Device for dispensing a fluid product

Abstract

A device for dispensing a fluid product comprises a metering valve mounted on a reservoir (1) containing at least one active ingredient suspended in a pressurized propulsion gas, the pressurized propulsion gas having a liquid density of less than or equal to 1.20 g / cm3 at 21 DEG C, the metering valve comprises a valve body (10) containing a metering chamber (20) and a valve closing member (30) axially sliding in the valve body (10) between a reset position and a dispensing position for dispensing the contents of the metering chamber (20), the metering chamber (20) being substantially isolated from the reservoir (1) when the valve closing member (30) is in the reset position, the valve body (10) comprises at least one fluid passage opening (11), the metering valve defines a settling volume V arranged below the at least one passage opening (11) in an inverted use position in which the metering chamber (20) is arranged below the reservoir (1), the settling volume V being greater than or equal to 500 mm3 and less than or equal to 1000 mm3.

Description

[0001] The present invention relates to a device for dispensing a fluid product, comprising a hold-up metering valve.

[0002] So-called metering valves dispensing a specific dose of fluid product at each actuation of the valve are known in the prior art and are generally assembled on a reservoir containing the fluid product and a propellant for performing the dose discharge.

[0003] In particular, two types of metering valves are known, namely first hold-up valves which, after filling the metering chamber, close said chamber in a leak-tight manner until the next actuation of the valve, and second valves which are filled only before a suitable actuation, and the second valves are sometimes called pre- prime free valves or ACT valves.

[0004] For hold-up valves, in particular after the valve has been stored for a certain time, problems of dose non-uniformity can arise at the dose discharge, which leads to the active ingredient no longer being distributed in the metering chamber in a completely uniform manner. In order to remedy this problem at least partially, a thorough shaking of the device before each use is required. However, this is not always sufficient, in particular due to the small volume of the metering chamber.

[0005] Furthermore, approximately fifteen years ago, the previously used propellants, which were generally based on CFCs, have been replaced by other propellants, namely the propellants HFA-134a and / or HFA-227, for ecological reasons. This changeover took many years, in particular due to the development of new sealing materials compatible with these new propellants.

[0006] Today, it has been proven that the gases HFA-134a and / or HFA-227 are also harmful to the environment and need to be replaced by gases which are less harmful to the environment, such as HFA-152a (1,1-difluoroethane), HFO-1234ze (1,3,3,3-tetrafluoropropene) or HFO-1234yf (2,3,3,3-tetrafluoropropene).

[0007] However, this replacement has a significant impact on the operation and reliability of the metering valve, in particular on the metering.

[0008] Thus, for an active ingredient suspended in the propellant gas HFA-152a in the form of an aerosol, the dose problem manifests itself as follows: the metering is higher at the beginning of the use of the device and lower at the end of the use.

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

[0010] This difference in the rate of sedimentation is explained by the difference in density between the particles of active ingredient (approximately 1.4 g / cm 3 ) and the different propellant gases. Indeed, while the gases HFA-134a and HFA-227 under pressure have a liquid density at 21 °C very close to or even identical to that 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), the gas HFA-152a under pressure has a liquid density at 21 °C of 0.91 g / cm 3 , thus a very significant difference with respect to the density of the particles of active ingredient, the gas HFO-1234yf under pressure has a liquid density at 21 °C of 1.11 g / cm 3 , thus a significant difference with respect to the density of the particles of active ingredient, and the gas HFO-1234ze under pressure has a liquid density at 21 °C of 1.17 g / cm 3 , thus also a significant difference with respect to the density of the particles of active ingredient (source of the densities of the propellant gases: NIST & Honeywell).

[0011] To compensate for this difference, the addition of excipients, such as surfactants, can be useful, but is not sufficient.

[0012] The documents WO2023039103, FR3114759, DE60213223 and US2002190477 describe prior art valves.

[0013] The present invention aims to improve the hold-up metering valve, i.e. the metering valve in which the metering chamber is hermetically sealed in the rest position of the valve when used with propellant gases less harmful to the environment.

[0014] In particular, the present invention aims to provide a device which improves the consistency of the metering between the beginning and the end of use of the device.

[0015] The present invention also aims to provide a device for which the variation in metering between the beginning and the end of use of the device is kept within an acceptable interval.

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

[0017] The aim of the application is therefore 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 having a liquid density at 21 °C of less than or equal to 1.20 g / cm 3 , said metering valve comprising a valve body containing a metering chamber, and a valve shut-off element axially sliding in said valve body between a rest position and a dispensing position to dispense the contents of said metering chamber, said metering chamber being substantially isolated from said reservoir in the rest position of the valve shut-off element, said valve body comprising at least one fluid passage opening, said metering valve defining a settling volume V arranged below said at least one passage opening in an inverted use position in which said metering chamber is arranged below said reservoir, said settling volume V being greater than or equal to 500 mm 3 and less than or equal to 1000 mm 3 .

