AP988A

AP988A - Valve for Aerosol container.

Info

Publication number: AP988A
Application number: APAP/P/1999/001587A
Authority: AP
Inventors: Giovanni Patrick Di; Cheryl Vanessa Rogerson
Original assignee: Glaxo Group Ltd
Priority date: 1996-12-27
Filing date: 1997-12-23
Publication date: 2001-08-01
Also published as: DE69711710T2; DK0958201T3; CY2578B1; DK1145987T3; PL189244B1; JP3549543B2; BR9714091A; ATE263721T1; AU734427B2; EG20819A; CN1094876C; DE69735247T2; ATE317812T1; EP1415934B1; DE69728580D1; CZ9902323A3; AU5762798A; DE69735247D1; US6315173B1; EA199900495A1

Abstract

Valve for an aerosol container for dispensing a suspension of a substance in a liquid propellant contained therein. The valve comprises a valve body (1) having at least one orifice (16) to allow a quantity " the suspension to pass from the container into the valve. The valve further comprises a ring (18) disposed around the valve body (1), the ring being positioned below the at least one orifice to reduce the volume of suspension that can be accommodated within the container below the at least one orifice when the container is orientated with the valve at the bottom, the ring having at least one portion of reduced axial thickness to provide a trough (19) around the valve body below the at least one orifice.

Description

VALVE FOR AEROSOL CONTAINER

This invention relates to a valve for an aerosol container with the aid of which a quantity of the contents thereof can be dispensed. The invention has particular application to the dispensing of metered doses of medicaments, though it is applicable to the dispensing of aerosols generally.

In dispensing a solid, in aerosol form it is common to use what is known as a suspension aerosol. This involves the use of a liquid propellant in which a solid to be dispensed is suspended. There is inevitably some difference, however slight, between the respective specific gravities of the propellant and the solid to be dispensed, which means that, with the passage of time and in the absence of other overriding interactions, the two components tend to separate in the container, with a lighter component going to the top or a heavier component going to the bottom over time.

In some pharmaceutical aerosols the particles of medicament are more dense than the propellant and hence the particles tend to sediment out to the bottom of the container. This phenomenon may be accentuated by the additional structuring of the medicament presentation necessary to enhance its physical stability, for example by controlled flocculation thereof. Controlled flocculation of ! the suspension may increase the effective particle size in dispersion from less than 10pm to greater than 100pm . A squared dependency on particle radius will directly increase the sedimentation rate in such circumstances.

Users of suspension aerosols are always instructed before use to shake the container well. However, even a short interval between the conclusion of the shaking and the act of dispensing a charge from the aerosol is sufficient to allow some sedimentation to occur. This represents a particular problem where the suspended material is a medicament, since it can result in the patient receiving a dose which, although of the correct volume, contains either too little or too much of the medicament.

This problem has been found to be particularly acute in the development of

CFC-free aerosol formulations using propellant 1,1,1,2-tetrafIuoroethane, also

AP/P/ 9 9/0 1 587 known as HFA134a, which is less dense than conventional CFC containing propellants. With some aerosol drug formulations using this propellant, when the container is orientated with the valve at the bottom, the drug particles rapidly sediment onto and around the valve, and with vibration caused by, for example, transportation, find their way into the valve body. The trapped drug is then not fully dispensed, even on shaking due to the confinement of the valve body, and on discharge of valve actuation the trapped drug enters the metering chamber which leads to a high drug content in the dose delivered by the following actuation. This problem is especially pronounced where the drug is fluticasone propionate.

UK Patent No, .2195986 describes an aerosol valve wherein the pick-up point,

i.e. the point at which liquid passes from the interior of the container into the sampling chamber of the valve, is at a location which, when the container is

15^. orientated with the valve at the bottom, is spaced an appreciable vertical c distance from the nearest substantially horizontal surface. Whilst this valve ensures that the liquid entering the metering chamber following a dispensing ?*..s operation comes from above the nearest. region where sedimented drug particles might gather, any sedimenting drug particles that might be drawn into

X'

20:^ the sampling chamber together with any drug particles that sediment out of the suspension within the sampling chamber tend to be trapped and are not dispensed on shaking. Furthermore, by deliberately placing the pick-up point appreciably higher than the lowest point in the container, a significant quantity of the contents of the container cannot be dispensed, which results in considerable wastage.

It is an object to provide a valve which alleviates these problems.

