NZ711668B2 - An inhaler comprising a tiotropium-containing-composition - Google Patents

Abstract

pressurised metered dose inhaler or asthma puffer comprising a canister, wherein the canister contains a formulation comprising a tiotropium salt, and organic acid and an HFA propellant is described. The inhaler has a resilient spring button (460) for applying a preload capable of actuating the internal valve of the canister (40) to release a metered dose of the formulation from the canister. It also includes a resisting mechanism (440. 495, 540) for stopping unwanted discharge of a dose. ternal valve of the canister (40) to release a metered dose of the formulation from the canister. It also includes a resisting mechanism (440. 495, 540) for stopping unwanted discharge of a dose.

Description

AN INHALER COMPRISING A TIOTROPIUM-CONTAINING-COMPOSITION This ation is a divisional application of New Zealand Patent Application No. 624160, the contents of which are incorporated herein by reference.

[Annotation] joshuaf None set by joshuaf [Annotation] f MigrationNone set by joshuaf [Annotation] joshuaf Unmarked set by joshuaf antagonists, such as atropine and ipratropium, are nonseiective muscarinic block Mi—Ms receptors. The longer activity of tiotropium has the effect that tiotropium may be dosed once daily whereas, say, ipratropium (Atrovent®) requires dosing four day (see MC. Durham opium (Spiriva): a once-daily inhaled olinergic for chronic obstructive pulmonary disease" BUMC Proceedings, 2004,17, 366—373 and Rennard, The Lancet, 2004, 364, 791-802).

Whilst the high potency and long—acting duration of action result in tiotropium being an extremely effective bronchodiiator, it carries with it the significant risk of undesirable side effects if tiotropium is inadvertently delivered to the eye. The reason tiotropium presents a particular risk is that muscarinic receptors regulate a number of important physiological processes in the eye. in particular, topical delivery to the eye may result in dilation of the pupils asis) and, in some instances, accommodation paralysis (cycloplegia).

This drawback has been widely reported. S.|. d, The Lancet, 2004, 364, 791—802 discusses the long half life of tiotropium (greater than 36 h) and warns at page 796 that "Local s can occur if directly sprayed in the eye." The Nurse’s Drug Handbook, Tenth Edition, Ed. A. Sibley, Jones & Bartlett Learning, 2011 refers to the risk of mydriasls and cycloplegia if tiotropium is inadvertentiy administered to the eye. The summary of product teristics (SmPC) for the commercial product presently on the market, the Spiriva® HandiHaler®, warns that nts should be cautioned to avoid getting the drug powder into their eyes. They should be advised that this may result in precipitation or worsening of narrow-angle glaucoma, eye pain or discomfort, temporary blurring of vision, visual halos or coioured images in association with red eyes from conjunctiva! congestion and l ." Simiiar warnings are provided for the soft»mist Spiriva® Respimat® t, The most significant risk of rtent administration to the eye comes with the use of a pressurised metered dose inhaler (pMDI). The pMDl is the most preferred approach for the pulmonary administration of medicaments outside of the emergency room.

Typically patient ance is r with a pMDl as they tend to be easier to use.

Moreover. the DPi and soft-mist inhalers suffer from the ck that only a small portion of the powdered active ingredient is ly d into the lungs. However, the pMDl is the most likely type of delivery device to lead to accidental delivery of the medicament to the eye. it is noteworthy that the two products on the market are a dry powder inhaler (HandiHaler®) which is not prone to accidental delivery to the eye because the inhaler is not pressurised, and a soft-mist inhaler (Respimat®) which produces a low pressure mist which is less iikely that a pMDI to be inadvertently spayed into the eye.

Moreover, Anticholinergic Agents in the Upper and Lower Airway, Ed. S.L. Spector, Marcel Dekker, Inc., 2005 explains in the discussion of pium at page 37 that "Side effects do not appear to be a problem at doses that are useful clinically, although it will be important to protect against eye contact; a dry powder inhaler formation rather than a metered dose inhaler may be the most appropriate." There are therefore sound technical reasons against using pMDIs for the delivery of tiotropium salts. There remains, therefore, a need in the art for an effective approach for administering tiotropium salts to the lungs without risking inadvertent ry to the eyes.

Accordingly, the present ion provides a pressurised d dose inhaler comprising a canister, wherein the canister contains a solution formulation comprising a tiotropium salt, an organic acid and an HFA propellant, wherein the inhaler is an inhalation-actuated inhaler.

