GB2552720A

GB2552720A - Improvements in and relating to inhalers

Info

Publication number: GB2552720A
Application number: GB1614508.8A
Authority: GB
Inventors: Stuart Harris David; Oakes Michael
Original assignee: Individual
Current assignee: Individual
Priority date: 2016-08-05
Filing date: 2016-08-25
Publication date: 2018-02-07
Anticipated expiration: 2036-08-25
Also published as: GB201614508D0; GB2552720B

Abstract

An apparatus for prompting the actuation of a metered dose inhaler (1, Fig 1), the apparatus comprising airflow responsive means 16 which is, in use, mounted on the inhaler and provides the user with an indication that the flow of air through the airway of the inhaler satisfies a predetermined criterion, for example a predetermined pressure drop in airflow through the airway, thereby to prompt the user to actuate the dispenser. The airflow responsive means 16 is preferably moveably mounted on the inhaler to interact with the flow of air created by the user inhaling through the airway, so as to be moved by the flow; said movement constituting the indication. A further apparatus is also taught for restricting the flow of air that passes through the airway, thus increasing the pressure drop of air flowing along the airway so as to prevent a user from inhaling too rapidly.

Description

(71) Applicant(s):

David Stuart Harris

Butt Lane, Milton, CAMBRIDGE, CB24 6DG, United Kingdom (51) INT CL:

A61M 15/00 (2006.01) (56) Documents Cited:

GB 2490770 A EP 0014814 A1 US 5724986 A (58) Field of Search:

INT CLA61B, A61M Other: WPI, EPODOC

A61B 5/087 (2006.01)

EP 1338296 A1 US 5758638 A

Michael Oakes

Millfield Gardens, Ipswich, Suffolk, IP24 4PQ, United Kingdom (72) Inventor(s):

David Stuart Harris Michael Oakes (74) Agent and/or Address for Service:

Nash Matthews LLP

Hills Road, Cambridge, Cambridgeshire, CB2 1 JP, United Kingdom (54) Title of the Invention: Improvements in and relating to inhalers Abstract Title: A device for prompting a user to actuate an inhaler (57) An apparatus for prompting the actuation of a metered dose inhaler (1, Fig 1), the apparatus comprising airflow responsive means 16 which is, in use, mounted on the inhaler and provides the user with an indication that the flow of air through the airway of the inhaler satisfies a predetermined criterion, for example a predetermined pressure drop in airflow through the airway, thereby to prompt the user to actuate the dispenser. The airflow responsive means 16 is preferably moveably mounted on the inhaler to interact with the flow of air created by the user inhaling through the airway, so as to be moved by the flow; said movement constituting the indication. A further apparatus is also taught for restricting the flow of air that passes through the airway, thus increasing the pressure drop of air flowing along the airway so as to prevent a user from inhaling too rapidly.

Γ/4 /

/¾ £

-ί

Ιί

BAM trigger flowrate (LPM)

X-Sectional Area Required for Specified BAM Trigger Flowrate

'όίΑ

g

Intellectual

Property

Office

Application No. GB1614508.8

RTM

Date :5 May 2017

The following terms are registered trade marks and should be read as such wherever they occur in this document:

Easi Breath, Pg 4, In 5 & 9

Autohaler, pg 4, In 6 & 9

Ventolin, pg 11, In 2

Evohaler, pg 11, In 2

Intellectual Property Office is an operating name of the Patent Office www.gov.uk/ipo

Title: Improvements in and relating to Inhalers

Field of the Invention

This invention relates to apparatus for prompting the actuation of a pressurised metered dose inhaler, apparatus for increasing the pressure drop of air flowing along an airway of a metered dose inhaler, and to an inhaler when fitted with either type of apparatus.

Background to the Invention

Pressurised metered dose inhalers (pMDIs) are the most common device used to treat asthmatics all over the world today, with over 1,400 doses taken per second globally (S. Stein, 3M Ltd., Drug Delivery to the Lungs conference, Edinburgh, UK, 2010). The pMDI was invented by Charles G. Thiel in 1956, and has not changed in function over the past six decades.

PMDIs use hydrofluoroalkane (HFA) propellants to atomise a propellant-drug liquid formulation into a respirable aerosol. As the vapour pressure of HFA is several times atmospheric pressure, even at low temperatures, a high quality aerosol can be formed simply by allowing the formulation to undergo flash evaporation through a small,

e.g. 0.3 to 0.5 mm, orifice. The sudden drop in pressure is sufficient to tear the liquid apart into respirable (sub 5 pm) droplets.

Standard pMDIs are a highly cost-effective solution, as a whole device comprises:

- An injection moulded actuator housing (single component, including spray orifice) * A canister assembly (including drug/propellant formulation, metering valve, drug product label) ⁴ Dose Counter (regulated markets only)

A pMDI can hold up to 200 doses - easily enough for a month's supply of medication. Given that the entire product can be manufactured for around a dollar, equating to a cent or less per dose, it's not surprising that they dominate the global market by volume.

