FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(Se section 10, rule 13)
TROVENTOL FORMULATION"
CIPLA LIMITED, of 289 Bellasis Road, Mumbai Central, Mumbai - 400 008, India.
The following specification particularly describes and ascertains the invention and the manner in which it is to be performed.

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Troventol formulation
Technical field
The present invention relates to pharmaceutical compositions comprising a : therapeutically effective amount of an inhaled bronchodilating agent optionally in ; combination with one or more therapeutic agents for the treatment of bronchospasms and related disorders thereof.
Background and prior art
Asthma is described as a chronic disease that involves inflammation of the pulmonary airways and bronchial hyperrespdnsiveness that results in the clinical expression of a lower airway obstruction that usually is reversible. The pathophysiology of asthma or related disorders involves bronchoconstriction resulting from bronchial smooth muscle spasm and airway inflammation with mucosal edema. Treatment of asthma and other related disorders have been known to employ b-2 agonists, also known as. b-2 adrenoreceptor agonists. Such P-b adrenoreceptor agonists are known to provide a bronchodilator effect to patients, resulting in relief from the symptoms of breathlessness. More particularly, b-2 adrenoreceptor agonists have been shown to increase the conductance of potassium channels in airway muscle cells, leading to membrane hyperpolarization and relaxation. Short-acting b-2 adrenoreceptors like salbutamol and terbutaline are recommended for the relief of acute symptoms, while long-acting agents like salmeterol, formoterol and bambuterol are used preferably in combination with other drugs for long-term asthma control.
Chronic Obstructive Pulmonary Disease (COPD) is a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. COPD (Chronic Obstructive Pulmonary Disease) is an umbrella term used to describe lung diseases associated with airflow obstruction. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking.
CONFIRMATION COPY

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Bronchodilators. are the mainstay of therapy for patients with established chronic obstructive pulmonary disease (COPD) but, at present, the majority of patients use p-agonists.
International application no. PCT/EP98/03533, describes solution compositions for use in an aerosol inhaler, comprising an active.. material, a propellant containing a hydrofiuoroalkane (HFA), a cosolvent and further comprising a low volatility component to increase the mass median aerodynamic diameter (MMAD) of the aerosol particles on actuation of the inhaler.
W094/13262 proposes the use of organic and inorganic acids as stabilisers preventing the
chemical degradation of the active ingredient in aerosol solution formulations comprising HFAs. Ipratropium bromide is among the selected medicaments, for which many composition examples are provided.
WO96/32099, WO96/32150, W096/32151 and W096/32345 disclose metered dose inhalers for the administration of different active ingredients in suspension in the propellant, wherein the internal surfaces of the inhaler are partially or completely coated with one or more fluorocarbon polymers optionally in combination with one or moire non-fluorocarbon polymers.
Nevertheless, some researchers have described formulations that do not require the use of any surfactant or cosolvent. WO 93/11743 describes formulations containing a fluorocarbon or hydrogen-containing fluorocarbon propellant in combination with sahneterol, salbutamol, fluticasone propionate, or beclomethasone dipropionate. It also describes formulations containing a fluorocarbon or hybtocarbon-containing fluorocarbon propellant that are free of any surfactants and may be used with nearly any drug. However, such formulations are unsatisfactory for some drugs, particularly ipratropium bromide.
Troventol is known from Soviet patent 1532047.