Thus, by using an inhalation-actuated inhaler (also known as breath-actuated r), one can obtain the benefits of administration using a pressurised propellant system t the significant risks of inadvertent administration to the eye.

The present invention will now be described with nce to the anying drawings, in which: Fig. 1 shows a section view of an inhalation-actuated inhaler according to the t ion; Fig. 2 shows an enlarged view of a diaphragm for use in the inhaler shown in Fig. 1; and Fig. 3 shows an enlarged view of the diaphragm in position in (a) a pre-actuated and (b) an actuated state.

The inhaler Standard pMDIs are well known in the art (see, for example, Drug Delivery to the Respiratory Tract, Eds. D. Ganderton and T. Jones, VCH Publishers, 1987, pages 87-88, or Pharmaceutics – The Science of Dosage Form Design, Second n, Ed. M.E. Aulton, Churchill Livingstone, 2002, page 476 et seq.). pMDIs typically have a medicament-containing canister located in an actuator housing having a mouthpiece. The canister is usually formed from an aluminium cup having a crimped lid which carries a metering valve assembly. The metering valve assembly is provided with a protruding valve stem which is inserted as a push fit into a stem block in the actuator housing.

To actuate, the user applies a ssive force to the closed end of the canister. The internal components of the metering valve assembly are spring loaded so that, compressive force of 15 to 30 N (usually around 20 N) is required to activate the se to this ssive force, the canister moves axially with respect to the valve stem by an amount varying between about 2 7470906_1 (GHMatters) P96916.NZ.1 KIRSTENA 29/02/16 and 4 mm. This degree of axial movement is sufficient to actuate the metering valve and cause a metered quantity of the formulation to be expelled through the valve stem. This is then released into the mouthpiece via an orifice in the dispensing nozzle of the stem block. A user inhaling through the mouthpiece of the device at this point will thus receive a dose of the active ingredient.

The inhalation-actuated inhaler operates on a similar principle, but the action of inhalation actuates the inhaler without the user having to apply the compressive force to the canister manually. Suitable breath-actuated inhalers are known in the art. See, for example, WO 92/09323, GB 2 264 238 and WO 01/93933.

Fig. 1 shows an inhaler having a main body 400 which is generally cylindrical in cross section, with a iece section 405 at one end and an end cap 407 housing air inlets 420 at the other end. A known type of aerosol dispensing canister 25 of generally cylindrical shape is housed within the main body of the inhaler. The aerosol dispensing canister has a stem 40 which contains an aerosol dispensing valve (not shown). The bore 15 is such that it forms an air tight seal on the stem 40 of the aerosol dispensing canister 25. A shoulder 45 limits and locates the position of the stem 40, which in turn locates the l dispensing er 25 in position in the main body 400. A passage 50 extends from the bore 15, continuing from the shoulder 45 to interconnect with a dispensing nozzle 55.

The te end of the sing canister is contained with a sleeve 420 of similar cross section to the main body 400. The longitudinal axis of both the sleeve 420 and main body 400 is generally coaxial. The sleeve is in loose sliding contact with the inner wall of the main body and may include several rebated grooves 430 in its walls to allow free passage of air in the main body past the sleeve. The sleeve 420 may be held in place by connection with a diaphragm 440 held in connection with the top of the main body 400, as will now be described.

Thus, the sleeve 420 effectively hangs from the top of the main body.

One end of an e.g. moulded flexible agm 440 (as shown alone in Fig. 2) comprising a rigid disc-like n 441, a le generally cylindrical wall section 445 and a stiffer connector section 447, is fitted around a purpose-made groove 450 in the sleeve, e.g. by snap-fitting. A r moulded lip 470 on the diaphragm es a snug fit for one end of a compression spring 460. The compression spring is thus located and free to act on the sleeve. The other end of the compression spring is located by an annular er 481 in a predominantly cylindrical d insert 480 housed in the top section of the main body 400. This insert includes a groove 490 into which the disc-like section 441 of the flexible diaphragm 440 is tted. 7470906_1 (GHMatters) P96916.NZ.1 KIRSTENA 29/02/16 The joint between the diaphragm connector section 447 and inner sleeve groove 450 is arranged to be air tight and the shape of the top surface of the sleeve 422 to conform to the internal shape of the diaphragm such that in the rest position of the r the two surfaces are in close proximity, and the enclosed space between them very small.

