Compounds for formulating moisture-sensitive active ingredients

Abstract

This invention relates to granules of microcrystalline mannitol and granular starch having a water activity of 0.3 or less. This invention also relates to a process for obtaining the same. This invention also relates to the use of such granules for formulating or stabilizing hygroscopic 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 technology]

[0002] The inventors have witnessed an increasing trend in the use of probiotics over the past several decades. Pharmaceutical forms such as capsules, powders, and drops are used in the production of probiotic dietary supplements. In the pharmaceutical industry, capsule-encapsulated probiotics marketed as dietary supplements are the most widespread. A multidisciplinary team is tasked with linking the requirements for optimal formulation that benefits the host microbiome with the technical requirements in the probiotic manufacturing process.

[0003] According to the World Health Organization (WHO) definition, probiotics are living organisms that contribute to human health when applied in optimal amounts. Probiotics are microorganisms, namely bacteria and yeasts, that contribute to host health by promoting the growth of beneficial bacteria and suppressing pathogens through inhibition of mucosal adhesion and the production of antimicrobial agents. Microorganisms with probiotic potential typically originate from Lactobacilli, Bifidobacterium species, and yeasts.

[0004] Water activity, followed immediately by storage temperature, are the main factors affecting the stability of probiotics over the product's shelf life. Downstream processing and manufacturing of the final product (nutritional supplement) must be carried out under strict temperature and humidity control conditions.

[0005] Since excipients constitute a significant portion of the formulation, it is crucial that they have low water activity. Therefore, establishing low-water-activity products begins with sourcing dry excipients to be blended with probiotics. Small amounts of high-water-activity components can be added as long as the total water activity remains low, ideally between 0.2 and 0.3. An Aw value greater than 0.5 is important because it marks the point at which some probiotic cells, such as Lactobacillus, degrade more rapidly.

[0006] Water activity indicates the amount of free water (water not bound to molecules) that allows biochemical reactions to proceed and affects the maintenance of probiotic survival. This is different from water content, which is the sum of bound and free water.

[0007] Unfortunately, sourcing excipients with low water activity is not sufficient. In fact, the water activity of the final formulation must also remain low during storage. Otherwise, as soon as the formulation comes into contact with water, its water activity increases, impairing cell viability.

[0008] Therefore, it would be advantageous to have an excipient that has low water activity without requiring an additional pre-drying step, and that can further maintain the water activity of the probiotic formulation, particularly within an acceptable range of 0.5 or less.

[0009] technical issues The object of the present invention was to provide an excipient suitable for formulating hygroscopic active ingredients, particularly probiotics, in their original form.

[0010] The object of the present invention was to provide an excipient that destabilizes a moisture-sensitive active ingredient to a limited extent, or further stabilizes a moisture-sensitive active ingredient.

[0011] The object of the present invention was to provide an excipient for formulating a hygroscopic active ingredient into tablets (particularly chewable tablets) or powdered compositions (e.g., fillers for sachets, stick packs, or hard capsules).

[0012] The object of the present invention was to provide an excipient having satisfactory or improved fluidity and / or compressibility and / or tableting ability and / or disintegration time.

[0013] The object of the present invention was to provide a direct compression excipient.

[0014] The object of the present invention was to provide an excipient having other necessary properties for this type of excipient, for example, with respect to particle size distribution, purity, and safety.

[0015] Presentation of the invention The inventors have solved the above problem by providing microcrystalline mannitol and granular starch granules having a water activity of 0.3 or less, measured at 25°C.

[0016] As demonstrated in sections 1.2 and 2.2 of the Examples, and in Figures 2 and 10, the granules according to this disclosure have a low water activity of less than 0.3. When the granules were used to formulate probiotics, the water activity of the resulting formulations increased slowly under both standard conditions (refrigerated or room temperature) and harsher conditions (30°C at 65% relative humidity) (Figures 4, 5, 7, 13, 14, and 16). Under standard storage conditions (25°C at 60% relative humidity), the water activity hardly increased in the powder formulations packaged in aluminum foil bags and was maintained in the tablet formulations packaged in aluminum blisters (Figures 13, 14, and 16).