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The present invention proposes to provide potent, effective and stable pharmaceutical compositions comprising troventol alone or in combination with one or more therapeutic agents preferably in a metered dose inhaler.
Objectives of the invention
The objective of the present invention is to provide a pharmaceutical composition comprising troventol and a pharmaceutically acceptable carrier or excipient and optionally with one or more therapeutic agents.
A still further objective is to provide a method for the manufacture of the pharmaceutical composition comprising troventol.
Yet another object of the present invention is to provide a method for the treatment in a mammal t such as a human, of respiratory disorders such as bronchospasm and related disorders, which method comprises administration of a therapeutically effective amount of a pharmaceutical composition according to present invention.
Summary of the invention
According to the present invention there is provided an aerosol composition, suitable for use in the treatment of bronchospasms and related disorders, comprising a therapeutically effective amount of troventol either alone or in combination with one or more suitable therapeutic agents and one or more pharmaceutically acceptable carriers.
According to the present invention there is also provided a process for the preparation of a metered dose inhaler comprising an aerosol composition according to any preceding claim, which process comprises the steps of
a) adding the active ingredients to a canister,
b) adding the pharmaceutical carriers to the mixture of (a);
c) crimping the canister with a metered valve; and charging the canister with propellent.


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The present invention also provides for a method for the treatment in a mammal, such as a human, of respiratory disorders such as bronchpspasms, disorders resulting in . bronchoconstriction, which method comprises . administration of a therapeutically effective amount of a pharmaceutical composition according to the present invention.
Detailed description of the invention
The present- invention relates to Troventol, a cholinolytic substance. Troventol is chemically known as 8-azoniabicyclo [3.2.1] octane or 3-[2-(hydroxymefhyl)-l-oxo-2-phenylbutoxyl]-8, 8-dimethyl-iodide. It is available as a white, microcrystalline powder and is odorless in nature. The molecular weight of this compound is 459.3 and the melting point is 253 - 255°C.
The broncholytic effect of troventol is expressed in various methods of administration — intravenous, subcutaneous, oral and inhalation. However, the effect of the drug when administered through inhalation is more powerful and durable than other routes.
As against ipratropium, troventol produces only mild mydriasis and its effect on the salivary gland secretion and intestinal muscles is less.potent and has no effect on the cholinoreactive systems of the CNS. Troventol possesses mild peripheral n-cholinolytic properties, insignificant adrenolytic, antihistarmnic and antiserotoninic action. Even at doses exceeding the normal therapeutic doses, it is less harmful to the CVS and respiratory system. Atropine is one of the anticholinergic drugs but has certain adverse reactions some of which are dryness of mouth, difficulty in swallowing, fever, constipation, blurring of vision, retention of urine in elderly.
Metered dose inhalers have proven to be effective oral and nasal delivery systems that have been used extensively for delivering bronchodilating and steroidal compounds to asthmatics, as well as delivering other compounds such as pentamidine and non-bronchodilator anti-inflammatory drugs. The rapid onset of activity of compounds administered in this manner and the absence of any significant side effects have resulted in a large number of compounds being formulated for administration via this route.


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Typically, the drag is delivered to the patient by a propellant system generally comprising one or more propellants, which have the appropriate vapor pressure and which are suitable for oral or nasal administration.
Accordingly, the present invention provides aerosol formulations which contain two or more particulate medicaments, which may be selected from suitable combinations mentioned herein or may be selected from any other suitable drug useful in inhalation therapy. The drugs are preferably presented in a form whioh is substantially completely insoluble in the selected propellant.
Suitable medicaments may be selected from, for example, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g, diltiazem; antiallergics, e.g. cronioglycate, ketotifen or nedocromil; antiinfectives e.g. cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g. methapyrilene; antiinflammatories, e.g. flunisolide, budesonide, tipredane or triamcinolone acetonide; antitussives, e.g. noscapine; bronchodilators, e.g. ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol phenylephrine, phenylpropanolamine, phbuterol reproterol rimiterol, terbutaline, isoetharine, tulobuterol orciprenaline, or (-)-ammo-3,5-dicMoi-o-[alpha]-[[[6-[2-(2-pyridinyl)ethoxy]hexyl] amino]methyl]benzenemethanol; diuretics, e.g. amiloride; .anticholinergics e.g. ipratropium, atropine or oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone; xanthines e.g. aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides, e.g. insulin or glucagon. It will be clear to a person skilled in the art that, where appropriate, the medicaments may be used in the form of salts (e.g. as alkali metal or amine salts or as acid addition salts) or as esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) to optimise the activity and/or stability of the medicament and/or to minimise the solubility of the medicament in the propellant.
Hence the present invention provides a pharmaceutical composition comprising troventol that avoids side effects associated with atropine.