The cylindrical insert 480 is retained in place by the end cap 407 fitted into the main body of the inhaler. This forms a chamber 590 between the air inlet slots 420 and the rigid part 441 of the diaphragm. The chamber is provided with one or more air pathways 580 such that air may pass from the air inlet slots 420 to the mouthpiece 405. The rigid disc-like section 441 of the diaphragm also includes a small valve port 495 which is normally covered by a valve seal (flap) 450 housed in a vane 550 pivotally ted to the insert 480.

The vane 550 in its rest position divides the chamber 590 n the air inlets 420 and the air pathways 580 that link to the mouthpiece such that it may move from its rest position by means of a pressure drop between the air inlets and the mouthpiece. On movement of the vane to the actuated position the valve seal (flap) 540 is sufficiently moved to open the port valve 495.

(The vane 550 may be biased closed by a light spring flexure, a weight or a magnet not shown).

As shown in Fig. 1, the end of the main body having a pivot 500 has a recess adapted to receive a cam 520 integral with a dust cap 510 operating on the pivot. The recess further includes a e communicating with a similar passage moulded into the internal wall of the main body 400. A cam-follower 530 extending from the lower edge of the inner sleeve 420 acts on the cam such that when the dust cap is in the closed position the inner sleeve is forced by the cam-follower to its uppermost position.

When the dust cap is rotated to its open position the cam e is such that the cam-follower is free to move downwards by an amount sufficient to allow actuation of the inhaler.

In its rest position the dust cap 510 is closed, the llower 530 restrains the inner sleeve 420 in its uppermost position such that the enclosed space trapped between the diaphragm 440 and the top surface 422 of the inner sleeve is at a minimum and the spring 460 is compressed.

The valve port 495 is closed by the valve seal (flap) 540 and the sleeve 420 is clear of the top of the aerosol can 25 which is thus unloaded.

The dust cap is opened rotating the al cam 520 allowing the cam-follower 530 to drop by amount AA. The inner sleeve is forced downwards under the action of the spring 460. As the inner sleeve moves rds the enclosed volume between the diaphragm 440 and inner sleeve is increased by a linear lent amount A’A’, less than or equal to AA. Since the valve port 495 is closed this creates a low pressure volume or near vacuum in the space 600 6_1 (GHMatters) P96916.NZ.1 KIRSTENA 29/02/16 (Fig. 2). The effect of the pressure differential between the enclosed volume 600 and atmospheric pressure is such that the inner sleeve tends to resist the action of the spring. As the inner sleeve moves downwards it contacts the aerosol can 25 and begins compression of the aerosol valve (not shown).

Downward movement of the inner sleeve will continue until there is a balance of forces between the compressive force in the spring 460 and ing forces created by the pressure differential and compression of the aerosol valve. The ry of the inhaler is arranged such that this balance occurs before the aerosol valve has been sufficiently ssed to actuate it.

A typical aerosol requires about 20N force to actuate. The spring 460 should accordingly provide a r force, ably 10% to 50% r.

It may also be possible to arrange for the balance of forces to take place before the inner sleeve has contacted the aerosol can, such that the spring force is ed by the resisting force produced on the inner sleeve by virtue of the pressure differential.

On inhalation by the patient through the mouthpiece 405, a small pressure differential is created across the vane 550 which is pivoted towards one end. The pressure differential causes the vane to move from the rest position to the actuated position. The vane and design of the air passageway 580 in the chamber 590 are such that in the actuated on air can flow freely from the air inlets 420 to the patient.

The movement of the vane 550 causes the valve seal (flap) 540 to be moved out of a sealing position with the valve port 495. Opening the valve port allows air into the gap 600 between the diaphragm and inner sleeve such that the enclosed space reaches atmospheric pressure. This causes an imbalance of forces acting on the sleeve 420 and canister 25. The sleeve and canister are thus forced downwards by the spring 460 resulting in the release of a measured dose of medicament through the sing nozzle 55 and into the mouthpiece at the same time as the t es in. Thus the patient inhales air with a metered dose of medicament.

After the inhalation dose by the patient, the dust cap 510 is returned to its closed position. This rotates the cam 520 and causes the cam-follower 530 to be forced upwards. This in turn acts on the inner sleeve 420 moving it upwards to compress the spring 460 and close the gap 600 between the diaphragm and inner sleeve top surface 422. This forces air out of the enclosed space 600 which escapes h the valve port 495 lifting the valve seal (flap) 540. Since the valve seal (flap) is only lightly biased to its closed position it presents little resistance to air flow 7470906_1 (GHMatters) P96916.NZ.1 KIRSTENA 29/02/16 out of the enclosed space. The aerosol can is free to return to the rest position under the action of its own aerosol valve spring.