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

[0019] Advantageously, said settling volume V is substantially equal to 700 mm 3 .

[0020] Advantageously, said metering chamber is defined between a valve seal and a chamber seal.

[0021] Advantageously, said valve is composed of two parts, a top part and a bottom part.

[0022] Advantageously, said bottom part comprises an internal passage for connecting said metering chamber to said reservoir, so as to fill said metering chamber, and, after each actuation of the valve, said valve shut-off element returns to its rest position.

[0023] Advantageously, said valve body comprises three fluid passage openings.

[0024] Advantageously, said at least one fluid passage opening is in the form of a longitudinal slot.

[0025] Advantageously, the device has no ring surrounding said valve body.

[0026] Advantageously, the 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).

[0027] Advantageously, the at least one active principle comprises salbutamol, in the form of a base or a salt, in particular salbutamol sulfate.

[0028] Advantageously, the at least one active principle is micronized.

[0029] The application also relates to the use of a device for dispensing a pharmaceutical preparation comprising at least one active principle suspended in a pressurized propellant gas having a liquid density less than or equal to 1.20 g / cm3at 21 °C, as described above. 3

[0030] Advantageously, the at least one active principle comprises salbutamol, in the form of a base or a salt.

[0031] Advantageously, the propellant gas comprises HFA-152a and / or HFO-1234ze and / or HFO-1234yf.

[0032] Advantageously, the active principle is salbutamol sulfate and the propellant gas is HFA-152a.

[0033] These features and advantages, as well as others, of the application will appear more clearly on examining the following detailed description of the application, given by way of non-limiting example and with reference to the attached drawings in which:

[0034] Figure 1 is a schematic cross-sectional view of a device with a holding dispensing valve in a rest position of the prior art,

[0035] Figure 2 is a schematic cross-sectional view of a device with a holding dispensing valve in a rest position according to an advantageous embodiment,

[0036] Figure 3 is a schematic cross-sectional view of the device of Figure 2 in a dispensing position of the valve shut-off element,

[0037] Figure 4 and Figure 5 are graphs comparing the dose of active principle of a device according to the application with the dose of active principle 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

[0038] Figure 6 ​The graph compares the dose of active ingredient of the device according to the application with the doses of active ingredient of several devices not according to the application at the end of the equilibration period, called T0, which is at least one week after filling.

[0039] Figure 1 and Figure 2 The valve is shown in the upright storage position, i.e. in the position in which the dosing chamber is arranged above the reservoir, while Figure 3 The valve is shown in the inverted use position, i.e. in the position in which the dosing chamber is arranged below the reservoir.

[0040] The retaining valve shown in the drawing comprises a valve body 10. Inside said valve body 10, a valve shut-off element 30 slides between a rest position and a dispensing position as shown in Figure 3 The rest position is the position shown in Figure 1 The dispensing position is the position in which the valve shut-off element 30 has been pushed into the valve body 10.

[0041] The valve is intended to be assembled on a reservoir 1, preferably by means of a fastener element 5, which can be crimpable, threadable or snap-fastenable, and a neck seal 6 is advantageously interposed between the fastener element and the reservoir.

[0042] In the prior art valve shown in Figure 1 , a ring 4 is assembled around the valve body, thereby significantly reducing the dead volume in the inverted position and limiting the contact of the fluid product with the neck seal. In the inverted use position, this ring 4 substantially occupies the volume arranged below the passage opening of the valve body.

[0043] Figure 2 and Figure 3 The valve according to the application shown in

[0044] The valve shut-off element 30 is pushed towards its rest position by a spring 8 which is provided in the valve body 10 and which first cooperates with the valve body 10 and secondly with a radial collar 320 of the valve shut-off element. This radial collar 320 slides in the valve body 10 when the valve shut-off element 30 moves between its rest position and its dispensing position.

[0045] A dosing chamber 20 is defined inside the valve body 10, inside which the valve shut-off element 30 slides in order to enable the contents of the dosing chamber 20 to be dispensed upon actuation of the valve. In a conventional manner, the dosing chamber 20 is preferably defined between two annular seals, namely the valve member seal 21 and the chamber seal 22. The dosing chamber 20 is filled with a dose of fluid product from the reservoir 1 before or after each actuation. The volume of the dosing chamber 20 can be defined by means of a substantially cylindrical chamber insert 40.

