Fluid product dispensing device

Abstract

A fluid product dispensing device comprising a metering valve mounted on a reservoir (1) containing at least one active ingredient suspended in a pressurized propellant gas having a liquid density at 21°C less than or equal to 1.20 g / cm3, said metering valve comprising a valve body (10) containing a metering chamber (20), and a valve (30) sliding axially in said valve body (10) between a rest position and a dispensing position, to dispense the contents of said metering chamber (20), said metering chamber (20) being, in the rest position of the valve (30), substantially isolated from said reservoir (1), said valve body (10) comprising at least one fluid passage opening (11), said metering valve defining a sedimentation volume V disposed below said at least one passage opening (11) in the inverted operating position, with said metering chamber (20) disposed below said reservoir (1),said sedimentation volume V being greater than or equal to 500 mm3 and less than or equal to 1000 mm3. "Figure for the abbreviation: Figure 2",

Description

Title of the invention: Fluid product dispensing device

[0001] The present invention relates to a fluid product distribution device comprising a dosing valve of the retention type.

[0002] So-called metering valves, in which a precise dose of fluid product is distributed at each actuation of the valve, are well known in the prior art, and are generally assembled on a tank containing the fluid product and a propellant gas used to expel the dose.

[0003] Two types of metering valves are known in particular, namely, on the one hand, so-called retention valves which, after filling the metering chamber, seal it tightly until the next actuation of the valve, and on the other hand, those which only fill up just before the actual actuation, and which are called primeless valves.

[0004] For retention valves, a problem of dose inhomogeneity may arise during expulsion, particularly if the valve has been stored for some time, resulting in the active ingredient no longer being perfectly distributed within the dosing chamber. To at least partially remedy this problem, it is necessary to shake the device thoroughly before each use. However, this is not always sufficient, especially due to the small volume of the dosing chamber.

[0005] Moreover, about fifteen years ago, for ecological reasons, the propellants previously used, which were generally CFC-based, were replaced by other propellant gases, namely HFA-134a and / or HFA-227 propellants. This transition took many years, particularly due to the development of new sealing materials compatible with these new propellants.

[0006] Today, it turns out that HFA-134a and / or HFA-227 gases are also harmful to the environment, and it is necessary to replace them with less environmentally harmful gases, such as HFA-152a (1,1-difluoroethane), HFO-1234ze (1,3,3,3-tetrafluoropropene) or HFO-1234yf (2,3,3,3-tetrafluoropropene).

[0007] However, again this replacement has an important impact on the operation and reliability of the metering valves, in particular on the metering.

[0008] Thus, for an active ingredient suspended in the propellant gas HFA-152a in aerosol form, dose problems manifest themselves as follows: a higher dosage at the beginning of use of the device and a lower one at the end of use.

[0009] This problem is mainly related to the sedimentation rate of the particles, which is faster in HFA-152a, HFO-1234ze and HFO-1234yf than in the HFA-134a and that in the HFA-227.

[0010] This difference in sedimentation rate is explained by the difference in density between the particles of the active ingredient (approx. 1.4 g / cm3) and the different propellant gases.Indeed, while HFA-134a and HFA-227 gases under pressure have liquid densities at 21°C very close to, or even identical to, those of the suspended active ingredient particles (1.40 g / cm³ for HFA-227 and 1.22 g / cm³ for HFA-134a), HFA-152a gas under pressure has a liquid density at 21°C of 0.91 g / cm³, a very significant difference compared to the density of the active ingredient particles; HFO-1234yf gas under pressure has a liquid density at 21°C of 1.11 g / cm³, a significant difference compared to the density of the active ingredient particles; and HFO-1234ze gas under pressure has a liquid density at 21°C of 1.17 g / cm³, also a substantial difference compared to the density of the active ingredient particles (sources for propellant gas densities: NIST (National Institute of Standards and Technology) & Honeywell). .

[0011] To overcome this difference, the addition of excipient(s), such as a surfactant, may be useful, but not sufficient.