Whilst pMDIs are arguably the most mature of inhaler technologies, they have two major shortcomings in terms of usability, both of which have remained unaddressed since the first products were launched sixty years ago.

I. Their airflow resistance is too low;

io 2. The coordination of pressing the canister is too difficult for many users.

PMDIs have barely changed since their introduction, and have always had a very low airflow resistance. When users inhale through a pMDI the only resistance to the airflow that they experience is caused by the portion of the airway defined by the is annular gap between the canister and the Actuator Housing. Even at its narrowest this is at least 1 mm, which equates to a cross-sectional area well in excess of 80 mm .

This is the equivalent to inhaling through an orifice of more than 10 mm in diameter, which offers very little restriction, and means that there is only a small pressure drop created across a pMDI even when a user inhales very quickly. The problem is that, in order to achieve optimum aerosol delivery to the deep lung, the user must inhale very slowly - e.g. 30-40 litres per minute (LPM). But the very low restriction provided by the inhaler means that users can often inhale at ten times this flowrate. And most asthmatics, especially when using their inhaler in a public space, would probably rather the event was over as quickly as possible, so inhaling too quickly achieves this.

However, inhaling more quickly than the recommended instruction of slowly and steadily means that the velocities of the air flowing through the user's upper bronchioles is proportionately higher, and, consequently even the fine, respirable particles can impact too early in the upper airways rather than travelling to the deep lung for maximum therapeutic effect. This phenomenon has huge impact on the overall efficacy of pMDIs - when used correctly, the fine particle fraction (FPF = percentage of delivered dose below 5 pm - the respirable fraction), can be as high as 50%. Typically, however, a more realistic figure for the FPF in vivo is approximately 8-12%, and this poor performance is mainly as a result of asthmatics inhaling too quickly.

In fact, pMDIs are notoriously difficult to use, and a fairly recent study by the National Asthma Council of Australia (2008), of over 3,000 users of pMDIs, revealed that 94% of asthmatics could not use their pMDI correctly. The majority of these users either inhaled too fast (for the reasons stated earlier), or did not actuate their medication at the correct point during their inhalation. The required coordination of io pressing the canister at the right time-point during the inspiratory manoeuvre is very difficult, and often overcome by the use of a spacer (or holding chamber), which is basically a vessel that is sufficiently large to catch the aerosol plume emitted by the pMDI upon actuation. The user is then able to inhale the captured plume at their leisure, without having to coordinate the action of actuating with inhaling. These is devices are necessarily much larger than pMDIs and other inhalers, and therefore not an ideal solution, with many users only using them at home rather than when they're out and about.

Perfect coordination is difficult, even with good training and a lot of practice. The user must press the canister as soon as they have reached a steady state inhaled flowrate of ideally between 30 and 40 LPM. They must then continue to inhale at this low flowrate until their lungs are fully inflated, then hold their breath for 10 seconds, or a long as is comfortable. Pressing the canister early on during the inhalation is necessary in order to enable a sufficient quantity of chase air to follow the aerosol down into the lungs, and ensure that it travels as deeply as possible. If the user presses the canister too late during their inhalation then there may not be enough respiratory volume remaining in their lungs to continue the airflow, meaning that the aerosol will deposit earlier on in the bronchiole tree and potentially not reach the deep lung for maximum therapeutic effect. If the user presses the canister too early,

e.g. before they have started inhaling fast enough, the inherent momentum of the aerosol plume will cause most of it to impact on the back of the throat, with very little of it being drawn down into the lungs at all.

Two commercialised inhaler products that address the issue of coordinating the firing of the pMDI at the optimum moment during the inhalation are TEVA's Easi Breathe and 3M's Autohaler. Both of these devices utilise a large, powerful, 30-40 N spring, which has sufficient force to press the canister down once the user has reached the optimum flowrate. The spring has to be primed (pre-loaded) by the user (with a button - Autohaler, or by opening the cap - Easi-Breathe), and a mechanism must io restrain the spring until the small pressure drop created by the user inhaling through the device triggers its release. It can be appreciated that this has to be a tightly toleranced, precision-designed mechanism, due to the huge difference in force between what is achievable by the user inhaling, and the powerful spring pre-load force required to drive the canister to fire the dose. Consequently, only two is successful pMDIs that have breath actuated mechanisms to overcome the coordination requirements have been launched in the sixty years following the launch of the first pMDI, and both of these products are significantly more expensive to produce than standard (non-breath actuated) pMDIs.

The two major issues of over-inhaling and insufficient coordination result in the majority of cases of incorrect use. Preventing over-inhaling and poor coordination in the first instance would go a long way to improving use, and delivery efficiency and consistency, resulting in better patient outcomes.

