Atmosphere control device

Abstract

This atmosphere control device (1), intended for regulating an atmosphere in a packaging or a medical device containing sensitive or odorous products, comprises a gas-permeable envelope (10) defining a chamber (13), the chamber (13) having in its inner volume a particulate mixture (6) comprising at least a first active substance (61) in particulate form having relatively large particles and a second active substance (62) in particulate form having relatively small particles. The particle size distribution of the particulate mixture (6) is such that the graph of the cumulative particle size distribution by mass Q3(x) of the particulate mixture includes, between the 3% percentile d3 and the 97% percentile d97, a portion in which the cumulative mass is increased by less than 10%, preferably less than 5%, when the particle size x is doubled.

Description

[0001] ATMOSPHERE CONTROL DEVICE

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to an atmosphere control device, such as a capsule, a canister, a closure, a packet, or a cavity in a vial or in a device, for regulating an atmosphere in a packaging or a medical device containing sensitive or odorous products. Such a device may be used, for example, in a packaging filled with sensitive products which may be food, nutraceutical products, pharmaceutical products or diagnostic products, or in a compartment defined in a medical device, notably in an inhaler such as a DPI (Dry Powder Inhaler) or in a diagnostic test cartridge. The invention also relates to a method for manufacturing an atmosphere control device and to a use of an atmosphere control device.

[0004] BACKGROUND OF THE INVENTION

[0005] It is known to use an atmosphere control device, comprising a gas-permeable envelope filled with an active substance, to regulate the atmosphere inside a packaging or a medical device containing sensitive or odorous products. The active substance may be selected, e.g., in the group of humidity absorbers, oxygen scavengers, odor absorbers, humidity emitters and / or emitters of volatile olfactory organic compounds. Thanks to the gas-permeability of the envelope, the active substance is capable of interacting with the gas present in the packaging or medical device as it flows through the envelope. In particular, the atmosphere control device may be a capsule, a canister or a packet intended to be dropped in a packaging or medical device, or a closure configured to close a packaging or medical device.

[0006] The active substance received in the gas-permeable envelope may be in particulate form, as is the case for example with silica gel, molecular sieve or activated clay, which can be used as humidity absorbers or humidity control substances. Silica gel or other active substances are typically used in the form of beaded or granular particles. In a packaging or a medical device for sensitive products, the space available for integration of an atmosphere control device is often reduced. Typically, the gas-permeable envelope of a capsule, a canister, a packet or a closure defines a chamber having a small volume of the order of 1 cm3to 30 cm3. Because of such a reduced volume, particulate active substances of relatively small particle size generally tend to be preferred for filling the gas-permeable envelope of an atmosphere control device such as a capsule, a canister, a packet or a closure.

[0007] Yet, there is a need to increase the performance of small atmosphere control devices by increasing the amount of active substance that can be filled in a gas permeable envelope of reduced volume. In particular, a difficulty arises to efficiently fill a particulate active substance in a reduced volume, especially at the high production rates existing on manufacturing lines for atmosphere control devices, which can reach 1000 devices per minute.

[0008] It is this drawback that the invention is intended more particularly to remedy by proposing an atmosphere control device and a manufacturing method ensuring that a maximum filling weight of a small volume gas-permeable envelope with a particulate active substance can be achieved efficiently, at even very high rates of production.

[0009] DISCLOSURE OF THE INVENTION

[0010] For this purpose, a subject of the invention is an atmosphere control device, such as a capsule, a canister, a closure, a packet, or a cavity in a vial or in a device, for regulating an atmosphere in a packaging or a medical device containing sensitive or odorous products, the device comprising a gas-permeable envelope defining a chamber, wherein the chamber has in its inner volume a particulate mixture comprising at least a first active substance in particulate form having relatively large particles and a second active substance in particulate form having relatively small particles, wherein the particle size distribution of the particulate mixture is such that the graph of the cumulative particle size distribution by mass Qs(x) of the particulate mixture includes, between the 3% percentile d3 and the 97% percentile d97, a portion in which the cumulative mass is increased by less than 10%, preferably less than 5%, when the particle size x is doubled, where the 3% percentile d3 corresponds to the particle size below which there are 3% of the smallest particles and the 97% percentile d97 corresponds to the size above which there are 3% of the largest particles.

[0011] In the context of the invention, the “relatively large particles” and the “relatively small particles” are defined in relation to each other. In particular, a median particle size d50 of the relatively large particles of the first active substance is higher than a median particle size d50 of the relatively small particles of the second active substance.

[0012] In the context of the invention, the first active substance and the second active substance may be exactly the same, except for their respective particle sizes. By way of example, the first active substance and the second active substance may both comprise silica gel, and differ in that the particles of the first active substance and the particles of the second active substance are of different particle size classes. In the context of the invention, the first active substance and the second active substance may also be substances of different chemical natures. It may be advantageous to combine active substances of different natures within the particulate mixture, for example by mixing at least two among a humidity absorber, an oxygen scavenger, an odor absorber, etc.

[0013] Conventionally, the cumulative particle size distribution by mass Q3 of a particulate mixture can be determined through a sieve analysis (ASTM D6913), or through other methods known in the art, such as Laser Diffraction (LD), Dynamic Light Scattering (DLS) or Dynamic Image Analysis (DIA). In the case where all the particles of a particulate mixture have the same density, the cumulative particle size distribution by mass Q3 of the particulate mixture is equivalent to the cumulative particle size distribution by volume.

[0014] The graph of the cumulative particle size distribution by mass Qs(x) of the particulate mixture is represented according to ISO 9276-1. Each value Qs(x) indicates the percentage by mass of the particulate mixture consisting of particles smaller than particle size x. Useful percentiles can be extracted from the cumulative particle size distribution by mass Q3, including: the median particle size d50, corresponding to the particle size dividing the particle size distribution into 50% of “smaller” particles and 50% of “larger” particles; the 3% percentile d3, corresponding to the particle size below which there are 3% of the smallest particles; the 10% percentile d10, corresponding to the particle size below which there are 10% of the smallest particles; the 97% percentile d97, corresponding to the particle size above which there are 3% of the largest particles.

[0015] According to a feature of the invention, the graph of the cumulative particle size distribution by mass Qs(x) of the particulate mixture is a gap-graded particle size distribution with a substantially horizontal plateau between the 3% percentile d3 and the 97% percentile d97, and in this plateau of the graph Qs(x), the cumulative mass is increased by less than 10%, preferably less than 5%, when the particle size x is doubled. The presence of at least one plateau in the graph of the cumulative particle size distribution by mass Qs(x) is characteristic of a particulate mixture comprising particles of at least two distinct particle sizes. Conversely, the absence of any plateau in the graph of the cumulative particle size distribution by mass Qs(x) is characteristic of a particulate mixture comprising particles of a single size class.

[0016] It is the merit of the inventors to have gone against the preexisting idea that the filling weight of a container decreases when the particle size becomes large compared to the inner dimensions of the container. Due to this preexisting idea, in the prior art, particulate active substances having a particle size substantially smaller than the inner dimensions of a container were preferred for filling containers of reduced sizes such as gas-permeable envelopes of atmosphere control devices, e.g. capsules, canisters, packets or closures, used to regulate an atmosphere in a packaging or a medical device containing sensitive or odorous products.

[0017] Now, the inventors have discovered that it is possible to increase the filling weight of active substance in a chamber having a small volume, lower than 30 cm3, when the chamber is filled with a multimodal particulate mixture comprising particles of several size classes, even including particles of a relatively large size class compared to the inner dimensions of the chamber, which is against the prior art preexisting idea. It has been discovered that, when introducing such a multimodal particulate mixture in a chamber of small volume lower than 30 cm3, the particles tend to flow more efficiently to fill the chamber, so that a predictable quantity of the at least a first and a second active substances can be introduced in the chamber while respecting the filling times imposed by the production rates existing on manufacturing lines for atmosphere control devices.

[0018] The imposed filling time may be, e.g., less than 750 ms for a production rate of 80 atmosphere control devices per minute, less than 120 ms for a production rate of 500 atmosphere control devices per minute, or even less than 60 ms for a production rate of 1000 atmosphere control devices per minute. Thanks to the specific gap- graded particle size distribution of the multimodal particulate mixture, an increased weight of active particles is filled into the chamber. It has also been observed that the efficiency of the filling of the chamber with a multimodal particulate mixture is enhanced both if the particles of the at least a first and a second active substances are premixed or if they are introduced from separate feeders, preferably simultaneously.