[0012] The present invention aims to improve metering valves of the retention type, i.e. those in which the metering chamber is hermetically sealed in the valve's rest position, when used with propellant gases that are less harmful to the environment.

[0013] The present invention aims in particular to provide a device improving the consistency of the dosage between the beginning and the end of use of the device.

[0014] The present invention also aims to provide a device for which the variations in dosage between the beginning and end of use of the device remain within an acceptable range.

[0015] The present invention also aims to provide a device that is simple and inexpensive to manufacture and assemble, and of reliable operation.

[0016] The present invention therefore relates to a fluid product distribution device comprising a metering valve mounted on a reservoir containing at least one active ingredient suspended in a pressurized propellant gas having a liquid density at 21°C less than or equal to 1.20 g / cm3, said metering valve comprising a valve body containing a metering chamber, and a valve sliding axially in said valve body between a rest position and a dispensing position, to dispense the contents of said dispensing chamber, said dispensing chamber being, in the valve's rest position, substantially isolated from said reservoir, said valve body comprising at least one fluid passage opening, said metering valve defining a sedimentation volume V disposed below said at least one passage opening in the inverted operating position, with said dispensing chamber disposed below said reservoir, said sedimentation volume V being greater than or equal to 500 mm3 and less than or equal to 1000 mm3.

[0017] Advantageously, said sedimentation volume V is greater than or equal to 550 mm3, in particular greater than or equal to about 600 mm3 and less than or equal to 900 mm3, in particular less than or equal to 800 mm3.

[0018] Advantageously, said sedimentation volume V is approximately equal to 700 mm3.

[0019] Advantageously, said dosing chamber is defined between a valve seal and a chamber seal.

[0020] Advantageously, said valve is made in two parts, an upper part and a lower part.

[0021] Advantageously, said lower part includes an internal channel for connecting said dosing chamber to said reservoir, for filling said dosing chamber when, after each actuation of the valve, said valve returns to its rest position.

[0022] Advantageously, said valve body has three fluid passage openings.

[0023] Advantageously, said at least one fluid passage opening is in the form of a longitudinal slot.

[0024] Advantageously, the device is devoid of a ring around said valve body.

[0025] Advantageously, said propellant gas comprises HFA-152a (1,1-difluoroethane) and / or HFO-1234ze (1,3,3,3-tetrafluoropropene) and / or HFO-1234yf (2,3,3,3-tetrafluoropropene).

[0026] Advantageously, said at least one active ingredient comprises salbutamol, in base or salt form, in particular salbutamol sulfate.

[0027] Advantageously, said at least one active ingredient is micronized.

[0028] The present invention also relates to the use of a device as described above to distribute a pharmaceutical formulation comprising at least one active ingredient suspended in a pressurized propellant gas having a liquid density at 21°C less than or equal to 1.20 g / cm3.

[0029] Advantageously, said at least one active ingredient comprises salbutamol, in salt or base form.

[0030] Advantageously, said propellant gas comprises HFA-152a and / or HFO-1234ze and / or HFO-1234yf.

[0031] Advantageously, said active ingredient is salbutamol sulfate and said propellant gas is HFA-152a.

[0032] These and other features and advantages of the present invention will become more apparent from the following detailed description thereof, made with reference to the accompanying drawings, given by way of non-limiting examples, and on which

[0033] [Fig. 1] Fig. 1 is a schematic cross-sectional view of a device comprising a retention dispensing valve, according to the prior art, in the rest position.

[0034] [Fig.2] Fig.2 is a schematic cross-sectional view of a device comprising a dispensing valve with retention, according to an advantageous embodiment, in the rest position,

[0035] [Fig.3] Fig.3 is a schematic cross-sectional view of the device [Fig.2], in the valve distribution position,

[0036] [Fig. 4] Figures 4 and 5 are graphs that compare the doses of the active ingredient of a device according to the invention with those of a reference device, respectively after an equilibration period of at least one week after filling, called T0, and after one month of storage, and

[0037] [Fig.5] cf [Fig.4]

[0038] [Fig.6] Fig.6 is a graph that compares the doses of the active ingredient of a device according to the invention with those of several devices not covered by the invention, at the end of an equilibration period of at least one week after filling called T0.