In use the patient loads the aerosol dispensing canister into the main body. The aerosol canister may be loaded by providing a coarse threaded screw in the main body 400, for example about the line I-I. When part of the main body 400 has been unscrewed, the aerosol can be inserted. The main body 400 can then be replaced locating the inner sleeve over the top end of the can, and the r is ready for use. As described previously, the inhaler could be manufactured as a sealed unit.

The inhaler may be provided with means to provide a regulated air flow to the user or inhaler.

Thus a sonic device, e.g. a reed, may be provided which sounds when the inspired air flow is greater than a pre-set level, e.g. above 30 to 50 litres per minute. The sonic device may be located in the mouthpiece 95 or below the air inlet 420. The sound produced warns the patient to e at a lower rate.

The r may also be provided with a means such that it will not operate below a n predetermined air flow rate, e.g. 10 to 30 litres per minute. In one embodiment the vane 550 or 110 will be biased by a spring such that the predetermined m air flow is necessary for it to move to its actuated on and enable the valve seal to open.

Accordingly, in a preferred embodiment, the inhaler of the present invention comprises a resiliently deformable member 460 for applying a d capable of actuating the internal valve of the canister to release a metered dose of the formulation from the canister, a mechanism 440, 495, 540 for ng a resisting tic force capable of preventing actuation of the aerosol valve 40 and an inhalation-actuated release device 540 e of releasing the resisting pneumatic force to allow the preload to actuate the l valve 40 and allow the metered dose of the formulation to be dispensed The main body of a inhaler is preferably manufactured from a plastic such as polypropylene, acetal or moulded polystyrene. It may however be manufactured from metal or another suitable material.

The formulation The formulation of the present invention is a solution formulation.

As tiotropium salts are generally insoluble in HFA propellants, without any further excipients a 7470906_1 (GHMatters) P96916.NZ.1 KIRSTENA 29/02/16 tiotropium salt will form a suspension ation. A suspension formulation is set out in US 2004/018153. This document discloses tiotropium bromide monohydrate in HFA 134a or 227 ated as a sion. The formulation may optionally contain other excipients to stabilise the suspension, such as a surfactant. Suitable surfactants are Polysorbate 20, Polysorbate 80, Myvacet 9-45, Myvacet 9-08, isopropylmyristate, oleic acid, propyleneglycol, polyethyleneglycol, Brij, ethyl oleate, glyceryl trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monostearate, yl monoricinoleate, cetylalcohol, sterylalcohol, cetylpyridinium chloride or combinations thereof.

In contrast, a solution formulation is a single homogeneous phase. The tiotropium salt is thus dissolved in the propellant and typically a vent is present to solubilise the active ingredient. As the active ingredient is dissolved in the propellant system, this approach avoids problems such as ial blockage of the pMDI sing nozzle orifice, physical instability of the suspended particles and the requirement to use suspending agents such as surfactants.

Solution formulations are also easier to manufacture.

A solution formulation does not require the presence of surfactants (which are used to stabilise suspended particles of the active ingredient in a sion formulation). Accordingly, it is not necessary to add surfactant to the formulation and hence the solution formulation of the present invention is preferably substantially free of surfactant (e.g. the solution formulation contains less than 0.0001% by weight of surfactant based on the total weight of the formulation).

The solution formulation of the present invention preferably further ses a first co-solvent, more ably ethanol. The ethanol is preferably dehydrated ethanol ing to the USP.

The ethanol is preferably included at 12-20%, more preferably , by weight based on the total weight of the formulation.

The solution ation may also contain water, preferably purified water, according to the USP. The water is preferably present at less than 1.00%, more preferably 0.15-0.75%, most preferably 0.30-0.60%, by weight based on the total weight of the formulation.

The solution formulation further comprises an organic acid. The acid helps prevent chemical degradation of the tiotropium salt in the ce of the co-solvent(s). The most preferred acid is citric acid, preferably ous citric acid according to the USP. The amount of acid is probably less than 0.5%, more preferably 0.05-0.10%, most preferably 0.05-0.08%, by weight based on the total weight of the formulation.