[0019] According to one embodiment, the particulate mixture is a binary system, consisting of particles of two distinct size classes. In this case, the particulate mixture consists of a first active substance in particulate form having relatively large particles and a second active substance in particulate form having relatively small particles, wherein the size classes of the first active substance and the second active substance are so distinct that the graph of the cumulative particle size distribution by mass Qs(x) of the particulate mixture includes, between the 3% percentile d3 and the 97% percentile d97, a portion in which the cumulative mass is increased by less than 10%, preferably less than 5%, when the particle size x is doubled.

[0020] According to another embodiment, the particulate mixture is a ternary system, consisting of particles of three distinct size classes. In this case, the particulate mixture consists of a first active substance in particulate form having relatively large particles, a second active substance in particulate form having particles with a median particle size d50 smaller than that of the first active substance, and a third active substance in particulate form having particles with a median particle size d50 smaller than that of the second active substance, wherein the size classes of the first active substance, the second active substance and the third active substance are so distinct that the graph of the cumulative particle size distribution by mass Qs(x) of the particulate mixture includes, between the 3% percentile d3 and the 97% percentile d97, two distinct portions in which the cumulative mass is increased by less than 10%, preferably less than 5%, when the particle size x is doubled.

[0021] According to one embodiment, in the graph of the cumulative particle size distribution by mass Qs(x) of the particulate mixture, for each portion in which the cumulative mass is increased by less than 10% when the particle size x is doubled, there are at least two values xi and X2 of the particle size such that X2 2 * xi and QS(X2) ^ 1.1 * Qs(xi ). In other words, the length of the or each substantially horizontal plateau in the graph of the cumulative particle size distribution by mass Qs(x) of the particulate mixture is such that the particle size is at least doubled in the plateau. In this way, a system with two distinct particle size classes is obtained, thus promoting homogeneous filling of the empty spaces between the relatively large particles with the relatively small particles. Advantageously, this homogeneous filling occurs even for particulate mixtures with great variability in particle shape and dimensions, and not only for particulate mixtures with well-calibrated particles.

[0022] According to one embodiment, in the graph of the cumulative particle size distribution by mass Qs(x) of the particulate mixture, for each portion in which the cumulative mass is increased by less than 10%, preferably less than 5%, when the particle size x is doubled, the maximum particle size ratio in said portion is less than or equal to 10, preferably less than or equal to 7. In other words, the length of each substantially horizontal plateau in the graph of the cumulative particle size distribution by mass Qs(x) of the particulate mixture is such that the particle size is at most multiplied by 10 in the plateau, preferably at most multiplied by 7 in the plateau. Such upper limits for the length of the plateau make it possible to avoid a percolation effect, which may occur when the size difference between the particles of the first active substance and the particles of the second active substance becomes too high, whereby the relatively small particles tend to flow without sufficient resistance into the empty spaces formed between the relatively large particles, resulting in a separation (or segregation) between the particles of the two particle size classes. The particle mixture then becomes unstable, leading to increased filling weight variability.

[0023] According to one feature, the inner volume of the chamber defined by the gas- permeable envelope is less than or equal to 30 cm3, preferably less than or equal to 10 cm3, preferably less than or equal to 5 cm3. When the inner volume of the chamber decreases, the specific gap-graded particle size distribution of the multimodal particulate mixture is used as a lever to increase the filling weight of active substance filled in the chamber, thus achieving maximum performance of the atmosphere control device.

[0024] According to one embodiment, the gas-permeable envelope defines a cylindershaped chamber which, according to the general definition of a cylinder, may have a circular base or any other form of base, such as an oval base, a quadrilateral base, etc. According to one feature, the ratio of the diameter of the cylinder to the 97% percentile d97 of the particulate mixture is higher than or equal to 3, where the diameter of the cylinder is defined as the diameter of a circle inscribed in a base of the cylinder. Such a ratio of the inner diameter of the chamber to the 97% percentile d97 of the particulate mixture makes it possible to avoid an effect which has been observed experimentally, whereby the filling weight of a chamber tends to decrease when the inner volume of the chamber decreases and becomes close to the particle size of the largest particles.

[0025] According to one embodiment, the 97% percentile d97 of the particulate mixture is less than or equal to 10 mm, preferably less than or equal to 6 mm. Such an upper limit value for the 97% percentile d97 of the particulate mixture makes it possible to avoid the above experimentally observed effect, whereby the filling weight of a chamber tends to decrease when the inner volume of the chamber decreases and becomes close to the particle size of the largest particles.

[0026] According to one embodiment, the 10% percentile d10, preferably the 3% percentile d3, of the particulate mixture is higher than or equal to 0.075 mm. In other words, the size of 90%, preferably 97%, of the particles of the particulate mixture is higher than or equal to 75 pm. Such a lower limit value for the 10% percentile d10, preferably the 3% percentile d3, of the particulate mixture ensures that the dosing of the particulate mixture can be implemented precisely, by avoiding the presence of fine particles of powder which are difficult to handle. In particular, when the particle size becomes lower than 75 pm, the particles become more sensitive to cohesive forces, particularly due to electrostatic interactions.

[0027] According to one embodiment, a percentage of weight of the first active substance having relatively large particles over the total weight of the particulate mixture is between 25 and 80 wt%. It has been found by the inventors that a particulate mixture with such a percentage of weight of the first active substance having relatively large particles over the total weight of the particulate mixture, corresponding to a relatively high mixing rate between the particles of the first active substance and the particles of the second active substance, enables higher filling weight of the chamber, corresponding to the best densification effect.

[0028] According to one embodiment, a percentage of weight of the first active substance having relatively large particles over the total weight of the particulate mixture is between 35 and 80 wt%. It has been observed empirically that the increase in the filling weight of the chamber is asymmetrical relative to the percentages by weight of the first and second active substances. In particular, it has been observed that the increase in the filling weight of the chamber is higher for high percentage by weight of the first active substance comprising relatively large particles.

[0029] According to one feature of the invention, a ratio of the median particle size d50 of the first active substance having relatively large particles to the median particle size d50 of the second active substance having relatively small particles, is higher than or equal to 4. It has been observed that the compactness of the particulate mixture can be increased when the particles of the second active substance having relatively small particles are small enough to be homogenously distributed in the porous matrix formed by the particles of the first active substance having relatively large particles. On the contrary, too small a difference in the median particle sizes d50 of the relatively large particles and the relatively small particles does not allow the particle mixture to be densified.

[0030] According to one feature of the invention, the particulate mixture further comprises a third active substance in particulate form having particles with a median particle size d50 smaller than the median particle size d50 of the second active substance, and a ratio of the median particle size d50 of the second active substance to the median particle size d50 of the third active substance is higher than or equal to 4. Here again, the compactness of the particulate mixture is increased because the particles of the second active substance are small enough to be homogenously distributed in the porous matrix formed by the particles of the first active substance having relatively large particles, whereas the particles of the third active substance are also small enough to be homogenously distributed in the porous matrix formed by the particles of the second active substance.

[0031] According to one feature of the invention, a ratio of the median particle size d50 of the first active substance having relatively large particles to the median particle size d50 of the second active substance having relatively small particles, is less than or equal to 25. It has been observed that such an upper limit avoids a “percolation effect”, which may occur when the size difference between the particles of the first active substance and the particles of the second active substance becomes too high, whereby the relatively small particles tend to flow without sufficient resistance into the empty spaces formed between the relatively large particles, resulting in a separation (or segregation) between the particles of the two particle size classes. The particle mixture then becomes unstable, leading to increased filling weight variability.

[0032] According to one feature of the invention, the 3% percentile d3 of the first active substance is at least two times higher than the 97% percentile d97 of the second active substance. Such a difference in particle size between the smallest particles of the first active substance having relatively large particles, on the one hand, and the largest particles of the second active substance having relatively small particles, on the other hand, guarantees that a system with two distinct particle size classes is obtained, thus promoting homogeneous filling of the empty spaces between the relatively large particles with the relatively small particles.

[0033] According to one feature of the invention, the 3% percentile d3 of the first active substance is at most 10 times higher, preferably at most 7 times higher, than the 97% percentile d97 of the second active substance. When the difference in particle size increases between the smallest particles of the first active substance having relatively large particles, on the one hand, and the largest particles of the second active substance having relatively small particles, on the other hand, the relatively small particles tend to flow without sufficient resistance into the empty spaces formed between the relatively large particles, resulting in a separation (or segregation) between the particles of the two particle size classes. The particle mixture then becomes unstable, leading to increased variability in the filling weight.