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The present invention therefore-provides a pharmaceutical composition comprising troventol and: a phannaceutically acceptable carrier or excipient and optionally one or
more other therapeutic agents.
The composition of the present invention comprising a therapeutically effective amount of troventol either alone or in combination with one or more suitable therapeutic agents and one or more phannaceutically acceptable carriers is a synergistic composition and exhibits surprising and unexpected results.
■The invention provides a formulation containing troventol, preferably provided in a metered dose inhaler (MDI) which may be used in the treatment of respiratory disorders. Containers for aerosol formulations commonly comprise a vial body (can or canister) coupled to a valve. The valve comprises a valve stem through which the formulations are dispensed. Generally the valve includes a rubber valve seal intended to allow reciprocal movement of the valve stem which prevents leakage of prppellant from the container. Metered dose inhalers comprise a valve which is designed to deliver a metered amount of an aerosol formulation, to the recipient, per actuation. Valves for use in MDIs are available from manufacturers well known in the aerosol industry, for example,.from ■ Valois, France, Bespak pic, United Kingdom and 3M-Neotechnic Limited, United Kingdom.
The present invention is administered by inhalation route ao as to provide effective amount of local action and thus avoiding undesirable systemic effects. The therapeutically effective dose range for troventol when administered as an inhalation is preferably 40mcg to 640mcg. The present invention may farther comprise phannaceutically acceptable exoipients in order to provide a suitable formulation and may be made available in the form of a metered dose inhaler.
The aerosol formulation according to the present invention may optionally comprise in addition to troventol one or more therapeutic agents and at least one prppellant, other phannaceutically acceptable agents like cosolvents, antioxidants or surfactants.
The prppellant according to the present invention includes atleast one prppellant selected
from propellant 11 (dichlorodifluoromemane), prppellant 12
(mcmofluorotricMaromethane), Prppellant 114 (dichlarotetrafluoroethane), 14,1,2-


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tetoafluoroethane (HFA134a) and' 1,1,1,2,3,3,3-heptafluoropropane (HFA227), or mixtures of two Or more such'halogen-substituted hydrocarbons.
However, there have been problems associated with stabilizing the pharmaceutical aerosol formulations prepared using the new class of HFA propellants. Pharmaceutical aerosol formulations generally comprise a solution or a suspension. A mixture of suspension and some (perhaps trace) amount of dissolved medicament is also possible, but.generally undesirable. Some solution formulations suffer the disadvantage that the drug substance contained therein is more susceptible to degradation. Furthermore there may be problems associated with controlling the size of the droplets that influence the therapeutic profile. For this reason, suspensions are generally preferred.
The formulations of the invention may be prepared by dispersal of the medicament in the selected propellent in an appropriate container, e.g. with the aid of sonication. The process is desirably carried out under anhydrous conditions to obviate any adverse effects of moisture on suspension stability.
The formulations according to the invention form weakly flocculated suspensions on standing but, surprisingly, these suspensions have been found to be easily redispersed by mild agitation to provide suspensions with excellent delivery characteristics suitable for use in pressurised inhalers, even after prolonged storage, Minimising and preferably avoiding the use of formulation excipients e.g. surfactants, cosolvents and such like in the aerosol formulations according to the invention is also advantageous since the formulations may be substantially taste and odour free, less irritant and less toxic than conventional formulations.
hi suspension formulations, particle size generally is controlled during manufacture by the size to which the solid medicament is reduced, usually by micronisation. However, where the suspended drug has a sufficient solubility in propellent, a process known as Ostwald Ripening can lead to particle size growth. Also, particles may have the tendency to aggregate, or adhere to parts of the MDI e.g. canister or valve. Furthermore the drag