[0046] The valve body 10 comprises one or more fluid passage openings 11, advantageously in the form of longitudinal slots, preferably three slots. These openings make it possible to fill the dosing chamber 20 after each actuation, when the valve shut-off element 30 returns from its dispensing position to its rest position.

[0047] The valve shut-off element 30 can be made up of two parts, namely a top part 31, also known as a valve shut-off element top, and a bottom part 32, also known as a valve shut-off element bottom.

[0048] The top part 31 comprises a central axial passage 35 provided with an axial outlet orifice 301 and a radial inlet passage 302 arranged in the dosing chamber 20 when the valve shut-off element 30 is in its dispensing position. The top part 31 also comprises a radial shoulder which supports, in a known manner, under the valve shut-off element seal 21 in the rest position represented in Figure 2 The bottom part 32 comprises a radial shoulder which supports, in a known manner, under the valve member seal 21 in the rest position represented in

[0049] In this embodiment, the bottom part 32 is assembled inside the top part 31.

[0050] An internal passage 33 is provided in the valve shut-off element 30, in particular in the bottom part 32, which makes it possible to connect the dosing chamber 20 to the reservoir 1 in order to fill said dosing chamber 20 after each actuation of the valve, when the valve shut-off element 30 returns to its rest position under the action of the spring 8. The filling is performed when the device is still in the inverted working position of the device in which the valve is arranged under the reservoir.

[0051] In the embodiment represented in Figure 1 In the embodiment represented in Figure 2 and Figure 3The valve shown in the figures is a holding valve.

[0052] The holding metering valves of the prior art have the following drawback with respect to metering when used with at least one active ingredient suspended in a pressurized propellant gas, in particular HFA-152a and / or HFO-1234ze and / or HFO-1234yf, i.e. whose liquid density at 21 °C is less than or equal to 1.20 g / cm 3 The first dose to be dispensed generally contains less active ingredient than the last dose, this difference can be substantial and is therefore disadvantageous when the aim of the dispensing device is to dispense a constant dose of active ingredient. The problem is not only the variation in dose, but also the amplitude of the variation and it is desirable to minimize this variation.

[0053] The inventors have found surprisingly that this particular drawback of holding valves used with propellant gases whose density is less than that of the particles of active ingredient, 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 below the fluid passage opening 11 of the inlet (illustrated by the dotted line L in Figure 3 This volume will be referred to below as the settling volume V.

[0054] One hypothesis to explain this phenomenon would be that, due to the presence of the ring, the size of the space around the valve body in the reservoir, combined with the funnel effect geometry of the ring, will promote a too rapid supply of the metering chamber with respect to the settling rate of the suspension. The agitation before releasing the dose will then be insufficient to re-suspend the particles uniformly.

[0055] Figure 1 The prior art metering valve shown in the figures comprises a settling volume V of zero, the entire volume being occupied by the ring 4.

[0056] There are also rings for metering valves in the prior art which are provided with a settling well, thus defining a settling volume according to the application, but these are limited. Thus, the document WO9829321 A1 describes a ring in which the settling volume V is about 470 mm 3 However, a too low settling volume makes it impossible to overcome the aforementioned drawback, i.e. to reduce the degree of variation in dose.

[0057] According to the application, the settling 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. In the case where V is lower than 500 mm 3 , the particles of the suspension, after agitation, do not have enough space to prevent the particles from passing too quickly through the slots of the body and then entering the dosing chamber, which can lead to an over-concentration of the suspension in the dosing chamber and to a too high dose of active ingredient.

[0058] Furthermore, the settling volume V is less than 1000 mm 3 , advantageously less than 900 mm 3 , preferably less than 800 mm 3 .

[0059] A settling volume that is too large, in particular greater than 1000 mm 3 , would be disadvantageous since it would create a too large dead volume in the reservoir.

[0060] Preferably, the settling volume V is equal to approximately 700 mm 3 .

[0061] Various comparative tests have been carried out in order to demonstrate the effectiveness of the application and in order to evaluate the dimensional characteristics of the different fluid passages.

[0062] In the tests of Figure 4 and Figure 5 , a prior art retention valve, in this case a valve called Zenith reference valve according to Figure 1 , was compared with a retention valve according to the application, called ringless Zenith valve.

[0063] The two valves were tested with a micronized salbutamol salt suspended in HFA-152a, in particular with a pharmaceutical formulation comprising salbutamol sulfate, 1,1-difluoroethane (HFA-152a) and ethanol.

[0064] Thus, at the beginning and at the end of use of the device, the delivered doses of salbutamol were quantified in individual doses 1, 2, 3, 198, 199 and 200.