Summary of the Invention

According to one aspect of the invention, there is provided apparatus for prompting the actuation of a pressurised metered dose inhaler having an airway through which a user inhales a substance to be administered and a manually actuated dispenser for dispensing said substance, the apparatus comprising airflow responsive means which is, in use, mounted on the inhaler and is operable to provide the user with an indication that the flow of air through the airway satisfies a predetermined criterion, thereby to prompt the user to actuate the dispenser.

Typically, prior attempts to solve the problem of inadequate coordination of inhalation with actuation have involved systems which use the breath of the inhaling user to trigger the actuation of the dispenser. The present inventors, however, have realised that a simpler, more reliable way of achieving correct timing of actuation is to prompt the user to actuate the inhaler manually, at the correct time point during inhalation. This has the added benefit of enabling the existing actuator mechanism of an inhaler to be used, so that the apparatus can be readily retro fitted to an inhaler.

Preferably, said criterion is that the airflow through the airway corresponds to a predetermined pressure drop in air flowing along the airway - the “trigger” pressure.

is Preferably, that pressure drop is between 1 and 2 kPa; more preferably that pressure drop is between 1.2 and 1.8 kPa and most preferably that pressure drop is between 1.4 and 1.6 kPa.

Said indication may conveniently be provided by the airflow responsive means.

Preferably, to that end, the airflow responsive means is moveably mounted on the inhaler to interact, in use, with the flow of air created by the user inhaling through the airway, so as to be moved by said flow, said movement constituting said indication. To that end, the airflow responsive means may be situated at or adjacent to the inlet to the airway, in use, so as to interact with air being drawn into said airway.

Preferably, the airflow responsive means comprises an indicator member which is, in use, so arranged relative to an actuator member of the inhaler that the user can operate the actuator member, to dispense said substance, by manipulating the indicator member.

The user can thus, for example, place a digit such as his or her finger on the indicator 5 member which will then give the user a tactile indication that the dispenser is to be actuated, whereupon this can be achieved simply by, for example, pressing the indicator member.

Preferably, the apparatus, in use, restricts the volumetric flowrate of air that travels 10 through the airway of the inhaler on which the apparatus is fitted.

To that end, the apparatus may present a flow restriction upstream with the inlet of the airway or downstream of the airway’s outlet. Preferably, however, the restriction is achieved by partially occluding the airway itself.

This enables the apparatus to increase the pressure drop of air flowing along the airway so as to prevent, or discourage, a user from inhaling too rapidly when using the inhaler.

Preferably, the indicator member comprises a button.

Preferably the button is biased away from the actuator member by a spring acting between the button and actuator member.

Preferably, the button is slidably mounted on a frame which is a push fit into an inlet end of the airway.

Preferably, the frame has an opening through which, in use, the actuator member extends.

Preferably, at least one of the button and the frame has passages for admitting air into 5 a portion of the airway downstream of the apparatus, the passages presenting the principle route for air into the airway. Thus the passages can be so sized and shaped as to provide the desired flow restriction.

Preferably, the passages comprise flutes on the button.

Preferably, the flutes have varying cross-sections so that as the button is pushed the restriction to the flow of air into the airway varies (preferably decreases).

According to a second aspect of the invention, there is provided apparatus for is increasing the pressure drop of air flowing along an airway of a pressurised metered dose inhaler, so as to prevent, or discourage, a user from inhaling too rapidly, when using the inhaler, the apparatus being mountable on the inhaler, and arranged to restrict the flow of air that passes through the airway.

Preferably, the apparatus achieves said restriction by partially occluding the airway itself.

The invention also lies in an inhaler when fitted with apparatus according to either the first or second aspect of the invention.

The invention addresses either or (preferably both) of the two primary issues of over-inhaling and lack of adequate coordination, whilst adding minimal production costs.

To achieve this, the concept does not attempt to automatically actuate the pMDI when the user inhales - rather to provide a timely cue, to prompt them to press the canister at the correct moment during their inhalation. It also increases the overall airflow resistance of the pMDI to prevent users over-inhaling, by restricting the passage of air into the top of the actuator housing (which in the described example is where all the inhaled air flows).

The modified pMDI will look very similar to a standard pMDI, except that the top of the canister will sit beneath a button, which is spring loaded against the top of the canister so that it pushes itself away from it. When the user inhales, the pressure drop across the inhaler caused by their inhalation creates a downwards force on the button, due to the reduction in pressure beneath it. At a desired point (the “trigger” point), the button is automatically driven downwards (towards the canister), by the force of the is user’s inhalation. The spring retainer (cruciform feature denoted by reference numeral 22 in Figure 3B and Figures 4A-4C) is designed to bottom out on the top of the canister so that the user can continue to push it downwards to fire the dose. By tailoring the initial airflow resistance of the inhaler together with the pre-load on the spring, an optimum trigger point can be established to promote consistency between different users. It is believed that the automatic movement of the button upon inhalation should be a sufficient cue to prompt users to continue to press the canister downwards to receive their medication.