[0034] According to one embodiment, the particulate mixture comprises particles of at least two distinct size classes, wherein the particles in each size class have a particle size distribution such that the ratio of the 97% percentile d97 to the 3% percentile d3 is less than or equal to 5, preferably less than or equal to 3. In this way, in each size class, the particle size distribution is tight, so that two categories of particles are clearly distinguished, respectively a first category of relatively large particles and a second category of relatively small particles. In other words, the differential particle size distribution of the particulate mixture includes two narrow Gaussian peaks which together compose a wider Gaussian curve. Such a system with two distinct particle size classes is advantageous for the homogeneous filling of the empty spaces between the relatively large particles with the relatively small particles, not only for particulate mixtures with well-calibrated particles but also for particulate mixtures with great variability in particle shape and dimensions.

[0035] According to one embodiment, the median particle size d50 of the first active substance having relatively large particles, is between 0.1 mm and 10 mm, preferably between 0.1 mm and 5 mm. Such ranges for the median particle size d50 of the relatively large particles ensure the absence of fine powder particles that are difficult to handle and dose due to their sensitivity to electrostatic interactions, while avoiding loss of filling capacity when the particle size becomes too large in relation to the inner volume of the chamber to be filled.

[0036] According to one embodiment, the median equivalent volume of the particles of the first active substance is less than 1 / 10 of the inner volume of the chamber, where the median equivalent volume of the particles of the first active substance is defined as the volume of a sphere having a diameter equal to the median particle size d50 of the first active substance. This avoids loss of filling capacity when the particle size becomes too large in relation to the inner volume of the chamber to be filled.

[0037] According to one embodiment, the particles of the first active substance having relatively large particles are in beaded form. Such a beaded form of the relatively large particles of the particulate mixture, compared to, e.g., a granular form, ensures that a more repeatable interstitial volume exists between the relatively large particles of the particulate mixture, thereby allowing the relatively small particles of the particulate mixture to fit into the interstitial volumes between the relatively large particles.

[0038] According to one embodiment, the ratio of the 97% percentile d97 to the 3% percentile d3 of the particulate mixture is higher than or equal to 9.5. Such a difference in size between the relatively large particles and the relatively small particles is significant enough to observe a densification effect, i.e. an increase in the filling weight of the chamber compared to what is obtained with only the relatively large particles or only the relatively small particles.

[0039] According to one embodiment, a difference between the 97% percentile d97 and the 3% percentile d3 of the particulate mixture is higher than or equal to 2.5 mm. Such a difference in size between the relatively large particles and the relatively small particles is significant enough to observe a densification effect, i.e. an increase in the filling weight of the chamber, while being compatible with the volumes of chambers used in the field of humidity control devices, i.e. small inner volumes of the order of 1 cm3to 30 cm3. According to one embodiment, the 97% percentile d97 of the particulate mixture is higher than 1 mm, preferably higher than 1.5 mm, preferably higher than 2 mm. This ensures that the larger particles in the particulate mixture are large enough to create enough void spaces to achieve a significant densification effect of the particulate mixture without having to use fine powder particles.

[0040] According to one embodiment, the inner volume of the chamber defined by the gas- permeable envelope is filled with the particulate mixture in such a way that the volume occupied by the particulate mixture is higher than or equal to 70%, preferably higher than or equal to 80%, of the inner volume of the atmosphere control device containing the particulate mixture. In this way, most of the inner working volume of the chamber is used to receive the particulate mixture and the atmosphere control capacity of the device is maximized.

[0041] According to one embodiment, the particulate mixture in the chamber has a densification factor of higher than or equal to 1 .15, where the densification factor is defined as: where Wmixis the filling weight when the chamber is filled with the particulate mixture; Wtis the filling weight of the chamber filled with 100% of particles of the active substance corresponding to the i-th size class; xtis the weight percentage in the particulate mixture of the active substance corresponding to the i-th size class; n is the number of distinct size classes in the particulate mixture.

[0042] The size classes in the particulate mixture can be detected by identifying, in the graph of the cumulative particle size distribution by mass Qs(x) of the particulate mixture, the portions of the graph, between the 3% percentile d3 and the 97% percentile d97, in which the cumulative mass is increased by less than 10%, preferably less than 5%, when the particle size x is doubled.

[0043] According to one embodiment, at least one active substance of the particulate mixture is a humidity absorber configured to absorb water vapor from the atmosphere surrounding the device. According to one embodiment, at least one active substance of the particulate mixture is a humidity control substance configured to control an equilibrium humidity, i.e. to both absorb and / or release water vapor from / to the atmosphere surrounding the device. It is understood that, within the meaning of the invention, the term "absorb", when referring to a given active substance, with respect to water, is used to encompass all chemical and physical phenomena by which water may be retained by said active substance. In particular, this includes bulk phenomena, generally referred to as “absorption”, where water molecules enter the material of the active substance; or surface phenomena, generally referred to as “adsorption”, where water molecules attach to the surface of the material of the active substance.

[0044] According to one embodiment, each active substance of the particulate mixture is selected from silica gel, molecular sieve, activated clay, and mixtures thereof.

[0045] According to one embodiment, each active substance of the particulate mixture is a silica gel in particulate form and the apparent density of the silica gel particulate mixture in the chamber is higher than or equal to 0.70 g / cm3, preferably higher than or equal to 0.75 g / cm3, preferably higher than or equal to 0.80 g / cm3, when measured according to DIN ISO 60 (equivalent to ASTM D1895 - Method A), when silica gel has a moisture content of less than or equal to 3%. The moisture content can be established according to the “Loss on Drying” test methods described for different types of desiccants in United States Pharmacopeia standard USP <670>.

[0046] According to one embodiment, the atmosphere control device has a water vapor absorption rate higher than or equal to 10 mg / 24h at 25°C, 60%RH, preferably higher than or equal to 30 mg / 24h, at 25°C, 60%RH. To assess the water vapor absorption rate, the initial weight wo of the atmosphere control device is recorded. The atmosphere control device is then placed in a climatic chamber regulated at 25°C, 60%RH. After 24h, the atmosphere control device is weighed again and the new weight W24 is recorded. The water vapor absorption rate is calculated from the difference wo - W24.

[0047] According to another embodiment, the atmosphere control device has a water vapor absorption capacity by volume higher than or equal to 195 mg / cm3, preferably higher than or equal to 205 mg / cm3, at 25°C, 60%RH. To assess the water vapor absorption rate, the initial weight wo of the atmosphere control device is recorded. The atmosphere control device is then placed in a climatic chamber regulated at 25°C, 60%RH. Every 24h, the atmosphere control device is weighed again and the new weight is recorded and compared to the previous weight. When the weight variation between two consecutive measurements is less than 2%, the equilibrium weight weqis recorded. The water vapor absorption capacity in mg is calculated from the difference wo - weq. The water vapor absorption capacity by volume in mg / cm3is expressed as the ratio of the water vapor absorption capacity to the volume occupied by the particulate material.

[0048] In one embodiment, the atmosphere control device is a capsule, a canister, a closure or a cavity in a vial or in a device, the envelope comprising a gas- impermeable body configured to receive the particulate mixture and at least one gas-permeable cover configured to close the body so that the particulate mixture is retained inside the envelope.

[0049] In another embodiment, the atmosphere control device is a packet or a bag, the envelope comprising a gas-permeable membrane configured to enwrap the particulate mixture, such as a non-woven fabric or a perforated polymer film.

[0050] Another subject of the invention is a method for manufacturing an atmosphere control device such as a capsule, a canister, a closure, a packet or a cavity in a vial or in a device, for regulating an atmosphere in a packaging or a medical device containing sensitive or odorous products, the device comprising a gas-permeable envelope defining a chamber, wherein the chamber has in its inner volume a particulate mixture comprising a first active substance in particulate form having relatively large particles and a second active substance in particulate form having relatively small particles, wherein the particle size distribution of the particulate mixture is such that the graph of the cumulative particle size distribution by mass Qs(x) of the particulate mixture includes, between the 3% percentile d3 and the 97% percentile d97, a portion in which the cumulative mass is increased by less than 10%, preferably less than 5%, when the particle size x is doubled, where the 3% percentile d3 corresponds to the particle size below which there are 3% of the smallest particles and the 97% percentile d97 corresponds to the size above which there are 3% of the largest particles, wherein the method comprises steps of:

[0051] - providing the envelope in an open configuration;

[0052] - introducing, in at least one part of the open envelope, each active substance of the particulate mixture;

[0053] - closing the envelope when a desired weight of each active substance of the particulate mixture is received in the at least one part of the open envelope, so that the particulate mixture is retained inside the chamber defined by the gas- permeable envelope.