[0017] While not bound by any particular theory, the inventors believe this is due to the combined action of mannitol and granular starch. When the formulation is prepared, the starch is likely to sequester the water contained in the overall formulation. The starch and mannitol then work together to prevent water from reaching the probiotics, with mannitol, due to its non-hygroscopic nature, repelling water and preventing the uptake of additional water, while the starch acts locally as a “sponge” by sequestering water contained in the microenvironment of the probiotics. Because the granular starch is insoluble, the water remains trapped. Looking at the water activity of the formulations in Figures 4, 5, 7, 13, 14, and 16, it can be seen that after 3 months of storage, the water activity of the formulations has not reached equilibrium, and the measured water activity is always lower than 0.60–0.65, i.e., lower than the equilibrium state at 60%–65% relative humidity during storage.

[0018] Both granular starch and mannitol are essential. When mannitol alone is used as an excipient, water is continuously repelled from the surface of the mannitol particles. As a result, the surface of the mannitol particles is covered with free water, which directly impairs cell viability. When starch alone is used, the entire surface of the starch adsorbs water, attracting it and creating a water flux, thus saturating more rapidly and increasing water activity more quickly.

[0019] The inventors also believe that the fact that mannitol and granular starch are processed simultaneously is important for maintaining both components in the same microenvironment. The importance of having mannitol and granular starch present in the same granules was confirmed in subsequent experiments, as shown in Section 3 of the Examples.

[0020] As demonstrated in Section 2.4, Figures 18 and 19 of the Examples, and Section 3.2, Figure 24, the granules according to the present disclosure enable the formulation of probiotics with improved stability. The inventors had considered excipients that were not "overly destabilized", but in fact developed excipients with a protective effect. Cell viability is improved when formulated into a powder composition and is hardly impaired when formulated into tablets.

[0021] Furthermore, since the granules according to the present disclosure have such unique behavior with respect to water, they may be useful for formulating hygroscopic components other than probiotics.

[0022] The granules according to the present disclosure are particularly useful for making chewable tablets. Their tableting ability is high enough for the tablets prepared from them to maintain their integrity during storage and transportation. At the same time, their tableting ability is low enough for the tablets to be chewable. This is particularly advantageous for use in patients who have difficulty swallowing, such as pediatric or elderly patients.

[0023] Granules having a dry weight ratio of mannitol to granular starch greater than 65:35 and lower than 85:15, particularly greater than 75:25 and lower than 85:15, have been found to be preferred for manufacturing tablets because they (i) have a satisfactory hardness and (ii) enable the acquisition of tablets in which cell viability is not overly impaired by compression. Granules having a dry weight ratio of mannitol to granular starch of at least 75:25, particularly at least 80:20, have been found to be even more suitable.

[0024] Finally, the granules according to the present disclosure exhibit excellent flowability, taste, and sensory properties.

[0025] The inventors have also developed a useful process for making such granules. This process can be carried out on an industrial scale. It has good productivity and can be carried out continuously.

[0026] The co-processed excipients of microcrystalline mannitol and granular starch were already described in previous patents in the name of the applicant (U.S. Patent No. 11,364,204 and U.S. Patent No. 9,839,610). However, these co-processed excipients had a water activity of 0.5, that is, higher than the water activity of the granules according to the present disclosure. Furthermore, since these products were developed for completely different purposes, neither document considered using such excipients for formulating hygroscopic components at all.

Summary of the Invention

[0027] The present invention relates first to granules of microcrystalline mannitol and granular starch having a water activity of 0.3 or less, measured at 25°C.

[0028] Preferably, the granules according to the present disclosure have a water activity of 0.2 or less. Preferably, in the granules according to the present disclosure, the dry weight ratio of mannitol to granular starch is 50:50 or more. Preferably, the granules according to the present disclosure have a water content of 5.0% by weight or less. Preferably, the granules according to the present disclosure have a bulk density of 350 g / L or more. Preferably, the granules according to the present disclosure have a tapped density of 400 g / L or more. Preferably, the granules according to the present disclosure have a specific surface area of 0.30 m 2 / g or more. Preferably, in the granules according to the present disclosure, mannitol contains α and β polymorphs. Preferably, the granules according to the present disclosure have a volume average diameter of 90 μm or more and 400 μm or less.