Further, the apparatus can be designed to dynamically change the airflow resistance as the user presses the canister - e.g. it may be advantageous to have a slightly higher resistance when the user begins their inhalation, which reduces upon pressing the canister. This would serve two distinct purposes: i) a higher resistance provides a higher pressure drop and greater initial driving force, and ii) the reduction in resistance when the user correctly presses the canister provides feedback that they have operated the inhaler correctly.

Brief description of the Drawings

The invention will now be described, by way of example only, with reference to the accompanying drawings in which:

Figure 1 is an isometric view of a conventional pressured metered dose inhaler;

Figure 2 is a corresponding view of such an inhaler when fitted with apparatus in accordance with the invention;

Figure 3 A is an exploded isometric view of the apparatus;

Figure 3B is a view of a button, forming part of the apparatus, from underneath, showing a cruciform feature that retains a spring (which is also a component of the io apparatus);

Figures 4A-4C are sectional side views of the apparatus, when installed in an inhaler, and show the apparatus at different stages in a cycle of use of the inhaler;

Figure 5 is an isometric view of the apparatus on an upper portion of an inhaler, and shows how the apparatus affects the flow of air into the inhaler;

is Figures 6A-6C show three different versions of the apparatus, when in place on an inhaler, the versions differing from each other only in the shape of the air inlet provided by the apparatus;

Figure 7 is a graph showing the relationship between the effect of a pre-load force applied by the spring on breath actuation mechanism trigger pressure;

Figure 8 is a graph representing the relationship between resistance of air flow through the airway of an inhaler fitted with the apparatus and the total cross-sectional area of the air inlet provided by the apparatus;

Figure 9 is a graph illustrating the relationship between the cross-sectional areas of the inlet required for specified breath actuator mechanism trigger flow rates; and

Figures 10A and 10B are sectional top views of the apparatus, when installed on an inhaler and show the apparatus in different stages in a cycle of use of the inhaler.

Detailed Description

Figure 1 shows a conventional pMDI 1 comprising an actuator housing 2 and a mouthpiece 4. The actuator housing 2 is often of a substantially D-shaped crosssection, but can be circular, and the housing is hollow so as to be able to accommodate a dispenser 6 for the medication to be inhaled. The dispenser comprises a generally cylindrical canister 8, at the bottom of which there is provided a spring loaded metered dosing / dispensing system (not shown). The top of the canister 8 functions as a button which, if pressed, actuates the dispensing system, causing the latter to eject a dose of atomised medication.

io

The canister 8 is spaced from the inner wall of the actuator housing 2 to define the upstream part of an airway for the dispenser, the inlet to which is shown at 10.

Mouthpiece 4 is at the outlet end of the airway, which in Figures 1 and 2 is covered by is a removable cap 12.

Figure 2 shows the same inhaler when fitted with apparatus according to the invention, the apparatus comprising a frame 14 which is removably attached to the upper portion of the actuator housing 2 and on which a button 16 is slidably mounted.

The button 16 also engages the upper portion of the canister 8 as discussed below. However, it will be appreciated that from Figures 1 and 2 that the apparatus allows the inhaler to be actuated in a very similar fashion to an inhaler not fitted with the apparatus: instead of pressing the top of the canister 8, the user will instead press the button 16.

With reference to Figure 3A, the apparatus comprises two simple injection moulded plastic components and a metal spring 18. The first component, is the button 16 (hereinafter referred to as the Hat), which loosely resembles a top hat, with multiple vertical flutes 21 (almost castellations). The Hat 16 fits snugly within the second plastic component, the frame 14, herein after referred to as the Ring. The Ring 14 is designed to push fit into various pMDI actuator housings - in the example shown below, it is designed to fit into a GSK Ventolin Evohaler (drug = salbutamol sulphate), which has almost a D-shaped cross-section To that end, the Ring 14 has three retainer clips 20. The Hat 16 has a perfectly circular cross section with the lower section having an internal diameter just a little larger than the outer diameter of a standard pMDI canister 8, to provide adequate clearance so that the Hat 16 can move freely over the top of the canister. The Ring 14 effectively fills the space between the actuator housing and the Hat 16, and thus provides a reasonably air-tight seal. The only way that the air can flow into the top of the modified inhaler is through io the flutes 21 on the Hat 16 - i.e. in the fluted gaps between the Ring 14 and the Hat 16. The Hat 16 includes radially and outwardly directed protuberances 24 that prevent it from being removed through the top of Ring 14, either by the force of the spring 18, or by the user attempting to disassemble the apparatus.