[0054] According to one embodiment of the manufacturing method, the particles of the first active substance and the particles of the second active substance are mixed to form a pre-mixed particulate mixture, and then the pre-mixed particulate mixture is introduced in the at least one part of the open envelope, the at least one part of the open envelope optionally being vibrated during the introduction of the pre-mixed particulate mixture.

[0055] According to another embodiment of the manufacturing method, the particles of the first active substance and the particles of the second active substance are introduced separately in the at least one part of the open envelope, for example from two separate feeders, and mixed inside the at least one part of the open envelope.

[0056] Another subject of the invention is a use of an atmosphere control device as described above, for regulating an atmosphere in a packaging or a medical device, in particular in a packaging containing moisture-sensitive products, such as tablets or capsules containing a pharmaceutical composition; nutraceuticals; herbalism products; diagnostic products.

[0057] BRIEF DESCRIPTION OF THE DRAWINGS Features and advantages of the invention will become apparent from the following description of embodiments of an atmosphere control device and a manufacturing method according to the invention, this description being given merely by way of example and with reference to the appended drawings in which:

[0058] Figure 1 is a perspective view of an atmosphere control device according to a first embodiment of the invention, which is a humidity control capsule having its chamber filled with a first particulate mixture, comprising 50 wt% of a first active substance, which is a silica gel in beaded form having relatively large particles with a particle size of between 3 mm and 5 mm, and 50 wt% of a second active substance, which is a silica gel in granular form having relatively small particles with a particle size of between 0.2 mm and 1 mm;

[0059] Figure 2 is a cross section along the line ll-ll of Figure 1 ;

[0060] Figure 3 is a graph of the cumulative particle size distribution by mass Qs(x) of the first active substance, i.e. the silica gel in beaded form with a particle size of between 3 mm and 5 mm;

[0061] Figure 4 is a graph of the cumulative particle size distribution by mass Qs(x) of the second active substance, i.e. the silica gel in granular form with a particle size of between 0.2 mm and 1 mm;

[0062] Figure 5 is a graph of the cumulative particle size distribution by mass Qs(x) of the first particulate mixture, comprising 50 wt% of a silica gel in beaded form with a particle size of between 3 mm and 5 mm as the first active substance, and 50 wt% of a silica gel in granular form with a particle size of between 0.2 mm and 1 mm as the second active substance;

[0063] Figure 6 is a graph showing the filling weight of the humidity control capsule of Figure 1 for several mixing ratios of a silica gel in beaded form with a particle size of between 3 mm and 5 mm as the first active substance and a silica gel in granular form with a particle size of between 0.2 mm and 1 mm as the second active substance; Figure 7 is a graph of the cumulative particle size distribution by mass Qs(x) of a second particulate mixture, comprising 50 wt% of a first active substance, which is a silica gel in beaded form having relatively large particles with a particle size of between 3 mm and 5 mm, and 50 wt% of a second active substance, which is a silica gel in granular form having relatively small particles with a particle size of less than 0.3 mm;

[0064] Figure 8 is a graph of the cumulative particle size distribution by mass Qs(x) of a third particulate mixture according to a comparative example, not being part of the invention, comprising 50 wt% of a first active substance, which is a silica gel in granular form having relatively large particles with a particle size of between 0.2 mm and 1 mm, and 50 wt% of a second active substance, which is a silica gel in granular form having relatively small particles with a particle size of less than 0.3 mm;

[0065] Figure 9 is a perspective view similar to Figure 1 for an atmosphere control device according to a second embodiment of the invention, which is a humidity control canister having its chamber filled with the first particulate mixture, comprising 50 wt% of a silica gel in beaded form with a particle size of between 3 mm and 5 mm as the first active substance, and 50 wt% of a silica gel in granular form with a particle size of between 0.2 mm and 1 mm as the second active substance;

[0066] Figure 10 is a cross section along the line X-X of Figure 9;

[0067] Figure 11 is a perspective view similar to Figure 1 for an atmosphere control device according to a third embodiment of the invention, which is a humidity control stopper having its chamber filled with the first particulate mixture, comprising 50 wt% of a silica gel in beaded form with a particle size of between 3 mm and 5 mm as the first active substance, and 50 wt% of a silica gel in granular form with a particle size of between 0.2 mm and 1 mm as the second active substance;

[0068] Figure 12 is a cross section along the line XII-XII of Figure 11 ;

[0069] Figure 13 is a perspective view similar to Figure 1 for an atmosphere control device according to a fourth embodiment of the invention, which is a humidity control packet having its chamber filled with the first particulate mixture, comprising 50 wt% of a silica gel in beaded form with a particle size of between 3 mm and 5 mm as the first active substance, and 50 wt% of a silica gel in granular form with a particle size of between 0.2 mm and 1 mm as the second active substance; and

[0070] Figure 14 is a cross section along the line XIV-XIV of Figure 13.

[0071] ILLUSTRATIVE EMBODIMENTS OF THE INVENTION

[0072] In the first embodiment shown in Figures 1 and 2, the atmosphere control device is a humidity control capsule 1 , e.g. intended to be dropped in a container (not represented) in which moisture-sensitive products are stored, such as a bottle, a pouch or any other type of container. The capsule 1 comprises a gas-permeable envelope 10 defining a chamber 13 in which a particulate mixture 6 is arranged. As shown schematically in Figure 2, the particulate mixture 6 is a bimodal particulate mixture of optimized composition, comprising 50 wt% of a first active substance 61 , which is a silica gel in beaded form having relatively large particles with a size of between 3 mm and 5 mm, and 50 wt% of a second active substance 62, which is a silica gel in granular form having relatively small particles with a size of between 0.2 mm and 1 mm.

[0073] The envelope 10 of the capsule 1 comprises a tubular body 11 which may advantageously be obtained by injection molding of a thermoplastic material such as polyethylene. The tubular body 11 comprises a bottom wall 12 and a side wall 14 delimiting a volume for receiving the particulate mixture 6, which is closed by a gas- permeable cover 16 to form the cylinder-shaped chamber 13. By way of example, the cylinder-shaped chamber 13 has an inner diameter D of 15.6 mm and the inner working volume of the tubular body 11 is 3.25 cm3. The gas-permeable cover 16 is a cardboard disc held in contact against a shoulder of the capsule body 11 by a thinner extension 15 of the side wall 14 which has been crimped.

[0074] Figures 3 and 4 show the cumulative particle size distributions by mass Qs(x) of the first active substance 61 and the second active substance 62, respectively. Each value Qs(x) indicates the mass of the sample consisting of particles smaller than size x. Useful percentiles can be extracted from the cumulative distributions by mass Qs, including: the median particle size d50, corresponding to the particle size dividing the particle size distribution into 50% of “smaller” particles and 50% of “larger” particles; the 3% percentile d3, corresponding to the size below which there are 3% of the smallest particles; the 97% percentile d97, corresponding to the size above which there are 3% of the largest particles.

[0075] As seen in the graphs of Figures 3 and 4, the median particle size d50 of the first active substance 61 , denoted d50-6i in Figure 3, is of the order of 4 mm, whereas the median particle size d50 of the second active substance 62, denoted d50-62 in Figure 4, is of the order of 0.58 mm. Thus, the ratio of the median particle size d50. 61 of the first active substance 61 to the median particle size d50-62 of the second active substance 62 is of the order of 7.

[0076] The graphs of Figures 3 and 4 also show the 3% percentile d3 of the first active substance 61 , i.e. the size below which there are 3% of the smallest particles of the first active substance 61 , which is denoted d3-6i in Figure 3 and is of the order of 3 mm, and the 97% percentile d97 of the second active substance 62, i.e. the size above which there are 3% of the largest particles of the second active substance 62, which is denoted d97-62 in Figure 4 and is of the order of 0.98 mm. Thus, the 3% percentile d3-6i of the first active substance 61 is more than 3 times higher than the 97% percentile d97-62 of the second active substance 62.