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may have the tendency to. be. absorbed into any untreated and/or uncoated rubber
components of the valve,, especially when stored for a prolonged period, In particular,
fine particles may be preferentially absorbed. The effect of Ostwald ripening and
especially of drug deposition may be particularly severe for potent drugs which are
generaUyformulated in low doses.,
In a preferred embodiment of the present invention the aerosol may comprise a therapeutically effective amount of troventol with one or more therapeutic agents and either propellant 11 or propellent 114 or a combination thereof, and/or propellent 12.
In another preferred embodiment of the present invention the aerosol may comprise a therapeutically effective amount of troventol with one or more therapeutic agents and either propellant 11 or propellant 114 or a combination thereof and/or propellantl2 with one or more surface-active agents.
Pharmaceutical aerosol formulations generally comprise a suspension of a medicament, one or more liquid propellants, optionally with a co-propellant, and optionally an adjuvant such as a solvent or a surfactant and/or other excipients. The aerosol formulation is under pressure in the canister. The problems mentioned above have been addressed by the addition of one or more adjuvants such as alcohols, alkanes, dimethyl ether, surfactants (e.g., including fluorinated and non-fiuorinated surfactants, carboxylic acids, polyethoxylates, etc.) and even conventional ohlorofluorocarbon propellants in small amounts intended to minimise potential ozone damage.
Various surfactants were tried 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 lecilhin, or sorbitan fatty acid esters like sorbitan oleate. Lecithin gave a comparatively good suspension quality when used in the formulation.
The surfactant can be used in a concentration of 0.001-100% of the weight of the drug, preferably in a range of l%-50%, more preferably in a concentration of 5%-30%. The


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concentration of surfactant according to the present invention can be, for example, about 10%
It is advantageous that every dose delivered from the MDI be within close tolerances. Therefore, it is advantageous that the formulation be substantially homogeneous throughout the administered dose at the time of actuation of the metering valve. It is also advantageous that the concentration of the suspension does not vary significantly when stored for a prolonged period of time.
Thus, in the compositions for inhalation, particle size is particularly important. The preferred particle size is between 2 mm to 5mm. It has also been found that the particle size has a considerable influence on the proportion of active substance in the aerosol which is delivered for inhalation.
In one trial, drugs were mixed with propellent 11 or propellant 114 or a combination thereof, filled in canisters, crimped and charged with propellant 12. It was found that this gave a low fine particle dose. Hence further trials were taken where both the drugs and/or surfactant were micro-milled with propellant 11 or propellant 114 or a combination thereof to form slurry and then filled in canisters, charging with propellant 12. This resulted in a better fine particle dose as compared to the CFC aerosols where the micro-milling as described herein was not done. Hence micro-milling can be done in order to achieve a better fine particle dose.
In a further embodiment of the present invention there is provided a process for the manufacture of an aerosol formulation of the invention, which process comprises (a) addition of the drugs and/or surfactant with either propellant 11 or propellant 114 or a combination thereol (b) filling the slurry in a canister (c) crimping with a suitable valve and (d) charging with propellant 12 through the valve.
In yet another preferred aspect of the present invention the aerosol composition may comprise a therapeutically effective amount of troventol with one or more therapeutic