According to the present invention there is provided a valve for an aerosol container for dispensing a suspension of a substance in a liquid propellant contained herein, the valve comprising a valve body having at least one orifice to allow a quantity of the suspension to pass from the container into the valve, characterised in that the valve further comprises a ring disposed around the valve body, the ring being positioned below the at least one orifice to reduce the volume of suspension that can be accommodated within the container below the

AP 00988 at least one orifice when the container is orientated with the valve at the bottom, the ring having at least one portion of reduced axial thickness to provide a trough around the valve body below the at least one orifice.

By providing a ring below the at least one orifice to reduce the volume of suspension that can be accommodated within the container below the orifice(s) when the container is orientated with the valve at the bottom, it ensures that most' of the contents of the container may be dispensed to reduce wastage, while the trough around the valve body below the orifice(s) provided by the at least one portion of reduced axial thickness serves to accommodate any drug particle sediment so ensuring that the suspension entering the sampling chamber comes from above the region where any sedimented drug particles might gather.

Preferably, the valve is a metering valve comprising a metering chamber, a sampling chamber, a transfer passage through which a quantity of suspension can pass from the sampling chamber to the metering chamber, and a valve stem having a dispensing passage through which a dose of suspension can be dispensed from the metering chamber, the valve stem being slideably moveable within the valve body such that in a first position the dispensing passage is isolated from the metering chamber and the metering chamber is in ••j communication with the sampling chamber via the transfer passage, and in a second position the dispensing passage is in communication with the metering chamber and the transfer passage is isolated from the metering chamber the valve body having a plurality of orifices to allow a quantity of the suspension to pass from the container into the sampling chamber.

By providing a valve body having a plurality of orifices to allow the suspension to pass from the container into the sampling chamber, the suspension may flow freely through the sampling chamber so allowing the suspension contained within the sampling chamber and the container to mix when the container is shaken and so disperse any drug particle sediment within the sampling chamber.

AP/P/ 9 9/01 5,87

Τ ·?» ·»'

Suitably the orifices are slots extending in a substantially axial direction.

Preferably the slots extend substantially the entire axial length of the sampling chamber.

By providing slots the length of the sampling chamber the suspension may flow freely through the entire sampling chamber, so allowing maximum dispersion of drug particle sediment within the sampling chamber.

Preferably there are more than two slots.

Suitably the ring further comprises a seat to locate a gasket between the container and valve for sealing the container.

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By providing a seat on the ring to locate the gasket, the gasket is reduced in 15 size, and the area of gasket exposed to the contents of the container is also 7 reduced.

Suitably the ring further comprises a plurality of vanes separated by slots at its 3 periphery and extending substantially upwardly when the container is orientated

2$. with the valve at the bottom.

*£*-*,«.

By providing vanes separated by slots at the periphery of the ring the suspension is made to flow around the vanes and through the slots when the container is shaken, and the resulting swirling motion of the suspension helps to disperse any drug particle sediment on and around the ring.

Suitably the substance to be dispersed is a medicament suspended in liquefied

HFA134a. Preferably the medicament is fluticasone propionate.

The invention will now be described further with reference to the accompanying drawings in which:

Figure 1 i? a section through a metering valve according to a first embodiment of the invention;

AP 00988

Figure 2 is a section through a metering valve according to a second embodiment of the invention; and

Figure 3 is a partly cut away perspective view of a ring for use with a valve according to the invention.

The valve according to a first embodiment of the invention as shown in Figure 1 comprises a valve body 1 sealed in a ferrule 2 by means of crimping, the ferrule itself being set on the neck of a container (not shown) with the interposition of a . 0 gasket 3 in a well-known manner. The container is filled with a suspension of a medicament in liquid propellant HFA134a. Medicaments suitable for this purpose are, for example for the treatment of respiratory disorders such as asthma, bronchitis, chronic obstructive pulmonary diseases and chest infections. Additional medicaments may be selected from any other suitable drug useful in inhalation therapy and which may be presented as a suspension. Appropriate medicaments may thus be selected from, for example, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem; antialiergics, e.g. cromoglycate, ketotifen or neodocromil; antiinfectives e.g. cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine.; antihistamines, e.g.

