GB2554090A - Pharmaceutical compound - Google Patents

Abstract

A pharmaceutical composition suitable for use with a metered dose inhaler (MDI) comprises (1). A drug component comprising at least one tiotropium compound selected from tiotropium and the pharmaceutically acceptable derivatives thereof; and (ii) a propellant component comprising 1,1- difluoroethane (HFA-152a). Preferably, the tiotropium compound is tiotropium bromide or tiotropium bromide monohydrate. Preferably, the composition also contains a long acting beta-2-agonist (LABA) (e.g. formoterol, salmeterol, olodaterol). Preferably, the composition also contains a corticosteroid (e.g. budesonide, mometasone, beclomethasone, fluticasone). Preferably, the composition comprises a surfactant (e.g. PVP, polyethylene glycol (PEG), oleic acid, lecithin). The composition may contain a polar excipient such as ethanol. Most preferably, the composition contains less than 5 ppm water. It is claimed that the use of HFA-152a increases the stability, and aerosolisation performance after storage, of the composition relative to the use of other HFA compounds.

Description

(54) Title of the Invention: Pharmaceutical compound

Abstract Title: Pharmaceutical composition comprising; a tiotropium compound as drug, and a propellant comprising HFA-152a (1,1-difiuoroethane) (57) A pharmaceutical composition suitable for use with a metered dose inhaler (MDI) comprises (1). A drug component comprising at least one tiotropium compound selected from tiotropium and the pharmaceutically acceptable derivatives thereof; and (ii) a propellant component comprising 1,1- difluoroethane (HFA-152a). Preferably, the tiotropium compound is tiotropium bromide or tiotropium bromide monohydrate. Preferably, the composition also contains a long acting beta-2-agonist (LABA) (e.g. formoterol, salmeterol, olodaterol). Preferably, the composition also contains a corticosteroid (e.g. budesonide, mometasone, beclomethasone, fluticasone). Preferably, the composition comprises a surfactant (e.g. PVP, polyethylene glycol (PEG), oleic acid, lecithin). The composition may contain a polar excipient such as ethanol. Most preferably, the composition contains less than 5 ppm water. It is claimed that the use of HFA-152a increases the stability, and aerosolisation performance after storage, of the composition relative to the use of other HFA compounds.

PHARMACEUTICAL COMPOSITION

The present Invention relates b the delivery et drug formulations: from a medical device, such as a metered dose inhaler (MDi), using a propellant eomprising 1,15 difiuoroethane· (HFA-I52a). More particularly, the present invention relates to pharmaceutical compositions comprising HFA-152a propeiiant and a drug formulation which is dissolved or suspended in the propeiiant and to medical devices containing those oompositioriS:, The pharmaceutlcai compositions ofthe invention are: particularly suited for delivery from a pressurised aerosol container using a metered dose inhaler (MDI).

MDIs are: the most significant type of inhalation drug delivery system and are well known to those skilled: in the art. They are designed to deliver, on demand, a discrete and accurate amount of a drug to the respiratory tract of a patient, using a liquefied propellant in which the drug is dissolved, suspended or dispersed. The design and operation of MDIs is described in many standard textbooks and in the patent iiterature. They all comprise a: pressurised container that holds: the drug formulation, a nozzle and a valve assembly that is capable of dispensing a controlled quantity of the drug through the nozzle when it is activated. The nozzle and valve assembly are typically located in a housing that is equipped with a mouth piece. The drug formulation: will comprise a propeiiant, in which: the drug Is dissolved,: suspended or dispersed, and may contain other materials such as polar excipients, surfactants and preservatives,

In order for a propeiiant to function satisfactorily In MDIs, it needs to have a number of properties. These Include an appropriate boiling point and vapour pressure so that it can be liquefied in a closed container at room temperature but develop a high enough pressure when the MDI is activated to deliver the drug as an atomised formulation even at low ambient temperatures. Further, the propellant should be of low acute and chronic toxicity and ha ve a high cardiac sensitisation threshold. If should have a high: degree of chemical stability in contact with the drug, the container and the metallic and non-metaiiie components of the MDI device, and have a low propensity to extract low molecular weight substances from any elastomeric materials in the MDI device. The propeiiant shouid aiso be capable of maintaining the drug in a homogeneous solution, in a stable suspension or in a stable dispersion for a sufficient time to permit reproducible delivery of the drug in use. When the drug is in suspension in the propellant, the density of the liquid propellant is desirably similar to that of the solid drug in order to avoid rapid sinking or floating of the drug particles In the liquid. Finally, the propellant should not present a significant flammability risk to the patient in use. In particular, it should form a non-flammable or low flammability mixture when mixed with air in the respiratory tract.

Dichlorodifluoromethane (R-12) possesses a suitable combination of properties and was tor many years Hie most widely used MDI propellant, often blended with trichlorefluoromethane (R~11). Due to international concern that, fully and partially

10: halogenated chlorofiuorocarbons (CFCs), such as dichlorodifluoromethane and triohlorofluoromethane, were damaging the earth's protective ozone layer, many countries entered into an agreement, the Montreal Protocol, stipulating that their manufacture and use should be severely restricted and eventually phased out completely. Dichlorodifluoromethane and triohlorofluoromethane were phased out for refrigeration use in the 199O’&, but are still used In small quantities in the MDI sector as a result of an essential use exemption In the Montreal Protocol .,1,1,2~tetrafluoroethane (HFA-134a) was introduced as a replacement refrigerant and MDI propellant for R-12, 1,1,1,2,3,3,3-heptafluoropropane (HFA-227ea) was also introduced as a replacement propellant for dtchiorotetraNuoroethane (R-114) in the MDI sector and is sometimes used alone or blended with HFA -134a for this application.

Although HFA-134a and HFA~227ea have low ozone depletion potentials (ODFs), they have global warming potentials (GWPs), 1430 and 3220 respectively, which are now considered to be too high by some regulatory bodies, especially for dispersive uses when they are released into the atmosphere.

One Industrial area that has received particular attention recently has been Hie automotive air-conditioning sector where the use of HFA-134a has come under regulatory control as a result of the European Mobile Air Conditioning Directive (2006/40/EC). Industry is developing a number of possible alternatives to HFA134a in automotive air conditioning and other applications that have a low greenhouse warming potential (GWP) as well as a low ozone depletion potential (ODP), Many of these alternatives include hydrofluoropropenes, especially the tetrafluoropropenes, such as 2_>3,3_<3-tetrafiuoroprope:ne (HFO-1234yf) and 1 ,3,3,3teirafluorQpropeh© (HFG~1234ze).

Although the proposed alternatives to HFA-134a haw a low GWF, the: toxicological status: of many of the components, such as certain of the fluoropropenes, is unclear and they are unlikely to be acceptable for use in the MDI .sector ter many years, if at all,

Tiotropium bromide ((1 α, 2β, 4β, So, 7^)-7-((hytiroxydl-2-thienyiae©tyl';exyj-9,9lp bimethyi~3“OxartAazGniatricyeip{3:<3>1>0²’⁴]nonane bromide)), particularly in the form of its monobydrate, is a long-acting: muscarinic anticholinergic (LAMA) bronchodilator used in the management of chronic obstructive pulmonary disease (COPD).

Unfortunately, it has proven difficult to formulate tiotropium in a form: that is suitable for delivery using a MDI due to its limited physical and chemical stability. The problem: of stability may be particularly evident when the tiotrepium is exposed to other components that are often used in pharmaceutical formulations:, including excipients, solvents, e.g. ethanol,: and other therapeutic agents.

The instability of pharmaceutical formulations of tiotropium can result in a limited shelf life at ambient temperatures and can necessitate refrigerated storage prior to use.

US20G3H71586 describes the manufacture ofcrystalline tiotropium hremid©: as its monohydrate and notes that It con be propelled in aerosol form using HFA-134a or HFA-227ea, US20Q3/171S88 also highlights the importance of chemical stability in determining the shelf life: and safety of medicaments and that any improvement in physical or chemical stability of tiotropium formulations is an Important advantage.

There Is a need for a pharmaceutical composition of tiotropium which can be delivered using a MDI and that uses a propellant having a reduced GWP in comparison with HFA-134a and HFA-227ea. There is also a need for a pharmaceutical composition of tiotropium which exhibits improved stability.

We have found that the issues: associated With: tbs use of tiotropium-based formulations in MDIs may be overcome by using a propellant that comprises 1,1difiuoroetharie (HFA-1S2a), particularly where the formulations contain low amounts of water. These formulations can exhibit improved chemical stability, improved aerosolisation performance for irnproved drug delivery, good suspension stability, reduced GWP, good compatibility with standard uncoated aluminium cans as well as good compatibility with standard valves and seals.

According to a first: aspect of the present invention, there is provided a pharmaceutical composition, e.g. a pharmaceutical suspension or a pharmaceutical solution, said composition comprising:

(i) a drug component comprising at: least one tiotropium compound selected from tiotropium and the pharmaceutically acceptable derivatives thereof; and (ii) a propellant component comprising 1,1-driiuoroethane (HFA-152a).