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agents and either 1,1,1,2-tetrafluoroeifliane (HFA134a) or 1,1,1,2,3,3,3-heptafluoroethane (HFA227) or a combhiation thereof.
In a further aspect of the present invention there; is provided a process for the manufacture of the above aerosol composition which method comprises (a) addition of the therapeutically effective amount of troventol with one or more therapeutic agents to a canister; (b) crimping the canister with a metered valve (c) charging a canister with either l.,1,1,2-tefrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-heptafluoroethane (HFA227) or a combination thereof
In another preferred aspect of the present invention the aerosol composition may comprise a therapeutically effective amount of troventol with one or more therapeutic agents, either 1,1,1,2-teteafluoroethane (HFA134a) or 1,1,1,2,3,3,3-heptafluoroethane (HFA227) or a combination thereof and a cosolvent. In such a case the cosolvent preferably has a greater polarity than the propellant
Typically the cosolvent is present in an amount of 0.01 to 5 % (by weight of the formulation). The cosolvent used may be selected from the group of glycols, particularly propylene glycol, polyethylene glycol and glycerol or alcohols like ethanol. Typically the cosolvent is ethanol.
In a preferred aspect of the present invention there is provided a process for the manufacture of the above composition which method comprises (a) addition of the drugs to the canister (b) addition of the cosolvent to (a) and sonication of the same, (c) crimping the canister with a metered valve (d) charging the canister with either 1,1,1,2-tetrafhioroethane (HFA134a) or 1,1,1,2,3,3,3-heptefluoroetnane (HFA227) or a combination thereof .
In yet another preferred embodiment the aerosol composition may comprise a therapeutically effective amount of troventol. with one or more therapeutic agents, and


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either l.ljl^TtetrafluorQethane (HFA134a) or l,l,l,2,3,3,3-heptafluoroethane (HFA227) .or a combination thereof, surfactant and the said cosolvent.
The surface-active agent stabilizes, the formulation and helps in the lubrication of a valve system in the inhaler. The surface active agents can, for example, be selected from among. Polysorbate 20, Polysorbate .80, Myvacet.9-45, Myvacet 9-08, isopropyhnyristate, oleic acid, Bry, 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.
The surface-active agents are preferably used in a concentration of 0.02-50% by weight oftroventol.
In another aspect of the present invention there is provided a process for the manufacture of the above composition which method comprises (a) Addition of the drugs 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 either 1,1,1,2-terrafmoroethane (HFA134a) or 1,1,1,2,3,3,3-heptafluoroethane (HFA227) or a combination thereof
In yet another aspect of the present invention the aerosol composition may comprise a therapeutically effective amount oftroventol, a bulking agent and the said propellant. 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% of the weight of the drug, more preferably in a range of 10-300%. The bulking agent may be selected from the class of saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as


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arabinose, glucose, fructose, ribose, mannose, sucrose, terhalose, lactose, maltose, starches, dextran or mannitol.
In a preferred aspect of the present invention there is provided a process for. the manufacture of the above aerosol composition which inefliod comprises (a) Addition of. the active ingredients to the canister, (b) Addition of the bulking agent to (a) (c) Griniping the canister with the metered valve (d) charging the canister with the propellant.
In a preferred aspect of the present invention the aerosol composition may comprise atleast one therapeutically effective isomer of troventol, a surfactant and either 1,1,1,2-tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-heptafluoroethane (HFA227) or a combination thereof. The surfactant may be selected from the class of salts of stearic acids, preferably the magnesium salt of stearic acid or esters such as ascorbyl pahnitate, isopropyl myristate, Tween 20, Tagat TO V, Myvacet and tocopherol esters, preferably isopropyl myristate. The surfactant is used in a concentration of 0.01% to 5%.
In a preferred aspect of the present invention there is provided a process for the manufacture of the above aerosol composition which method comprises (a) Addition of the drugs to the canister, (b) Addition of the surfactant to (a) (c) Crimping the canister with the metered valve (d) chargiiig the canister with either 1,1,1,2-tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-heptafluoroethane (HFA227) or a combination thereof
The formulations of the present invention may optionally contain antioxidants like citric acid, benzalkonium chloride.
The present invention further provides for a method for the treatment in a mammal, such as a human, of respiratory disorders such as asthma, disorders resulting in bronchoconstriction, which method comprises ad-ministration of a therapeutically effective amount of a pharmaceutical composition according to present invention.