Two suitable ations are as follows: 7470906_1 (GHMatters) P96916.NZ.1 KIRSTENA 29/02/16 [Annotation] joshuaf None set by joshuaf [Annotation] joshuaf MigrationNone set by f [Annotation] joshuaf Unmarked set by joshuaf l Ingredient 'WCongcentration 3 Concentration i (% w/w) t i (% wlw) l Tiotropium bromide l 5M5i107 0.01107 Ethanol,anhydrous, EP 1 20.0 20.0; Citric acid, EP g 0.06 0.06 iPurified water, EP E "6.50 0.50 l Glycerol EP 1.50 "i i HFA134a 77.93 79.43 [Total ‘ 100.0 'ioo.0 They deliver 5.25 pg tiotropium as 6.3 pg tiotropium bromide (ex-valve) per actuation from a 50 pL valve.

As described hereinabove, on actuation of the inhaler, a metered dose of the formulation is released from the inhaler. The metered dose of the formulation passes through the valve stem and stem block where it is discharged via an orifice in the dispensing nozzle of the stem block into the mouthpiece and hence to the patient. On release, the propellant rapidly evaporates leaving the active ingredient dissolved in small droplets of ethanol and water which will in turn evaporate to some extent. The particle size of the droplets will depend on a number of factors, including the e amounts of l and water used, the size of the orifice in the dispensing nozzle, the spray force, the plume geometry, etc. Typically, r, the droplets will be less than 5 microns in diameter. For some applications, the droplet sizes will be too small for l lung deposition. In such cases, a second co-solvent having a higher boiling point than the first vent may be used. For example, the first co—solvent may be ethanol and the second co~solvent may be ol. Glycerol is less volatile than l and hence experiences less evaporation on actuation, thereby providing larger droplets (by larger is meant that they have a higher mass median aerodynamic as ed by an NGl). Accordingly, in a preferred embodiment, the solution formulation of the present invention further comprises glycerol. .

The present invention is applicable to tiotropium salts generally, but preferably the present formulation contains tiotropium bromide which is the most commonly used salt and the salt tly on the market. The formulations set out hereinabove are particularly, but not exclusively, designed for use with pium e as the tiotropium salt.

The amount of tiotropium salt present will vary depending on the dose of tiotropium required for the particular product. Typically, the pium salt (preferably the present in an amount to provide 2—10 micrograms of tiotropium base, ex valve, per Tns, the amount of free base equivalent in the metered dose as measured as it [Annotation] joshuaf None set by joshuaf [Annotation] f MigrationNone set by joshuaf [Annotation] joshuaf Unmarked set by joshuaf valve. This corresponds to a preferred amount of tiotropium bromide of 0.00422- wt%.

The ation also contains a hydrofluoroalkane (HFA) propellant. Such propellants are well known in the art. The preferred HFAs of the present invention are HFA 134a and/or HFA 227. Preferably HFA 1343 is used.

Claims (1)

Claims 1. A pressurised metered dose inhaler comprising a canister, wherein the canister contains a solution formulation comprising a tiotropium salt, an organic acid and an HFA 5 propellant, wherein the inhaler is an inhalation-actuated inhaler. 2. An inhaler as claimed in claim 1, wherein the tiotropium salt is tiotropium e. 3. An r as claimed in claim 1 or 2, wherein the HFA lant is HFA 134a and/or 10 HFA 227. 4. An inhaler as claimed in claim 1, wherein the solution formulation further comprises a first co-solvent. 15 5. An inhaler as claimed in claim 4, wherein the solution formulation further comprises a second co-solvent having a higher boiling point than the first co-solvent. 6. An inhaler as claimed in any one of claims 1, 4 or 5, wherein the solution formulation comprises a tiotropium salt, ethanol, water, citric acid, HFA 134a and ally glycerol. 7. An inhaler as claimed in any preceding claim, wherein the inhaler comprises a resiliently deformable member for applying a preload capable of actuating the al valve of the canister to release a metered dose of the formulation from the canister, a mechanism for applying a resisting pneumatic force capable of preventing actuation of the aerosol valve and an inhalation- 25 actuated e device capable of releasing the ing pneumatic force to allow the d to actuate the aerosol valve and allow the metered dose of the formulation to be dispensed. 6847323_1 ters) P96916.NZ.1 JOSHUAF [Annotation] joshuaf None set by joshuaf [Annotation] joshuaf MigrationNone set by joshuaf [Annotation] f Unmarked set by joshuaf 530 1.1.1 1.20 550 590

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