The improved chemical stability Is observed, in particular, when the pharmaceutical composition contains less than 100 ppm, preferably less than 50 ppm, more preferably less than 10 ppm and particularly lass than 5 ppm of water based on the total weight of the pharmaceutical composition. In referring to the water content of the pharmaceutical composition, we are referring to the content of free water in the composition and not any water that happens: to be present in any hydrated drug compounds that: may be used as part of the drug component in an especially preferred embodiment, the pharmaceutical composition is water-free. Alternatively, the pharmaceutical composition of the first aspect may contain greater than 0.5 ppm of water, e.g greater than 1 ppm, but less than the amounts discussed above, as it can In practice be difficult to remove all the water from the com position and then retain it in: such a water-free state.

Accordingly a preferred embodiment of the first aspect of the present Invention provides a pharmaceutical composition, e.g, a pharmaceutical suspension or a pharmaceutical solution, said composition comprising:

(I) a drug component comprising at least one tiotropium compound selected from tiotropium and the pharmaceutically acceptable derivatives thereof; and (ii) a propellant component comprising 1,1-dlfluoroethane (HFA-I52a), wherein the composition contains less than WO ppm, preferably less than 50 ppm, mere preferably iessthan 10 ppm and especially less than 5 ppm of water based on the total: weight of The pharmaceutical composition.

The pharmaceutical composition of the present invention is suitable tor delivery to the respiratory tract using a metered dose inhaler (MDI).

The at least one tiotepium compound may be dispersed or suspended in the: propellant. The drug particles In such: suspensions preferably have a diameter of te less than 1Θ0 microns, e.g. less than 50 microns. However, in an alternative embodiment the pharmaceutical: compositions of the Invention are solutions with the at least one tletroplum compound dissolved In the propellant e.g. with the assistance of a polar excipient, such as ethanol.

'15 Suitable pharmaceuficaSiy acceptable derivatives of tiotropium Include, inter alia, pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, phaTPiaeeutieaily acceptable solvates, pharmaceutically acceptable: hydrates, pharmaceutically acceptable esters, solvates of pharmaceutically acceptable sails, solvates of pharmaceutically aeceptable prodrugs, hydrates of pharmaceutically acceptable salts and hydrates of pharmaceutically acceptable prodrugs, A preferred pharmaceutically acceptable derivative of tiotroplum is tiotropium bromide, preferably tiotroplum bromide monohydrate. In a particularly preferred embodiment, tie at least one tiofropium compound in the pharmaceutical composition of the first aspect of the invention is tiotroplum bromide and/or tiotropium bromide: monPhydrate and more: preferably is tiotropiurn bromide monohydrate.

Accordingly, in the above described pharmaceutical compositions of the Invention, the at least one tiotropium compound is preferably selected iron; tiotroplum bromide and tiotropium bromide monohydrate.

The amount of the drug component in the pharmaceutical composition of the first aspect of the present invention will typically be in the range of from 0.01 to 2.5 weight % based on the total weight of the pharmaceutical composition, Preferably, the drug component will comprise from 0,01 to 2.0 weight %, more preferably from 0,05 to 2>Q weight % and especially from 0,05 to 1,5 weight % of the total weight of the: pharmaceutical composition. The drug component may consist essentially of or consist entirely of the at least one tiotroplum compound selected from tiotroplum and the pharmaceutically acceptable derivatives therect By the term “consists essentiaiiy of’, we mean that at least 98 weight more preferably at least 89 weight % and especially at least 99.9 weight % of the drug component consists of the least one tiotroplum compound. Alternatively, the drug component may contain other drugs, such as at least one long acting beta-2 agonist (LABA) and/or at least: one corticosteroid, io The propellant component in the pharmaceutical composition of the first: aspect of the present invention comprises 1,1-diflus:i'oethane (HFA-152 a). Thus, we do not exclude the possibility that the propellant component may include other propellant compounds in addition to the HFA-152a. For example, the propellant component may additionally comprise one or more additional hydrofiucrocarbon or hydrocarbon propellant compounds, e.g. selected from HFA~227ea, HFA-134a, diiluoromethane (HFA-32X propane, butane,. Isobutane and dimethyl ether. The preferred additional propellants are KFA-227©a and HFA-134a.

If an additional propellant compound is included, such as HFA-134a orH:FA-227ea, at least 5 % by weight, preferably at least 19 % by Weight and more preferably at least 50 % by weight of the propellant component should be HFA-152a. Typically, the HFA-152a will constitute et least 90 weight. e.g. from 9Q to 99 weight %, of the propellant component. Preferably, the HFA-1 S2a wili constitute at least 95 weight %·, e.g. from 95 to 99 weight %, and more preferably at least 99 weight

2.5 ot the propellant component

In an especially preferred embodiment, the propellant component consists entirely ol HFA-152a so that the pharmaceutical composition of the invention comprises HFA-152a as the sole propellant. By the term consists entirely of” we do not, of course, exclude the presence of minor amounts, e g. up to a few hundred parts per million, of impurities that may be present ioliowing the process that is users to make the HFA-152a providing that they do not affect the suitability of the propellant in med lea I applications.

The amount of propellant component in the pharmaceutical compos t on of the invention will vary depending on the amounts of the drugs and other eomoonents;

in the pharmaceutical composition. Typically, the propellant cempenent will comprise from SO to 99,99 weight % of the total weight of the phsrmaeeuMcai composition. Preferably, the propellant component will comprise from 90,0 to 99.99 weight %, more preferably from 96.5. to 99.99 weight % and ©specially from 97.5 to 99,96 weight fe of the total weight of the pharmaceutical composition, lri one embodiment the pharmaceutical composition of the first aspect of the present Invention consists essentially of and more preferably consists entirely of the two components (I) and (ii) listed above. By the term “consists essentially of, we mean that at least W weight more preferably at least 99 weight % and especially at least 90>@: weight % of the pharmaceutical composition consists of the: two listed components,.

In another embodiment, the pharmaeeuficaf composition of the first aspect: of the present invention additionally includes a polar excipient, such as ethanol. Polar excipients have been used previously in pharmaceutical compositions for treating respiratory disorders that are delivered using; metered dose Inhalers (MDfs). They are also referred to as: solvents, co-solvents, carrier solvents and adjuvants. Their inclusion can serve to solubilise the surfactant of the drug In the propellant and/or inhibit: deposition of drug particles on the surfaces of the metered dose Inhaler that are contacted by the pharmaoeutical composition as it passes from the container in which it is stored to· the nozzle outlet. They are also used as bulking agents in two-stage filling processes where the drug is mixed: with a suitable polar excipient. The most commonly used polar excipient is ethanol, if a polar excipient is used, it will typically be present in an amount of from: 0,5 to t o % by weight, preferably in an amount of from 1 to: 5 % by weight based on the total weight of the pha rm aceutica I com position.

in one preferred embodiment, the pharmaceutical composition of the present, invention Is free of polar excipients such as ethanol.

The pharmaceutical composition of the first aspect of tho present invention may also include a surfactant component comprising at least one surfactant compound. Surfactant cbm pounds of the: type that have been in use hitherto in pharmaceutical formulations for MDis may be used: in the pharmaceutical compositions of the present invention. Preferred surfactants are selected from polyvinylpyrrolidone, polyethylene glycol surfactants, oleic acid and lecithin. By the term oleic acid, we are not necessarily referring to pure (9Z)~octadec-9-enoie acid. When sold for surfactant, use in medical applications, oleic acid is typically a mixture of several fatty acids, with (8Z}~ootadec-9-enoio acid being the predominant fatty acid, e.g.

present in an amount of at least §5 wight % based on the total weight of the surfactant in a preferred embodiment, file surfactant component consists essentially of and still more preferably co nsists entirely of at; least one surfactant compound selected from polyvinylpyrrolidone, polyethylene glycols,: oleic acid and lecithin In a particular!'/ preferred embodiment the surfactant: component consists essentiaily of and stiil more preferably consists entirely of at least one surfactant compound selected from polyvinylpyrrolidone and polyethylene glycols. By the term “consists essentially off we mean that at least 95 weight %, more preferably at least 98 is weight % and especially at least; 99 weight % of the surfactant component is composed of the listed surfactants.

If a surfactant component is used, it will typically be present in an amount of from 0.1 to 2.5 % by weight preferably In an amount of from 0.2 to 1.5 % by weight based on the total weight of the pharmaceutical composition.