[0077] As shown in Figure 5, the graph of the cumulative particle size distribution by mass Qs(x) of the bimodal particulate mixture 6 of optimized composition as described above, with 50 wt% of the first active substance 61 and 50 wt% of the second active substance 62, corresponds to a gap-graded particle size distribution including, between the 3% percentile d3 (equal to 0.2 mm) and the 97% percentile d97 (equal to 4.9 mm), a portion P which is a substantially horizontal plateau where the cumulative mass is increased by less than 5% when the particle size x is doubled.

[0078] A method for manufacturing the humidity control capsule 1 comprises the following steps. First, the capsule body 11 is filled with a given weight of the bimodal particulate mixture 6, e.g. in a filling station. To this end, a given weight of particles of the first active substance 61 and a given weight of particles of the second active substance 62 can be mixed to form a pre-mixed particulate mixture 6, which is then introduced in the capsule body 11 . In order to promote a homogeneous filling, the capsule body 11 may be vibrated during the introduction of the pre-mixed particulate mixture 6. As a variant, a given weight of particles of the first active substance 61 and a given weight of particles of the second active substance 62 can be introduced separately in the capsule body 11 , e.g. from two separate feeders, and mixed inside the capsule body 11 . In this case, the mixing of the particles inside the capsule body 11 may result from the simultaneous introduction of the first active substance 61 and the second active substance 62 and / or be assisted using a stirring tool.

[0079] Once it has been filled with the given weights of particles of the first active substance 61 and the second active substance 62, the capsule body 11 is closed with a gas- permeable cover 16, e.g. in a closing station. The gas-permeable cover 16 is fastened on the tubular body 11 by crimping, so that the particulate mixture 6 is retained inside the chamber 13 defined by the gas-permeable envelope 10. The filled and closed capsule 1 can then be moved successively through, e.g., a marking station, a control station and a packing station. The packing station may comprise a rotating drum, from which the capsule 1 falls into a storage package 202 which is suitable for the storage of a plurality of capsules 1 before they are used as humidity control devices. In particular, the storage package may be a heat-sealable pouch made from a multilayer material comprising at least one barrier layer providing gas barrier properties, more specifically moisture barrier properties, e.g. an aluminum layer, and at least one heat-sealable layer, e.g. a polyethylene layer. In one embodiment, the heat-sealable pouch has a Water Vapor Transmission Rate (WVTR) of less than or equal to 0.1 g / m2.24h when measured according to ASTM E398 at 38°C, 90%RH.

[0080] The method for manufacturing humidity control capsules 1 comprising a bimodal particulate mixture 6, as defined in the invention, can easily be implemented on existing manufacturing lines. In particular, the step of mixing the particles of the first active substance 61 and the second active substance 62 to form the bimodal particulate mixture 6 is easily integrated in the filling station of an existing manufacturing line. Advantageously, the step of filling the capsule body 11 with the bimodal particulate mixture 6 can be totally automated, so that a predictable quantity of the first and second active substances is introduced in the chamber 13 while respecting the filling time imposed by the production rates existing on manufacturing lines for capsules. In particular, for a capsule body 11 having an inner working volume of 3.25 cm3and the bimodal particulate mixture 6 of optimized composition as described above, it was possible to produce more than 500 capsules per minute.

[0081] Tests have also been carried out to determine the effect on the filling efficiency of the particle size distribution of the particulate mixture and the mixing ratio of the first active substance and the second active substance. The test conditions and results are described below in EXAMPLE 1 , EXAMPLE 2 and COMPARATIVE EXAMPLE 3.

[0082] EXAMPLE 1 :

[0083] Several sets of capsules 1 , comprising a capsule body 11 and a gas-permeable cover 16 forming a gas-permeable envelope 10 as shown in Figures 1 and 2, were produced and filled with a bimodal particulate mixture 6 comprising a first active substance 61 having relatively large particles and a second active substance 62 having relatively small particles. The first active substance 61 was a beaded silica gel available from SINCHEM, with a particle size of between 3 mm and 5 mm. The second active substance 62 was a granular silica gel available from YIMING, with a particle size of between 0.2 mm and 1 mm.

[0084] Each capsule body 11 was injection-molded from polypropylene. The inner working volume of the capsule body 11 , defined between the bottom wall 12 and the crimping plane of the gas-permeable cover 16, was of the order of 3.25 cm3. It is understood that, when filling the capsule body 11 with the bimodal particulate mixture 6, an empty space is kept at the top of the capsule body 11 to allow the positioning and crimping of the gas-permeable cover 16 on the capsule body, as shown in Figure 2. A volumetric dosing system with a dosing unit having a volume of 2.67 cm3was used, resulting in about 80% of the capsule body being filled with the bimodal particulate mixture 6.

[0085] For each set of capsules 1 , a specific mixing ratio of the first active substance 61 and the second active substance 62 was used. In Table 1 below and in Figure 6, the mixing ratios are identified in wt% BIG - wt% SMALL, where “BIG” refers to the first active substance 61 having relatively large particles and “SMALL” refers to the second active substance 62 having relatively small particles. When the mixing ratio corresponds to 0 wt% BIG or 0 wt% SMALL, the particulate mixture comprises silica gel particles of a single size class. In all other cases, the particulate mixture is a bimodal particulate mixture comprising silica gel particles of two distinct size classes.

[0086] The weight of the capsule body 1 1 filled with the bimodal particulate mixture 6 was measured for each set of capsules 1 . The results of the filling weight (in grams) for each sample are given in Table 1 below, where “Increase” is the percentage increase in the filling weight obtained using the bimodal particulate mixture, compared to a reference filling weight of a capsule calculated from the proportion between the ‘BIG’ and ‘SMALL’ particles.

[0087] As an example, the reference weight for a capsule filled with 87.5 wt% BIG - 12.5 wt% SMALL is: 87.5 / 100 * 1.612 + 12.5 / 100 * 1.750 = 1.629 g where 1.612 g is the average filling weight of the capsule filled with 100 wt% of ‘BIG’ particles; and 1 .750 g is the average filling weight of the capsule filled with 100 wt% of ‘SMALL’ particles.

[0088] For the mixing ratio 87.5 wt% BIG - 12.5 wt% SMALL, the average filling weight of the capsules bodies measured experimentally was 1.907 g, resulting in an “Increase” of: (1 .907 - 1 .629) / 1 .629 = 17%.

[0089] It is understood that the “Increase” indicated in Table 1 (as well as Table 2 and Table 3) corresponds to the “densification factor” defined above as: where Wmixis the filling weight when the chamber is filled with the particulate mixture; Wtis the reference filling weight of the capsule filled with 100% of particles of the active substance corresponding to the i-th size class; xtis the weight percentage in the particulate mixture of the active substance corresponding to the 5 i-th size class; n is the number of distinct size classes in the particulate mixture.

[0090] In Example 1 , the particulate mixture comprises particles of two size classes (n = 2). Then, by way of example, for the mixing ratio 87.5 wt% BIG - 12.5 wt% SMALL: Wmix=1 907 g, x-i = 87.5%, = 1.612 g, x2= 12.5%, W2= 1.750 g, so that the densification factor is: 1.907 / (87.5 / 100 * 1.612 + 12.5 / 100 * 1.750) = 1.17. io

[0091] Table 1

[0092] As can be seen from Table 1 and Figure 6, an increase in the filling weight is obtained using a bimodal particulate mixture, compared to reference capsules as defined above. This also results in an increase in the moisture uptake capacity of 15 the capsule in the same proportion as the increase in filling weight.

[0093] The results of Table 1 and Figure 6 also show that a higher increase in the filling weight of the capsule is reached when the percentage of weight of the first active substance 61 having relatively large particles over the total weight of the particulate mixture 6 is between 25 and 87.5 wt%, with a maximum increase for the mixing ratio 75 wt% BIG - 25 wt% SMALL.

[0094] It can be observed that the increase in the filling weight of the chamber is asymmetrical relative to the percentages by weight of the first and second active substances, in particular the increase in the filling weight of the chamber is higher when the percentage by weight of the first active substance comprising relatively large particles is higher than that of the second active substance comprising relatively small particles.

