Device for dispensing a fluid product

Abstract

Device for dispensing a fluid product comprising a metering valve mounted on a reservoir (1) containing at least one active principle suspended in a pressurized propellant gas whose liquid density at 21°C is 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 closure member (30) sliding axially in said valve body (10) between a rest position and a dispensing position, for dispensing the contents of said metering chamber (20), said metering chamber (20) being, when the valve closure member (30) is in the rest position, 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 arranged under said at least one passage opening (11) in the inverted position of use, with said metering chamber (20) arranged below said reservoir (1), said sedimentation volume V being greater than or equal to 500 mm3 and less than or equal to 1000 mm3.

Description

[0001] Fluid product dispensing device

[0002] The present invention relates to a fluid product dispensing device comprising a retention-type metering valve.

[0003] So-called metering valves, in which each time the valve is actuation, a precise dose of fluid product is dispensed, are well known in the state of the art, and are generally assembled on a reservoir containing the fluid product and a propellant gas used to expel the dose.

[0004] In particular, two types of metering valves are known: 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 just before the actual actuation, and which are called primeless valves or primeless valves.

[0005] For retention valves, there may be a problem of uneven dose expulsion, particularly if the valve has been stored for some time, which means that the active ingredient is no longer perfectly evenly distributed in the dosing chamber. To at least partially remedy this problem, it is necessary to shake the device well before each use. However, this is not always sufficient, particularly due to the small volume of the dosing chamber.

[0006] Furthermore, about fifteen years ago, for environmental reasons, the previously used propellants, which were generally CFC-based, were replaced by other propellants, namely HFA-134a and / or HFA-227 propellants. This transition took many years, particularly due to the development of new seal materials compatible with these new propellants.

[0007] 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).

[0008] However, once again this replacement has a significant impact on the operation and reliability of the metering valves, particularly on the metering.

[0009] 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 start of use of the device and a lower dosage at the end of use.

[0010] This problem is mainly linked to the sedimentation rate of the particles, which is faster in HFA-152a, HFO-1234ze and HFO-1234yf than in HFA-134a and HFA-227.

[0011] This difference in sedimentation rate is explained by the difference in density between the particles of the active ingredient (approx. 1.4 g / cm 3 ) and the various propellant gases. Indeed, while the HFA-134a and HFA-227 gases under pressure have liquid densities at 21°C very close or even identical to those of the particles of active ingredient in suspension (1.40 g / cm 3 for HFA-227 and 1.22 g / cm 3 for HFA-134a), HFA-152a gas under pressure has a liquid density at 21°C of 0.91 g / cm 3 , with therefore a very significant difference compared to the density of the active ingredient particles, the HFO-1234yf gas under pressure has a liquid density at 21 °C of 1.11 g / cm 3 , with therefore a significant difference compared to the density of the active ingredient particles, and the HFO-1234ze gas under pressure has a liquid density at 21 °C of 1.17 g / cm 3, with therefore also a substantial difference compared to the density of the active ingredient particles (sources for the densities of propellant gases: NIST (National Institute of Standards and Technology) & Honeywell).

[0012] To compensate for this difference, the addition of excipient(s), such as a surfactant, can be useful, but is not sufficient.

[0013] Documents WO2023039103, FR3114759, DE60213223 and US2002190477 describe valves of the state of the art. The aim of the present invention is to improve metering valves of the retention type, i.e. those in which the metering chamber is sealed in the rest position of the valve, when they are used with propellant gases that are less harmful to the environment.

[0014] The present invention aims in particular to provide a device improving the consistency of the dosage between the start and the end of use of the device.

[0015] The present invention also aims to provide a device for which the variations in dosage between the start and the end of use of the device remain within an acceptable range.

[0016] The present invention also aims to provide a device which is simple and inexpensive to manufacture and assemble, and which operates reliably.

[0017] The present invention therefore relates to a device for dispensing a fluid product comprising a metering valve mounted on a reservoir containing at least one active ingredient suspended in a pressurized propellant gas whose liquid density at 21°C is less than or equal to 1.20 g / cm 3, 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, for dispensing the contents of said metering chamber, said metering chamber being, in the rest position of the valve, substantially isolated from said reservoir, said valve body comprising at least one fluid passage opening, said metering valve defining a sedimentation volume V arranged under said at least one passage opening in the inverted position of use, with said metering chamber arranged below said reservoir, said sedimentation volume V being greater than or equal to 500 mm 3 and less than or equal to 1000 mm 3 .

[0018] Advantageously, said sedimentation volume V is greater than or equal to 550 mm 3 , in particular greater than or equal to approximately 600 mm 3 and less than or equal to 900 mm3 , in particular less than or equal to 800 mm 3 Advantageously, said sedimentation volume V is approximately equal to 700 mm 3 .