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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 thpse- -skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.
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 A)

Ingredients Qty/can
Troventol 9.6 mg
Lecithin 0.96 mg
Propellant 11 4.5 gms
Propellant 12 11.6 gms
a) Add Troventol to the canister
b) Add Propellant 11 and surfactant solution to (a) and Sonicate of the same
c) Crimp with the suitable valve and sonicate
d) Charge with propellant 12 through the valve. B)

Ingredients Qty/can
Troventol 9.6 mg
Sorbitan Trioleate 2.4 mg
Propellant 11 4.S gms
Propellant 12 11.6 gms
a) Add Troventol to the canister
b) Add Propellant 11 and surfactant solution to (a) and Sonicate of the same
c) Crimp with the suitable valve and sonicate
d) Charge with propellant 12 through the valve.

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Example.2: HFA inhaler A)
Ingredients Qty/cnn
Troventol 9.6 mg
HFA 134a • 18.2 gms

Ingredients Qty/can
Troventol 19.2 mg
HFA 134a 18.2 gms

B)
Q

a) Add the drug to the canister.
b) Crimping the canister with the metered valve
c) Charge the canister with 1,1,1,2-teteafluoroethane (HFA134a).

Ingredients Qty/can
Troventol 9.6 mg
Abs. Ale. 2% 0.364 gms
lecithin 0.02% 0.00192 mg
HFA134a 17.83 gms
a) Add drug to the canister.
b) Add alcohol and surfactant splution to (a) and Sonicate of the same
c) Crimp the canister with the metered valve
d) Charge the canister with 1,1,1,2-tetrafiuoroethane (HFA134a).

Ingredients Qty/can
Troventol 9.6 mg
HFA 227 20.6 gms
a) Add the drug to the canister.
b) Crimp the canister with the metered valve
c) Charge the canister with either 1,1,1,2,3,3,3-heptafluoroethane (HFA227).

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CLAIMS
1. An aerosol composition, suitable for use in the treatment of bronchospasms and
related disorders, comprising a therapeutically effective amount of troventol either
alone or in combination with one or more suitable therapeutic agents and one or
;? more pharmaceutically acceptable carriers.
2. An aerosol composition according to claim 1, wherein said troventol is present in an amount of 40 - 640mcg.
3. An aerosol composition according to claim 2, comprising one or more other therapeutic agents.
4. An effective amount present in a therapeutically aerosol composition according to claim 1, 2 or 3 wherein said suitable therapeutic agents are selected from the group consisting of analgesics, e.g. codeine, dmydrornorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem; antiallergics, e.g. cromoglycate, ketotifen or nedocromil; antiinfectives e.g. cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g. methapyrilene; anti-inflamrnatories, e.g. flunisolide, budesonide, tipredane or triamcinolone acetonide; antitussives, e.g. noscapine; bronchodiktors, e.g. ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol phenylephrine, phenylpropanolamine, pirbuterol reproterol rimiterol, terbutaline, isoetharine, tulobuterol orciprenaline, or (-)-amino-3,5-dichloro-[alpha]-[[[6-[2-(2-pyridinyl)ethoxy]hexyl] amino] methyl] benzene methanol; diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, atropine or oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone; xanthines e.g. aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides, e.g. insulin or glucagon.
5. An aerosol composition according to any preceding claim, wherein said pharmaceutical carrier is suitably selected from the group consisting of propellants, cosolvents, antioxidants, surfactants, surface active agents and bulking agents used either alone or in combination.
6. A composition according to any preceding claim, comprising a propellent selected from the group consisting of propellant 11 (dichlorodifluoromethane),


