Compounds for formulating moisture-sensitive active ingredients

Abstract

The present invention relates to granules of microcrystalline mannitol and granular starch, the granules having a water activity equal to or lower than 0.3. The invention also relates to a method for obtaining the same. The invention also relates to the use of such particles for formulating or stabilizing moisture-sensitive active ingredients, such as probiotics.

Description

Technical Field

[0001] The present invention relates to the field of compounds or excipients for formulating moisture-sensitive active ingredients such as probiotics. Background Art

[0002] We have witnessed an increasing trend in the use of probiotics over the past few decades. The following pharmaceutical forms are used in the production of probiotic food supplements: capsules, powders, drops, etc. In the pharmaceutical industry, the most common are capsule probiotics sold as dietary supplements. The task of the multidisciplinary team is to link the requirements for the best formulation that benefits the host microbiota with the technical needs in the probiotic manufacturing process.

[0003] According to the definition of the World Health Organization (WHO), probiotics represent living organisms that, when administered in optimal amounts, contribute to human health. Probiotics are microorganisms - bacteria and yeasts that contribute to the health of the host by stimulating the growth of beneficial bacteria, inhibiting pathogens by inhibiting mucosal adhesion and producing antimicrobials. Microorganisms with probiotic potential usually come from the genera Lactobacillus, Bifidobacterium, and yeasts.

[0004] Water activity is the main factor affecting the stability of probiotics during the shelf life of the product, followed by storage temperature. The downstream processing and manufacturing of the final product (dietary supplement) need to be carried out under strict temperature and humidity control conditions.

[0005] Since excipients account for a significant proportion of the formulation, it is crucial that these excipients have a low water activity. Therefore, establishing a low water activity product begins with obtaining dry excipients that will be blended with the probiotics. As long as the total water activity remains low, ideally between 0.2 and 0.3, a small amount of high water activity ingredients can be added. An Aw value greater than 0.5 is critical because this is when some probiotic cells, such as Lactobacillus, degrade faster.

[0006] The water activity value indicates the free water (water not bound to molecules) that allows biochemical reactions to occur and has an impact on maintaining the viability of probiotics. This is different from the water content, which is the sum of bound water and free water.

[0007] Unfortunately, obtaining excipients with a low water activity is not enough. In fact, the water activity of the final formulation must also be maintained at a low level during storage. Otherwise, once the formulation comes into contact with moisture, the water activity will increase and cell viability will be impaired.

[0008] Therefore, it is advantageous to have excipients that have a low water activity without the need for additional pre-drying steps and that can further maintain the water activity of the probiotic formulation within an acceptable range, particularly not exceeding 0.5.

[0009] Technical problem

[0010] The object of the present invention is to provide an excipient that is suitable as such for formulating moisture-sensitive active ingredients, in particular probiotics.

[0011] The object of the present invention is to provide an excipient that destabilizes, or even stabilizes, moisture-sensitive active ingredients to a limited extent.

[0012] The object of the present invention is to provide an excipient for formulating moisture-sensitive active ingredients into tablets (in particular chewable tablets) or powder compositions (e.g., fillers for sachets, sticks or hard capsules).

[0013] The object of the present invention is to provide an excipient having satisfactory or improved flowability and / or compressibility and / or tableting ability and / or disintegration time.

[0014] The object of the present invention is to provide a direct compression excipient.

[0015] The object of the present invention is to provide an excipient having other desired properties of such excipients, such as in terms of particle size determination, purity, safety.

[0016] Introduction of the present invention

[0017] The inventors have solved the above problems by providing granules of microcrystalline mannitol and granular starch, which granules have a water activity equal to or lower than 0.3, which water activity is measured at 25 °C.

[0018] As demonstrated in Examples 1.2 and 2.2, Figure 2 and Figure 10 the granules according to the present disclosure have a low water activity below 0.3. When the granules are used for formulating probiotics, the water activity of the resulting formulations increases slowly under standard conditions (refrigerator or room temperature) or more demanding conditions (30 °C, 65% relative humidity) Figure 4 、 Figure 5 、 Figure 7 、 Figure 13 、 Figure 14 、 Figure 16 ). Under standard storage conditions (25 °C, 60% relative humidity), the water activity in the powder formulation packaged in an aluminum foil bag hardly increases, and the water activity in the tablet formulation packaged in an aluminum blister is maintained Figure 13 、 Figure 14 、 Figure 16 ).

[0019] Without being bound by any theory, the inventors believe that this is due to the combined action of mannitol and granular starch. When formulating the recipe, the starch may sequester the water contained in the entire formulation. Then, the starch and mannitol act together to prevent moisture from reaching the probiotics: while mannitol can repel water due to its non-hygroscopic nature and prevent additional water absorption, the starch acts locally as a "sponge" by sequestering the water contained in the microenvironment of the probiotics. Since the granular starch is insoluble, the water remains trapped. When observing Figure 4 , Figure 5 , Figure 7 , Figure 13 , Figure 14 and Figure 16 of the water activity of the formulations, it can be seen that after 3 months of storage, the water activity of the formulations has not reached equilibrium: the measured water activity is always lower than 0.60 - 0.65, i.e., lower than the equilibrium at 60% - 65% relative humidity during storage.

[0020] Both granular starch and mannitol are essential. If mannitol alone is used as an excipient, water is continuously repelled at the surface of the mannitol granules. As a result, the surface of the mannitol granules is covered with free water, which directly impairs cell viability. If starch alone is used, all surfaces of the starch adsorb water and thus attract water, resulting in a water flux, so it saturates faster and the water activity increases faster.

[0021] The inventors also believe that the fact that mannitol and granular starch are co-processed is important because it keeps the two components in the same microenvironment. The importance of the presence of mannitol and granular starch in the same granule was confirmed in the later experiments, as shown in Example Section 3.

[0022] As demonstrated in Example Sections 2.4 ( Figure 18 and Figure 19 ) and 3.2 ( Figure 24 ), the granules according to the present disclosure allow formulating probiotics with improved stability. Although the inventors focused on excipients that are not "too unstable", they actually developed excipients with a protective effect. When formulated into a powder composition, cell viability is improved, and when formulated into tablets, it is hardly damaged.

[0023] In addition, because the granules according to the present disclosure have this unique behavior towards water, they can be used to formulate moisture-sensitive components other than probiotics.

[0024] Particles according to the present disclosure are particularly useful for preparing chewable tablets. Their tableting ability is high enough so that the tablets prepared therefrom maintain their integrity during storage and transportation. At the same time, their tableting ability is low enough so that the tablets are chewable. This is particularly advantageous for use in patients with swallowing difficulties, such as pediatric or elderly patients.

[0025] It has been found that particles with a mannitol to granular starch dry weight ratio higher than 65:35 and lower than 85:15, particularly higher than 75:25 and lower than 85:15, are preferably used for preparing tablets because they allow obtaining (i) tablets with satisfactory hardness, and (ii) tablets in which cell viability is not too much impaired by pressing. Particles with a mannitol to granular starch dry weight ratio of at least 75:25, particularly at least 80:20, have been found to be even more suitable.

[0026] Finally, the particles according to the present disclosure exhibit excellent flowability, taste and sensory properties.

[0027] The inventors have also developed a useful method for preparing such particles. The method can be carried out on an industrial scale. It has good productivity and can be carried out in a continuous manner.

[0028] Co-processed excipients of microcrystalline mannitol and granular starch have been described in previous patents of the applicant (US11,364,204 and US 9,839,610). However, these co-processed excipients have a water activity of 0.5, i.e., higher than the water activity of the particles according to the present disclosure. In addition, neither of the two documents has ever considered using such excipients for formulating moisture-sensitive ingredients because these products were developed for completely different purposes.

[0029] Brief description of the present invention

[0030] The present invention first relates to particles of microcrystalline mannitol and granular starch having a water activity equal to or lower than 0.3, which water activity is measured at 25 °C.

[0031] Preferably, the particles according to the present disclosure have a water activity equal to or lower than 0.2. Preferably, in the particles according to the present disclosure, the dry weight ratio of mannitol to granular starch is equal to or higher than 50:50. Preferably, the particles according to the present disclosure have a water content equal to or lower than 5.0 wt%. Preferably, the particles according to the present disclosure have a bulk density equal to or higher than 350 g / L. Preferably, the particles according to the present disclosure have a tapped density equal to or higher than 400 g / L. Preferably, the particles according to the present disclosure have an angle of repose equal to or higher than 0.30 m 2The specific surface area per g. Preferably, in the particles according to the present disclosure, mannitol contains α-polymorph and -β polymorph. Preferably, the particles according to the present disclosure have a volume average diameter equal to or higher than 90 μm and equal to or lower than 400 μm.

[0032] The present invention also relates to a method for preparing the particles according to the present disclosure, the method comprising the step (a) of agglomerating microcrystalline mannitol and granular starch by spraying dissolved mannitol onto the granular starch and drying, the step (b) of drying the particles obtained in step (a), and the step (c) of cooling the particles obtained in step (b), wherein steps (b) and (c) are carried out using drying air and cooling air respectively, and the water content of the drying air and the cooling air is equal to or lower than 3.0 g / kg of drying air.