is Many pMDIs are designed to last one month in use, then to be thrown away and replaced. These devices do not require any maintenance whilst they are in use, so the apparatus could be attached permanently, as the user does not need to access and remove the canister at all. In this scenario, the retainer clips 20 would be designed to be a very tight (even permanent) fit within the actuator housing 2. A supplementary measure can be to place an adhesive label around the actuator housing 2 and the Ring 14 after assembly, meaning that the adhesive label would have to be removed or broken in order to remove the apparatus from the standard pMDI device. Some pMDIs require regular cleaning - usually once a week, so several times during the use period of one month. To clean the device, the user must be able to access the canister in order to be able to remove it, and rinse the actuator housing with warm water, and leave it to dry thoroughly before replacing the canister. For devices that require cleaning during normal use, grip features, or flanges, could be included on the Ring 14 to enable the user to remove the apparatus from the top of the inhaler in order to access the canister and be able to rinse the actuator housing 2 clean. Additional small “bump” features on the Hat 16 can be included to prevent it from separating from the Ring 14 when it is removed from the top of the actuator housing 2 for the purposes of cleaning.

The design of the flutes 21 achieves the desired control of the airflow resistance of the modified pMDI. If the total cross-sectional area (normal to the direction of airflow) is too great; the airflow resistance will be too low, and the user will be able to inhale too quickly - i.e. just as is the case with the current, standard unmodified pMDI. If, on the other hand, the total cross sectional area of the fluted features is too small, the airflow resistance will be too high, and the user will not be able to inhale fast enough, and potentially experience discomfort during the inhalation. An ideal airflow resistance would be for a pressure drop of 4 kPa across the inhaler to result in an airflow rate io through it of 30 to 40 LPM. In the United States Pharmacopeia (USP) the flowrate through an inhaler device corresponding to a pressure drop across it of 4 kPa is defined as Q_out, as a pressure drop of 4 kPa is understood to represent a normal (typical) peak inhalation force. This is highly simplified, as the maximum inspiratory mouth pressure is directly related to the airflow resistance of the inhaler device. For is example, any person will always be able to create a higher inspiratory mouth pressure when inhaling through a higher resistance device, albeit at a lower flowrate, and vice versa. Airflow resistance is calculated as the square-root of the pressure drop divided by the flowrate. So say an inhaler device was designed to have a Q_out of 35 LPM at a pressure drop of 4 kPa, its airflow resistance (R) would be a/4000/35, so

R= 1.81 Pa² min L'¹. The unit of resistance is both awkward to write and to say, so from here on will be referred to as Flohms, or FQ.

Figure 5 is a diagram showing airflow paths (indicated by arrows 26) into the top of the Actuator Housing via the flute features of the Hat. Note that these are to scale to achieve an airflow resistance of 1.81 FQ.

By tailoring the number and size of the flute features 21, it is possible to accurately set and control the airflow resistance of the modified pMDI. Further, as the fluted features are vertically arranged, it is possible to design them so that their crosssectional area changes with their height in relation to the Hat 16. Advantageously, this means that the airflow resistance of the modified pMDI can be different with different positions of the Hat 16 relative to the Ring 14, and, for example, enable the airflow resistance to decrease slightly (but noticeably) once the user has correctly pressed the canister 8 during inhalation to provide positive feedback. It should also be noted that, generally, a higher number of smaller flutes will provide a more evenly distributed airflow into the top of the inhaler, such that the airflow is very well established by the time it reaches the spray orifice and entrains the aerosol plume.

Operation & Design

To calculate the required spring pre-load force (for spring 18) for a given breath actuation mechanism (BAM) trigger pressure, it is a case of knowing the internal io cross-sectional area of the Hat 16 normal to the direction of travel (i.e. downwards).

The BAM trigger flowrate can be calculated using the initial airflow resistance and the BAM trigger pressure.

An Excel model was created to allow quick calculations:

Varans© W

Standard fiowrale Q,_)vt

Airflow resistance R

BAMtrigger pressure Internal Hat diameter 0

Cross-sectional area A

Pre-load spring force F

8AM trigger flowrate Q&am


35 LPM	S.83E-04_:m7s
LSI FC!	1.08B05 VPa s/m
1.4 kPa	1400 Pa
23 mm	0,023 m
415 mof	4.1SE-O4 rrf
	0.58 N
20.7) LPM	3.45E-04 m^s/s

This means that, for a specific device airflow resistance (i.e. the Ring 14 and Hat 16 components are geometrically fixed), the BAM trigger pressure can be changed only by changing the pre-load force of the spring, in accordance with the following table:


'1.0 kPa	O.4Z δ	: 17 δ ,.Ρ?ν·:
1..1 kPa	j δ 40	; 1&44.ΡΜ
1.2 kPa	: δδο	ί 19.2 (ΡΜ
1.3 kPa	: δγο	ί ΜΟΙΡΜ
1.4 kPa	j Ο.δδ δ	j 2δδ LPM
1.5 kPa	,, δ 52 δ,	ί 21,4 LPM
i.G kPa	, , δδδ Ν 3	ΟδΗΡΜ
1.7 kPa	i δδδδΐ/δ
1.8 kPa	; \|4δ?4 δ;	Οδ,ΜδΜ
1.9 kPa	....... δ 74 δ ,	ί 24.1 LPM
2,0 kPa		i 24.7 LPM

The operating flowrate at the BAM trigger point changes in relation to the BAM trigger pressure, and these data can be plotted for quick reference as shown in Figure 7.