[0095] For the particulate mixture with the mixing ratio 75 wt% BIG - 25 wt% SMALL, corresponding to the maximum densification effect, the apparent density of the silica gel particulate mixture filled in the chamber is 0.79 g / cm3, measured according to DIN ISO 60 (equivalent to ASTM D1895 - Method A), when silica gel has a moisture content of less than or equal to 3%. The moisture content can be established according to the “Loss on Drying” test methods described for different types of desiccants in United States Pharmacopeia standard USP <670>.

[0096] The moisture absorption capacity of the capsule was established by placing the capsule of Example 1 in a climatic chamber regulated at 25°C, 60%RH. The weight gain was measured over time, until the equilibrium was reached, i.e. less than 2% weight variation between two consecutive weight measurements taken at 24h ±4h of time interval.

[0097] Table 2 hereafter shows the adsorption capacity in mg:

[0098] Table 2

[0099] The data of Table 2 show that it is possible to increase by more than 15% the moisture absorption capacity of the capsule by using a particulate mixture comprising silica gel particles of two distinct size classes, compared to a capsule filled with silica gel particles of a single size class with a particle size of the order of 0.2 - 1 mm.

[0100] EXAMPLE 2:

[0101] Another set of capsules 1 , comprising a capsule body 11 and a gas-permeable cover 16 forming a gas-permeable envelope 10 as shown in Figures 1 and 2, were filled, in a way similar to Example 1 , with another particulate mixture 6 comprising a first active substance 61 having relatively large particles and a second active substance 62 having relatively small particles. In this second example, the first active substance 61 was a beaded silica gel available from SINCHEM, with a particle size of between 3 mm and 5 mm, and the second active substance 62 was a granular silica gel available from OKER, with a particle size of less than 0.3 mm.

[0102] The graph of the cumulative particle size distribution by mass Qs(x) of the particulate mixture, for a mixing ratio of 50 wt% of the first active substance 61 and 50 wt% of the second active substance 62, is shown in Figure 7. It can be seen that the median particle size of the first active substance 61 , denoted d50-6i in Figure 7, is of the order of 4 mm, whereas the median particle size of the second active substance 62, denoted d50-62 in Figure 7, is of the order of 0.17 mm. Thus, the ratio of the median particle size d50-6i of the first active substance 61 to the median particle size d50-62 of the second active substance 62 is of the order of 23. In addition, the 3% percentile d3 of the first active substance 61 , which is of the order of 3 mm, is more than 9 times higher than the 97% percentile d97 of the second active substance 62, which is of the order of 0.315 mm.

[0103] It can also be seen in Figure 7 that the graph of the cumulative particle size distribution by mass Qs(x) of the bimodal particulate mixture 6 corresponds to a gap- graded particle size distribution including, between the 3% percentile d3 (equal to 0.04 mm) and the 97% percentile d97 (equal to 4.9 mm), a portion P which is a substantially horizontal plateau where the cumulative mass is increased by less than 5% when the particle size x is doubled.

[0104] By a comparison between the graph of Figure 5, corresponding to Example 1 , and the graph of Figure 7, corresponding to Example 2, it can be seen that the length of the substantially horizontal plateau P is greater in Example 2. In Example 2, the cumulative mass is increased by less than 5% when the particle size is multiplied by 6 (from 0.5 mm to 3 mm) whereas, in Example 1 , the cumulative mass is increased by less than 5% when the particle size is multiplied by 3 (from 1 mm to 3mm). In other words, the difference in particle size between the particles of the first active substance 61 and the particles of the second active substance 62 is greater in Example 2 than in Example 1. In addition, in Example 2 the ratio of the median particle size d50-6i of the first active substance 61 to the median particle size d50-62 of the second active substance 62 is of the order of 23, whereas in Example 1 it is of the order of 7. Furthermore, in Example 2 the ratio of the 3% percentile d3-6i of the first active substance 61 to the 97% percentile d97-62 of the second active substance 62 is of the order of 10, whereas in Example 1 it is of the order of 3.

[0105] For each set of capsules 1 , a specific mixing ratio of the first active substance 61 and the second active substance 62 was used. In Table 2 below, the ratios are identified in wt% BIG - wt% SMALL, where “BIG” refers to the first active substance 61 having relatively large particles and “SMALL” refers to the second active substance 62 having relatively small particles. When the mixing ratio corresponds to 0 wt% BIG or 0 wt% SMALL, the particulate mixture comprises silica gel particles of a single size class. In all other cases, the particulate mixture is a bimodal particulate mixture comprising silica gel particles of two distinct size classes. The weight of the capsule body 11 filled with the bimodal particulate mixture 6 of Example 2 was measured for each set of capsules 1 . The results of the filling weight (in grams) for each sample are given in Table 3 below, where “Increase” is the percentage increase in the filling weight obtained using the bimodal particulate 5 mixture, compared to a reference filling weight of a capsule calculated from the proportion between the ‘BIG’ and ‘SMALL’ particles, as explained above in Example 1.

[0106] Table 3

[0107] 10 Similar to Example 1 , Table 3 shows that in Example 2, an increase in the filling weight is obtained using the bimodal particulate mixture compared to reference capsules as defined above. In the same way as in Example 1 , the results of Table 3 also show that a higher increase in the filling weight of the capsule is reached when the percentage of weight of the first active substance 61 having relatively large

[0108] 15 particles over the total weight of the particulate mixture 6 is between 25 and 87.5 wt%, with a maximum increase for the mixing ratio 75 wt% BIG - 25 wt% SMALL.

[0109] It can be noted that, for all the tested mixing ratios except for the mixing ratio 87.5 wt% BIG - 12.5 wt% SMALL, the increase in the filling weight of the capsule is higher in Example 2 than that obtained in Example 1. This may be explained by the fact that, in Example 2, the difference in particle size between the particles of the first active substance 61 and the particles of the second active substance 62 is greater, so that the empty spaces formed between the larger particles can accommodate an increased number of smaller particles. The results of Table 3 show a particularly positive effect on densification in the case of the mixing ratio 75 wt% BIG - 25 wt% SMALL, corresponding to an increase of 36% in Example 2, compared to 28% in Example 1 .

[0110] For the mixing ratio 87.5 wt% BIG - 12.5 wt% SMALL, however, greater variability is observed in the measurements of Example 2, with an RSD value higher than 10%, which was not observed in Example 1. It appears that, for this mixing ratio, the increased size difference in Example 2 between the particles of the first active substance 61 and the particles of the second active substance 62, was detrimental. In particular, in Example 2, a percolation threshold in terms of mixing ratio and particle size of the second active substance 62 is observed, at which the relatively small particles tend to flow without sufficient resistance into the empty spaces formed between the relatively large particles, resulting in a separation between the particles of the two particle size classes. The particle mixture then becomes unstable, leading to an increased filling weight variability as observed in Table 3.

[0111] Similar to Example 1 , the increase in the filling weight of the chamber in Example 2 is asymmetrical relative to the percentages by weight of the first and second active substances, in particular the increase in the filling weight is higher when the percentage by weight of the first active substance 61 is higher than that of the second active substance 62.

[0112] For the particulate mixture with the mixing ratio 75 wt% BIG - 25 wt% SMALL, corresponding to the maximum densification effect, the apparent density of the silica gel particulate mixture filled in the chamber is 0.88 g / cm3, measured according to DIN ISO 60 (equivalent to ASTM D1895 - Method A), when silica gel has a moisture content of less than or equal to 3%. The moisture content can be established according to the “Loss on Drying” test methods described for different types of desiccants in United States Pharmacopeia standard USP <670>.

[0113] COMPARATIVE EXAMPLE 3:

[0114] Another set of capsules 1 , comprising a capsule body 11 and a gas-permeable cover 16 forming a gas-permeable envelope 10 as shown in Figures 1 and 2, were filled with another particulate mixture 6 outside the scope of the invention. In this comparative example, the particulate mixture 6 still comprises a first active substance 61 having relatively large particles and a second active substance 62 having relatively small particles, but the particle size distribution of the particulate mixture is not a gap-graded particle size distribution. In this third example, the first active substance 61 was a granular silica gel available from YIMING, with a particle size of between 0.2 mm and 1 mm, and the second active substance 62 was a granular silica gel available from OKER, with a particle size of less than 0.3 mm.