methapyrilene; anti-inflammatories e.g. fluticasone propionate, beclomethasone ) dipropionate, fiunisolide, budesonide, or triamcinolone acetonide; antitussives, e.g. noscapine; bronchodilators, e.g. salmeterol, salbutamol, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuteroi orciprenaline, or(-)-4-amino-3,5-dichloro-a-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl] benzenemethanoi; diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, atropine or oxitropium; hormones, e,g, cortisone, hydrocortisone or prednisolone; xanthines e.g. aminophyliine, choline theophyllinate, lysine theophyllinate or theophylline and therapeutic proteins and peptides, e.g. insulin or glucagon. It will be clear to a person skilled in the art that, where appropriate, the medicaments may be used in the form of salts (e.g. as alkali metal or amine salts or as acid addition salts) or as esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) to optimise the activity and/or stability of the medicament Preferred medicaments are salbutamol, salbutamol

Si 0/66 /d/dV sulphate, salmeteroi, salmeteroi xinafoate, fluticasone propionate, beclomethasone dipropionate and terbutaline sulphate. It is to be understood that the suspension of medicament may consist purely of one or more active ingredients.

The valve body 1 is formed at its lower part with a metering chamber 4, and its upper part with a sampling chamber 5 which also acts as a housing for a return spring 6. The words upper and lower are used for the container when it is in a use orientation with the neck of the container and valve at the lower end of the container which corresponds to the orientation of the valve as shown in Figure

1. Inside the valve body 1 is disposed a valve'stem 7, a part 8 of which extends outside the valve through lower stem seal 9 and ferrule 2. The stem part 8 is formed within an inner axial or longitudinal canal 10 opening at the outer end of _w the stem and in communication with a radial passage 11.

c- The upper portion of stem 7 has a diameter such that it can pass slideably through an opening in an upper stem seal 12 and will engage the periphery of ‘ that opening sufficiently to provide a seal. Upper stem seal 12 is held in position against a step 13 formed in the valve body 1 between the lower and upper parts

20/ by a sleeve 14 which defines the metering chamber 4 between lower stem seal 9 and upper stem seal 12. The valve stem 7 has a passage 15 which, when the stem is in the inoperative positive shown, provides a communication between the metering chamber 4 and sampling chamber 5, which itself communicates with the interior of the container via orifices 16 formed in the side of the valve body 1. The orifices 16 comprise three slots arranged equi-angularly around the valve body 1 and extending in an axial direction with respect thereto, each slot having a width of approximately 1mm and a length slightly less than the length of the sampling chamber 5 so that the suspension within the container can flow freely through the entire sampling chamber 5.

Valve stem 7 is biased downwardly to the inoperative position by return spring 6 and is provided with a shoulder 17 which abuts against lower stem seal 9. In the inoperative position as shown in Figure 1 shoulder 17 abuts against lower stem seal 9 and radial passage 11 opens below lower stem seal 9 so that the

AP 00988 metering chamber 4 is isolated from canal 10 and suspension Inside cannot escape.

A ring 18 is disposed around the valve body below the slots, and is formed with a number of portions of reduced axial thickness giving a U shaped cross section extending in a radial direction so as to form a number of troughs 19 around the valve body. As seen in Figures 1 and 3, the ring is formed as a separate component made of nylon or any other suitable material, and has an inner annular contacting rim of a diameter suitable to provide a friction fit over »0 the upper part of valve body 1, the ring seating against step 13 below the slots 16. However, the ring 18 may alternatively be formed as an integrally moulded part of valve body 1.

The outer wall of the ring is extended in an axial direction and is formed with a number of equi-angularly spaced slots to create vanes 20 which extend upwards from the lower part of the ring, as best seen in Figure 3. In the ring depicted in Figure 3, there are six slots and six vanes, though not all are shown in view of the cut away portion. However, it will be clear that more or fewer slots and vanes could be used. The lower part of the ring is further provided with a seat 21 for gasket 3 which helps to locate the gasket in the correct position during assembly and also allows the inner diameter of the gasket to be increased, thereby ) reducing the mass of the gasket and the area of gasket exposed to the material within the container. This can offer a significant advantage where there are problems with impurities being leached out of the gasket into the material contained.

To use the device, the container is shaken to homogenise the suspension within the container. As the container is shaken, the suspension in the container flows freely through the slots 16 in the sampling chamber 5, so ensuring that the suspension in the sampling chamber is thoroughly mixed with the suspension in the container. Not only does this ensure homogeneity of suspension within the container and sampling chamber, but the flow of suspension also serves to disperse any drug particle sediment that may have precipitated out of suspension within the sampling chamber 5. Shaking of the container also causes the suspension to flow around the vanes 20 and the resulting turbulence

AP/F/ 9 9/0 1 5 87 and swirling motion of the suspension helps to disperse any drug particle sediment on and around the ring.