[0029] The present invention also relates to a process for producing granules according to the present disclosure, comprising the steps of: (a) agglomerating microcrystalline mannitol and granular starch by spraying solubilized mannitol onto granular starch and drying it; (b) drying the granules obtained in step (a); and (c) cooling the granules obtained in step (b), wherein steps (b) and (c) are carried out using dry air and cooling air, respectively, and both the dry air and the cooling air have a water content of 3.0 g or less per 1 kg of dry air.

[0030] The present invention also relates to granules of mannitol and granular starch that can be obtained or obtained by the process described herein.

[0031] The present invention also relates to a product comprising the granules according to this disclosure and another component.

[0032] Preferably, the other component is a moisture-sensitive active ingredient. Preferably, the other component is a probiotic. Preferably, the product is a powder composition, a tablet, or a chewable tablet.

[0033] The present invention also relates to the use of granules according to this disclosure for formulating or stabilizing a moisture-sensitive active ingredient. [Brief explanation of the drawing]

[0034] Other features, details, and advantages are shown in the detailed description and drawings below. [Figure 1] This is a suitable device scheme for carrying out the process described herein. [Figure 2] This table shows the results of the characterization of the granules according to this disclosure. [Figure 3] This graph shows the tableting ability of the granules according to this disclosure. [Figure 4] This bar graph shows the water activity and water content of the granules and powdered compositions containing probiotics according to this disclosure after 3 months of storage at 30°C / 65%RH. [Figure 5] This bar graph shows the water activity and water content of granules and tablets containing probiotics according to the present disclosure, obtained by applying a compressive force of 15 kN, after storage for 3 months at 30°C / 65% RH. [Figure 6] This is a bar graph showing the hardness and disintegration time of tablets containing granules and probiotics according to the present disclosure, obtained by applying a compressive force of 15 kN, after storage for 3 months at 30°C / 65% RH. [Figure 7] This is a bar graph showing the water activity and water content of granules and tablets containing probiotics according to the present disclosure, obtained by using a compressive force of 20 kN, after storage for 3 months at 30°C / 65% RH. [Figure 8] This is a bar graph showing the hardness and disintegration time of tablets containing granules and probiotics according to the present disclosure, obtained by applying a compressive force of 20 kN, after storage for 3 months at 30°C / 65% RH. [Figure 9] Figure 9(a) is a graph showing the cell viability of formulations (tablets and powder compositions) containing granules according to this disclosure. Figure 9(b) is a graph showing the cell viability of tablets containing granules and probiotics according to this disclosure after compression. [Figure 10] This table shows the results of the characterization of the granules according to this disclosure. [Figure 11] This graph shows the tableting ability of the granules according to this disclosure. [Figure 12] This is an SEM image of the granules as disclosed in this document. [Figure 13] This bar graph shows the water activity and water content of the granules and powdered compositions containing probiotics according to this disclosure after 3 months of storage at 25°C / 60%RH or after 3 months of storage in a refrigerator. [Figure 14]This is a bar graph showing the water activity and water content of tablets containing granules and probiotics according to the present disclosure, obtained by applying a compressive force of 12.5 kN, after storage for 3 months at 25°C / 60% RH or in a refrigerator for 3 months. [Figure 15] This is a bar graph showing the hardness and disintegration time of tablets containing granules and probiotics according to the present disclosure, obtained by applying a compressive force of 12.5 kN, after storage for 3 months at 25°C / 60% RH or in a refrigerator for 3 months. [Figure 16] This is a bar graph showing the water activity and water content of tablets containing granules and probiotics according to the present disclosure, obtained by applying a compressive force of 16.5 kN, after storage for 3 months at 25°C / 60% RH or in a refrigerator for 3 months. [Figure 17] This is a bar graph showing the hardness and disintegration time of tablets containing granules and probiotics according to the present disclosure, obtained by applying a compressive force of 16.5 kN, after storage for 3 months at 25°C / 60% RH or in a refrigerator for 3 months. [Figure 18] This graph shows the cell viability of formulations (tablets and powder compositions) containing granules and probiotics according to this disclosure after 3 months of storage at 25°C / 60%RH or after 3 months of storage in a refrigerator. [Figure 19] The graphs show four charts illustrating the cell viability and water activity of formulations containing a probiotic (Lb. rhamnosus) alone or in combination with the granules described herein, either in powder form or tablet form (compression force of 12.5 kN or 16.5 kN), after 3 months of storage at 25°C / 60% RH. [Figure 20] The graphs show the water activity of a probiotic tablet (as disclosed herein or comparable), having a thickness of 6.9 mm, after 3 months of storage at 25°C / 60%RH or 3 months of storage in a refrigerator. [Figure 21]The graphs show the moisture content of probiotic tablets (as disclosed herein or comparable) having a thickness of 6.9 mm after 3 months of storage at 25°C / 60%RH or 3 months of storage in a refrigerator. [Figure 22] The graphs show the hardness of a probiotic tablet (as disclosed herein or comparable) having a thickness of 6.9 mm after 3 months of storage at 25°C / 60%RH or 3 months of storage in a refrigerator. [Figure 23] The graphs show two graphs illustrating the disintegration time of a probiotic tablet (as disclosed herein or comparable), having a thickness of 6.9 mm, after 3 months of storage at 25°C / 60%RH or 3 months of storage in a refrigerator. [Figure 24] The graphs show two cell viability rates for probiotic tablets (as disclosed herein or comparable) having a thickness of 6.9 mm, after 3 months of storage at 25°C / 60%RH or 3 months of storage in a refrigerator. [Modes for carrying out the invention]