[0115] The graph of the cumulative particle size distribution by mass Qs(x) of the particulate mixture, for a mixing ratio of 50 wt% of the first active substance 61 and 50 wt% of the second active substance 62, is shown in Figure 8. It can be seen that the median particle size of the first active substance 61 , denoted d50-6i in Figure 8, is of the order of 0.58 mm, whereas the median particle size of the second active substance 62, denoted d50-62 in Figure 8, is of the order of 0.17 mm. Thus, the ratio of the median particle size d50-6i of the first active substance 61 to the median particle size d50-62 of the second active substance 62 is of the order of 3.4. However, the 3% percentile d3 of the first active substance 61 is of the order of 0.3 mm, whereas the 97% percentile d97 of the second active substance 62 is also of the order of 0.3 mm.

[0116] As can be seen in Figure 8, in this Example 3, the graph of the cumulative particle size distribution by mass Qs(x) of the particulate mixture 6 does not correspond to a gap-graded particle size distribution. In particular, between the 3% percentile d3 (equal to 0.04 mm) and the 97% percentile d97 (equal to 0.92 mm), there is no substantially horizontal plateau or portion P where the cumulative mass is increased by less than 5% when the particle size x is doubled. In other words, in Example 3, the particulate mixture comprises silica gel particles of a single size class.

[0117] For each set of capsules 1 , a specific mixing ratio of the first active substance 61 and the second active substance 62 was used. In Table 3 below, the ratios are 5 identified in wt% BIG - wt% SMALL, where “BIG” refers to the first active substance 61 having relatively large particles and “SMALL” refers to the second active substance 62 having relatively small particles.

[0118] The weight of the capsule body 11 filled with the particulate mixture 6 of Example 3 was measured for each set of capsules 1 . The results of the filling weight (in grams) 10 for each sample are given in Table 4 below, where “Increase” is the percentage increase in the filling weight obtained using the particulate mixture 6, compared to a reference filling weight of a capsule calculated from the proportion between the ‘BIG’ and ‘SMALL’ particles, as explained above in Example 1 .

[0119] 15 Table 4

[0120] Table 4 shows that in Example 3, there is no significant increase in the filling weight obtained using the particulate mixture not being part of the invention, compared to reference capsules as defined above. In Example 3, the difference in particle size between the particles of the first active substance 61 and the particles of the second active substance 62 is too small and does not result in the graph of the cumulative particle size distribution by mass Qs(x) of the particulate mixture 6 of Example 3 being a gap-graded particle size distribution with a substantially horizontal plateau. As shown in Table 4, this does not allow a densification effect, i.e. an increase in the filling weight of the chamber.

[0121] In the second embodiment shown in Figures 9 and 10, the atmosphere control device is a humidity control canister 3. In the same way as the capsule 1 of the first embodiment, the canister 3 is intended to be dropped in a container (not represented) in which sensitive products are stored, such as a bottle, a pouch or any other type of container. The canister 3 comprises a gas-permeable envelope 30 defining a chamber 33 in which a particulate mixture 6 is arranged. As shown schematically in Figure 10, the particulate mixture 6 is a bimodal particulate mixture of optimized composition, comprising 50 wt% of a first active substance 61 , which is a silica gel in beaded form having relatively large particles with a size of between 3 mm and 5 mm, and 50 wt% of a second active substance 62, which is a silica gel in granular form having relatively small particles with a size of between 0.2 mm and 1 mm.

[0122] The envelope 30 of the canister 3 comprises a tubular canister body 31 , with a bottom wall 32 and a side wall 34 delimiting a volume for receiving the particulate mixture 6, and a gas-permeable cover 36, configured to close the canister body 31 to form the cylinder-shaped chamber 33. The canister body 31 and the gas- permeable cover 36 may be obtained by injection molding of a thermoplastic material such as polyethylene. The gas-permeable cover 36 is provided with a plurality of perforations 38 and is configured to be fastened on the tubular body 31 , e.g. by clipping using complementary clipping members 35 and 37 of the body and the cover, as shown in Figure 10. By way of example, the cylinder-shaped chamber 33 has an inner diameter D of 11 .7 mm and the inner working volume of the canister body 31 is 1.5 cm3. Depending on the sizes of the particles of the particulate mixture 6, a porous membrane (not shown in the figures) may also be used to cover the perforations 38 of the gas-permeable cover 36, in order to avoid escape of particles of the particulate mixture 6 through the perforations 38 that may contaminate the products contained in the packaging. Such escape of particles may happen when the size of at least some particles of the particulate mixture 6 is less than that of the perforations 38. In this case, a porous disc may advantageously be placed against the internal face of the cover 36, e.g. a disc of non-woven fabric comprising polyethylene fibers such as TYVEK manufactured by DuPont, or a disc of gas-permeable cardboard. In this case, the porous disc may be assembled with the cover 36 by inserting the disc in the cover 36 or by over-molding the cover 36 around the disc.

[0123] In the third embodiment shown in Figures 11 and 12, the atmosphere control device is a humidity control closure 5 intended to close an opening of a container 9 in which sensitive products are stored. The closure 5 is configured to exchange water vapor with the inner volume of the container 9. The closure 5 comprises a gas-permeable envelope 50 defining a chamber 53 in which a particulate mixture 6 is arranged. As shown schematically in Figure 12, the particulate mixture 6 is a bimodal particulate mixture of optimized composition, comprising 50 wt% of a first active substance 61 , which is a silica gel in beaded form having relatively large particles with a size of between 3 mm and 5 mm, and 50 wt% of a second active substance 62, which is a silica gel in granular form having relatively small particles with a size of between 0.2 mm and 1 mm.

[0124] More precisely, the envelope 50 comprises a top wall 52 of the closure and an annular wall 54 projecting from the top wall 52, thus defining a hollow body 51 for receiving the particulate mixture 6. The hollow body 51 is closed by a gas-permeable cover 56, which retains the particulate mixture 6 inside the hollow body, thus forming the cylinder-shaped chamber 53. By way of example, the cylinder-shaped chamber 53 has an inner diameter D of 17.2 mm and the inner working volume of the hollow body 51 is 3.2 cm3. In the represented example, the gas-permeable cover 56 is a cardboard held in contact against a shoulder at its periphery by thinner extensions 55 of the annular wall 54 which have been crimped. As shown in Figure 12, when the closure 5 is closed onto the container 9, the annular wall 54 extends towards the inside of the container 9 so that water vapor can be exchanged between the inner volume of the container 9 and the particulate mixture 6.

[0125] The closure 5 also comprises a sealing skirt 57 which extends from the top wall 52 and is configured to establish a sealing contact with an inner wall surface of the container 9 surrounding its opening. Radially outside the sealing skirt 57 and concentrically arranged relative to the sealing skirt 57 is an outer rim 58. The rim 58 can for example cooperate with the sealing skirt 57 to establish a moisture-tight seal with the wall of the container 9 surrounding its opening. The rim 58 can also be connected to a tamper evident ring for providing a visual indication of first opening to an end user. The rim 58 can also comprise a surface, a cavity or any geometry facilitating the opening of the container 9 by the end user.

[0126] In the fourth embodiment shown in Figures 13 and 14, the atmosphere control device is a humidity control packet 7. Here again, the packet 7 is intended to be dropped in a container (not represented) in which sensitive products are stored, such as a bottle, a pouch or any other type of container. The packet 7 comprises an envelope 70 defining a chamber 73 in which a particulate mixture 6 is arranged. As shown schematically in Figure 14, the particulate mixture 6 is a bimodal particulate mixture of optimized composition, comprising 50 wt% of a first active substance 61 , which is a silica gel in beaded form having relatively large particles with a size of between 3 mm and 5 mm, and 50 wt% of a second active substance 62, which is a silica gel in granular form having relatively small particles with a size of between 0.2 mm and 1 mm. The envelope 70 is formed by a gas permeable membrane 71 , shaped in such a way as to delimit a volume for receiving the particulate mixture 6. In the example represented in Figures 13 and 14, the envelope 70 comprises a longitudinal seal 74 and two side seals 77, 78.

[0127] The invention is not limited to the examples described and shown.

[0128] In particular, the invention has been illustrated for a capsule, a canister, a stopper or a packet. However, it may also be implemented for other types of receptacles known in the art for atmosphere regulation, for example for the filling of cavities arranged at the bottom of vials conventionally used for diagnostic test strips or provided in a device (e.g., a Dry Powder Inhaler) to contain at least one active substance.

[0129] In addition, in the previous examples, the particulate mixture comprises silica gel as the active substance, with different particle sizes. It is understood that other active substances in particulate form may also be used in the particulate mixture as defined in the invention. Advantageously, each active substance of the particulate mixture is selected from silica gel, molecular sieve, activated clay, active carbon, and mixtures thereof. In particular, it may be advantageous to combine active substances of different natures within the particulate mixture, for example by mixing at least two among a humidity absorber, an oxygen scavenger, an odor absorber, etc.