[0033] The present invention also relates to particles of mannitol and granular starch obtained or obtainable by the method according to the present disclosure.

[0034] The present invention also relates to a product comprising the particles according to the present disclosure and another ingredient.

[0035] Preferably, the other ingredient is a moisture-sensitive active ingredient. Preferably, the other ingredient is a probiotic. Preferably, the product is a powder composition, a tablet or a chewable tablet.

[0036] The present invention also relates to the use of the particles according to the present disclosure for formulating or stabilizing a moisture-sensitive active ingredient. Description of the Drawings

[0037] Other features, details and advantages will be shown in the following detailed description and the drawings, wherein:

[0038] Figure 1

[0039] Figure 1 is a schematic diagram of an apparatus suitable for carrying out the method according to the present disclosure.

[0040] Figure 2

[0041] Figure 2 is a table showing the results of the characterization of the particles according to the present disclosure.

[0042] Figure 3

[0043] Figure 3 is a graph showing the tableting ability of the particles according to the present disclosure.

[0044] Figure 4

[0045] Figure 4 ​​​​is a bar graph showing the water activity and water content of a powdered composition containing the particles according to the present disclosure and probiotics when stored at 30 °C / 65% RH for 3 months.

[0046] Figure 5

[0047] Figure 5 is a bar graph showing the water activity and water content of a tablet containing the particles according to the present disclosure and probiotics when stored at 30 °C / 65% RH for 3 months, the tablet being obtained using a pressing force of 15 kN.

[0048] Figure 6

[0049] Figure 6 is a bar graph showing the hardness and disintegration time of a tablet containing the particles according to the present disclosure and probiotics when stored at 30 °C / 65% RH for 3 months, the tablet being obtained using a pressing force of 15 kN.

[0050] Figure 7

[0051] Figure 7 is a bar graph showing the water activity and water content of a tablet containing the particles according to the present disclosure and probiotics when stored at 30 °C / 65% RH for 3 months, the tablet being obtained using a pressing force of 20 kN.

[0052] Figure 8

[0053] Figure 8 is a bar graph showing the hardness and disintegration time of a tablet containing the particles according to the present disclosure and probiotics when stored at 30 °C / 65% RH for 3 months, the tablet being obtained using a pressing force of 20 kN.

[0054] Figure 9

[0055] Figure 9 is a graph showing the cell viability of a preparation (tablet and powdered composition) containing the particles according to the present disclosure. Figure 9 (a) is a bar graph showing the cell viability of a tablet containing the particles according to the present disclosure and probiotics after pressing. Figure 9 (b) is a graph showing the cell viability and water activity of a preparation (tablet and powdered composition) containing the particles according to the present disclosure and probiotics when stored at 30 °C / 65% RH for 2 weeks.

[0056] Figure 10

[0057] Figure 10 is a table showing the results of the characterization of the particles according to the present disclosure.​​​​​​

[0058] Figure 11

[0059] Figure 11 is a graph showing the tableting ability of the particles according to the present disclosure.

[0060] Figure 12

[0061] Figure 12 is an SEM image of the particles according to the present disclosure.

[0062] Figure 13

[0063] Figure 13 is a bar graph showing the water activity and water content of a powder composition containing the particles according to the present disclosure and a probiotic when stored at 25°C / 60% RH for 3 months or when stored in a refrigerator for 3 months.

[0064] Figure 14

[0065] Figure 14 is a bar graph showing the water activity and water content of a tablet containing the particles according to the present disclosure and a probiotic when stored at 25°C / 60% RH for 3 months or when stored in a refrigerator for 3 months, the tablet being obtained using a pressing force of 12.5 kN.

[0066] Figure 15

[0067] Figure 15 is a bar graph showing the hardness and disintegration time of a tablet containing the particles according to the present disclosure and a probiotic when stored at 25°C / 60% RH for 3 months or when stored in a refrigerator for 3 months, the tablet being obtained using a pressing force of 12.5 kN.

[0068] Figure 16

[0069] Figure 16 is a bar graph showing the water activity and water content of a tablet containing the particles according to the present disclosure and a probiotic when stored at 25°C / 60% RH for 3 months or when stored in a refrigerator for 3 months, the tablet being obtained using a pressing force of 16.5 kN.

[0070] Figure 17

[0071] Figure 17 is a bar graph showing the hardness and disintegration time of a tablet containing the particles according to the present disclosure and a probiotic when stored at 25°C / 60% RH for 3 months or when stored in a refrigerator for 3 months, the tablet being obtained using a pressing force of 16.5 kN. ​​​​​​​

[0072] Figure 18

[0073] Figure 18 is a graph showing the cell viability of a preparation (tablet and powder composition) containing particles according to the present disclosure and probiotics when stored at 25 °C / 60% RH for 3 months or when stored in a refrigerator for 3 months.

[0074] Figure 19

[0075] Figure 19 represents four graphs showing the cell viability and water activity of a preparation in the form of a powder composition or tablet (12.5 kN or 16.5 kN pressing force) containing probiotics (Lactobacillus rhamnosus) alone or in combination with particles according to the present disclosure when stored at 25 °C / 60% RH for 3 months.

[0076] Figure 20

[0077] Figure 20 represents two graphs showing the water activity of probiotic tablets (according to the present disclosure or comparative) when stored at 25 °C / 60% RH for 3 months or when stored in a refrigerator for 3 months, the tablets having a thickness of 6.9 mm.

[0078] Figure 21

[0079] Figure 21 represents two graphs showing the water content of probiotic tablets (according to the present disclosure or comparative) when stored at 25 °C / 60% RH for 3 months or when stored in a refrigerator for 3 months, the tablets having a thickness of 6.9 mm.

[0080] Figure 22

[0081] Figure 22 represents two graphs showing the hardness of probiotic tablets (according to the present disclosure or comparative) when stored at 25 °C / 60% RH for 3 months or when stored in a refrigerator for 3 months, the tablets having a thickness of 6.9 mm.

[0082] Figure 23

[0083] Figure 23 represents two graphs showing the disintegration time of probiotic tablets (according to the present disclosure or comparative) when stored at 25 °C / 60% RH for 3 months or when stored in a refrigerator for 3 months, the tablets having a thickness of 6.9 mm.

[0084] Figure 24

[0085] Figure 24 ​​​​​​​Two figures representing the cell viability of probiotic tablets (according to the present disclosure or comparative) when stored at 25 °C / 60% RH for 3 months or when stored in the refrigerator for 3 months, the tablets having a thickness of 6.9 mm. Detailed Description

[0086] The accompanying drawings and the following detailed description essentially contain some exact elements. They can be used to enhance the understanding of the invention and, if necessary, can also be used to define the invention.

[0087] Particles of mannitol and granular starch

[0088] The present invention first relates to particles of microcrystalline mannitol and granular starch, the particles having a water activity equal to or lower than 0.3, the water activity being measured at 25 °C.

[0089] The expression "particles of mannitol and granular starch" classically refers to particles having a variable non-spherical shape and an irregular surface when observed by scanning electron microscopy at a magnification of, for example, x200.

[0090] Typically, at a magnification of X2500, fine particles of small agglomerated mannitol crystals can be seen at the surface of the particles.

[0091] The expression "microcrystalline" generally refers to a structure that essentially presents microcrystals at its surface and very few crystals of larger size when observed by electron microscopy at a magnification of, for example, X2500. Microcrystals can be defined as crystals with the sum of length, width and thickness lower than 25 μm. Microcrystals can have very different shapes, from round to elongated.

[0092] Preferably, the mannitol of the particles according to the present disclosure comprises the α-crystalline form and the β-crystalline form. A person skilled in the art can determine the crystalline polymorphism (crystalline form and proportion) of mannitol by infrared spectroscopy or by X-ray diffraction on the powder, preferably by X-ray diffraction on the powder. For example, it can be determined according to the method described in Example section 1.2. Preferably, the mannitol of the particles according to the present disclosure comprises less than 10%, preferably less than 5%, preferably less than 1%, preferably 0% of the δ-crystalline form. Also preferably, the mannitol of the particles according to the present disclosure does not contain the δ-crystalline form, i.e., consists only of the α-crystalline form and the β-crystalline form. Generally, the % ratio of the α-form to the β-form is from 5:95 to 95:5, preferably from 10:90 to 90:10, preferably from 15:85 to 85:15.

[0093] The expression "granular starch" classically refers to starch whose granular structure is substantially retained. Granular starch typically has an alternating structure organized into crystalline, semi-crystalline, and amorphous layers. The characteristics of this organization are typically characterized by a birefringence pattern observed when exposed to polarized light, also known as the "Maltese cross". Granular starch is insoluble in water at room temperature (20 °C - 25 °C).

[0094] The granular starch according to the present disclosure can be from any plant source. It is preferably a super white starch, preferably super white corn starch.

[0095] It can be chemically, enzymatically, or physically modified, as long as its granular structure is maintained. However, the granular starch according to the present disclosure is preferably unmodified, i.e., it is preferably natural granular starch.

[0096] Typically, starch in granular form can also be seen. The granular starch is insoluble in water and can be recovered by dissolving the granules according to the present disclosure in water at room temperature.