The pharmaceutical composition of the invention may also Include a long acting beta-2-agonist (LAB,A). Any of the long acting beta~2~agonisis that have been In use hitherto for treating asthma and chronic obstructive pulmonary diseases and

2.5 that can be delivered using a MDI can be used in the pharmaceutical compositions of the present Invention;. Suitable long acting beta-2-agonists include formoterol, arformoterol, bambuterol, cienbuterol, salmeterol, indacateroi, olodaterei and vllanteroi as well as their pharmaceutically acceptable derivatives, such as their pharmaceutically acceptable salts. Preferred compounds include formoterol, salmeterol and olodaterol. and the pharmaceutieaily acceptable salts thereof. Particularly preferred compounds include formoterol fumarate, formoterol fumarate dlhydrate, salmeterol .xinafoate and oiadateroL

Accordingly, a second aspect of the present invention provides a pharmaceutical composition, e g. a pharmaceutieai suspension or a pharmaceutical solution, said composition comprising:

(i) a drug component comprising at: least one tiotropium compound .selected from tiotroplum arsd the pharmaceutically acceptable derivatives thereof, especially tiotropium bromide and tiotropium bromide monohydraie, and at least one· long acting beta~2~agonisf (LABA). especially at least one long acting beta-2 agonist (LABA) selected from formoterot, ealmcteroi and olodaterol and the pharmaceutically acceptable salts thereof; and (ii) a propellant component comprising 1.1 -diOuoroethane (HFA-152a).

in this second aspect of the present invention, the pharmaceufeal composition m preferably contains less than 100 ppm, more preferably less than 50 ppm. particularly less than 10 ppm and especially less than 5 ppm of water based on the total weight of the pharmaceutical: composition, It has been found that small amounts of water alongside the use of HFA-152a as the propellant can result in a pharmaceuticai composition with improved chemical stability. In referring to: the i s water content of the pharmaceutical composition, we are referring to the content of free wafer in the composition arid not any water fnat happens to be present in any hydrated drug compounds that may be used as part of the drug component, in ah especially preferred embodiment,, the pharmaceuticai composition of the second: aspect of the present invention is water-free. Alternatively, the pharmaceutical composition of the second aspect may contain greater than 0.5 ppm: of water, e.g. greater than 1 ppm, but less than the amounts discussed above, as It can in practice be difficult to remove all the water from the composition and then retain it in such a water-free state.

Preferred tiotroplum compounds: are as discussed above 'for the pharmaceutical composition of the first aspect of the present invention.

Typical and preferred amounts of the drug component and the propellant component in the pharmaceuticai composition of the second aspect of the present invention and suitable, typical and preferred compositions for the propellant component are as discussed above for the pharmaceutical composition of the first aspect of the invention. The drug component may consist essentially of or consist entirely of the at least one tiotroplum compound and the at least one long acting beta-2 agonist (LABA). By the term “consists essentially of’, we mean that at least

98 weight %, more preferably at least 99 weight % and especially at least 99.9 weight % of the drug component consists of the at least one tiotropium compound and the at least one long acting beta-2 agonist (LABA).

in one embodiment, the pharmaceutical composition of the second aspect of the •5 present invention consists essentially of arid more preferably consists entirely of the two components (I) and (ii) listed above. By the term “consists essentially of, we. mean that at least 98 weight more preferably at least 99 weight % and especially at least: 99,9 weight % of the pharmaceutical composition consists of the two listed components, to in another embodiment, the pharmaceutical composition of the second aspect: of the invention may contain: one: or both of a polar excipient and a surfactant component as discussed above for the pharmaceuticai composition of the first aspect of the invenfibn. Suitable and preferred polar excipients and surfactants are is as discussed above for the pharmaceuticai composition of the first: aspect, of the invention. Typical and preferred amounts of the polar excipient and the surfactant component are as discussed above for the pharmaceutical composition of the first aspect of the invention,

In an especially preferred embodiment of the second aspect of the invention:, the drug component .comprises at least one tiotropium compound selected from tiotropium bromide and tiotropium bromide: monohydrate, and at least one Song acting beta-S-agomst selected from formoterol, saimeteroi and olodateroi and the pharmaceutically acceptable: salts thereof. Preferably, the at least one selected tiotropium eompcund and the at least: one: selected long acting beta-2-agonist are the only pharmaceutical actives in the pharmaceutical composition of the second aspect of the invention.

The pharmaceutical composition of the invention may also include a corticosteroid,

Any of the corticosteroids that have been In use hitherto for treating asthma and chronic obstructive pulmonary diseases and that can be delivered using a MDI can be used in the pharmaceutical compositions of the present invention, Suitable corticosteroids Include budesonide, mometasone, beclomethasone and fluticasone as well as their pharmaceutically acceptable derivatives, such as their pharmaceutically acceptable salts and esters. Preferred compounds inci tdo budesonide, mometasone furcate, beclomethasone dipropionate and fluticasone propionate. The most preferred corticosteroids are budesonid©, mometasone, fiutlcasone and beeiomethasone, particularly budesonide and mometasone and esp eclah y bud esonide.

s Accordingly, a third aspect of the present invention provides a pharmaceutical composition, e.g, a pharmaceutical suspension or a pharmaceutical solution, said co mpos ition com prisi ng:

(I) a drug component comprising at least one tiotropium compound selected from tiotropium and the pharmaceutically acceptable derivatives thereof, to especially fiofropiurn bromide and tiotropium bromide monohydrate, and at least one cortioosteroid, particularly at least one corticosteroid selected from fluticasone, budesonide, mometasone and beclomeihasono and the pharmaceutically acceptable derivatives thereof, especially budesonide;

and (ii) a propellant component comprising 1,1-difluoroethane (HFA-152a).

In this third aspect of the present invention, the pharmaceutical composition preferably contains less than 100 ppm, more preferably less than 50 ppm, particularly loss than 10 ppm and especially less than S ppm of water based on the total weight of the pharmaceutical composition. It has been: found that small amounts of wafer alongside the use of HFA-152a as the propellant can result in a pharmaceutical composition with: improved chemical stability, in referring to the water content of the pharmaceutical composition, we are referring to the content of tree water in the composition: and not any water that happens to be present in any hydrated drug compounds that may be used as part of the drug component In an especially preferred embodiment, the pharmaceutical composition of the third aspect of the present invention is water-free. Alternatively, the pharmaceutical composition of the third aspect may contain greater than 0.5 ppm of water, e.g. greater than 1 ppm, but less than the amounts discussed above, as it par; in .20 practice bo difficult to remove ail the water from the composition and then retain It in such a water-free state.

Preferred tiotropium compounds are as discussed above for the pharmaceutical composition of the first aspect of the present invention.

3S

Typical and preferred amounts of the drug component and the propellant component in the pharmaceutical composition of the third aspect of the present invention and suitable, typical and preferred compositions for the propellant component are as discussed above for the pharmaceutical composition of the first aspect of the Invention, The drug component may consist essentially of or consist entirely of the at least one tiofreplum_: compound and the at least one corticosteroid,: By the term “consists essentially of’, we mean that at least 98 weight %, more preferably at least 93 weight % and especially at least 99,9 weight % of the drug component consists of the at least one tiotroplum compound and: the al least one io corticosteroid.

In one embodiment, the pharmaceutical composition of the third aspect of the present invention consists essentially of and more preferably consists entirely of the two components (i) and (Ii) listed above. By the term “consists essentially of, we mean that at least 98 weight %, more preferably at least 99 -weight % and especially at least 99,9 weight % of the pharmaceutics! compositionconsists of the two listed components.

in another embodiment, the pharmaceutical composition of the third aspect: of the 20 invention may contain one or both: of a polar excipient and a surfactant component as discussed above for the pharmaceutical composition of the first aspect of the invention. Suitable and preferred polar excipients and surfactants are as discussed above for the pharmaceutics! composition of the first aspect of the invention.

Typical and preferred amounts of the polar excipient and the surfactant component 25 are as discussed above for the; pharmaceutical composition of the first aspect of the Invention.

In an especially preferred embodiment of the third aspect of the invention, the drug component comprises at least one tiotroplum compound selected from tiotroplum

3Θ bromide and tiotroplum bromide monohydrate, and budesonide. Preferably, the at least one selected tiotroplum compound and budesonide are the only pharmaceutical actives in the pharmaceutical composition of the third aspect of the Invention.

The pharmaceutical composition of the invention may also Include a long acting beta-2-agonist (LABA) and a corticosteroid, Any of the long acting beta-2~agonists and oerticosfemids that have beep In use hitherto for treating asthma and chronic obstructive pulmonary diseases and that can be delivered using a MO! can be used in the pharmaceutical compositions of the present invention. Suitable and preferred long acting heta-2-agonists are as discussed above for the second aspect of the invention. Suitable: and preferred corticosteroids are as discussed above for the third aspect of the present, invention.