[0130] In addition, within the scope of the invention, the particulate mixture may comprise more than two active substances in particulate form. In particular, in one embodiment, the particulate mixture may comprise a third active substance in particulate form having particles with a median particle size d50 smaller than the median particle size d50 of the second active substance. More generally, the particulate mixture may comprise as many distinct size classes as desired, as long as the cumulative particle size distribution by mass Qs(x) of the particulate mixture corresponds to a gap-graded particle size distribution.

[0131] As explained above, in a preferred embodiment, the 10% percentile d10, preferably the 3% percentile d3, of the particulate mixture remains higher than or equal to 0.075 mm to make dosing easier. However, in a variant, the particulate mixture may comprise an active substance in powder form.

[0132] Of course, many other variants can be considered, falling within the scope of the appended claims.

Claims

CLAIMS1 . Atmosphere control device (1 ; 3; 5; 7), such as a capsule, a canister, a closure, a packet, or a cavity in a vial or in a device, for regulating an atmosphere in a packaging (9) or a medical device containing sensitive or odorous products, the device comprising a gas-permeable envelope (10; 30; 50; 70) defining a chamber (13; 33; 53; 73), wherein the chamber (13; 33; 53; 73) has in its inner volume a particulate mixture (6) comprising at least a first active substance (61 ) in particulate form having relatively large particles and a second active substance (62) in particulate form having relatively small particles, wherein the particle size distribution of the particulate mixture (6) is such that the graph of the cumulative particle size distribution by mass Qs(x) of the particulate mixture (6) includes, between the 3% percentile d3 and the 97% percentile d97, a portion (P) in which the cumulative mass is increased by less than 10%, preferably less than 5%, when the particle size x is doubled, where the 3% percentile d3 corresponds to the particle size below which there are 3% of the smallest particles and the 97% percentile d97 corresponds to the size above which there are 3% of the largest particles.

2. Atmosphere control device according to claim 1 , wherein the inner volume of the chamber (13; 33; 53; 73) is less than or equal to 30 cm3, preferably less than or equal to 10 cm3, preferably less than or equal to 5 cm3.

3. Atmosphere control device according to claim 1 or claim 2, wherein, in the graph of the cumulative particle size distribution by mass Qs(x) of the particulate mixture (6), for each portion (P) in which the cumulative mass is increased by less than 10%, preferably less than 5%, when the particle size x is doubled, the maximum particle size ratio in said portion is less than or equal to 10, preferably less than or equal to 7.

4. Atmosphere control device according to any one of the preceding claims, wherein the 10% percentile d10, preferably the 3% percentile d3, of the particulate mixture is higher than or equal to 0.075 mm.

5. Atmosphere control device according to any one of the preceding claims, wherein a percentage of weight of the first active substance (61 ) having relatively large particles over the total weight of the particulate mixture (6) is between 25 and 80 wt%, preferably between 35 and 80 wt%.

6. Atmosphere control device according to any one of the preceding claims, wherein a ratio of the median particle size (d50-6i) of the first active substance (61 ) to the median particle size (d50-62) of the second active substance (62) is higher than or equal to 4.

7. Atmosphere control device according to any one of the preceding claims, wherein a ratio of the median particle size (d50-6i) of the first active substance having relatively large particles to the median particle size (d50-62) of the second active substance having relatively small particles, is less than or equal to 25.

8. Atmosphere control device according to any one of the preceding claims, wherein the 3% percentile (d3-6i) of the first active substance (61 ) is at least two times higher than the 97% percentile (d97-62) of the second active substance (62).

9. Atmosphere control device according to any one of the preceding claims, wherein the 3% percentile (d3-6i) of the first active substance (61 ) is at most 10 times higher, preferably at most 7 times higher, than the 97% percentile (d97-62) of the second active substance (62).

10. Atmosphere control device according to any one of the preceding claims, wherein the particulate mixture (6) comprises particles of at least two distinct size classes, wherein in each size class the particles have a particle size distribution such that the ratio of the 97% percentile d97 to the 3% percentile d3 is less than or equal to 5, preferably less than or equal to 3.11 . Atmosphere control device according to any one of the preceding claims, wherein the inner volume of the chamber (13; 33; 53; 73) defined by the gas-permeable envelope (10; 30; 50; 70) is filled with the particulate mixture (6) in such a way that the volume occupied by the particulate mixture is higher than or equal to 70%, preferably higher than or equal to 80%, of the inner volume of the atmosphere control device.

12. Atmosphere control device according to any one of the preceding claims, wherein the particulate mixture (6) in the chamber (13; 33; 53; 73) has a densification factor of higher than or equal to 1.15, where the densification factor is defined as:where Wmixis the filling weight when the chamber is filled with the particulate mixture; Wtis the filling weight of the chamber filled with 100% of particles of the active substance corresponding to the i-th size class; xtis the weight percentage in the particulate mixture of the active substance corresponding to the i-th size class; n is the number of distinct size classes in the particulate mixture.

13. Atmosphere control device according to any one of the preceding claims, wherein at least one active substance (61 , 62) of the particulate mixture (6) is a humidity absorber or a humidity control substance.

14. Atmosphere control device according to any one of claims 1 to 13, wherein the atmosphere control device is a capsule (1 ), a canister (3), a closure (5), or a cavity in a vial or in a device, wherein the envelope (10; 30; 50) comprises a gas-impermeable body (11 ; 31 ; 51) configured to receive the particulate mixture (6) and at least one gas-permeable cover (16; 36; 56) configured to close the body so that the particulate mixture (6) is retained inside the envelope.

15. Atmosphere control device according to any one of claims 1 to 13, wherein the atmosphere control device is a packet (7) or a bag, wherein the envelope (70) comprises a gas-permeable membrane (71 ) configured to enwrap theparticulate mixture (6), such as a non-woven fabric or a perforated polymer film.

16. Method for manufacturing an atmosphere control device (1 ; 3; 5; 7), such as a capsule, a canister, a closure, a packet, or a cavity in a vial or in a device, for regulating an atmosphere in a packaging (9) or a medical device containing sensitive or odorous products, the device comprising a gas-permeable envelope (10; 30; 50; 70) defining a chamber (13; 33; 53; 73), wherein the chamber (13; 33; 53; 73) has in its inner volume a particulate mixture (6) comprising at least a first active substance (61 ) in particulate form having relatively large particles and a second active substance (62) in particulate form having relatively small particles, wherein the particle size distribution of the particulate mixture (6) is such that the graph of the cumulative particle size distribution by mass Qs(x) of the particulate mixture (6) includes, between the 3% percentile d3 and the 97% percentile d97, a portion in which the cumulative mass is increased by less than 10%, preferably less than 5%, when the particle size x is doubled, where the 3% percentile d3 corresponds to the particle size below which there are 3% of the smallest particles and the 97% percentile d97 corresponds to the size above which there are 3% of the largest particles, wherein the method comprises steps of:- providing the envelope (10; 30; 50; 70) in an open configuration;- introducing, in at least one part of the open envelope, each active substance (61 , 62) of the particulate mixture (6);- closing the envelope when a desired weight of each active substance (61 , 62) of the particulate mixture (6) is received in the at least one part of the open envelope, so that the particulate mixture (6) is retained inside the chamber (13; 33; 53; 73) defined by the gas-permeable envelope.

17. Method according to claim 16, wherein the particles of the first active substance (61 ) and the particles of the second active substance (62) are mixed to form a pre-mixed particulate mixture (6), and then the pre-mixed particulate mixture (6) is introduced in the at least one part of the open envelope (10; 30;50; 70), the at least one part of the open envelope optionally being vibrated during the introduction of the pre-mixed particulate mixture (6).

18. Method according to claim 16, wherein the particles of the first active substance (61 ) and the particles of the second active substance (62) are introduced separately in the at least one part of the open envelope (10; 30; 50;70) and mixed inside the at least one part of the open envelope.

19. Use of an atmosphere control device (1 ; 3; 5; 7) according to any one of claims 1 to 15, for regulating an atmosphere in a packaging (9) or a medical device containing moisture-sensitive products, such as tablets or capsules containing a pharmaceutical composition; nutraceuticals; herbalism products; diagnostic products.

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