The user then depresses the valve stem 7 against the force of the spring 6. 5 When the valve stem is depressed, both ends of the passage 15 come to lie on the side of upper stem seal 12 remote from the metering chamber 4. Thus a dose is metered within the metering chamber. Continued depression of the valve stem will move the radial passage 11 into the metering chamber 4 while the upper stem seal 12 seals against the valve stem body. Thus, the metered dose can exit through the radial passage 11 and the outlet canal 10.

Releasing the valve stem causes it to return to the illustrated position under the m force of the spring 6. The passage 15 then once again provides communication between the metering chamber 4 and the sampling chamber 5. Accordingly, at

T5 this stage liquid passes under pressure from the container through slots 16, through the passage 15 and thence into the metering chamber 4 to fill it.

- It can be seen that in the operative orientation of the container and valve as shown, the U shaped configuration of the ring 18 around the valve body

26, provides a trough 19 which lies an appreciable distance below the slots 16. The > trough serves to accommodate any drug particle sediment that fails to be redispersed into suspension, and thus ensures that the suspension entering the sampling chamber 5 through the slots 16 is drawn from a region containing homogenous suspension which is free of drug particle sediment.

The ring 18 further serves to reduce the volume of suspension that can be accommodated within the container below the slots 16. This ensures that most of the contents of the container may be dispensed, the only quantity of suspension that need be wasted' corresponding to the reduced volume remaining below the slots after the suspension level has fallen below the level from which it may enter the sampling chamber.

Tables 1 and 2 present end of life actuation weights in mg delivered from two sets of five inhalers each. Both tables show data derived from inhalers containing the equivalent of 160 actuations of a suspension of fluticasone • 'V.

AP 00988 propionate in liquefied HFA134a with a target delivery of 120 actuations plus a 40 actuation overfill to allow for ullage and leakage. Only data from actuation number 115 is shown as the data for both sets of inhalers is consistent up to this point. Table 1 shows data from the first set of five conventional inhalers having valves without a ring. Table 2 shows data from the second set of five inhalers having valves with a ring according to the invention:

Table 1:

End of Life Actuation weights for valve without ring

Actuation No.	Inhaler 1	Actuation weights (mg)	Inhaler 5
Inhaler 2	Inhaler 3	Inhaler 4
115	61	60	62	62	61
116	62	62	62	61	61
117	61	60	62	61	60
118	61	61	62	60	60
119	42	60	62	45	31
120	61	61	62	61	62
121	60	59	61	62	60
122	60	59	61	61	60
123	62	61	62	61	61
124	63	61	62	61	60
125	62	42	47	47	59
126	62	59	64	63	60
127	49	61	53	42	37
128	61	61	63	61	62
129	63	57	39	63	63
130	63	62	63	63	62
131	60	41	34	38	45
132	62	61	61	60	59
133	44	43	39	49	61
134	60	62	58	62	60
135	32	60	17	26	44
136	58	61	60	59	61

ΑΡ/Γ/ 9 9/01 587

Actuation No.	Inhaler 1	Actuation weights (mg)	Inhaler 5
Inhaler 2	Inhaler 3	Inhaler 4
137	49	54	58	.51	59
138	48	45	34	59	59
139	25	, 16	14	29	16
140 ·.	37	18	20	5	12
141	6	8	5	7	18
142	47	23	30	27	38
143	' 10	29	23	15	22
144	9	16	18	31	36
145	30	37	29	33	48
146	42	41	32	30	46

Table 2:

End of Life Actuation weights for valve with ring

Actuation No.	Inhaler 1	Actuation weights (mg)	Inhaler 5
Inhaler 2	Inhaler 3	Inhaler 4
115	60	61	61	60	62
116	62	61	61	61	63
117	61	60	60	60	61
118	61	61	61	60	62
119	60	59	60	60	61
120	60	61	60	60	62
121	60	59	60	59	62
122	60	60	59	59	60
123	61	61	61	61	61
124	61	60	61	61	63
125	61	60	60	59	31
126	61	60	61	60	62
127	61	59	61	60	61
128	61	61	61	60	63
129	62	58	61	61	57

AP 00988

Actuation No.	inhaler 1	Actuation weights (mg)	Inhaler 5
Inhaler 2	inhaler 3	Inhaler 4
130	62	61	61	61	63
131	60	61	61	60	60
132	61	60	61	61	62
133	61	•61	61	60	62
134	61	61	61	61	62
135	61	60	60	60	62
136	61	60	60	60	62
137	59	60	59	58	60
138	59	59	59	59	60
139	59	55	59	60	55
140	31	61	61	59	60
141	25	48	61	60	33
142	61	60	61	60	60
143	21	9	23	20	26
144	17	25	32	26	25
145	44	32	36	25	35
146	17	9	26	19	28

From Table 1 it can be seen that actuation weight starts to become fairly inconsistent after actuation number 124 for valves without the ring, whereas from Table 2 it can be seen that actuation weight remains fairly consistent up to actuation number 137 and thereafter rapidly tails off for those valves according to the invention incorporating the ring. It is therefore clear that the ring has a significant effect on end of life actuation weight delivered.