Accordingly, a fourth aspect of the present Invention provides a pharmaceutieat composition, e.g, a pharmaceutical suspension:or a pharmaceutieai solution, said to composition comprising:

(!) a drug component comprising at least one tiotroplum compound selected from: tiotrepium and the pharmaceutically acceptable derivatives thereof,, especially tiotropium bromide and tiofropium bromide monahydrate, at least one long acting beta-2-agonist (LABA), especially at least one long acting beta-2 agonist (LABA) selected from formoterol, saimetero! and oiodatero!

and the pharmaceutically acceptable salts thereof and at least one corticosteroid, particularly at least one corticosteroid selected from fluticasone, budesonide, momstasone end beclomethasone and the pharmaceutically acceptable derivatives thereof, especially budesonide;

and (ii) a propeiiant component comprising 1,1 -diflueroethane (HFA-152a).

in this fourth aspect of the present invention:, the pharmaceutical composition preferably contains less: than 100 ppm, more preferably less than SO ppm, particularly less than 10 ppm arid especially less than S ppm of water based on the total weight of the pharmaceutical composition, it has been found that small amounts of wafer alongside the use of HFA-152a as the propeiiant can result in a pharmaceutical composition, with improved chemical stability, In referring to the wafer content of the pharmaceutical composition, we are referring to the: content of free water in the composition and not any water that happens to be present In any hydrated drug compounds that may be used as part of the drug component. In an especially preferred embodiment, the pharmaceutical composition of the fourth aspect of the present invention is water-free. Alternatively, the pharmaceutical composition of the fourth aspect may contain greater than 0 5 ppm of water, e.g, greater than 1 ppm, but less than the amounts discussed above, as if can in practice be difflcuit to remove ai! the water from -he composition and then retain it in such a water-free state.

Preferred tiotropium compounds are as discussed above for the pharmaceutical composition of the first aspect of the present invention..

Typical and preferred amounts of fine drug component and the propellant component in the pharmaceutical composition of the fourth aspect of the present invention and suitable, typical and preferred compositions for the propellant to component are as discussed above for the pharmaceutical composition of the first aspect cf the invention. The drug component may consist essentially of or consist entirely of the at least one tiotropium compound, the at least one lone acting beta2 agonist (LABA) and the at least one corticosteroid. By the term “consists essentially of, we mean that at least 98 weight %_; mere preferabiy at least 99 * weight % and especially at least 99.9 weight % of the drug component consists of the at least one tiotropium compound, the at feast one long acting beta-2 agonist (LABA) and the at least one corticosteroid.

In one embodiment, the pharmaceutical composition of the fourth aspect of the present invention consists essentially of and more preferably consists entirely of the two components (I) and (ii) listed above. By the term “consists essentially off we mean that at least 98 weight %, more preferabiy at least 99 weight % and especially at least 99.9 weight % of the pharmaceutical composition consists of the two listed components.

In another embodiment, the pharmaceutical composition of the fourth aspect of the Invention may contain one or both of a polar excipient and a surfactant component as discussed above for the pharmaceutical composition of the first aspect of the invention. Suitable and preferred polar excipients and surfactants are as discussed

3b above for the pharmaceutical composition of the first aspect of the invention. Typical arid preferred amounts of the polar excipient and the surfactant component are as discussed above for the pharmaceutical composition of the first aspect of the invention.

In an especially preferred embodiment of the fourth aspect of the invention, the drug component comprises at least one tiotropium compound selected from 14 ifotropium bromide and tiotropium bromide monohydrate, at least one long acting beta-2-agonist selected from formoterol, saimeterol and oiodataroi and the phannaeeUtioaliy acceptable salts thereof and budesonide. Preferably, the at least one selected tiotropium compound, the at least one selected long acting beta~2~ agonist end the budesonide are the only pharmaceutical actives in the pharmaceutical composition of the fourth aspect of the invention.

it has been found that the use of propellants comprising 1,1 -difiuoroethane (HFA~ 152a) in pharmaceutical compositions containing a tiotropium compound, such as tiotropium bromide monohydrate,, and the propellantean unexpectedly Improve the chemical stability of the tiotropium compound compared to the stability it exhibits in formulations containing either HFA-134a or HFA-227ea as the propellant.

Accordingly, in a fifth aspect of the present invention there is provided a method of improving the stability of a pharmaceutical composition comprising a propellant component and a drug component comprising at least one tiotropium compound selected from tiotropium and the pharmaceutically acceptable derivatives thereof, said method comprising using a propellant component comprising 1,1dlfkioroethane (HFA-152a).

The pharmaceutical composition in the stabilisation method of the fifth aspect of the present Invention may be a suspension or a solution.

The improved chemical stability can result, in particular, when the pharmaceutical composition contains less than 100 ppm, preferably less than 50 ppm, more preferably less than: 10 ppm and particularly less than 5 ppm of water based on the total weight of the pharmaceutical composition, in referring tc the water content of the pharmaceutical composition, we are referring to the content of free water in the composition and not any water that happens to be present in any hydrated drug compounds that may be used as part of the drug component, in an especially preferred embodiment, the pharmaceutical composition Is water-free, Alternatively, the pharmaceutical composition recited in the fifth aspect of the present invention may contain greaterthan 0.5 ppm of water, e.g. greater than 1 ppm, but less than the amounts discussed above, as it can In practice he difficult to remove ail the water from the composition and then retain it in such a water-free state.

IS

Accordingly, in a preferred embodiment of the fifth aspect of the present invention there is provided a method of improving the stability of a pharmaceutical composition comprising a propeilant component and a drug component comprising at least one tiotropium compound selected from tiotropium end the s pharmaceutically acceptable derivatives thereof, sard method comprising using a propellant component comprising 1,1 difluoroethane (HFA-152a) and selecting the components arid conditions for the preparation of the pharmaceutical composition to maintain the water content of rise pharmaceutical composition below 100 ppm, preferably below 50 ppm, more preferably below 10 ppm and particularly below 5

W ppm based on the total weight of the pharmapeutioal composition'

In practice, preparing a pharmaceutical composition with the low water levels recited above involves using a propellant component with a suitably low water content, as it Is the propellant component that can tend to contain adventitious

IS amounts of water, and then preparing the pharmaceutical composition under suitably dry conditions, e.g. in a dry nitrogen atmosphere. Preparing pharmaceutical compositions under dry conditions Is well known and the techniques involved are well understood by those skilled in the art. However, if the pharmaceutical composition contains significant, amounts of ether components,

e.g, a pharmaceutical excipient such as ethanol, then it may also be Important to control the water content of those components as well as the propeilant, e.g. by drying to reduce the water content to suitably low levels. Suitable drying techniques are well known to those skilled in the art and include the use of a molecular sieve or other inorganic desiccant and membrane drying processes.

In the stabilisation method of the fifth aspect of the present invention suitable and preferred iiotropium compounds and derivatives thereof are as described above for the pharmaceutical composition of the first aspect of the present invention. In addition, typical and preferred amounts of the drug component and the propellant component in the stabilisation method of the fifth aspect of the present invention and suitable, typical and preferred compositions for the propellant component are as discussed above for the pharmaceutical composition of the first aspect of the invention.

The drug component in the stabilisation method of tire fifth aspect of the present invention may consist essentially of or consist, entirely of the at least one tiotropium

S3 compound selected from flotropiurn and the pharmaceutically acceptable derivatives thereof. By the term “consists essentially of, we mean that et least 98 weight %, more preferably at least 99 weight % and especially at least 99.9 weight % of the drag component consists of the least one tiotropium compound. Alternatively, the drug component may additionally compose at least one corticosteroid and/or at least one long acting beta-2-agonlst. When a corticosteroid and/or a long acting beta-2-agonist are Included, suitable and preferred corticosteroids arid suitable and preferred long acting beta-2-agonlsts are as described above fcr the pharmaceutical compositions of the second arid third aspects of the present invention.

In one embodiment, the pharmaceutical composition in the fifth aspect of the present invention consists essentially of and more preferably consists entirely of the drug component and the propellant component as defined above. By the term “consists essentially of”, we mean that at least 98 'weight %, more preferably at east 99 weight % and especially at least 99.9 weight % of the pharmaceutical composition consists of the two components.

In an alternative embodiment, the pharmaceutical composition in the fifth aspect of the invention may contain one or both of a polar excipient and a surfactant component as discussed above for the pharmaceutical composition of the first aspect of the Invention. Suitable and preferred polar excipients and surfactants are as discussed above for the pharmaceutical composition of the first aspect, of the invention. Typical and preferred amounts of the polar excipient and the surfactant component are as discussed above for the pharmaceutical composition of the first aspect of the Invention.

In one preferred stabilisation method, the resulting pharmaceutical composition after storage at 40”C and 75 % relative humidity for 1 month will produce less than 0.2 $4 by weight, preferably less than 0.1 % by weight and more preferably less than 0.05 % by weight of impurities from the degradation of the at least one tiotropium compound based on the total weight of the at least one tlotropium compound and the impurities.

In another preferred stabilisation method in which the pharmaceutical composition also comprises at least one corticosteroid and/or at least one long acting beta-2agonist, the resulting pharmaceutical composition after storage at 4O''C and 75 % relative humidify for 1 month will produce less than 0.2 % by weight, preferably less than 0.1 % by weight and more preferably less than 0.05 % by weight of impurities from the degradation of ihe at least one tiotropium compound based on the total weight of the at least one tiotropium compound and the impurities.