[0097] The granules according to the present disclosure can generally be obtained by agglomerating microcrystalline mannitol and granular starch. Thus, the granules according to the present disclosure comprise or consist of co-processed (or "co-agglomerated") microcrystalline mannitol and granular starch. They can be obtained by spraying a liquid containing dissolved mannitol and granular starch into a fluidized bed and drying. They can be obtained by spraying a mannitol solution into a fluidized bed containing granular starch, which is introduced into the fluidized bed in a powdered state. During the drying stage, the liquid containing dissolved mannitol evaporates, resulting in the formation of mannitol microcrystals, which will agglomerate with the granular starch.

[0098] Agglomeration can be obtained by multi-stage spray drying or by fluidized bed granulation. Generally, these methods include the recycling of fine particles.

[0099] In this regard, the inventors have observed that the granules of the present disclosure prepared by a method comprising a spray drying step carried out in a fluidized bed exhibit advantageous characteristics, particularly a higher volume average diameter and improved flowability, compared to those obtained by the same method comprising spray drying but not carried out in a fluidized bed. Thus, the granules prepared by a method comprising a spray drying step carried out in a fluidized bed can be suitable for, for example, equipment for tabletting or for filling sachets or strip packs or hard capsules.

[0100] The water activity of the granules according to the present disclosure is equal to or lower than 0.30, preferably lower than 0.30, preferably equal to or lower than 0.20, preferably lower than 0.20. Preferably equal to or higher than 0.10.

[0101] It should be noted that the expression "water activity", also known as "Aw", is the relative availability of water in a substance. The term "water activity" is typically defined as the vapor pressure of water in a sample divided by the vapor pressure of pure water at the same temperature. The water activity of pure distilled water is exactly one. Water activity is temperature-dependent. That is, water activity changes with temperature. In the present disclosure, water activity is measured at 25 °C.

[0102] The water activity of a product can be determined by measuring the relative humidity of the air surrounding the sample at equilibrium. Thus, the measurement of water activity in a sample is typically carried out in an enclosed (usually insulated) space where such equilibrium can occur. At equilibrium, the water activity of the sample and the relative humidity of the air are equal, and thus the equilibrium relative humidity (ERH) of the air in the measurement chamber provides a measure of the water activity of the sample. At least two different types of water activity instruments are commercially available. One type of water activity instrument uses the chilled mirror dew point technique (e.g., the water activity meter available from Decagon Devices, Inc.), while other types of water activity instruments use sensors that change resistance or capacitance to measure relative humidity (e.g., the water activity meter available from

[0103] The water activity can be determined by a person skilled in the art, for example, by a capacitance hygrometer and a dew point hygrometer, preferably by a dew point hygrometer, for example, according to the method described in Example Section 1.2 below.

[0104] Preferably, the mannitol to granule starch dry weight ratio of the particles according to the present disclosure is equal to or higher than 50:50, preferably equal to or higher than 55:45, preferably equal to or higher than 60:40, preferably equal to or higher than 65:35, more preferably higher than 65:35, preferably equal to or higher than 70:30, preferably equal to or higher than 75:25, more preferably higher than 75:25. It is preferably equal to or lower than 95:5, preferably equal to or lower than 90:10, preferably equal to or lower than 85:15, more preferably lower than 85:15. It is, for example, equal to approximately 80:20.

[0105] It should be understood that this weight ratio refers to the dry weights of mannitol and granule starch used to prepare the particles. This dry weight ratio may be slightly different from the amounts of mannitol and granule starch measured in the final particles. For example, and as is apparent from the examples below, for a dry weight ratio of 80:20 of mannitol / granule starch, it can be seen that the measured mannitol content is 75% to 84%; this percentage is the weight percentage of mannitol relative to the total weight of the particles.

[0106] The amount of mannitol can be determined by a person skilled in the art by high performance liquid chromatography on an ion exchange resin in the calcium form. Quantification is carried out using an external calibration method, for example, determined according to the method described in Example section 1.2 below. Preferably, the measured amount of mannitol in the particles according to the present disclosure is equal to or higher than 50% by weight, preferably equal to or higher than 55%, preferably equal to or higher than 60%, preferably equal to or higher than 65%, more preferably higher than 66%, preferably equal to or higher than 70%, more preferably higher than 70%, preferably equal to or higher than 75%. It is preferably equal to or lower than 95% by weight, preferably equal to or lower than 90%, preferably equal to or lower than 85%. It is, for example, equal to about 75% to equal to about 85%.

[0107] Preferably, the water content (also referred to as "loss on drying") of the particles according to the present disclosure is equal to or lower than 5.0% by weight, preferably equal to or lower than 4.0%, preferably equal to or lower than 3.0%, preferably equal to or lower than 1.4%, preferably equal to or lower than 2.0%, preferably equal to or lower than 1.5%, preferably equal to or lower than 1.3%, preferably equal to or lower than 1.2%. It is generally higher than 0.1%, even higher than 0.2%. The water content can be determined by a person skilled in the art using a halogen moisture analyzer, or most preferably, by drying the test portion in an electrically heated oven at a temperature range of 130 °C to 133 °C under air pressure for 1 hour and 30 minutes, for example, determined according to the method described in Example section 1.2 below.

[0108] Preferably, the bulk density of the particles according to the present disclosure is equal to or higher than 350 g / L, preferably equal to or higher than 400 g / L, preferably equal to or higher than 450 g / L. It is generally equal to or lower than 750 g / L, even equal to or lower than 700 g / L, even equal to or lower than 650 g / L.

[0109] The bulk density can be determined by a person skilled in the art by the following method: allowing the sample to flow through a defined funnel into a test tube of known volume. Measure the mass of a defined volume of the product in the test tube at a specified temperature, and determine the volume of the test tube by measuring the mass of an equal volume of water at the same temperature. Calculate the specific gravity of the product by dividing the mass of the product by the volume of the test tube. For example, determine the specific gravity according to the method described in Example section 1.2 below.

[0110] Preferably, the tapped density of the particles according to the present disclosure is equal to or higher than 400 g / L, preferably equal to or higher than 450 g / L, preferably equal to or higher than 500 g / L. It is generally equal to or lower than 800 g / L, even equal to or lower than 750 g / L.

[0111] The tapped density can be determined by those skilled in the art by the following method: measuring the mass of a certain volume of the product after compaction and the mass of an equal volume of distilled water at the same temperature. The specific gravity is calculated by dividing the mass of the certain volume of the product by the volume of the product itself. For example, the specific gravity is determined according to the method described in Example Part 1.2 below.

[0112] The Hausner ratio can be calculated by those having the following density:

[0113] [Formula 1]

[0114]

[0115] According to Table 1 below, the flow characteristics can be determined from the Hausner ratio:

[0116] [Table 1]

[0117] Hausner ratio Flow characteristics 1.00 to 1.11 Excellent 1.12 to 1.18 Good 1.19 to 1.25 Reasonable 1.26 to 1.34 Fair 1.35 to 1.45 Poor 1.46 to 1.59 Very poor ≥1.60 Very very poor

[0118] Preferably, the particles according to the present disclosure have good or excellent flow characteristics (i.e., a Hausner ratio of 1.00 to 1.18), preferably excellent flow characteristics (i.e., a Hausner ratio of 1.00 to 1.11).

[0119] Preferably, the specific surface area of the particles according to the present disclosure is equal to or higher than 0.30 m 2 / g, preferably equal to or higher than 0.40 m 2 / g, preferably equal to or higher than 0.50 m 2 / g, preferably equal to or higher than 0.80 m 2 / g, preferably equal to or higher than 1.00 m 2 / g, preferably equal to or higher than 1.20 m 2 / g, preferably equal to or higher than 1.40 m 2 / g, preferably equal to or higher than 1.50 m 2 / g. It is generally equal to or lower than 2.50 m 2 / g, even equal to or lower than 2.00 m 2 / g. The specific surface area can be determined by those skilled in the art, for example, by using the BET method, for example, according to the method described in Example Part 1.2 below.

[0120] Preferably, the volume average diameter of the particles according to the present disclosure is equal to or higher than 90 μm and equal to or lower than 400 μm. It is preferably equal to or higher than 100 μm, preferably equal to or higher than 110 μm. It is preferably equal to or lower than 350 μm, preferably equal to or lower than 300 μm, preferably equal to or lower than 250 μm, preferably equal to or lower than 200 μm, preferably equal to or lower than 150 μm.

[0121] Preferably, the volume D10 of the particles according to the present disclosure is equal to or lower than 100 μm, preferably equal to or lower than 80 μm, preferably equal to or lower than 60 μm, preferably equal to or lower than 50 μm. It is generally equal to or higher than 10 μm, even equal to or higher than 20 μm, even equal to or higher than 30 μm, even equal to or higher than 40 μm.

[0122] Preferably, the volume D50 of the particles according to the present disclosure is from 50 μm to 180 μm, preferably from 70 μm to 160 μm, preferably from 90 μm to 140 μm, preferably from 100 μm to 130 μm, preferably from 110 μm to 120 μm.

[0123] Preferably, the volume D90 of the particles according to the present disclosure is equal to or lower than 250 μm, preferably equal to or lower than 230 μm, preferably equal to or lower than 210 μm, preferably equal to or lower than 200 μm. It is generally equal to or higher than 120 μm, even equal to or higher than 140 μm, even equal to or higher than 150 μm, even equal to or higher than 160 μm, even equal to or higher than 170 μm.