[0039] Figures 1 and 2 represent the valve in the upright storage position, i.e. the position in which the dosing chamber is arranged above the tank, while [Fig.3] represents the valve in the reversed operating position, i.e. the position in which the dosing chamber is arranged below the tank.

[0040] The metering valve with retention shown in the figures comprises a valve body 10. Inside said valve body 10, a valve 30 slides between a rest position, which is that shown in Figures 1 and 2, and a distribution position, shown in [Fig.3], in which the valve 30 is pushed into the inside of the valve body 10.

[0041] This valve is intended to be assembled on a reservoir 1, preferably by means of a fixing element 5, which may be a crimp, screw or snap-on cap, and advantageously with the interposition of a neck seal 6.

[0042] In the prior art valve shown in [Fig. 1], a ring 4 is assembled around the valve body, notably to reduce the dead volume in the inverted position and to limit the contact of the fluid product with the neck seal. In the inverted operating position, this ring 4 occupies substantially the volume located below the passage openings of the valve body.

[0043] The valve according to the present invention shown in figures 2 and 3 is devoid of such a ring.

[0044] The valve 30 is forced towards its rest position by a spring 8, which is disposed in the valve body 10 and which cooperates on the one hand with this valve body 10, and on the other hand with a radial collar 320 of the valve. This radial collar 320 slides in the valve body 10 when the valve 30 moves between its rest and distribution positions.

[0045] A dosing chamber 20 is defined inside the valve body 10, the valve 30 sliding within the dosing chamber 20 to allow the contents of the chamber to be dispensed when the valve is actuated. The dosing chamber 20 is preferably defined between two annular seals, a valve seal 21 and a chamber seal 22, in a well-known manner. This dosing chamber 20 is filled before or after each actuation with a dose of fluid product from the reservoir 1. The volume of the dosing chamber 20 can be defined by means of a chamber insert 40, which is substantially cylindrical in shape.

[0046] The valve body 10 has one or more fluid passage openings 11, advantageously in the form of longitudinal slots, preferably three slots. These openings allow the metering chamber 20 to be filled after each actuation. When in the reversed operating position (with the valve positioned under the reservoir), the valve 30 returns from its dispensing position to its rest position.

[0047] The valve 30 can be made in two parts, namely an upper part 31 (also called valve top) and a lower part 32 (also called valve bottom).

[0048] The upper portion 31 comprises a central axial channel 35 provided with an axial outlet 301 and a radial inlet channel 302 which is disposed in the metering chamber 20 when the valve 30 is in the dispensing position. The upper portion 31 also comprises a radial shoulder 310 which, in the rest position shown in [Fig. 2], rests under the valve seal 21 in a known manner.

[0049] In this embodiment, the lower part 32 is assembled inside the upper part 31.

[0050] An internal channel 33 is provided in the valve 30, in particular in the lower part 32, which allows the dosing chamber 20 to be connected to the reservoir, in order to fill said dosing chamber 20 when, after each actuation of the valve, the valve 30 returns to its rest position under the effect of the spring 8. This filling takes place when the device is still in the reversed position of use, with the valve disposed below the reservoir.

[0051] In the example of [Fig. 2], when the valve 30 is in its rest position, the metering chamber 20, outside the valve 30, is substantially isolated from the reservoir 1 by the interaction between the lower part 32 of the valve 30 and the chamber seal 22. In this rest position, the metering chamber 20 therefore remains connected to the reservoir only via the internal channel 33. The valve shown in Figures 2 and 3 is therefore a retention valve.