In a further preferred stabilisation method, the resulting pharmaceutical composition after storage at 40”G and 75 % relative humidity for 3 months will produce less than 0.3 % by weight, preferably less than 0.2 % by weight, and more preferably less than 0.15 % by weight of Impurities from the degradation of the at least one tiofrop-um compound based on the total weight of the at least one tiotropium compound and the impurities.

In anoifter preferred stabilisation method in which the pharmaceutical composition

IS also comprises at least one corticosteroid and/or at least one long acting beta-2agonist, the resulting pharmaceutical composition after storage at 40°C and 75 % relative humidity for 3 months will produce less than 0.3 % by weight, preferably loss than 0.2 % by weight and more preferably less than 0.15 % by weight of impurities from the degradation ofthe at least one tiotropium compound based on the total weight of the at least one tiotropium compound and the impurities.

in yet another preferred stabilisation method, at least 97.0 % by weight, preferably at least 9S.0 % by weight and more preferably at least 98.5 % by weight of the at least one tiotropium compound that is contained originally in the pharmaceutical composition immediately following preparation will be present In the composition after storage at. 4QC and 75 % relative humidity for 3 months.

In still another preferred stabilisation method in which the pharmaceutical composition also comprises at least one corticosteroid and/or at least one long acting beta-2-agonist, at least 97.0 % by weight, preferably at least 98.0 % by weight and more preferably at least 98.5 % by weight of the at least one tiotropium compound that is contained originally In the pharmaceutical composition immediately following preparation will be present in the composition after storage at 40°C and 75 % relative humidify for 3 months.

in a further preferred stabilisation method, at feast 97.0 %, preferably et least 98.0 % and more preferably at least 98.5 % of the anginal pharmaceutical activity of the composition Is retained after storage at 40’C and 75 % relative humidity for 3 months.

One preferred pharmaceutical composition of the first, second, third and fourth aspects of the present inventions will produce less than 0.2 % by weight, preferably less than 0.1 % by weight and more preferably less than 0.05 % by weight cf total Impurities from the degradation of the at least one tiotropium compound after

1C> storage at 40^eC and 75 % relative humidity for 1 month.

Another preferred pharmaceutical composition of the first, second, third ano fourth aspects of the present invention will produce less than 0,3 % by weight, preferably less than 0.2 % by weight and more preferably less than 0.15 % by weight of total

IS impurities from the degradation of the at least one tiotropium compound after storage at 40^eC and 75 % relative humidity for 3 months.

The weight % of Impurities indicated above are based on the total weight of the at least one tiotropium compound and the impurities.

In a further preferred pharmaceutical composition of the first, second, third and fourth aspects of the present invention at least 97.0 % by weight, preferabiy at least 98.0 % by weight and more preferably at feast 98.5 % by weight of the at least one tiotropium compound that Is contained originally in the pharmaceutical composition of the Invention immediately following preparation will be present In the composition after storage at 40°C and '75 % relative humidity for 3 months.

In yet another preferred pharmaceutical composition of the first, second, third and fourth aspects of the present invention at least 97.0 %, preferably at least 98.0 % and more preferably at least 98.5 % of the original pharmaceutical activity of the pharmaceutical composition of the invention is retained after storage at 40°C and 75 % relative humidity for 3 months.

In referring to the storage of the pharmaceutical compositions in the above described stabilisation methods, we are referring, in particular, to the storage of those compositions in unooated aluminium containers. Similarly, in referring to the storage of the above described pharmaceutical compositions, we are referring, in particular, to their storage in uncoated aluminium containers.

it has been found that the use of a propellant comprising 1 ,1-difluoroethane (HFA$ 152a) In pharmaceutical compositions containing a fiofropium compound, such as tiotropium bromide monohydrate, and the propellant that are designed to be delivered using a metered dose inhaler cart unexpectedly Improve the aerosoiization performance of the pharmaceutical composition after storage when that composition is delivered from the metered dose inhaler compared to tine performance that Is observed when either HFA-134a or HFA-227ea is used as the propellant. -In particular, the fine particle fraction of the tiotropium compound In the emitted dose after storage of the pharmaceutical composition at 50^t;C and 75 % relative humidity for 15 days is at least 45 weight % of the emitted dose of the tiotropium compound,

Accordingly, in a sixth aspect of the present invention there Is provided a method of Improving the aerosoiization performance after storage of a pharmaceutical composition comprising a propellant component and a drug component comprising at least one tiotropium compound selected from tiotropium and the pharmaceutically acceptable derivatives thereof, said method comprising using a propellant component comprising 1,1-difluoroethane (HFA-152a).

The pharmaceutical composition In the method of the sixth aspect of the present invention may be a suspension or a solution.

In a preferred embodiment of the sixth aspect of the present invention there is provided a method of improving the aerosoiization performance after storage of a pharmaceutical composition comprising a propellant component and a drug component comprising at least one tiotropium compound selected from tiotropium and the pharmaceutically acceptable derivatives thereof, said method comprising using a propellant component comprising 1,1-difluoroethane (HFA-152a) and providing a pharmaceutical composition which when delivered from a metered dose inhaler yields a fine particle fraction of the at least one tiotropium compound which is at least 45 weight % of the emitted dose of the at least one tiotropium compound even after storage of the pharmaceutical composition at 50^:>C and 75 % relative humidity for 15 days.

increasing the fine particle fraction of the emitted dose is highly beneficial, because it is the fine drug particles that are able to penetrate into the deep bronchiole passages and the alveolar passages of the lung to maximise relief from the effects of an asthma attack or GOPD.

SO

The fine particle fraction is a widely recognised term in the art, it Is a measure ot the mass fraction of emitted aerosol particles having a diameter below 5 pm which Is generally accepted as being the most desirable particle size range for effective alveolar drug delivery.

in the method of the sixth aspect of the present invention suitable and preferred tiotropium compounds are as described above for the pharmaceutical composition of the first aspect of the present invention. In addition, typical and preferred amounts of the drug component and tbs propellant component in the method of the sixth aspect of the present invention and suitable, typical arid preferred compositions for the propellant component are as discussed above for the pharmaceutical composition of the first aspect of the Invention.

The drug component in the method of the sixth aspect of the present invention may consist essentially of or consist entirely ot the at least one tiotropium compound, such as tiotropium bromide monohydrate. By the term “consists essentially of, we mean that at least 98 weight %, more preferably at least 99 weight % and especially at least 99.9 weight % of the drug component consists of the least one tiotropium compound. Alternatively, the drug component may additionally comprise at least one long acting beta-2 agonist (LABA) and/or at least one corticosteroid. When a long acting beta-2 agonist and/or a corticosteroid are included, suitable arid preferred long acting beta-2 agonists and suitable and preferred corticosteroids are as described above for the pharmaceutical compositions of the second and third aspects of the present Invention.

In one embodiment, the pharmaceutical composition in the sixth aspect of the present invention consists essentially of and more preferably consists entirely of the drug component and the propellant component as defined above. By the term “consists essentially of”, we mean that at least 98 weight %, more preferably at least 99 weight % and especially at least 99.9 weight % of the pharmaceutical composition consists of the two components.

In an alternative embodiment, the pharmaceutical composition in the sixth aspect of the invention may contain one or both of a polar excipient and a surfactant component as discussed above for the pharmaceutical composition of the first aspect of the Invention, Suitable and preferred polar excipients and surfactants are as discussed above for the pharmaceutical composition of the first aspect of the invention, Typical and preferred amounts of the polar excipient and the surfactant component are as discussed above for the pharmaceutical composition of the first aspect of the invention.

The pharmaceutical compositions of the invention find particular utility in the delivery of the tiotropium compounds, and where included the corticosteroid arid long acting beta-2 agonist compounds, from a pressurised aerosol container, e.g, using a metered dose inhaler (MDi). For this application, the pharmaceutical compositions are contained in the pressurised aerosol container and the HFA-152a propeilant functions to deliver the drug as a fine aerosol spray,

The pharmaceutical compositions of the Invention may comprise one or more other additives of the type that are conventionally used in drug formulations for pressurised MDIs, such as valve lubricants, Where other additives are included in the pharmaceutical compositions, they are normally used in amounts that are conventional in the art.

The pharmaceutical compositions of the invention are normally stored in a pressurised container or canister which is to be used In association with a medication delivery device. When so stored, the pharmaceutical compositions are normally a liquid. In a preferred embodiment,, the pressurised container Is designed for use in a metered dose Inhaler (MDI), In a particularly preferred embodiment, the pressurised container Is a coated aluminium can or an uncoated aluminium can, especially the latter.

Accordingly, a seventh aspect of the present invention provides a pressurised container holding the pharmaceutical composition of the first, second, third or fourth aspect of the present invention. In an eighth aspect, the present invention provides a medication delivery device, especially a metered dose Inhaler, having a pressurised container holding the pharmaceutical composition of the first, second, third or fourth aspect ofthe present invention.

The pharmaceutical compositions of the present invention are for use in medicine for treating a patient suffering or likely to suffer from a respiratory disorder and especially asthma or a chronic obstructive pulmonary disease.