[0124] It should be reminded that the D10, D50 and D90 values of the volume are the sizes (in μm) at which 10 volume%, 50 volume% and 90 volume% of the particles respectively have lower particle size measurements.

[0125] The volume average diameter and the volume particle size distribution can be determined by measuring the particle size distribution of the powdery product by laser diffraction, for example, determined according to the method described in Example 1.2 below.

[0126] The particles according to the present disclosure may be characterized in that they are "particles for direct compression" or "directly compressible particles". They are usually also referred to as "direct compression excipients". Thus, the particles according to the present disclosure can be directly compressed, that is, without any prior texturization treatment or physical transformation, such as, for example, a prior dry granulation or wet granulation step. This generally means that, in the presence of an effective amount of lubricant, the particles can form tablets with sufficient hardness by direct compression. This "effective amount" means that it effectively allows the formation of tablets, that is, typically, when producing, for example, 10 tablets, there is no adhesion, no agglomeration, and the ejection force of the tablets from the press is less than 1000 Newtons. This effective amount of lubricant generally does not exceed 3% by weight relative to the total weight of the powder to be compressed. It should be reminded that "agglomeration" corresponds to the adhesion of part of the material to the matrix, and this adhesion persists after the ejection of the tablets. Agglomeration can be seen on the tablets: there are vertical stripes and these vertical stripes correspond to the positions where the product adheres to the matrix.

[0127] This ability to form satisfactory tablets can be determined, for example, by directly compressing a powdery composition consisting of the excipient to be tested and a lubricant (such as magnesium stearate) to form a round, flat tablet with a diameter of 11.28 mm and a weight of 400 ± 5 mg. The tablets can be formed by a rotary press or by a single-punch compaction simulator simulating the compaction on an industrial rotary press, such as the single-punch compaction simulator used in Example section 1.2. The speed of the press can be set at 25 revolutions per minute. A pre-compression force of 1.0 kN to 1.3 kN can be applied. When using a compaction simulator (STYL'One Evolution, Medelpharm) simulating a FETTE 2090 (EU-B) rotary tablet press, this speed corresponds to 54,000 tablets per hour on an industrial scale.

[0128] On the tablets thus obtained, hardness measurements are carried out by a tablet hardness tester, such as the tablet hardness tester used in the Example section below. The hardness of tablets prepared from the excipient to be tested in the presence of only the lubricant is expressed in Newtons (N) and is commonly referred to as the "tableting ability" of the excipient.

[0129] According to "Test A" in the present disclosure, the tableting ability of the excipient to be tested is evaluated as follows: on a single-point development press simulating the compaction on an industrial rotary press (simulating on a FETTE 2090 (EU-B) rotary press at a speed of 25 rpm corresponding to 54,000 tablets per hour), using a pre-compression force of 1.0 kN to 1.3 kN and a compaction force of 3 kN to 15 kN, round, flat tablets with a diameter of 11.28 mm and a weight of approximately 400 ± 5 mg are prepared. Then, the hardness of the tablets is measured. According to this test, the tableting ability is the maximum hardness obtained within this compaction force range, and there is no cracking, adhesion, or sticking in the production of, for example, 3 to 10 tablets, preferably 3 or 10 tablets.

[0130] According to this Test A, the tableting ability of the particles according to the present disclosure is preferably equal to or higher than 40 N, preferably equal to or higher than 50 N, more preferably higher than 50 N, preferably equal to or higher than 60 N, preferably equal to or higher than 70 N, more preferably higher than 70 N, preferably equal to or higher than 80 N, preferably equal to or higher than 90 N, preferably equal to or higher than 100 N, preferably equal to or higher than 110 N, preferably equal to or higher than 120 N. This tableting ability is preferably equal to or lower than 300 N, preferably equal to or lower than 250 N, preferably equal to or lower than 200 N, preferably equal to or lower than 150 N, preferably equal to or lower than 140 N, preferably equal to or lower than 130 N, preferably equal to or lower than 120 N.

[0131] The particles according to the present disclosure are particles of microcrystalline mannitol and particulate starch, but they may include minor amounts of other components, provided that they do not interfere with the desired properties, especially in terms of efficacy and safety. Examples of such other components are: binders such as hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), carboxymethylcellulose (CMC), cellulose derivatives, gum arabic, gelatin, starch derivatives such as maltodextrin, tragacanth; minerals; carbohydrates other than mannitol such as sugars and sugar alcohols; food additives, colorants; pharmaceutical, nutritional, veterinary or cosmetic active ingredients; preservatives; stabilizers. Preferably, the amount of other components in the particles according to the present disclosure is less than 15.0% (w / w), preferably less than 10.0% (w / w), preferably less than 5.0% (w / w), preferably less than 2.0% (w / w), preferably less than 1.0% (w / w), preferably less than 0.5% (w / w).

[0132] Also preferably, the particles of mannitol and particulate starch according to the present disclosure do not contain other components. In the latter case, this means that the particles consist only of mannitol and particulate starch, including their moisture and impurities.

[0133] Method for preparing particles of mannitol and granular starch

[0134] The present invention also relates to a method for preparing the particles according to the present disclosure, the method comprising the steps of: (a) agglomerating microcrystalline mannitol and particulate starch by spraying a dissolved mannitol onto the particulate starch and drying; (b) drying the particles obtained in step (a); and (c) cooling the particles obtained in step (b), wherein steps (b) and (c) are carried out using dry air and cooling air respectively, and the water content of the dry air and the cooling air is equal to or less than 3.0 g / kg of dry air.

[0135] Preferably, the method according to the present disclosure is a continuous method.

[0136] Step (a)

[0137] In a first embodiment, step (a) is carried out by spraying a liquid (usually an aqueous composition) containing dissolved mannitol and particulate starch into a fluidized bed. The particulate starch is insoluble in water and is suspended in the aqueous mannitol solution.

[0138] In a second more preferred embodiment, step (a) is carried out by spraying a mannitol solution, especially an aqueous mannitol solution, into a fluidized bed while introducing powdered particulate starch into the fluidized bed.

[0139] Agglomeration can be carried out by multi-stage spray drying or by fluidized bed granulation. Step (a) is usually carried out in the chamber of a spray dryer or a fluidized bed granulator respectively. Both the spraying and drying of step (a) will be carried out in this unit.

[0140] Preferably, step (a) is carried out by multi-stage spray drying.

[0141] It can be carried out in a multi-stage spray dryer (e.g., type spray dryer), especially a multi-stage spray dryer equipped with high-pressure drying nozzles, where the fine particles are recycled at the top of the spray dryer.

[0142] Although the water content of the air in drying step (b) must be carefully controlled, such control is not required for the water content of the drying air in step (a).

[0143] A person skilled in the art can easily adjust the temperature of the drying air in step a) according to the equipment used. This temperature is usually higher than 100 °C.

[0144] Preferably, the dry weight ratio of mannitol to granular starch for carrying out step (a) is as described before for the granules according to the present disclosure. Thus, the dry weight ratio of mannitol to granular starch for preparing the liquid to be sprayed in step (a) can especially be in the range of 50 / 50 to 95 / 5.

[0145] Preferably, the liquid or solution sprayed in step (a) contains 30% to 50% solids, preferably 35% to 45%, for example about 40%; said percentage is expressed as the dry weight of the solids relative to the total weight of the liquid or solution.

[0146] Steps (b) and (c)

[0147] In the method according to the present disclosure, the drying air and the cooling air in steps (b) and (c) have a water content equal to or lower than 3.0 g / kg of dry air. Preferably, the water content of the drying air and the cooling air in steps (b) and (c) is equal to or lower than 2.5 g / kg of dry air, preferably equal to or lower than 2.0 g / kg of dry air, preferably equal to or lower than 1.5 g / kg of dry air, preferably equal to or lower than 1.0 g / kg of dry air. It is generally equal to or higher than 0 g / kg of dry air, even equal to or higher than 0.5 g / kg of dry air. It is, for example, equal to about 0.6 g / kg of dry air.

[0148] The drying and cooling steps (b) and (c) can be carried out in a unit separate from the fluidized bed granulator or the spray drying chamber, especially when a continuous method is used.

[0149] Preferably, the drying step (b) is carried out in a fluidized bed, preferably selected from a static fluidized bed and / or a vibrated fluidized bed. It is still preferably carried out in a static fluidized bed and preferably subsequently in a vibrated fluidized bed.

[0150] Preferably, the cooling step (c) is carried out in a vibrated fluidized bed, preferably in the same vibrated fluidized bed as used for the drying step (b).

[0151] Those skilled in the art can easily adjust the temperatures of the drying air and the cooling air in step (b) according to the equipment used and based on the detailed methods given in the examples below.