The plot 28 is of pre-load spring force versus BAM trigger pressure, and plot 30 is of BAM trigger flow rate versus BAM trigger pressure. To calculate the required open cross-sectional area (normal to the direction of airflow) for a specific (target) device airflow resistance, a second Excel model was created. This model is based upon the is following equation:

2ΔΡ

P

Where;

1

Q = volumetric flowrate, m s'

Cd = discharge coefficient, typically 0.6 0.95, and calibrated empirically, dimensionless

A = cross-sectional area normal to direction of airflow, m²

AP = differential pressure across inhaler (pressure drop), Pa p = upstream air density, kg m~

As an initial estimate, we have taken Ca to be 0.85, as injection moulded components have radiused edges, which reduce the vena contractor effect and hence the losses as the air flows in through the open fluted inlets. This value would need to be calibrated empirically, as it is dependent upon the effective inlet radii, which are unknown at io present, but can be determined using standard metrology techniques on the moulded components.

The Excel model estimates that a total open cross-sectional area of 8.42 mm is required to achieve a target airflow resistance of 1.81 FQ, equivalent to a flowrate of is 35 FPM at 4 kPa:

ϊ?5'« PS ' SC WStS S.S SAtSiti ΑΡ» 'SAP'S ftr M ί.ί*·5 W W Wfcw tA.ssjWst'e of Sfs e ft ts>e

ί-ΑΑ'ίίΑίΐίίΐ;'!'	SWsof
f>.A'.Aa\'\'A\'S :Sf tSAST S	Of OPiSK
Standard f ipwrate	0«.,	;s !.pm	S S3E-04 rr’-’/s
Airfiow resist anas	R	1.81 im	i.OStn&iVPa s/nrp
8AM trigger pressure		1.4 kPa	1400 Ps
8A M tn gge r if owr ate	Q&a'.-s	20.7LPM	iS.4SE.- 04 n?/s
Discharge coefficient	Cci		0.85
Air density	P		1 205 fcg/m’
Open X· sectional arse	Ao?!»	3.42 mnfl	8.42E-06
Number of flute features			8;
Open X-seceres per flute		1.0S ;nm·’	i.05£-06 m²

In fact, changing the cross-sectional area (normal to the direction of airflow) will alter the airflow resistance of the inhaler in accordance with the following table:


16,9 2-34	2,11 90 :
31.9 L.934	2.90 60 :
32.9 6934	1,98 80 :
33.9:.934	1.82 90 :
34,98934	1.86 90 :
39.9 LPM	1,81.90 :
36.91.934	1.76 80 :
37.0 8934	1.7180: :
38.08934	1.68 90 :
39,0 8934	1,62 90 :
49.91.934	1.98 60 :

Αί'!ΐ·,ί 7,22 mts* 7.46 nra* 7,70 mtrri 7.34 if·:»8.1S mnf 8.42 nW 8.66 Kirtf 8,30 ram* 9,14 j ηίϊ·)' 9,39 nW 9.63 rms*

Again, these data can be plotted for quick reference, as shown in Figure 8.

However, as mentioned earlier, it may be advantageous to design the inhaler to have a slightly higher airflow resistance initially, as this will create the same initial driving io force on the Hat 16 at a lower BAM trigger flowrate. Say, for example, it is required that the BAM trigger flowrate is 14 LPM, then the initial airflow resistance of the device would need to be 2.67 FQ, and the initial open cross-sectional area would have to be 5.69 mm . A table showing the calculations of the airflow resistances and corresponding cross-sectional areas is shown below, a graphical representation of these data being provided by Figure 9.