[0052] Prior art retention metering valves, when used with at least one active ingredient suspended in the new propellants, in particular HFA-152a and / or HFO-1234ze and / or HFO-1234yf, i.e., pressurized propellants with a liquid density at 21°C of 1.20 g / cm³ or less, present a disadvantage in terms of metering, which results in a decrease in the delivered doses with successive uses of the valve. In other words, the first doses dispensed are larger than the last doses, this difference sometimes being substantial and therefore disadvantageous when the dispensing device is intended to deliver constant doses of the active ingredient. The problem is not simply the variation in doses, but rather the magnitude of this variation, and it is this variation that must be minimized.

[0053] The inventors have surprisingly discovered that this specific drawback of retention valves used with propellant gases whose density is lower than the density of the active ingredient particles, such as HFA-152a and / or HFO-1234ze and / or HFO-1234yf, can be substantially reduced by modifying, in particular by increasing, the dead volume located below the fluid passage openings 11 forming the inlet of the valve body (illustrated by the dashed line L in [Fig. 3]), in the inverted operating position. This volume will be referred to as the sedimentation volume V hereafter.

[0054] One hypothesis to explain this phenomenon would be the congestion of the space around the valve body in the reservoir due to the presence of the ring, which, combined with the ring's funnel-like geometry, would facilitate a feeding of the dosing chamber that is too rapid relative to the sedimentation rate of the suspension. Agitation before dose release would then not be sufficient to homogenously resuspend the particles.

[0055] The prior art metering valve shown in [Fig. 1] has a sedimentation volume V which is zero, the whole of this volume being occupied by the ring 4.

[0056] Prior art also exists for metering valve rings equipped with a sedimentation well, thus defining a sedimentation volume according to the present invention, but these sedimentation volumes are limited. For example, document WO9829321A1 describes such a ring, in which the sedimentation volume V is approximately 470 mm³.

[0057] According to the invention, the sedimentation volume V is greater than or equal to 500 mm3, advantageously greater than or equal to 550 mm3, preferably greater than or equal to 600 mm3.

[0058] Moreover, this sedimentation volume V is less than 1000 mm3, advantageously less than 900 mm3, preferably less than 800 mm3.

[0059] Preferably, this sedimentation volume V is approximately equal to 700 mm3.

[0060] Various comparative tests were carried out to demonstrate the effectiveness of the invention and to evaluate the dimensional characteristics of the different fluid passages.

[0061] In the tests in Figures 4 and 5, a prior art retention valve, in this case a valve according to [Fig.1], called Zenith valve ref, was compared with a retention valve according to the present invention, called Zenith valve without ring.

[0062] Both valves were tested with a micronized salbutamol salt suspended in HFA-152a, in particular with a pharmaceutical formulation consisting of salbutamol sulfate, 1,1-difluoroethane (HFA-152a), and ethanol.

[0063] The delivered doses of salbutamol were quantified at individual doses 1, 2, 3, 198, 199 and 200, therefore at the beginning and end of use of the devices.

[0064] The graphs in Figures 4 and 5 illustrate the impact of the increase in volume on the dosages, respectively at T0 (after equilibration following filling of the device) and Tl (after one month of stability after T0), under respective temperature and relative humidity conditions of 40 °C and 75% which comply with the guidelines of the International Council for Harmonisation for Pharmaceutical Quality (ICH Q1 Stability Guidelines).

[0065] It is observed that the doses of the reference valve are at least partially outside the desired intervals, in this case + / - 35% of the target delivered dose of 90 pg, advantageously + / - 25% of the target delivered dose of 90 pg.

[0066] On the contrary, with the valve according to the invention, all doses are within the desired range of + / - 35%, and even within the preferred range of + / - 25%, with the exception of dose 1.

[0067] These results are all the more surprising as they were obtained with a pharmaceutical formulation which does not include any surfactant, whereas surfactants are known to be compounds whose role is to help disperse the particles of active ingredient in the propellant gas.

[0068] Similar tests were carried out with other formulations, including the addition of a surfactant such as polyethylene glycol in the presence of ethanol, and the results were always similar. Likewise, other molecules, particularly in micronized form, also gave similar results.