[0152] For example, the temperature of the drying air in step (b) can be selected from 50 °C to 130 °C, preferably selected from 60 °C to 120 °C, preferably selected from 70 °C to 110 °C, for example selected from about 75 °C to about 100 °C. When a static fluidized bed and a vibrated fluidized bed are used for the drying step (b), the air temperature of the static fluidized bed can be 50 °C to 100 °C, preferably 60 °C to 90 °C, preferably 70 °C to 80 °C, for example about 75 °C. When a static fluidized bed and a vibrated fluidized bed are used for the drying step (b), the air temperature of the vibrated fluidized bed can be 70 °C to 130 °C, preferably 80 °C to 120 °C, preferably 90 °C to 110 °C, for example about 100 °C.

[0153] The temperature of the cooling air in step (c) can be 5 °C to 30 °C, preferably 10 °C to 25 °C, for example about 20 °C.

[0154] Preferably, the method includes the recycling of fine particles. They can be recycled in a powder state or via dissolution into the sprayed mannitol liquid. It is preferably recycled in a powder state. Those skilled in the art can easily carry out the recycling step. The recycling can be carried out by extracting the fine particles at the top of the chamber. After being extracted, before being reintroduced into the chamber, for example, at the top of the chamber, the fine particles can then be separated from the coarse particles that may finally be present by a cyclone separator.

[0155] When the granular starch is introduced in powder form, it can advantageously be introduced via the inlet for recycling powdered fine particles.

[0156] Preferably, the method according to the present disclosure further includes a step (d) of recovering the particles thus obtained.

[0157] Those skilled in the art can easily adjust other method parameters according to the equipment used and based on the detailed methods given in the examples below. Examples of such other method features are: spray pressure, type and number of nozzles used, flow rate of the spray solution or liquid in step (a), flow rate of the granular starch when it is introduced in powder form.

[0158] If the particles according to the present disclosure comprise other components, such other components are generally introduced during step (a). They may be introduced via the sprayed liquid or solution, via the inlet for recycling the fine particles, via the inlet for introducing granular starch, or via an additional inlet.

[0159] Figure 1 is a schematic diagram of a preferred apparatus for carrying out the method according to the present disclosure. In this apparatus, a mannitol solution (1) is sprayed via a nozzle into the drying chamber (2) of a multi-stage spray dryer (3). Granular starch in powder form is introduced via the inlet (4) which is also used for recycling the powdered fine particles. Drying air (5) is introduced into the chamber (2) for drying in step (a). The drying step (b) is carried out as follows: drying air (7) having a water content equal to or lower than 3.0 g / kg of drying air is fed into the static fluidized bed (6), and then drying air (9) having a water content equal to or lower than 3.0 g / kg of drying air is fed into the vibrating fluidized bed (8). The cooling step (c) is carried out as follows: cooling air (10) having a water content equal to or lower than 3.0 g / kg of drying air is fed into the vibrating fluidized bed (8). The fine particles are recycled via the inlet (4).

[0160] Once prepared, the particles according to the present disclosure are preferably stored under conditions that enable the water activity to be maintained at or below 0.3 over time, in particular conditions that protect the particles from environmental moisture, especially considering their potential combination with moisture-sensitive components. As an example, the particles may be stored at room temperature, i.e., 18 °C to 25 °C, or in a refrigerator. Preferably, the particles according to the present disclosure are stored in an aluminum foil package.

[0161] The invention also relates to particles of microcrystalline mannitol and granular starch obtainable or obtained by the method according to the present disclosure.

[0162] Product comprising particles of mannitol and granular starch

[0163] The invention also relates to a product comprising the particles according to the present disclosure and another component, preferably a moisture-sensitive active ingredient.

[0164] Preferably, the product is selected from powder compositions and / or tablets.

[0165] Preferably, the product contains a moisture-sensitive active ingredient. The active ingredients according to the present disclosure include non-pharmaceuticals and pharmaceuticals. The expression "active ingredient" traditionally refers to any substance with a pharmaceutical, veterinary, food, nutritional or cosmetic purpose. Preferably, the active ingredient according to the present disclosure is a nutritional or pharmaceutical active ingredient. The active ingredient, especially when it is a pharmaceutical active ingredient, can be selected from the so-called small molecules, but can also be selected from the so-called "biopharmaceuticals", as is the case for active substances based on or derived from proteins, nucleic acids (such as DNA or RNA), cells or viruses, for example.

[0166] The expression "moisture-sensitive active ingredient" is well known in the art. It generally refers to an active ingredient that exhibits undesirable changes when exposed to moisture, which can come from various sources - excipients, manufacturing processes, environmental conditions, etc. A common result of the contact between a moisture-sensitive active ingredient and moisture is the formation of one or more different chemical substances. The result may be the hydration of the drug molecule, leading to changes in physical properties (e.g., different dissolution profiles), or the result may produce different compounds or degradation products, leading to a loss of potency. For probiotics, it is known that moisture exposure needs to be limited to minimize the reduction in cell viability caused by harmful chemical reactions.

[0167] In some cases, drug stability is demonstrated by the slow rate of formation of degradation product compounds over time. The drug must remain stable, i.e., the period during which its potency and / or the impurity content in the formulation remains unchanged varies according to the commercial specifications set by the manufacturer. For example, it may be required that a particular product maintain certain potency specifications for a period of six months, one year, two years or some other time after manufacture. The established shelf life of the product assumes that it is kept in its original packaging in a specified temperature and humidity environment.

[0168] Non-limiting examples of moisture-sensitive active ingredients are probiotics, such as bacteria or yeast, preferably from the genus Lactobacillus or Bifidobacterium, drug molecules, such as dabigatran, enalapril, ranitidine, omeprazole, aspirin, ascorbic acid. It is preferably selected from probiotics, preferably from bacteria, more preferably from Lactobacillus, such as Lactobacillus rhamnosus.

[0169] Preferably, in the product according to the present disclosure, the weight ratio of the particles according to the present disclosure to the moisture-sensitive active ingredient is from 1:1 to 10:1, preferably from 1:1 to 8:1, preferably from 1:1 to 5:1, preferably from 1:1 to 4:1, preferably from 2:1 to 4:1. It is, for example, equal to about 3:1.

[0170] Preferably, the water activity of the product according to the present disclosure is equal to or lower than 0.50, preferably equal to or lower than 0.45, preferably equal to or lower than 0.40, preferably equal to or lower than 0.35, preferably equal to or lower than 0.30, preferably equal to or lower than 0.25, preferably equal to or lower than 0.20. It is preferably equal to or higher than 0.01, preferably equal to or higher than 0.05.

[0171] This water activity can be determined by a person skilled in the art, for example, by a capacitance hygrometer and a dew point hygrometer, preferably by a dew point hygrometer, for example, according to the method described in Example Part 1.3 below.

[0172] Preferably, the water content (also referred to as "loss on drying") of the product according to the present disclosure is equal to or lower than 5.0% by weight, preferably equal to or lower than 4.0% by weight, preferably equal to or lower than 3.0% by weight, preferably equal to or lower than 2.0% by weight. Generally, it is higher than 0.5%, even higher than 1.0%. This water content can be determined by a person skilled in the art by a halogen moisture analyzer or a water furnace at 130 °C, most preferably a halogen moisture analyzer, for example, according to the method described in Example Part 1.3 below.

[0173] In a first preferred embodiment, the product according to the present disclosure is a tablet, preferably a chewable tablet. It should be understood that once tabletted, some of the particulate characteristics (such as its diameter or density) may not be found in the final tablet. Thus, alternatively, the tablets according to the present disclosure can be defined by the fact that they are obtained or can be obtained from a powdery composition comprising the particles according to the present disclosure.

[0174] Preferably, the tablets according to the present disclosure are biconvex cachets, preferably having a width of 9.5 mm and a length of 19 mm.

[0175] Preferably, the tablets according to the present disclosure have a weight of about 1 g.

[0176] Preferably, the hardness of the tablets according to the present disclosure is equal to or higher than 40 N, preferably equal to or higher than 50 N, preferably equal to or higher than 60 N, preferably equal to or higher than 70 N. Preferably, the hardness of the tablets according to the present disclosure is equal to or lower than 250 N, preferably equal to or lower than 200 N, preferably equal to or lower than 150 N, preferably equal to or lower than 140 N, preferably equal to or lower than 130 N, preferably equal to or lower than 120 N. It is, for example, selected from 60 N to 130 N, or selected from 70 N to 120 N.

[0177] In a second preferred embodiment, the product according to the present disclosure is a powdery composition. The powdery composition can be a powdery composition suitable for preparing another product (such as a premix for preparing tablets). The powdery composition can be a filler for hard capsules, sachets or strip packs.

[0178] In a first preferred embodiment, the particles or products according to the present disclosure are stored in a refrigerator, i.e., at a temperature of 4°C to 8°C.

[0179] In a second preferred embodiment, the particles or products according to the present disclosure are stored at a temperature of 15°C to 30°C, preferably 20°C to 30°C, still preferably 20°C to 25°C, still preferably about 25°C, at a relative humidity equal to or lower than 60%. This relative humidity is preferably as low as possible, for example, about 20% - 30%.

[0180] Preferably, the product according to the present disclosure is in an aluminum foil package. The product according to the present disclosure can be packaged in bags, bottles, blisters, sachets or strips. Preferably, the tablets according to the present disclosure are packaged in bags, bottles or blisters, still preferably packaged in blisters, preferably packaged in aluminum blisters. Preferably, the powdered composition according to the present disclosure is packaged in bags, sachets or strips, preferably packaged in aluminum sachets or aluminum strips. The powdered composition can be used as a filler for hard capsules. In this case, the hard capsules are preferably packaged in bags, bottles or blisters, still preferably packaged in blisters, preferably packaged in aluminum blisters.