Asm*	n
10.,0 LPM	3.79 PO:	4,0? mm²
11.0 LPM	3.40 PO	4,4? mrn²
12.0 LPM	3.12 PO	4,88 mm²
13.0 LPM	2.88 PO	5.29 mm¹
14,0 LPM	2.67 PO	S.69 mm*
15.0 LPM	2,49 PO	6..10 mm²
16.0 LPM	2,34 PO	6,51 mm¹
17.0 LPM	2,20 PO	6,92 mm²
18.0 LPM	2.08 PO	7.32 mra²
19.0 LPM	1,9? PO:	7.73 mm²
20,0 LPM	1.8? PO:	8.19 mm²

In Figures 6A-6C, alternative flute geometries are shown above to control the dynamic nature of the airflow resistance:

(A) Parallel, constant-section flutes 21 do not change the airflow resistance as the Hat 16 is pressed and moves downwards into the Ring 14;

(B) Progressively expanding flutes 21 gradually reduce the airflow resistance as io the Hat 16 is pressed and moves downwards into the Ring 14;

(C) Flutes 21 with a step-change in cross-sectional area (normal to the direction of the airflow) provide a sudden, noticeable reduction in airflow resistance when the Hat 16 is pressed and moves downwards into the Ring 14.

is It can be appreciated that the flute features 21 could be designed as part of the Ring 14 component rather than the Hat 16. This would, however, limit the control over airflow resistance to the scenario corresponding to (A) in Figure 6A as the Ring 14 does not move with the canister, the airflow resistance could only ever remain constant as the user presses the Hat 16 and canister 8. The same (constant) resistance could equally be achieved with a number of discrete orifices around the top of the Ring 14 to allow the airflow into the top of the actuator housing, rather than having flute features 21 in either component. It is believed that the inclusion of the flute features 21 on the Hat 16 (button) component is advantageous, as it enables the resistance to dynamically change during the course of the inhalation, providing positive feedback whilst simultaneously controlling the maximum achievable inspiratory flowrate.

Figures 10A and 10B show sectional top views of the concept in two states of operation. Figure 10A shows the initial unprimed state - i.e. before the user inhales, and Figure 10B shows the final (third) state, when the user has pressed the Hat 16 during inhalation. The callouts in Figures 10A and 10B show a magnified view of the flutes 21, through which the air flows into the actuator housing 2. Comparing the io initial unprimed state (Figure 10A) with the final state (Figure 10B) it is clear that the cross-sectional area normal to the direction of airflow (indicated by cross-hatching) of the flutes 21 has increased due to the change in the relative position of the Hat 16 to the Ring 14, resulting in a small reduction in airflow resistance as felt by the user. These are necessarily small features, so for clarity, the minimum cross-sectional area is normal to the direction of flow of the flutes 21 is indicated by light cross-hatching, and the effective total cross-sectional area of each flute 21 is indicated by heavier cross-hatching, combined with the lighter cross-hatching. The effective total cross-sectional area (of all the flutes 21) normal to the direction of airflow is defined as the open area of a sectional plane that is coincident with the uppermost face of the

Ring 14 - i.e. the minimum open area formed between the Ring 14 and the Hat 16. Thus it can be appreciated that the heavier cross-hatched areas shown in the callouts of Figures 10A and 10B represent only the cross-sectional area normal to the direction of airflow that changes between the initial and final states of inhalation.

The radial depth of the flutes 21 remains constant at 0.5 mm, but the effective circumferential length increases from 1.62 mm (Figure 10A) to 2.34 mm (Figure 10B), in order to achieve the target initial and final airflow resistances of 2.67 FQ and 1.81 FQ respectively. The radial depth of the flutes 21 is feasible within the geometrical space constraints of current pMDI products - i.e. in the space between the outside of the canister 8 and the inner wall of the actuator housing 2. It is feasible that the radial depth of the flutes could be reduced or increased for manufacturing benefits, but if it is reduced, for example, then the circumferential length of each flute 21 would have to increase proportionately in order to match the required open cross-sectional area for a given airflow resistance.

The addition of the concept to a standard pMDI barely changes the sequence of use it simply provides a prompt as to when the user should press the Hat 16 (and canister 8) to receive their medication, whilst limiting how quickly they are able to inhale through the device to prevent over-inhaling.

io Figures 4A-4C show three discrete states during inhalation and actuation:

Figure 4A Initial “unprimed” state - Hat 16 is pushed away from top of canister 8 by the spring 18 - its uppermost position;

Figure 4B The user inhales and when they reach the desired trigger flowrate (and corresponding pressure drop) the Hat 16 automatically drops down until is the spring retainer cruciform 8 reaches the top of the canister 8;

Figure 4C The user continues to inhale, and takes the automatic cue to press the Hat 16 down and fire the pMDI to receive their medication.

Using a Standard pMDI * Remove cap ⁴ Shake 4 to 5 times, holding vertically ⁴ Breath out, as far as is comfortable ⁴ Place inhaler mouthpiece in mouth and ensure your lips are sealed around the mouthpiece ^s Begin to inhale slowly and steadily ⁴ Press the canister down shortly after you begin inhaling ⁴ Continue to inhale until your lungs are full io ⁴ Remove inhaler from mouth and hold your breath for 10 seconds, or as long as is comfortable ⁴ Breathe out and replace cap.