[0069] Similar tests were also carried out with other prior art metering valves, notably those equipped with a ring having a sedimentation well, and therefore a sedimentation volume, although this volume was significantly lower than the claimed values. Thus, the Zenith ref valve is that shown in Figures 4 and 5, the Zenith Pre7 valve has another ring without a sedimentation volume (V = 0 mm3), and the Zenith PrelO valve has another ring with a sedimentation volume V = 340 mm3. The results are shown in the graph in [Fig. 6]. These results clearly show the favorable impact of increasing the sedimentation volume, with the valve according to the invention (Zenith valve without ring) showing the best results.

[0070] Although the present invention has been described with reference to an embodiment, it is understood that it is not limited by the examples described. On the contrary, a person skilled in the art may make any useful modifications to it without departing from the scope of the present invention as defined by the appended claims.

Claims

Demands

1. A fluid product dispensing device characterized in that it comprises a metering valve mounted on a reservoir (1) containing at least one active ingredient suspended in a pressurized propellant gas having a liquid density at 21°C less than or equal to 1.20 g / cm3, said metering valve comprising a valve body (10) containing a metering chamber (20), and a valve (30) sliding axially in said valve body (10) between a rest position and a dispensing position, to dispense the contents of said metering chamber (20), said metering chamber (20) being, in the rest position of the valve (30), substantially isolated from said reservoir (1), said valve body (10) comprising at least one fluid passage opening (11), said metering valve defining a sedimentation volume V disposed under said at least one passage opening (11) in the inverted operating position,with said dosing chamber (20) disposed below said reservoir (1), said sedimentation volume V being greater than or equal to 500 mm3 and less than or equal to 1000 mm3.

2. Device according to claim 1, wherein said sedimentation volume V is greater than or equal to 550 mm3, in particular greater than or equal to about 600 mm3 and less than or equal to 900 mm3, in particular less than or equal to 800 mm3.

3. Device according to claim 2, wherein said sedimentation volume V is approximately equal to 700 mm3.

4. Device according to any one of the preceding claims, wherein said dosing chamber (20) is defined between a valve seal (21) and a chamber seal (22).

5. Device according to any one of the preceding claims, wherein said valve (30) is made in two parts, an upper part (31) and a lower part (32).

6. Device according to claim 5, wherein said lower part (32) has an internal channel (33) for connecting said dosing chamber (20) to said reservoir (1), for filling said dosing chamber (20) when, after each actuation of the valve, said valve (30) returns to its rest position.

7. Device according to any one of the preceding claims, wherein said valve body (10) has three fluid passage openings (11).

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16. Device according to any one of the preceding claims, wherein said at least one fluid passage opening (11) is in the form of a longitudinal slot. Device according to any one of the preceding claims, which is devoid of a ring around said valve body (10). Device according to any one of the preceding claims, wherein said propellant gas comprises HFA-152a (1,1-difluoroethane) and / or HFO-1234ze (1,3,3,3-tetrafluoropropene) and / or HFO-1234yf (2,3,3,3-tetrafluoropropene). Device according to any one of the preceding claims, wherein said at least one active ingredient comprises salbutamol, in base or salt form, in particular salbutamol sulfate. Device according to any one of the preceding claims, wherein said at least one active ingredient is micronized. Use of a device according to any one of claims 1 to 12 for dispensing a pharmaceutical formulation comprising at least one active ingredient suspended in a pressurized propellant gas having a liquid density at 21°C less than or equal to 1.20 g / cm3. Use according to claim 13, wherein said at least one active ingredient comprises salbutamol, in salt or base form. Use according to claim 13 or 14, wherein said propellant gas comprises HFA-152a and / or HFO-1234ze and / or HFO-1234yf. Use according to any one of claims 13 to 15, wherein said active ingredient is salbutamol sulfate and said propellant gas is HFA-152a.

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