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propellant 12 (monofluorotrichloromethane), Propellant 114
(dichlorotetrafluoroethane), l,ljl,2-tetrafiuoroethane . (HFA134a) and 1,1,1,2,3,3,3-heptafluoropropane (IIFA227),.or.rnixtures thereof.
7. . A composition according to. any preceding claim, comprising a surface aotiye.
agent selected from the group consisting of vegetable oils such as com oil, olive oil, cottonseed oil and sunflower .seed oil; mineral oils like liquid paraffin, oleic acid and phospholipids such as lecithin, or sorbitan fatty acid esters like sorbitan oleate; or mixtures of one or more thereof
8. A composition according to claim 7, wherein said surface active agent is used in an amount of 0.001 to 100%; preferably in an amount of 5% to 30% with respect to the weight of me drug troventol.
9. A composition according to any preceding claim, comprising a cosolvent selected from the group of glycols such as propylene glycol, polyethylene glycol, and glycerol or alcohols like ethanol.
10. A composition according to claim 9,. wherein said co-solvent is present in an amount of 0.01 to 5% with reference to the weight of the drug.
11. A composition according to any preceding claim comprising a surfactant selected from Polysorbate 20, Polysorbate 80, Myvacet 9-45, Myvacet 9-08, isopropylmyristate, oleic acid, Brij, ethyloleate, glyceryl trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monosterate, glyceryl monorioinoleate, oetylaloohol, sterylaloohol, 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; or mixtures of one or more thereof.
12. A composition according to any preceding claim, comprising a surface-active agent(s) in a concentration of 0.02% to 50% by weight of the drug troventol.


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13. A composition according to any preceding claim, comprising a bulking agent
selected from the class of saccharides, including monosaccharides, disaccharides,
polysaccharides and sugar alcohols such as arabinose, glucose, fructose, riboso,
' mannose, sucrose;'trehalose, lactose, maltose, starches, dextran or mannitol.
14. A composition according to any preceding claim, comprising a bulking agent at a concentration of 10-500% by weight of the drag troventol.
15. A process for the preparation of a metered dose inhaler comprising an aerosol composition according to any preceding claim, which process comprises the steps of:

d) adding the active ingredients to a canister;
e) adding the pharmaceutical carriers to the mixture of (a);
f) crimping the canister with a metered valve; and
g) charging the canister with propellant.

16. A metered dose inhaler (MDI) comprising a composition as defined in any one of claims 1-14.
17. An aerosol formulation comprising troventol in an amount of 40-640mcg, a propellant, a surfactant and a cosolvent
18. An aerosol formulation according to claim 17 wherein the surfactant is lecithin, oleic acid, or sorbitan trioleate.
19. An aerosol formulation according to claim 17or 18 wherein the co-solvent is ethanol.
20. An aerosol formulation according to any preceding claim comprising troventol in an amount of 40-640mcg; a propellant which is Pll, P12, P114, HFA 134a or HFA 227 or mixture thereof; optionally a co-solvent present in an amount of 0.01 - 5% by weight of troventol; optionally a surfactant present in an amount of 0.001 to 100% by weight of troventol; and optionally a second active.
21. An aerosol formulation according to any one of claim 1-14 or 17-19 wherein the active(s) optionally in admixture with one or more surfactants have been micro-milled with propellant.
22. An aerosol formulation according to claim 1 consisting of troventol and HFA 134a or HFA 227.


WO 2007/034207

PCT/GB2006/003538

23.. An aerosol formulation according.to claim 1 comprising troventol, lecithin and a
propellant
24.' ' An aerosol fomiulation according to claim 1 comprising troventol, ethanol in, an
-amount of from 1 -3 % by weight of the formulation lecithin in an amount of from
OJOrto 0.1% by weight of the active, and apropellant •
ABSTRACT
Title : "TROVENTOL FORMULATION"
An aerosol composition suitable for use in the treatment of bronchospasms and related disorders comprises a therapeutically effective amount of troventol either alone or in combination with one or more suitable therapeutic agents and one or more pharmaceutically acceptable carriers. The composition preferably contains 40-640mcg of troventol and may comprise a carrier chosen from one or more of propellants, cosolvents, antioxidants, surfactants, surface active agents, and bulking agents.