[0181] The product according to the present disclosure can be packaged together with a desiccant package (for example, a package containing silica beads). This may be of interest, especially to protect the product from environmental moisture generated by the user opening the package multiple times. Such desiccant packages can usually be added to bottles.

[0182] Use of particles of microcrystalline mannitol and granular starch

[0183] The present invention also encompasses the use of the particles according to the present disclosure for formulating or stabilizing moisture-sensitive active ingredients.

[0184] Preferably, the particles are as described above. Preferably, the moisture-sensitive active ingredients are as described above. In particular, it is preferably selected from bacteria or yeasts, preferably selected from the genus Lactobacillus or Bifidobacterium, or selected from pharmaceutical molecules such as dabigatran, enalapril, ranitidine, omeprazole, aspirin, ascorbic acid. It is preferably selected from probiotics, preferably selected from bacteria, more preferably selected from Lactobacillus, such as Lactobacillus rhamnosus.

[0185] Preferably, the particles are used to formulate the product preferably as described above. In particular, the product is preferably selected from tablets or powdered compositions.

[0186] Preferably, the particles are used as a filler and / or binder and / or direct compression excipient.

[0187] The ability to stabilize the moisture-sensitive active ingredient can be determined, for example, by storing a preparation consisting of particles, a moisture-sensitive active ingredient, and 1 wt% to 3 wt% of a lubricant at a temperature of 30 °C and a relative humidity of 65% for a given duration, such as at least 3 months, or from 3 months to 12 months, or from 3 months to 6 months, such as 3 months. It can also be determined at a temperature of 25 °C and a relative humidity of 60%. If the loss of activity in the preparation is lower compared to the active ingredient alone, the active ingredient can be considered stable. For probiotics, this can be done by measuring cell viability, for example, according to the method given in Example section 1.4.

[0188] Preferably, the particles according to the present disclosure and products containing them, in particular tablets according to the present disclosure, are used for individuals with dysphagia, and / or children and / or the elderly and / or pediatric patients and / or geriatric patients and / or patients suffering from swallowing difficulties.

[0189] In the present disclosure, the amounts of the components are generally expressed as weight percentages. Unless otherwise stated, these weights are for the components themselves, in their powdered or oily forms. The powdered components generally include a small amount of water (also referred to as moisture % or "loss on drying") and / or a small amount of impurities.

[0190] Other characteristics and advantages of the present invention will become apparent upon reading the embodiments given below, which illustrate but do not limit the present invention.

[0191] Examples

[0192] 1. Prototype of mannitol and starch particles

[0193] 1.1. Preparation of particles of mannitol and starch in batch mode using a fluidized air bed granulator

[0194] According to the present disclosure, different compositions consisting of mannitol and granular starch are prepared by agglomeration and drying, with the dry weight ratios of mannitol and granular starch being 85:15, 80:20, 75:25, and 65:35, respectively.

[0195] By dissolving mannitol ( 50C, ROQUETTE) in softened water at 55 °C and suspending the extra-white corn starch to prepare a solution of mannitol and granular starch with the desired solid content. Stirring is carried out to obtain a fluid and homogeneous solution without lumps.

[0196] The operating conditions for manufacturing these particles in an AGT 150 type batch fluidized air bed granulator sold by Glatt are shown in Table 2 below. The nozzle is in the "bottom spray" position.

[0197] [Table 2] – Step (a)

[0198]

[0199] For drying step (b), the obtained granules are placed in a ventilated oven and dried for 48 hours at a temperature of 80 °C using air with a controlled humidity (less than 3.0 g / kg of dry air). For drying step (c), the granules are cooled to room temperature for 24 hours using air with a controlled humidity (less than 3.0 g / kg of dry air).

[0200] 1.2. Characterization of the particles

[0201] The granules thus obtained are characterized according to the following method.

[0202] 1. Water activity (Aw) . Using the device Waterlab, Aw is measured. The analysis is carried out at 25 °C. The analysis is carried out based on the device recommendations (WATERLAB_MU_ENG_Rev2_2020).

[0203] 2. Mannitol content . The mannitol content is determined by high performance liquid chromatography on an ion exchange resin in the calcium form. Quantitative analysis is carried out using the external calibration method. The following materials and parameters are used: eluent: water; flow rate: 0.5 ml / min; column temperature: 85 °C; injection volume: 20 μL; ion exchange resin column in calcium form: BIORAD HPX87C in Ca++ form (300 mm × 7.8 mm) (e.g. reference 125 - 0095); detector: differential refractometer.

[0204] 3. Water content . According to the following protocol: Introduce a test portion of approximately 5 g (accurately weighed) of the test sample. The water content is determined by drying the test portion in an electrically heated oven at a temperature in the range of 130 °C to 133 °C under air pressure for 1.5 hours. Disperse it in a uniform thin layer on the bottom of the capsule. Starting from the moment when the oven is adjusted again to the defined temperature range, place the uncovered capsule in the oven and leave the lid nearby for 1 hour 30 minutes. Do not open the oven during drying.

[0205] 4. Bulk density and tapped density, Hausner ratio . The bulk density is determined by the following method: Allow the sample to flow through a defined funnel into a test tube of known volume. Measure the mass of a certain volume of the product in the test tube at the specified temperature and determine the volume of the test tube by measuring the mass of an equal volume of water at the same temperature. Calculate the bulk density of the product by dividing the mass of the product by the volume of the test tube. The following materials and parameters are used: temperature: 20 °C; stainless steel funnel: upper diameter 12 cm, lower diameter 12 mm, cone height 9 cm, tube length 2 cm. Place the funnel on a stand such that the distance between the funnel and the test tube is 10 cm.

[0206] The tapped density is determined by the following method: Measure the mass of a certain volume of the product after compaction and the mass of an equal volume of distilled water at the same temperature. The tapped density is calculated by dividing the mass of the certain volume of the product by the volume of the product itself. The procedure is as follows: Weigh 20 g of the powder in a test tube. Place the test tube on a tapped density tester (STAV 2003 tapped density tester) and turn it on for 50 strokes. Read the volume in the test tube.

[0207] 5. Specific surface area . The specific surface area of the powdered particles is measured based on the three-point Brunauer, Emmett, and Teller (BET) theory. The physical principle for determining the specific surface area is based on low-temperature gas adsorption. Instrument - Beckman-Coulter SA3100.

[0208] 6. Crystal polymorphism . The crystalline polymorphism is determined by X-ray diffraction on the powder. A powder X-ray diffractometer (Bruker) with a copper anode tube (wavelength: ) is used for the determination and quantification of the crystalline forms of mannitol. Using a rotating sample holder, the analysis is carried out continuously within the 5° to 60° reflections. The sample is hand-compacted and spread out in a single layer on the sample holder. The crystalline forms of mannitol are determined by comparing the positions of the diffraction lines of the sample for the α, β, and δ forms of mannitol using the fundamental parameter method with the structure files available in the COD (Crystallography Open Database) and CSD (Cambridge Structural Database) databases. References: α reference CSD1142501 / β reference CSD1142500 / δ reference CSD662815.

[0209] 7. Volume mean diameter and volume particle size distribution . The volume average diameter and volume particle size distribution are determined by laser diffraction on the powdered product. The diffraction of a laser beam by the particles of the sample to be analyzed is measured. These particles diffract individually. The resulting diffraction light intensity is a function of the particle size. The computer processing of these light intensities provides access to the particle size distribution. Equipment: Laser diffraction particle size analyzer HELOS KR brand SYMPATEC equipped with R5 and R7 lenses. RODOS M system associated with a 6 mm gun and VIBRI system. Vacuum cleaner Nilfisk IBVI5.

[0210] 8. Tableting abilityThe excipient to be tested was mixed with 1% magnesium stearate. Circular flat tablets with a diameter of 11.28 mm and a weight of approximately 400 mg were prepared using a pre-compression force of 1.0 kN to 1.3 kN on a single punch compaction simulator (STYL'One Evolution, Medelpharm) simulated on a FETTE 2090 (EU-B) rotary press at a speed corresponding to 54,000 tablets per hour at 25 rpm. Different compaction forces were tested, ranging from approximately 3 kN to 20 kN. The hardness of the tablets thus obtained was measured using a tablet hardness tester (ERWEKA TBH 425, ERWEKA GmbH).

[0211] The results are shown in Figure 2 and Figure 3 .

[0212] The granules according to the present disclosure all have a low water activity of less than 0.3. The water activity and tableting ability increase with the mannitol to dry weight ratio of the granule starch ( Figure 2 and Figure 3 ).

[0213] The granules according to the present disclosure have satisfactory tableting ability ( Figure 3 ). Thus, they are suitable for preparing tablets with sufficient hardness, i.e., tablets that do not break during storage and transportation. On the other hand, the hardness is not too high, so the tablets can be easily chewed. Therefore, the granules according to the present disclosure are particularly suitable for preparing chewable tablets.