[0019] Advantageously, said metering 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 comprises 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 comprises 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 does not have 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 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 / cm 3 .

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

[0031] These and other features and advantages of the present invention will become more clearly apparent from the following detailed description thereof, given with reference to the accompanying drawings, given by way of non-limiting examples, and in which

[0032] Figure 1 is a schematic cross-sectional view of a device comprising a retention dispensing valve, according to the prior art, in the rest position,

[0033] Figure 2 is a schematic cross-sectional view of a device comprising a retention dispensing valve, according to an advantageous embodiment, in the rest position,

[0034] Figure 3 is a schematic cross-sectional view of the device of Figure 2, in the valve dispensing position,

[0035] Figures 4 and 5 are graphs which compare the doses of active ingredient of a device according to the invention with those of a reference device, respectively at the end of an equilibration period of at least one week after filling called T0 and after one month of storage, and

[0036] Figure 6 is a graph which compares the doses of 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.

[0037] Figures 1 and 2 show the valve in the upright storage position, i.e. the position in which the dosing chamber is arranged above the reservoir, while Figure 3 shows the valve in the inverted use position, i.e. the position in which the dosing chamber is arranged below the reservoir.

[0038] The retention metering valve 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 dispensing position, shown in figure 3, in which the valve 30 is pressed inside the valve body 10. This valve is intended to be assembled on a reservoir 1, preferably by means of a fixing element 5, which can be a crimping, screwing or snap-on cap, and advantageously with the interposition of a neck seal 6.

[0039] In the valve of the prior art shown in Figure 1, a ring 4 is assembled around the valve body, in particular 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 position of use, this ring 4 substantially occupies the volume arranged below the passage openings of the valve body.

[0040] The valve according to the present invention shown in Figures 2 and 3 is devoid of such a ring.

[0041] The valve 30 is biased towards its rest position by a spring 8, which is arranged 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.

[0042] A metering chamber 20 is defined within the valve body 10, said valve 30 sliding within said metering chamber 20 to allow the contents thereof to be dispensed when the valve is actuated. The metering chamber 20 is preferably defined between two annular seals, a valve seal 21 and a chamber seal 22, in a well-known manner. This metering chamber 20 fills before or after each actuation with a dose of fluid product from the reservoir 1. The volume of the metering chamber 20 may be defined by means of a chamber insert 40, of substantially cylindrical shape.

[0043] The valve body 10 comprises one or more fluid passage openings 11, advantageously in the form of longitudinal slots, preferably three slots. These openings allow the filling of the dosing chamber 20 after each actuation, when in the inverted position of use (with the valve arranged under the reservoir), the valve 30 returns from its dispensing position to its rest position.

[0044] 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).

[0045] The upper part 31 comprises a central axial channel 35 provided with an axial outlet orifice 301 and a radial inlet channel 302 which is arranged in the metering chamber 20 when the valve 30 is in the dispensing position. The upper part 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.

[0046] The lower part 32 is in this embodiment assembled inside the upper part 31.

[0047] An internal channel 33 is provided in the valve 30, in particular in the lower part 32, which makes it possible to connect the dosing chamber 20 to the reservoir, 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 is done when the device is still in the inverted position of use, with the valve arranged below the reservoir.

[0048] In the example of Figure 2, when the valve 30 is in the rest position, the metering chamber 20, outside the valve 30, is substantially isolated from the reservoir 1 by the cooperation 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 said internal channel 33. The valve shown in Figures 2 and 3 is therefore a retention valve.

[0049] The retention metering valves of the prior art, when used with at least one active ingredient suspended with the new propellant gases, in particular HFA-152a and / or HFO-1234ze and / or HFO-1234yf, i.e. pressurized propellant gases whose liquid density at 21°C is less than or equal to 1.20 g / cm 3 , have a disadvantage in terms of dosage, which decreases in the doses emitted as the valve is used successively. In other words, the first doses dispensed are larger than the last doses, this difference can sometimes be substantial and therefore disadvantageous when the dispensing device is intended to dispense constant doses of active ingredient. The problem is not in fact the only variation in doses, but rather the importance of this variation, and it is this variation that it is desirable to minimize.

[0050] The inventors have surprisingly noticed 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 significantly reduced by modifying, in particular by increasing, the dead volume arranged under the fluid passage openings 11 forming the inlet of the valve body (illustrated by the dotted line L in FIG. 3), in the inverted position of use. This volume will be called the sedimentation volume V hereinafter.

[0051] One hypothesis to explain this phenomenon would be the congestion of the space around the valve body in the tank by the presence of the ring which, combined with the geometry of the ring with funnel effect, would facilitate too rapid feeding of the dosing chamber in relation to the sedimentation speed of the suspension. Agitation before the release of the dose would then not be sufficient to resuspend the particles homogeneously.