Accordingly, the present invention also provides a method lor treating a patient to suffering or likely to suffer from a respiratory disorder, especially asthma or a chronic obstructive pulmonary/ disease, which comprises administering to the patient a therapeutically or prophylactically effective amount of a pharmaceutical composition as discussed above. The pharmaceutical composition is preferably delivered to the patient using a MDi.

The pharmaceutical compositions of the Invention can be prepared and the MQ1 devices filled using techniques that are standard in the art, such as pressure filling and cold filling. For example, the pharmaceutical compositions can be prepared by a simple blending operation in which the at feast one tiotropium compound, optionally the at least one corticosteroid and/or the at least one long acting beta-2 agonist, optionally Hie surfactant component arid the HFA-i52a~containing propellant are mixed together in the required proportions in a suitable mixing vessel. Mixing can be promoted by stirring as is common in the art. Conveniently, the HFA-152a~containing propellant is liquefied to aid mixing, lithe pharmaceutical composition is made in a separate mixing vessel, it can then be transferred to pressurised containers for storage, such as pressurised containers that are used as part of medication delivery devices and especially MDis,

The pharmaceutical compositions of the invention can also be prepared within the confines of a pressurised container, such as an aerosol canister or vial, from which the compositions are ultimately released as an aerosol spray using a medication delivery' device, such as a MDL In this method, a weighed amount of the at least one tiotropium compound and optionally the at least one corticosteroid and/or at least one long acting beta-Ξ agonist compound, is introduced into the open container. A valve Is then crimped onto the container and the HFA-152a-containlng propellant component, In liquid form, introduced through the valve into the container under pressure, optionally after first evacuating the container through the valve, 'the surfactant component, if Included, can be mixed wltti the drug(s) or, alternatively, introduced Into the container after the valve has been fitted, either alone or as a premix with the propellant component. The whole mixture can then be treated to disperse the drugs in the prepeliant/sunactant mixture, e.g. by vigorous shaking or using an ultrasonic bath. Suitable containers may be made of plastics, metal, e.g, aluminium, or glass. Preferred containers are made of metal, especially aluminium which may be coated or uncoated. Unooated aluminium containers ate especially preferred.

The container may be filled with enough of the pharmaceutical composition to provide for a plurality of dosages. The pressurized aerosol canisters that are used in MDIs typically contain 50 to 150 individual dosages.

The present invention is now illustrated but not limited by the following examples.

Example 1

A number of experiments were conducted to investigate the />? vitro aerosolization performance of pharmaceutical formulations of tiotropium bromide monohydrate delivered from a metered dose inhaler (MDI) using either HFA-134a or HFA-152a as the propellant.

Pharmaceutical formulations of tiotropium bromide monohydrate were prepared in either HFA-134a or HFA-152a (Mexichem, UK). The drug was weighed directly into standard unseated 14 mi aluminium canisters (C12.8, Presspart, Blackburn, UK). The canisters were then crimped with a 50 piL valve (Bespak, Kings Lynn, UK) following which the propellant was filled into the canisters through the valve using a manual Pamasol crimper/Rller (Pamasol, Switzerland). Finally, the canisters 'were 30 sonicated for 20 minutes to aid dispersion of the drug in the suspension. The nominal dose of tiotropium bromide monohydrate was 10pg,

High performance liquid chromatography (HPLC) was used to determine drug content following aerosolization studies (see below). A 150 mm x 3 mm Zorbax SB35 C3 propyl-silica column with a 3.5 pm particle size was used for the analysis. The column was coupled to a UV detector operating at a wavelength of 240 nm. The autosarnpier was operated at ambient temperature and 100 μΙ samples were injected into the column for the analyses. The chromatographic conditions are shown In Table i below.

5: Table 1

Drug	Pump Flow Rate (mimin'*)	Mobile Phase (gradient elution)	UV Wavelength (nm)	Column Temperature fC)
Tiotropium Bromide Monohydrate	1.2C	Mobile Phase A; Sodium methane sul pho n ate/pota ss I u m d 1 hydrogen phosphate Mobile Phase B: Methanoi/Acetonitrile (10:40 v/v)	240	50

The /n v/fro aerosoiization performance of the formulations was studied using a Next Generation Impactor (NGI, Copley Scientific, Nottingham UK), which was connected to a vacuum pump (GE Motors, NJ, USA). Prior to testing, the cups of the NGI system were coated with 1 % v/v silicone oil in hexane to eliminate particle bounce. For each experiment, three actuations of the valve 'were discharged into the NCI at 30 Lmin · as per pharmacopeia guidelines. Following aerosoiization, the NGI apparatus was dismantled and the actuator and each part of the NGI was • 5 washed down into known volumes of the HPLC mobile phase. The mass of drug deposited on each part of the NGI was determined by HPLC using the methodology described above. This protocol was repeated three times for each canister, following which, the fine particle dose (FPD) and fine particle fraction of the emitted dose (FPFew) were determined. The results are shown in Table 2 below.

2<l

Table 2. fa vitro aerosoiization performance of tiofropium bromide monohydrate in HFA-134a and HFA-152a as characterised by the emitted dose, fine particle dose, fine particle fraction of the emitted dose (FPFeo %), mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD).

.........—......,........................,,,,,^	i HFA~134a j t 1	HFA--! 52.-i
Emitted Dose	7 «£· A Ί i	7 9 -tz ή 9
(pg ± S.D.)	i ,4* fo. > ;	< 3( v,Z
I Fine Particle Dose (ug 7 S.D)	2.4 ±0.2 |	27 ± 0.1
FPFsd % ± S.D.	31.4 ±2.5	38.0 ± 0.3
MMAD (pm)	4.8 f	4.S
| GSD	2.1 | 2.1

A number of experiments were conducted to investigate the in vitro aerosoiization performance of pharmaceutical formulations of tiotroplum bromide monohydrate delivered from a metered dose inhaler (MDi) using either HFA-134a, HFA-227ea or HFA-152a as the propellant after initial preparation and after storing under stress storage conditions, The experimental protocol described above was used to prepare the pharmaceutical formulations and the fa vitro aerosoiization performance of the formulations was tested immediately after preparation (time t zero) with a Next Generation Impactor using the method described in Example 1 above. The formulations were then stored under stress storage conditions (valve

7.0 down) at 50”C and 75 % relative humidity for 5 days and 15 days. After storing for 5 days and 15 days under the stress storage conditions, the fo vitro aerosoiization performance of the pharmaceutical formulations was tested again as before with a Next Generation impactor using the method described in Example 1 above. The results are shown in Tables 3 to 5 below.

Table 3. fe vitro aerosolizafion performance of tiotropium bromide monohydrate delivered from a MDI using HFA-227ea. BFA-134a or HFA~152a as the propellant at time t - aerb as characterised by the fine particle dose, fine particle fraction of the emitted dose (FPF;;» %), mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD).

	i HFA-22'7ea	HFA-tS-ta	HFA-152a i
	T=0	TW	to i
{ J Sk~· i W! UviV	2.26	5.67	2.70 1
Dose (pg)			ί j
FPfe%	41.07	47.22	44.12
h'lMAD (pm):	3.12	2.68	2.58
GSD	1.84	1,68	1.65

Table 4, to v/tro aerosoiiaation performance of tiotropium bromide monobydrate Ki delivered from a MDi using HFA-»227ea. HFA-134a or HFA*I 52a as the propellant after storage (vaive down) for 5 days at 50^c'C and 75 % relative humidity as characterised by the fine particle dose, fine particle fraction of the emitted dose (FPFeb %), mass median aerodynamic diameter (MM AD) and geometric standard deviation (GSD).

	HFA-227sa 7=5 days @ 50°C and 75% RH	HFA-134a T-5 days fol 50 Ό and 75% RH	HFA-152a i T'=5 days @ 50C arid 75% RH 1
Fine Particle	Π QO	9 TO
Dose (pg)		jS. >?3<7	zTx : <£
FPFso %	13.77	31.82	47.47
MMAD (pm)	8.57	2.07	2.73
| GSD	2.06	: 1.80	1.72

Table 5. /n v/fra aerosoiizafien performance of tiotropium bromide monohydrate delivered from a MDI using HFA~227ea, HFA~134a or HFA-152a as the propellant, after storage (valve down) for 15 days at SO^C and 75 % relative humidity as characterised by the fine particle dose, fine particle fraction of the emitted dose (FPFgo %), mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD),

Fins Particle Dose (ug)	HFA-227ea T“15 days @ 5CFC and 75% RH •3.78	............. 1 HFA-l34a I TM5 days 50C and 75% RH 3.72	HFA-152a j T~15 days @ 58“ G 1 and 75% RH 5.51 i
FPFuc %	13,02	J 41,10	5027
-----------------------------------	--------------------—„	-----.........-------	....................
MMAD (pm)	8.54	2.12	2.81
GSD	1.38	1.67	•I 7^
			! J v

When HFA-227ea was used as the propellant to aerosolize the tiotropium bromide 10 monohydrate, the aerosoiization performance decreased dramatically after the pharmaceuticai formulation containing the drug and the propellant had been stored under stress storage conditions for 5 days and 15 days at 50°C and 75% relative humidity, in particular, the fine particle dose and fine particle fraction of the emitted dose decreased dramatically.