[0214] For chewable tablets, there is no ideal hardness value as it will depend on the size and shape of the tablets. However, generally, the hardness is preferably at least 60 N - 70 N. Thus, granules with a mannitol to dry weight ratio of granule starch greater than 65:35 are preferably used for preparing tablets due to their higher tableting ability. Even more preferably, granules with a mannitol to dry weight ratio of granule starch of at least 75:25 are used.

[0215] The granules according to the present disclosure generally exhibit a volume average diameter and size distribution that make them suitable for tableting or filling, such as hard capsules, sachets, or strip packs. This allows them to flow properly into the devices used to manufacture and package the formulations containing them. It also enables uniform blending with most active ingredients.

[0216] 1.3. Stability of the preparation comprising the particles and probiotics

[0217] Lactobacillus rhamnosus was selected as the model strain because it is a well-known and well-studied probiotic strain and is found in many commercial probiotic preparations for multiple age groups.

[0218] Two types of formulations were tested: tablets and powder compositions.

[0219] The formulations used after optimization are as follows: 1% by weight of magnesium stearate, 74.25% by weight of the prototype, and 24.75% by weight of Lactobacillus rhamnosus. The same formulation is used for tablets and powder compositions.

[0220] Tablets are prepared as follows: On a single punch compaction simulator (STYL'One Evolution, Medelpharm) simulated on a FETTE 2090 (EU - B) rotary press at a speed corresponding to 25 rpm for 54,000 tablets per hour, double - convex tablets with a length of 19 mm, a width of 9.5 mm, and a weight of approximately 1 g are prepared using a pre - compaction force of 1.0 kN to 1.3 kN and a compaction force of 15 kN or 20 kN (optimized choice).

[0221] For the stability study, tablets and powder compositions are packaged into aluminum foil bags with a low headspace to minimize the amount of air in contact with the particles.

[0222] Stability is evaluated by measuring Aw and water content when stored at 65% RH / 30 °C according to the following method.

[0223] 1. Water activity The water activity is measured at 25 °C using a water activity meter (Aqualab 4TE Duo, Meter Group, USA). The powder composition sample is measured immediately after opening the package, with a sample weight of 1 g (±0.05 g), while the tablets (sample weight of 1 g (±0.05 g)) are crushed before analysis to reduce the equilibration time in the water activity chamber.

[0224] 2. Water content The loss on drying (LOD) is measured at a drying temperature of 105 °C using a halogen moisture analyzer (Mettler Toledo, HC103). The powder composition sample is measured immediately after opening the package, with a sample weight of 1 g (±0.05 g), while the tablets (sample weight of 1 g (±0.05 g)) are crushed before analysis.

[0225] For tablets, the hardness and disintegration time during storage are also determined. The disintegration time is carried out according to the European Pharmacopoeia tablet and capsule disintegration test (EP 5.0 2.9.1.) using a disintegration tester (PTZ Auto, Pharma Test Apparatebau AG, Germany).

[0226] The results are shown in Figures 4 to 8 .

[0227] These results indicate that the tablets and powder compositions obtained from the particles according to the present disclosure have good stability.

[0228] After storage at 65% RH / 30 °C for 3 months, the water activity of Lactobacillus rhamnosus increased to 0.27. An increase in water activity was observed for the powder composition and the tablets. The water activity of the powder composition increased in the range of 0.18 to 0.26, and the water activity of the tablets increased in the range of 0.26 to 0.34. In general, it was observed that incorporation of the granules into the formulation did not result in an increased uptake of free water during storage to the extent that the final water activity after 3 months was comparable to the final water activity of Lactobacillus rhamnosus alone. Thus, unexpectedly, these results show that the granules did not introduce any additional free water into the formulation.

[0229] As a further unexpected effect, the data presented below compare on the one hand the cell viability of Lactobacillus rhamnosus alone and on the other hand the cell viability of a mixture of Lactobacillus rhamnosus and the granules, and surprisingly demonstrate that not only is the cell viability not negatively impaired by the granules over time, but on the contrary, the presence of the granules even enables an improvement in cell viability over time and thus protects Lactobacillus rhamnosus from moisture.

[0230] The hardness and disintegration time of the tablets were stable over time, which is a sign of the physical stability of the tablets.

[0231] The prototypes containing the granules [G-MS-lowAw-85 / 15_#1] and [G-MS-lowAw-80 / 20_#1] consistently resulted in higher tablet hardness, followed by [G-MS-lowAw-75 / 25_#1], and then [G-MS-lowAw-65 / 35_#1], which is consistent with the tableting ability data shown in Section 1.2. The disintegration time increased with tablet hardness.

[0232] 1.4. Cell viability in the preparation with probiotics

[0233] The inventors examined the effect of compression on cell viability. Cell viability was determined using the 3M Petrifilm lactic acid bacteria count plate method. The sample was aseptically weighed (equivalent to 1.0 ± 0.1 g) and added to 9 mL of peptone water diluent (3M). The suspension was mixed for 5 min using a Turbula mixer (Turbula T2F, Glen Mills) and visually inspected for homogeneity. If the sample was not well dispersed, the suspension was mixed for an additional 5 min. After mixing for 5 min, the suspension was allowed to stand at room temperature for 25 min to constitute a total of 30 min for sample hydration. The total time for mixing and sample standing was 30 min. If the mixing step took 10 min, the standing time would be 20 min accordingly. After obtaining a homogeneous suspension, the suspension was diluted to achieve a theoretical concentration that would result in counting between 20 and 300 colonies. Before the dilution and plating steps for each sample, the sample was vortexed for 30 seconds. The appropriately diluted sample was plated on a 3M Petrifilm lactic acid bacteria count plate according to the manufacturer's instructions and incubated at 28 °C - 37 °C for 48 ± 3 hours.

[0234] The 3M Petrifilm lactic acid bacteria count plate method was verified using the ISO 15214 pour plate method, and no significant difference was observed between the two test methods (p = 0.43) based on the average of sample replicates determined by paired t-test.

[0235] Tablets were prepared as in Section 1.3.

[0236] The results are shown in Figure 9 (a).

[0237] It was observed that the effect of compression force on cell viability was secondary to the ratio of mannitol to granular starch. Regardless of the ratio of mannitol to granular starch, tablets compacted at 20 kN always had 13% lower cell viability compared to tablets compacted at 15 kN. Using a compression force of 20 kN, the lowest cell viability (56% cell viability) was obtained with granules having a mannitol to granular starch dry weight ratio of 85:15. Using a compression force of 15 kN, the highest cell viability (94% cell viability) was obtained with granules having a mannitol to granular starch dry weight ratio of 75:25.

[0238] As a comparison, commercial excipients (made of different materials) for probiotic tablets showed 30% - 40% cell viability when using a compression force of 15 kN and approximately 20% cell viability when using a compression force of 20 kN.

[0239] These results also showed that the higher the granular starch content, the higher the cell viability. In this regard, a mannitol to granular starch dry weight ratio below 85:15 is therefore preferred when granules are used to prepare tablets.

[0240] Then, the cell viability of the tablets and powder compositions prepared as described in Section 1.3 was evaluated and stored for two weeks at 30 °C / 65% RH. Particles with a mannitol to granulated starch dry weight ratio of 85:15 were selected for this evaluation. In fact, since these particles had the highest water activity and the lowest cell viability after compaction, it was assumed that other particles with a higher starch content would perform at least the same, if not better. For the tablets, a compaction force of 20 kN was selected for similar reasons, i.e., because using this compaction force resulted in the lowest cell viability.

[0241] The results are shown in Figure 9 (b).

[0242] After 2 weeks of storage, both the tablet and powder formulations showed higher cell viability compared to the probiotic alone. These results demonstrate the protective effect of the particles according to the present disclosure. Even though the cell viability was impaired by tableting, this loss was rapidly balanced by the fact that the cell viability in the tablets decreased much more slowly than that of the untableted probiotic.

[0243] 2. Pilot batch of starch and mannitol particles

[0244] For scale-up, a mannitol to granulated starch dry weight ratio of 80:20 was selected because this mannitol to granulated starch dry weight ratio was identified as the preferred mannitol to granulated starch dry weight ratio for preparing chewable tablets in a previous set of experiments. In fact, particles with a mannitol to granulated starch dry weight ratio higher than 75:25 and lower than 85:15 represent the best compromise between Aw, tableting ability, and cell viability.

[0245] 2.1. Preparation of starch and mannitol particles in continuous mode using a multi-stage spray dryer (MSD)

[0246] Particles consisting of mannitol and granulated starch in a dry weight ratio of 80:20 were prepared by multi-stage spray drying. Crystalline mannitol sold by the applicant under the name 50C, which exhibited a laser volume average diameter of approximately 50 μm, and "Extra White" corn starch were used. A mannitol solution with the desired solids content was prepared by dissolving the crystalline mannitol in softened water at 80 °C. The granulated starch was introduced in powder form into the system for recycling fine particles via a powder weight metering device. The operating conditions for manufacturing these particles in an MSD type spray dryer sold by Niro with an evaporation capacity of 400 kg / h are shown in Table 3 below. The fine particles were recycled at the top of the chamber.

[0247] [Table 3]

[0248]

[0249]

[0250] 2.2. Characterization of the particles

[0251] Characterize the particles thus obtained according to the method described in Section 1.2.