Using the Modified pMDI is ^s Remove cap ^s Shake 4 to 5 times, holding vertically ^s Breath out, as far as is comfortable ⁴ Place inhaler mouthpiece in mouth and ensure your lips are sealed around the mouthpiece ⁴ Begin to inhale slowly and steadily ⁴ When you feel the button move down, press it down ⁴ Continue to inhale until your lungs are full ⁴ Remove inhaler from mouth and hold your breath for 10 seconds, or as long as is comfortable ⁴ Breathe out and replace cap.

Advantages

The advantages of the concept, when added to a standard pMDI are:

1. Increasing and dynamically controlling the airflow resistance limits how quickly the user can inhale, and ensures that the airflow velocities in the bronchioles (in particular the upper airways) are not too high to cause premature aerosol deposition and prevent respirable droplets or particles from travelling into the deep lung. This results in improving the fine particle fraction - i.e. it increases the fine particle mass delivered to the deep lung, and io also improves the consistency of delivery between different users; by restricting and hence limiting the typical maximum flowrate, there will be greater consistency in the inspiratory flow profiles between users, resulting in an increased delivered dose content uniformity in vivo:

2. Adding a tactile cue / prompt button over the canister that drops down is automatically once the user has reached the correct time-point during their inhalation should improve the consistency of actuation timings between users, especially with practice. Further, providing a small but noticeable reduction in the airflow resistance following the pressing of the button will give positive feedback that the correct action has been undertaken;

3. The concept comprises two simple plastic components and a compression spring, and is likely to cost a few cents to produce and assemble onto existing and proven pMDIs;

4. The result is that the two primary issues with current pMDIs are addressed users cannot inhale too quickly, and they are given a positive, tactile cue as to when to press the canister. The concept should significantly improve the quantity, quality and consistency of the delivered fine particle dose from pMDIs across different users and user groups, and ultimately result in better patient outcomes and fewer hospital visits.

Claims

1. Apparatus for prompting the actuation of a metered dose inhaler having an airway through which a user inhales a substance to be administered and a

5 manually actuated dispenser for dispensing said substance, the apparatus comprising airflow responsive means which is, in use, mounted on the inhaler and is operable to provide the user with an indication that the flow of air through the airway satisfies a predetermined criterion, thereby to prompt the user to actuate the dispenser.

io

2. Apparatus according to claim 1, in which said criterion is that the airflow through the airway corresponds to a predetermined pressure drop in air flowing along the airway.

is

3. Apparatus according to claim 2, in which that pressure drop is between 1 kPa and 2 kPa.

4. Apparatus according to any of the preceding claims, in which the airflow responsive means is operable to provide said indication.

5. Apparatus according to claim 4, in which the airflow responsive means is moveably mounted on the inhaler to interact, in use, with the flow of air created by the user inhaling through the airway, so as to be moved by said flow, said movement constituting said indication.

6. Apparatus according to claim 5, in which the airflow responsive means is situated at or adjacent to the inlet to the airway, in use, so as to interact with air being drawn into said airway.

7. Apparatus according to any of claims 4 to 6, in which the airflow responsive means comprises an indicator member which is, in use, so arranged relative to an actuator member of the inhaler that the user can operate the actuator member, to dispense said substance, by manipulating the indicator member.

8. Apparatus according to any of the preceding claims, in which the apparatus, in use, restricts the flow of air that travels through the airway of the inhaler on which the apparatus is fitted.

io

9. Apparatus according to claim 8, in which the restriction is achieved by partially occluding the airway itself.

10. Apparatus according to claim 7, in which the indicator member comprises a button.

11. Apparatus according to claim 10, in which the button is biased away from the actuator member by a biasing means acting, in use, between the button and actuator member.

20

12. Apparatus according to claim 11, in which the biasing means comprises a spring.

13. Apparatus according to any of claims 10 to 12, in which the button is slidably mounted on a frame which is a push fit into an inlet end of the airway.

14. Apparatus according to claim 13, in which the frame has an opening through which, in use, the actuator member extends.

15. Apparatus according to any of claims 10 to 14, in which at least one of the button and the frame has passages for admitting air into a portion of the airway downstream of the apparatus, the passages presenting the principal route for air into the airway.

16. Apparatus according to claim 15, in which the passages comprise flutes on the button.

17. Apparatus according to claim 16, in which the flutes have varying crosslo sections so that as the button is pushed the restriction to the flow of air into the airway varies.

18. Apparatus for increasing the pressure drop of air flowing along an airway of a metered dose inhaler, so as to prevent, or discourage, a user from inhaling too is rapidly, when using the inhaler, the apparatus being mountable on the inhaler, and arranged to restrict the flow of air that passes through the airway.

19. Apparatus according to claim 18, in which the apparatus achieves said restriction by partially occluding the airway itself.

An inhaler when fitted with apparatus according to any of the preceding claims.

Intellectual

Property

Office

Mr Geraint Davies

5 May 2017

GB1614508.8

1-17 & 20 (in part)

Application No: Claims searched: