg
Propellant 11 + Propellant 114 3.22 gms
Propellant 12 8.0 gms
Example 3 CFC inhaler

Ingredients Qty/can
ciclesonide 0.16 mg
carmoterol 0.32 mg
Oleic acid 0.304mg
Propellant 11 3.22 gms
Propellant 12 8.0 gms
Example 4 CFC inhaler

Ingredients Qty/can
Tiotropium bromide monohydrate 1.980 mg
carmoterol 0.64 mg
ciclesonide 0.16mg
Sorbitan trioleate 0.304mg
Propellant 11 3.22 gms
Propellant 12 8.0 gms
Example 5 CFC inhaler

Ingredients Qty/can
Tiotropium bromide monohydrate 1.980 mg
carmoterol 0.32 mg
Oleic acid 0.304mg
Propellant 11 + Propellant 114 3.22 gms
Propellant 12 8.0 gms
11

Example 6 CFC inhaler

Ingredients Qty/can
ciclesonide 0.16 mg
carmoterol 0.64 mg
Sorbitan trioleate 0.304mg
Propellant 11 + Propellant 114 3.22 gms
Propellant 12 8.0 gms
Example 7 HFA inhaler

Ingredients Qty/can
Tiotropium bromide monohydrate 1.980mg
carmoterol 0.32mg
ciclesonide 0.16mg
HFA 134a 8.0gms
Example 8 HFA inhaler

Ingredients Qty/can
ciclesonide 0.16mg
carmoterol 0.64mg
P227 9.6gms
Example 9 HFA inhaler

Ingredients Qty/can
Tiotropium bromide monohydrate 1.980mg
carmoterol 0.32mg
Ethanol 0.16gms
HFA134a 8.0gms
Example 10 HFA inhaler

Ingredients Qty/can
Tiotropium bromide monohydrate 1.980mg
carmoterol 0.64mg
Ciclesonide 0.16mg
Ethanol 0.192gms
P227 9.6gms
12

Example 11 HFA inhaler

Ingredients Qty/can
Tiotropium bromide monohydrate 1.980mg
carmoterol 0.32mg
Oleic acid 0.000616mg
Ethanol 0.192gms
P227 9.6gms
Example 12 HFA inhaler

Ingredients Qty/can
ciclesonide 0.16mg
carmoterol 0.64mg
Oleic acid 3.08mg
Ethanol 0.192gms
HFA134a 9.6gms
Example 13 HFA inhaler

Ingredients Qty/can
Tiotropium bromide monohydrate 1.98mg
carmoterol 0.32mg
ciclesonide 0.16mg
Lactose 3.036mg
HFA134a 8.0gm
Example 14 HFA inhaler

Ingredients Qty/can
ciclesonide 0.16mg
carmoterol 0.64mg
Lactose 3.036mg
P227 9.6gms
Example 15 HFA inhaler

Ingredients Qty/can
Tiotropium bromide monohydrate 1.98mg
carmoterol 0.32mg
13

Magnesium stearate 0.3035mg
P227 9.6gms
Example 16 HFA inhaler

Ingredients Qty/can
Tiotropium bromide monohydrate 1.98mg
carmoterol 0.64mg
Ciclesonide 0.16mg
Magnesium stearate 0.3035mg
HFA134a 8.0gms
Example 17 HFA inhaler

Ingredients Qty/can
Ciclesonide 0.16mg
carmoterol 0.32mg
Isopropyl myristate 0.3035mg
P227 9.6gms
Example 18 HFA inhaler

Ingredients Qty/can
Tiotropium bromide monohydrate 1.98mg
carmoterol 0.64mg
Isopropyl myristate 0.3035mg
HFA134a 8.0gms
Dated this 19th day of February 2007
Dr. P. Aruna Sree Agent for the Applicant
14