[0252] They were also examined by scanning electron microscopy (Quanta 200F, FEI).

[0253] The results are shown in Figure 10 、 Figure 11 and Figure 12 .

[0254] These results confirm the good tableting ability of the particles according to the present disclosure, as well as the robustness of the method used.

[0255] The particles according to the present disclosure have excellent flowability ( Figure 10 ).

[0256] In addition, the taste and sensory properties of the resulting tablets were evaluated during chewing. The panel found the overall taste and feel to be good. The tablets were slightly sweet, had no unpleasant aftertaste, and had no gritty or chalky mouthfeel.

[0257] For further characterization and evaluation, the pilot batch G-MS-lowAw-80 / 20_#22 was selected. In fact, this batch had the highest Aw, which means that if the inventors can show that it is good for formulating probiotics, it can be expected that other batches will be at least equally effective, if not more effective.

[0258] 2.3. Stability of the preparation comprising the particles and probiotics

[0259] Prepare probiotic-containing formulations (powdered compositions and tablets) as described in Section 1.3, except that the tablets are packaged in aluminum blisters. To prepare the tablets, the compaction force was selected to match the hardness obtained previously using compaction forces of 15 kN and 20 kN with the prototype G-MS-lowAw-80 / 20_#1. Such compaction forces were 12.5 kN and 16.5 kN, respectively.

[0260] The friability of the tablets thus prepared was measured as follows: Samples corresponding to at least 6.5 g of the whole tablets were used for evaluation. Before evaluation, the tablets were carefully dusted on a 1 mm sieve, then the tablet samples were weighed and placed in the drum of a friability tester (PTF 20E, Pharma Test Apparatebau AG). The drum was rotated 100 times, then the tablets were removed. Loose dust was removed from the tablets as before and the tablets were weighed. The percentage of mass loss as a function of the initial mass was determined.

[0261] Determine the stability as described in Section 1.3.

[0262] The results are shown in Figures 13 to 17 .

[0263] Given that the initial starting Aw and moisture content of the pilot batch G-MS-lowAw-80 / 20_#22 were 0.111% and 0.33% respectively, the results obtained for the resulting formulation showed a significant Aw and moisture contribution from Lactobacillus rhamnosus. This further emphasizes the need for excipients with low Aw and moisture content to maintain an overall acceptable Aw and moisture content of the final formulation.

[0264] For the powder composition, a marginal increase in water activity and moisture was observed. For the refrigerator samples, the water activity was maintained throughout the 3-month storage period. The room temperature samples showed an increase in water activity of 0.2.

[0265] The results obtained for the tablets were significantly better. For both storage conditions, the water activity and moisture were maintained throughout the 3-month period. Additionally, for both the storage conditions and the compaction force, the increase in hardness and disintegration time was minimal, indicating good stability of the tablets obtained from the granules according to the present disclosure.

[0266] Furthermore, it can be seen that the compaction force significantly affects the hardness and friability: the lower the compaction force, the lower the hardness and the higher the friability.

[0267] 2.4. Cell viability in the preparation with probiotics

[0268] Determine the cell viability in the formulation to evaluate whether the granules according to the present disclosure are suitable for formulating probiotics and, more generally, moisture-sensitive ingredients. Determine the cell viability as described in Section 1.4.

[0269] The results are shown in Figure 18 and Figure 19 . In Figure 19 , the inventors plotted the cell viability and water activity under storage conditions of 25 °C / 60% RH.

[0270] Figure 18 It is shown that refrigeration can maintain the viability of Lactobacillus rhamnosus in all formulations. Different from the standard excipients, this indicates that the granules according to the present disclosure do not destabilize the probiotics. At room temperature, the granules according to the present disclosure even have a protective effect: in the formulation containing the granules according to the present disclosure and (Lactobacillus rhamnosus), the decrease in cell viability is not significant compared to that of Lactobacillus rhamnosus alone. When formulated into tablets, the cell viability hardly decreases.

[0271] When observing Figure 19When the water activity is increased, it can be seen that the cell viability of Lactobacillus rhamnosus alone is significantly reduced. In contrast, when combined with the particles according to the present disclosure, the cell viability of Lactobacillus rhamnosus is improved. This further highlights the ability of the particles according to the present disclosure to limit the addition of free water to the probiotic formula, thereby protecting the probiotics from the effects of moisture.

[0272] 3. Comparison with particles of starch and mannitol with a higher Aw (not particles according to the present disclosure) and with a blend of mannitol and starch (not a blend according to the present disclosure) 3.1. Stability of the preparation comprising the particles or blend and probiotics .

[0273] To confirm the importance of mannitol and granular starch being present in the same granule (i.e., by co-processing) and of having low water activity, the inventors compared the granules according to the present disclosure with the following comparative samples:

[0274] - Directly compressible mannitol ( 200SD) and granular starch (corn starch), the mixture having a mannitol to granular starch dry weight ratio of 80:20, an Aw of 0.276 and a moisture content of 1.81% (hereinafter referred to as "a blend of mannitol and granular starch with low Aw"); the Aw and moisture content are determined according to the method given in Section 1.3.

[0275] - Co-processed mannitol and starch according to patent US 9839610, having a mannitol to granular starch dry weight ratio of 80:20, an Aw of 0.545 and a moisture content of 2.32% ( Flash, hereinafter referred to as "granules of mannitol and granular starch with high Aw"); said Aw and water content are determined according to the method given in section 1.3.

[0276] Comparative blends of mannitol and granular starch with low Aw were obtained by using a granular starch grade with a particularly low moisture content in order to obtain a blend with the lowest possible moisture and Aw.

[0277] Figures 20 to 23

[0278] Tablets containing probiotics were prepared as described in section 2.3. For tablet preparation, the compression force was chosen to match the thickness obtained with a sample according to the present disclosure (pilot batch G-MS-lowAw-80 / 20_#22) using a compression force of 16.5 kN (which was 6.9 mm).

[0279] Stability was determined as described in section 1.3.

[0280] The results are shown in 3.2. Cell viability in the preparation with probiotics middle.

[0281] When compacted to a similar thickness, tablets containing the particles according to the present disclosure are harder and, surprisingly, exhibit the shortest disintegration times.

[0282] The hardness and disintegration times of the tablets were stable over time under both conditions (refrigerator and 25 °C / 60% RH), which is indicative of the physical stability of the tablets of all three formulations.

[0283] When using the particles according to the present disclosure, the lowest water activities were obtained under both conditions. For these tablets, the water activity of the tablets remained within the desirable range of 0.2 - 0.3 over a three-month period.

[0284] Figure 24

[0285] Cell viability was determined as described in Section 1.4.

[0286] The results are shown in Figure 24 .

[0287] The particles according to the present disclosure showed a significant probiotic protection effect. After storage at 25 °C / 60% RH for three months, the cell viability of tablets containing the particles according to the present disclosure was much higher than that obtained in comparative tablets containing particles with an Aw greater than 0.3 or a blend of mannitol and granulated starch with a low Aw.

[0288] These results indicate that it is necessary for both mannitol and granulated starch to be present in the same particle (i.e., by co-processing), while exhibiting a low Aw.

Claims

1. Particles of microcrystalline mannitol and granular starch, said particles having a water activity equal to or lower than 0.3, which water activity is measured at 25 °C.

2. The particles according to claim 1, said particles having a water activity equal to or lower than 0.

2.

3. The particles according to any one of claims 1 to 2, wherein the dry weight ratio of mannitol to granular starch is equal to or higher than 50:

50.

4. The particles according to any one of claims 1 to 3, said particles having a water content equal to or lower than 5.0% by weight.

5. The particles according to any one of claims 1 to 4, said particles having a bulk density equal to or higher than 350 g / L.

6. The particles according to any one of claims 1 to 5, said particles having a tapped density equal to or higher than 400 g / L.

7. The particles according to any one of claims 1 to 6, said particles having a specific surface area equal to or higher than 0.30 m2 / g.

8. The particles according to any one of claims 1 to 7, wherein the mannitol comprises α-polymorph and -β polymorph.

9. The particles according to any one of claims 1 to 8, said particles having a volume average diameter equal to or higher than 90 μm and equal to or lower than 400 μm.

10. A method for preparing the particles according to any one of claims 1 to 9, said method comprising the following steps: Step (a) of agglomerating microcrystalline mannitol and granular starch by spraying dissolved mannitol onto granular starch and drying, step (b) of drying the particles obtained in step (a), step (c) of cooling the particles obtained in step (b), wherein steps (b) and (c) are carried out using drying air and cooling air respectively, and the water content of both the drying air and the cooling air is equal to or lower than 3.0 g / kg of dry air.

11. A product, said product comprising the particles according to any one of claims 1 to 9 and another ingredient.

12. The product according to claim 11, wherein the other ingredient is a moisture-sensitive active ingredient.

13. The product according to any one of claims 11 or 12, wherein the other ingredient is a probiotic.

14. The product according to any one of claims 11 to 13, wherein the product is a powder composition, a tablet or a chewable tablet.

15. Use of the particles according to any one of claims 1 to 9 for formulating or stabilizing a moisture-sensitive active ingredient.

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