When HFA-134a was used as the propellant to aerosolize the tiotropium bromide monohydrate, the aerosoiization performance decreased significantly after the pharmaceutical formulation containing the drug and the propellant had been stored under stress storage conditions for 5 days and 15 days at 5C4C and 75% relative humidity. In particular, the fine particle dose and fine particle fraction of the emitted dose decreased appreciably.

in contrast, when HFA-152a was used as the propellant to aerosolize the tiotropium bromide monohydrate, a good aerosoiization performance was maintained after 25 the pharmaceutical formulation containing the drug and the propellant had been stored under stress storage conditions for 5 days and 15 days at 50'· C and relative humidity.

»? Λ f i At?

The chemical stability of tiotropium bromide monohydrate in HFA~134a end HFA~ 152a was investigated at time zero (7-0) and after storage, valve down, for 1 month (T”1M) and 3 months (T~3M) at 4O'^:'C and 75% relative humidity (RH) and at 25^<:C and 60% relative humidity (RH) in uncoated aluminium cans.

The drug formulations were prepared as described in Example 1 above and analysed using high performance liquid chromatography (HPLC). A 150 mm x 4.6 mm Accucore CIS column with a 2 6 pm particle size was used for the analysis. The column was coupled to a UV detector operating at. a wavelength of 240 nm. The autosampler was operated at ambient temperature and 100 pi samples were injected into the column for the analyses. The chromatographic conditions are shown sn Table 6 below.

Table 6

Pomp Flow Rate (mimin'1)	Mobile Phase (gradient elution)	UV Wavelength (nmj	Column Temperature rc)
1.0	Mobile Phase A: 1QmM Ammonium formate (pH 3.0) Mobile Phase: g,Acetonitrile	240	45

The composition of the mobile phase was vaned as shown in Table 7 below.

Table 6

The fssuits of investigating the chemical stability :©f the tiotropium bromide monohydrate drug formulations in HFA-152a and HFA-134a in uneoatsd aluminium cans are shown,, respectively, in Tables 8and 9 below.

Table 8. Chemical stability of tiotropium bromide monohydrate in HFA-134a in uneoatsd aluminium cans based on percentage assay and total impurities upon storage at T~0, T~1 M 40*C,7S % RR and 2§^:'C/60 % RH and T”3IV1 @ 40*C/7S % RH and 25=C/60 % RH,

} Time	% Assay (LC)	% total impurities
| Initial time T ~ 0	99,8	0.08
| T ~ 1M ©25/60:	99,8	0.13
T= 1M© 40/75	99.5	0.28
T 3M © 25/60	97.8	0.32
ΓΤ = 3M © 40/75	98.4	0.44

Table 9. Chemical stability of tiotropium bromide monohydrate (TBM) in HFA~152s in uncoated aluminium cans based on percentage assay and total impurities upon storage at T~0, T-1M © 40°C/75 % RH and 25°C/60 7« RH and Ϊ-3Μ @ 48=0,75 % RH and 25=0/80 % RH,

Time	% Assay (LC)	% total Impuritiss
Initial time T = 0	100.5	<LoQ
T ~ 1M @ .25/60	99.9	<LoQ
T~ 1M© 40/75	99,8	<LoQ
T ~ 3M ©25/80	98.9	0.08
T - 3M @ 40/75	98.5	0.13

It can be seen from the above data that pharmaceutical formulations of tiotropium bromide monohydrate exhibit superior chemical, stability when blended together with HFA-162a as the aerosoiization propellant,

Formulations containing tiotropium bromide monohydrate and either HFA-134a or HFA~152a were prepared in PET vials and the suspension stability of the ^:.z<

formulations determined using a Turbiscan MA 2000. The Turbfecan instrument has a reading head that moves along a flat-bottomed, 5 mL. cylindrical glass ceil, and takes readings of transmitted and backscattered light every 40 pm on a maximum sample height of 80 mm. The reading head uses a pulsed near infrared light source and two synchronous: detectors. The transmission detector picks up light transmitted through the suspension tube at :0^s and back scattering defector receives light back by the product at 135°,

The sedimentation: and: size of floes for the different formulations are shown in ni Table TO below.

Table 10. Suspension stability profiles of tiotropium bromide monohydrate formulations in HFA-I34a and HFA~tS2a.

Formulation	Size Start (microns)	Timo to sediment (mins)
Tiotropium bromide monehydrate and HFA~134a	3.45	0.82
Tiotroplum bromide: monohydrate: and HFA-152a	3.55	0,91

Claims (25)

1. Claims:

   1. A pharmaceutical composition: comprising' (I) a drug component comprising at tesst one tiotropium compound selected ,S from tiotropium and the pharmaceutically acceptable derivatives thereof;

   and (ii) a propellant component comprising ll-diiluoroethahe (HFA-152a),
2. 2. The pharmaceutical composition of claim 1, wherein the composition to contains less than 100 ppm. preferably less than 50 ppm, more preferably less than

   10 ppm and especially less than 5 ppm of water based on the total weight of the pharmaceutical compo s ill an.
3. 3. The pharmaceutical composition of claim 1 or 2, wherein the at least one is tiotropium compound Is selected from tiotropium bromide and tiotropium bromide monobydrste.
4. 4. The pharmaceutical composition of any one of the preceding claims, wherein the drug component additionally comprises at least one long acting beta20 2 -agonist (LABA).
5. 5. The pharmaceutical composition: of claim 4, wherein the at least one long acting beta-2-agonist :ls. selected from the group consisting of formoferat, salmeterol, oiodatsrol and the pharmaceutically acceptable salts thereof.

   :
6. 6. The pharmaceutical composition of claim 5, wherein the at least one long acting beta-2-agonlsf is selected from the group consisting of iormoterol femarate, formoterol fumarate bihydrate, salmeterol xlnafoate and oladaterol.

   30
7. 7. The pharmaceutical composition of any one of the preceding claims, wherein the drug component additionally comprises at least one corticosteroid,
8. 8. The pharmaceutical composition of claim 7, wherein the at least one corticosteroid is selected from budesonide, momefasone, beclomethasone,

   35 fluticasone and the pharmaceutically acceptable derivatives thereof.
9. 9. The pharmaceutical composition of claim 8, wherein the at least one corticosteroid Is selected from budesonide:, mometasone, mometasone furcate, beclomethasone, becldroethasohe dipropionate, fluticasone and fluticasone propionate.
10. 10. The pharmaceutical composition, of any one of the preceding claims, wherein the drug component comprises from 0.01 to 2.5 weight %, preferably from 0,01 to 2,0 weight %, more: preferably from: 0.05 to 2.0 weight % and: especially from 0.05 to 1.5 weight % of the total weight; of the pharmaceutical composition.
11. 11. The pharmaceutical composition of any one of the preceding claims, wherein the propellant component comprises from 80.0 to 99.99 weight %, preferably from 90,0 to 99.99 weight %, more preferably from 98,5 to 99.99 weight % and especially from 97.5 to 99.95 weight % of the total weight of the is pharmaceutical composition,
12. 12. The pharmaceutical composition of any one of the preceding claims, wherein at feast SG weight %, preferably at least 95 weight % and more preferably at least 99 weight % of the propellant component is 1,1-difiuoroethane (HP'A-152a).
13. 13. The pharmaceutical composition of any one of claims 1 to 11, wherein the propellant component is entirely 1,1-difiuoroethane (HrA-152a).
14. 14. The pharmaceutical composition of any one of the preceding claims, 25 wherein at least 95 weight %, preferably at least 98 weight % and more preferably at least 99 weight % of the composition consists: of the two components (1) and (ii).
15. 15. The pharmaceutical composition: of any one of the preceding claims further comprising a surfactant component comprising at least one surfactant compound.
16. 18, The pharmaceutical composition of claim 15, wherein the surfactant component comprises at least one surfactant compound selected from polyvinylpyrrolidone, polyethylene glycol surfactants, oleic acid and lecithin.