[0065] Figure 4 and Figure 5 The graphs in

[0066] It was found that the doses of the reference valve were at least partially outside the desired range, in this case + / - 35% of the target delivered dose of 90 pg, advantageously + / - 25% of the target delivered dose of 90 pg.

[0067] On the contrary, with the valve according to the application, all the doses, except dose 1, are within the desired range of + / - 35% and even within the preferred range of + / - 25%.

[0068] These results are all the more surprising because they were obtained with a pharmaceutical formulation that does not comprise any surfactant, whereas surfactants are known as compounds whose action is to help the dispersion of the particles of active ingredient in the propellant gas.

[0069] Similar tests have been carried out with other formulations, in particular with formulations in which a surfactant such as polyethylene glycol is added in the presence of ethanol, and the results are always similar. Similarly, other molecules, in particular in micronized form, also give similar results.

[0070] Similar tests have also been carried out with other metering valves of the prior art, in particular provided with a ring comprising a sink well and therefore a sink volume, however this volume is substantially less than the claimed value. Thus, the Zenith reference valve is Figure 4 and Figure 5 The Zenith Preload 7 valve comprises another ring without a sink volume (V = 0 mm 3 ) and the Zenith Preload 10 valve comprises another ring with a sink volume V = 340 mm 3 . The results are shown in the graph in Figure 6 . These results clearly show the advantageous effect of increasing the sink volume, in which the valve according to the application (Zenith valve without ring) has the best results.

[0071] Although the application has been described above with reference to the embodiments, naturally the application is not limited to the described embodiments. On the contrary, a person skilled in the art can apply any useful modification to it without going beyond the scope of the application as defined by the appended claims.

Claims

1. An apparatus for dispensing fluid products, characterized in that, The device includes a metering valve mounted on a reservoir (1) containing at least one active ingredient suspended in a pressurized propellant having a liquid density of less than or equal to 1.20 g / cm³ at 21°C. 3 The metering valve includes a valve body (10) housing a metering chamber (20) and a valve shut-off element (30) that slides axially within the valve body (10) between a reset position and a dispensing position to dispense the contents of the metering chamber (20). The metering chamber (20) is substantially isolated from the reservoir (1) in the reset position of the valve shut-off element (30). The valve body (10) includes at least one fluid passage opening (11). The metering valve defines a settling volume V, which is greater than or equal to 500 mm², located below the at least one fluid passage opening (11) in an inverted use position where the metering chamber (20) is located below the reservoir (1). 3 and less than or equal to 1000 mm 3 .

2. The apparatus according to claim 1, wherein, The settlement volume V is greater than or equal to 550 mm. 3 Specifically, greater than or equal to approximately 600 mm 3 and less than or equal to 900 mm 3 Especially less than or equal to 800 mm 3 .

3. The apparatus according to claim 2, wherein, The settlement volume V is approximately 700 mm. 3 .

4. The apparatus according to any one of the preceding claims, wherein, The metering chamber (20) is defined between the valve shut-off element seal (21) and the chamber seal (22).

5. The apparatus according to any one of the preceding claims, wherein, The valve shut-off element (30) consists of two parts, namely a top part (31) and a bottom part (32).

6. The apparatus according to claim 5, wherein, The bottom portion (32) includes an internal channel (33) for connecting the metering chamber (20) to the reservoir (1) for filling the metering chamber (20) when the valve shut-off element (30) returns to its reset position after each actuation of the valve.

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

8. The apparatus according to any one of the preceding claims, wherein, The at least one fluid passage opening (11) is in the form of a longitudinal slot.

9. The device according to any one of the preceding claims, wherein the device does not have a ring surrounding the valve body (10).

10. The apparatus according to any one of the preceding claims, wherein, The propellant gas includes HFA-152a (1,1-difluoroethane) and / or HFO-1234ze (1,3,3,3-tetrafluoropropylene) and / or HFO-1234yf (2,3,3,3-tetrafluoropropylene).

11. The apparatus according to any one of the preceding claims, wherein, The at least one active ingredient includes salbutamol in the form of a base or salt, particularly salbutamol sulfate.

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

13. Use of the apparatus according to any one of claims 1 to 12, the apparatus being used to dispense a pharmaceutical preparation comprising at least one active ingredient suspended in a pressurized propellant gas having a concentration of less than or equal to 1.20 g / cm³ at 21°C. 3 The density of the liquid.

14. The use according to claim 13, wherein, The at least one active ingredient includes salbutamol in the form of a salt or base.

15. The use according to claim 13 or 14, wherein, The propellant gas includes HFA-152a and / or HFO-1234ze and / or HFO-1234yf.

16. The use according to any one of claims 13 to 15, wherein, The active ingredient is salbutamol sulfate and the propellant gas is HFA-152a.

Images