[0052] The prior art metering valve shown in Figure 1 has a sedimentation volume V which is zero, the whole of this volume being occupied by the ring 4.

[0053] There also exist in the prior art rings for metering valves provided with a sedimentation well thus defining a sedimentation volume according to the present invention, but these sedimentation volumes are limited. Thus, document WO9829321A1 describes such a ring, in which the sedimentation volume V is approximately 470 mm 3 However, a sedimentation volume that is too low does not overcome the aforementioned disadvantage, namely reducing the significance of dose variations.

[0054] According to the invention, the sedimentation volume V is greater than or equal to 500 mm 3 , advantageously greater than or equal to 550 mm 3 , preferably greater than or equal to 600 mm 3 . Below 500 mm 3, the particles of the suspension after stirring do not have enough space to prevent them from passing too quickly through the slots in the body and then into the dosing chamber, which can lead to overconcentration of the suspension in the latter and an active ingredient dose that is too high.

[0055] Furthermore, this sedimentation volume V is less than 1000 mm 3 , advantageously less than 900 mm 3 , preferably less than 800 mm 3 .

[0056] Too much sedimentation volume, especially greater than 1000 mm 3 , would be disadvantageous due to too large a dead volume created in the tank.

[0057] Preferably, this sedimentation volume V is approximately equal to 700 mm 3 .

[0058] Various comparative tests were carried out to demonstrate the effectiveness of the invention and to evaluate the dimensional characteristics of the different fluid passages.

[0059] In the tests of Figures 4 and 5, a retention valve of the state of the art, in this case a valve according to Figure 1, called Zenith valve ref, was compared with a retention valve according to the present invention, called Zenith valve without ring.

[0060] Both valves were tested with micronized salbutamol salt suspended in HFA-152a, specifically with a pharmaceutical formulation consisting of salbutamol sulfate, 1,1-difluoroethane (HFA-152a), and ethanol.

[0061] 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.

[0062] The graphs in Figures 4 and 5 illustrate the impact of the volume increase on the dosages, respectively at T0 (after equilibration following device filling) and T1 (after one month of stability after T0), under respective temperature and relative humidity conditions of 40°C and 75% which comply with the International Council for Harmonisation for Pharmaceutical Quality (ICH Q1 Stability Guidelines).

[0063] It is found that the doses of the reference valve are at least partially outside the desired ranges, in this case + / - 35% of the target delivered dose of 90 pg, advantageously + / - 25% of the target delivered dose of 90 pg.

[0064] 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.

[0065] 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.

[0066] Similar tests have been carried out with other formulations, notably with the addition of a surfactant such as polyethylene glycol in the presence of ethanol, and the results have always been similar. Similarly, other molecules, notably in micronized form, have also given similar results.

[0067] Similar tests were also carried out with other prior art metering valves, in particular provided with a ring comprising a sedimentation well, and therefore a sedimentation volume, this volume being however significantly lower than the claimed values. Thus, the Zenith valve ref is that of figures 4 and 5, the Zenith Pre7 valve comprises another ring without sedimentation volume (V = 0 mm 3 ), and the Zenith Pre10 valve has another ring with a sedimentation volume V = 340 mm 3. The results are shown in the graph of Figure 6. These results clearly show the favorable impact of the increase in sedimentation volume, with the valve according to the invention (Zenith valve without ring) which presents the best results. 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 can make any useful modifications thereto without departing from the scope of the present invention as defined by the appended claims.

Claims

Claims 1. Device for dispensing a fluid product, 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 whose liquid density at 21°C is less than or equal to 1.20 g / cm 3, 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, for dispensing 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 arranged under said at least one passage opening (11) in the inverted position of use, with said metering chamber (20) arranged below said reservoir (1), said sedimentation volume V being greater than or equal to 500 mm 3 and less than or equal to 1000 mm 3 .

2. Device according to claim 1, wherein said sedimentation volume V is greater than or equal to 550 mm 3, in particular greater than or equal to approximately 600 mm 3 and less than or equal to 900 mm 3 , in particular less than or equal to 800 mm 3 .

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

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

5. Device according to any one of the preceding claims, in which 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) comprises 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) comprises three fluid passage openings (11).

8. 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.

9. Device according to any one of the preceding claims, which is devoid of a ring around said valve body (10).

10. A device according to any preceding claim, 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).

11. Device according to any one of the preceding claims, in which said at least one active ingredient comprises salbutamol, in base or salt form, in particular salbutamol sulfate.

12. Device according to any one of the preceding claims, wherein said at least one active ingredient is micronized.

13. 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 / cm 3 .

14. Use according to claim 13, wherein said at least one active ingredient comprises salbutamol, in salt or base form.

15. Use according to claim 13 or 14, wherein said propellant gas comprises HFA-152a and / or HFO-1234ze and / or HFO-1234yf.

16. 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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