    15 17. The pharmaceutical composition of any one of the preceding claims further comprising a polar excipient, ί 8. The pharmaceutical oom pos ition of claim 17, wherein the polar excipient is ethanol.

    s
17. 19:. The pharmaceutical composition of any one of claims 1 to 1 δ which Is free: of polar excipients.
18. 20. The: pharmaceutical composition of any one of claims 1 to 16 which Is free of ethanol to
19. 21. The pharmaceuticat composition of any one of claims 1 to 13 which consists entirely of the two components (i) and (ii).
20. 22. The pharmaceutical composition of any one of the preceding claims: which

    15 after storage in uncoated aluminium containers at 4Q^CC and 75 % relative humidity for 1 month will produce less than 0.2 % by weight, preferably less than 0.1 % by weight and more preferably less than 0.05 % by weight of impurities from the degradation of the at least one tiotropium compound: based on the total weight of the at least one tiotropium compound and the impurities.
21. 23. The pharmaceutical composition of any one of the preceding claims which after storage in uncoated aluminium containers at 40”C and 75 % relative humidity for 3 months will produce: less than 0.3 % by weight, preferably less than 0.2 % by weight and more preferably less than 0,1 § % by weight of impurities from the

    25 degradation of the at least' one tiotropium compound based on the total: weight of the at least one tiotropium compound and the Impurities.
22. 24. The pharmaceutical composition of any one of the preceding claims, wherein at least 97.0 % by weight,: preferably at least 98.0 % by weight and more

    30 preferably at least 98,8 % by weight of the at least one tiotropium compound that is contained originally In the pharmaceutical composition immediately following preparation will be present in the composition after storage in uncoated aluminium containers at 40^c‘C and 75 % relative humidity for 3 months.

    35 25. The pharmaceutical: composition of any one of claims 1 to 23, wherein at least 97.0 %, preferably at least 98.0 % arid more preferably at least 98.5 % of the •ύ»original pharmaceuiioai activity of the composition is retained after storage in uncoafod aSuminium containers at 4:0°C and 75 % relative humidity tor 3 months,

    28, The pharmaceutical composition of any one of the preceding claims in the form of a suspension,

    27. The pharmaceutical composition of any one of claims 1 to 25 in the form of a solution.

    w 28. A sealed; container that contains: a pharmaceutical composition as claimed: in any one of claims 1 to 27.

    29. The sealed container of claim 28 which is an uncoated aluminium can.

    15 30. The sealed: container of claim 28 or claim 29 which Is a pressurized aerosol container for use with a metered dose inhaler (MDi),

    31. A metered dose inhaler (MDI) fitted with a sealed container as cialmed: in claim 30.

    32. A method for treating: a patient suffering or likely to suffer from a respiratory disorder which comprises administering to the patient: a therapeutically or ptophyiactieslly effective amount of a pharmaceutical composition as claimed in any one of claims: 1 to 27,

    2.5

    33. The method of claim 32. wherein the respiratory disorder is asthma or a chronic obstructive pulmonary disease,:

    34. The method of claim 32 or 33, wherein the pharmaceutical composition is 30 delivered to the patient using a metered dose inhaler (MDI),

    35. A method of improving the stability of a pharmaceutical composition comprising a propellant component and a drug component comprising at least one tiotropium compound selected from tiotropium arid the pharmaceutically

    35 acceptable derivatives thereof, said method comprising: using a propellant component comprising 1,1-difiuoroethane (HFA-152a).

    36. The method of claim 35, further comprising selecting the components and conditions for the preparation of the pharmaceutical composition to maintain the water content of the pharmaceutical composition below 100 ppm, preferably below 50 ppm, more preferably below 10 ppm and particularly below 5 ppm hosed on the total weight of the pharmaceutical composition.

    37. The method of claim 35 or 36, wherein the at least one tlotropium compound is selected from tictroplum bromide and holropium bromide monohydrate,

    38. The method of any one of claims 35 to 37, wherein the drug component additionally comprises at least one long acting beta~2~agonist (LABA),

    39. The method of claim 38. wherein the at least one long acting beta-2-agonist

    15 is selected from ttie group consisting of formoteroi, saimeterol, oiodaterol and the pharmaceutically acceptable salts thereof.

    40. The method of claim 39, wherein the at least one long acting beta-2-agonist is selected from the group consisting of formoteroi fumarate, formoteroi fumarate

    20 dihydrate, saimeterol xinafoate and oladatsrol.

    41. The method of any one of claims 35 to 40, wherein the drug component additionally comprises at least one corticosteroid.
23. 25 42. The method of claim 41, wherein the at least one corticosteroid is selected from budesonide, mometasone, beciomethascne, fluticasone and the pharmaceutically acceptable derivatives thereof.

    43. The method of claim 42, wherein the at least one corticosteroid is selected
24. 30 from budesonide, mometasone, mometasone furoate, beolornethasone, beciomethascne dipropionate, fluticasone and fluticasone propionate.

    44. The method of any one of claims 35 to 43, wherein the drug component comprises from 0.01 to 2,5 weight %, preferably from 0.01 to 2,0 weight %, more
25. 35 preferably from 0.05 to 2.0 weight % and especially from 0,05 to 1.5 weight % of the total weight of the pharmaceutical composition,

    45. The method of any one of claims 35 to 44, wherein: the propellant component comprises from 30.0 to 99,09 weight preferably from 90,0 to 99.99 weight more preferably from 98,5 to 99.99 weight % and especially from 97.5 to 99.95 weight % of the total weight of the pharmaceutical composition.

    46. The method of any one of claims 35 to 45, wherein at least 90 weight preferably at least 95 weight % and more preferably at least 99 weight % of the propellant component is 1,1-diftuoroethane (HFA-152a).

    io

    47. The method of any one of claims 35 to 45,. wherein the propellant component i:s entirely 1,1 -dlfiuoroethano (HFA-152 a).

    48 The method of any one of claims 35 to 47, wherein at least So weight %, 15 preferably at least 98 weight % and more preferably at least 99 weight % of the pharmaceutical composition consists of the drug component and the: propellant component,

    49, The method of any one of claims 35 to 43, wherein the pharmaceutlcai 20 composition further comprises a surfactant component comprising at least one surfactant compound,

    50, The method of claim 49, wherein the surfactant component comprises at least one surfectarrt: compound selected from poiyyinyipyrrolidone, polyethylene

    25 glycol surfactants, oleic acid and lecithin.

    51, The method of any one of claims 35 to SO further comprising a polar excipient,

    30 52. The method of claim 51, wherein the polar excipient is ethanol.

    53. The method of any one of claims 35 to 50, wherein the pharmaceutical composition is free polar excipients,

    35 54. The method of any one of claims 35 to 50, wherein the pharmaceutical composition is free of ethanol,

    55. The method of any one of claims 35 to 47 wherein the pharmaceutical composition consists entirely of the drug componentand the propellant component,

    5 55. The method of any one of claims 35 to 55, wherein the pharmaceutical composition after storage In uncoated aluminium containers at 4G^<:C and 75 % relative humidity for 1 month wtll produce less than 0.2 % by weight, preferably less than 0.1 % by weight and more preferably less than 0.05 % by weight of Impurities from the degradation of the at least one tiotropium compound based on the total io weight of the at least one tiotropium compound and the impurities.

    57. The method of any one of claims 35 to 55, wherein the pharmaceutical composition after storage in uncoated aluminium containers at 40’C and 75 % relative humidity tor 3 months will produce less than 0,3 % by weight, preferably

    IS less than 0.2 % by weight and more preferably less than 0,15 % by weight of impurities from the degradation of the at least one tiotropium compound based on the total weight of the at least one tiotropium compound and the Impurities.

    58. The method of any one of claims 35 to 57, wherein at least 97,0 % by

    20 weight, preferably at least 98.0 % by weight and more preferably at least 98.5 % by weight of the at least one tiotropium compound that is contained originally in the pharmaceutical composition immediately following preparation will be present in the composition after storage in uncoated aluminium containers at 40⁴C and 75 % relative humidity for 3 months.

    59. The method of any one of claims 35 to 57, wherein at least 97.0 %, preferably at least 98.0 % gnd more preferably at least 98,5 % of the original pharmaceutical activity of the composition Is retained after storage In uncoated aluminium containers at 4CT C and 75 % relative humidity for 3 months.

    80. The method of any one of claims 35 to 59, wherein the pharmaceutical composition is in the form of a suspension,

    81. The method of any one of claims 35 to 59, wherein the pharmaceutical

    35 composition is in the form of a solution.

    64. A method of improving the aerosolization performance after storage of a pharmaceutieai composition comprising a propeiiant component and a drug component comprising at least one ttetropium compound selected from tiotropium and the pharmaoeuticaliy acceptable derivatives thereof, said method comprising

    5 using a propellant: component comprising 1. 1 -dlflUdroefhane (HFA-152a).

    86, The method of claim: 54, wherein the method provides a pharmaceutical composition which when delivered from a metered dose inhaler yields a fine particle fraction of the at least one flpfroplum compound which Is at least 46 weight > of the emitted dose of the at least one tiotropium compound even after storage of the pharmaceutieai composition at 50°C and 75 % relative humidityTot 15 days.

    88. The method of claim 64 or 65, wherein the pharmaceutical composition is a composition as claimed in any one: of claims 1 to 27.

    87. The pharmaceutical composition of any one of claims 1 to 27 which when delivered from a metered dose inhaler yields a fine particle fraction of the at least one tiotropium compound which: is at feast 45 weight % of the emitted dose of the at least one tiofropium compound even after storage of the pharmaceuffcai

    20 composition at 5O'^:'C and 75 % relative humidity for 15 days.

    Intellectual

    Property

    Office

    Application No: GB1615912.1 Examiner: Mr Robert Goodwill