A valve according to a second embodiment of the invention as shown in Figure

2 is a variant of the valve shown in Figure 1 in which corresponding elements have been given the same reference numerals as are used in Figure 1. The main difference between the two embodiments is that the valve of Figure 2 uses a different design of valve body 1 which has a single orifice 26 allowing communication between sampling chamber 5 and the interior of the container.

The valve is operated in exactly the same manner as described with respect to

AP/P/ 9 9/0 1 5 87 .‘V the valve shown in Figure 1. The valve shown in Figure 2 might be used with suspensions wherein the problem of sedimentation within the sampling chamber is not so acute but wherein sedimentation around the valve nonetheless remains a problem.

Table 3 demonstrates the improved dose reproducibility achieved using a valve according to the first embodiment of the invention with a body having three slots as shown in Figure 1 compared to a valve according to the second embodiment of the invention with a body having a single orifice as shown in Figure 2 when used to dispense a suspension of fluticasone propionate in liquefied HFA134a. The figures given in the table are average dose weights dispensed from at least five inhalers. For each inhaler, doses from two actuations were measured prior to to subjecting each inhaler to a vibration test to simulate the effects of i* transportation, after which doses from two further actuations were measured:

Table 3:

Effect of vibration on dose delivered

Valve type	Dose (pg) prior to vibration	Dose (pg) after vibration
1 st actuation	2nd actuation	1 st actuation	2nd actuation
Body with single orifice	233	246	217	688
Body with three slots	288	285	275	317

The data presented in Table 3 clearly shows that the characteristics of extreme dose variability experienced with valves having a single sampling point (orifice), which is due to the highly sedimentary nature of fluticasone propionate in liquefied HFA134a, are considerably reduced with the three slot body.

It will be understood that the present disclosure is for the purpose of illustration only and the invention extends to modifications, variations and improvements thereto.

Claims

Claims

1. Valve for an aerosol container for dispensing a suspension of a substance in a liquid propellant contained therein, the valve comprising a valve body having

5 at least one orifice to allow a quantity of the suspension to pass from the container into the valve, characterised in that the valve further comprises a ring disposed around the valve body, the ring being positioned below the at least one orifice to reduce the volume of suspension that can be accommodated within the container below the at least one orifice when the container is orientated with the

0 valve at the bottom, the ring having at least one portion of reduced axial thickness to provide a trough around the valve body below the at least one orifice.
2. Valve according to claim 1, characterised that the valve is a metering valve 15 comprising a metering chamber, a sampling chamber, a transfer passage through which a quantity of suspension can pass from the sampling chamber to the metering chamber, and a valve stem having a dispensing passage through which a dose of suspension can be dispensed from the metering chamber, the valve stem being slideably moveable within the valve body such that in a first

20 position the dispensing passage is isolated from the metering chamber and the metering chamber is in communication with the sampling chamber via the transfer passage, and in a second position the dispensing passage is in communication with the metering chamber and the transfer passage is isolated from the metering chamber, the valve body having a plurality of orifices to allow

25 a quantity of the suspension to pass from the container into the sampling chamber.
3. Valve according to claim 2, characterised in that the orifices are slots extending in a substantially axial direction.
4. Valve according to claim 3, characterised in that the slots extend substantially the entire axial length of the sampling chamber.
5. Valve according to any preceding claim, characterised in that there are more

35 than two slots.
6. Valve according to any preceding claim, characterised in that the ring further comprises a seat to locate a gasket for sealing the container.

5
7. Valve according to any preceding claim, characterised in that the ring further comprises a plurality of vanes separated by slots at its periphery and extending substantially upwardly when the container is orientated with the valve at the bottom.

10
8. Aerosol container comprising a valve according to any preceding claim for dispensing a suspension of a medicament in liquefied HFA134a.
9. Aerosol container according to claim 8, wherein the medicament is _;i<. fluticasone propionate.