[0035] The drawings and the following detailed description contain several precise elements. They can be used to enhance the understanding of the invention and, where necessary, to define the invention.

[0036] Mannitol and granular starch granules The present invention relates, firstly, to microcrystalline mannitol and granular starch granules having a water activity of 0.3 or less, measured at 25°C.

[0037] The expression "granules of mannitol and granular starch" classically refers to particles that, when observed, for example, by scanning electron microscopy at 200x magnification, have a variable, non-spherical, and irregular surface.

[0038] Generally, at a magnification of 2500x, tiny aggregated mannitol crystals can be seen on the surface of the granules.

[0039] The term "microcrystal" typically refers to a structure that, when observed, for example, by scanning electron microscopy at 2500x magnification, essentially presents microcrystals on its surface, rarely showing larger crystals. Microcrystals are sometimes defined as crystals whose sum of length, width, and thickness is less than 25 μm. Microcrystals can have a wide variety of shapes, from round to elongated.

[0040] Preferably, the granular mannitol according to this disclosure contains both α and β crystalline forms. The crystalline polymorphism (crystalline form and proportion) of mannitol can be determined by those skilled in the art by infrared spectroscopy or by diffraction X-rays on the powder, preferably by X-ray diffraction on the powder. It can be determined, for example, according to the method described in Section 1.2 of the Examples. Preferably, the granular mannitol according to this disclosure contains less than 10%, preferably less than 5%, preferably less than 1%, and preferably 0% of the δ crystalline form. Even more preferably, the granular mannitol according to this disclosure does not contain the δ crystalline form, i.e., it consists only of α and β crystalline forms. Typically, the ratio % of α form to β form is 5:95 to 95:5, preferably 10:90 to 90:10, and preferably 15:85 to 85:15.

[0041] The term "granular starch" classically refers to starch in which its granular structure is essentially preserved. Granular starch typically has a structure organized as alternating crystalline, semicrystalline, and amorphous layers. This organization is generally characterized by the observation of a birefringence pattern upon exposure to polarized light, also known as the "Maltese cross." Granular starch is insoluble in water at room temperature (20-25°C).

[0042] The granular starch according to this disclosure may be of any plant origin. It is preferably extra white starch, preferably extra white corn starch.

[0043] It can be chemically, enzymatically, or physically modified, as long as its granular structure is preserved. However, the granular starches according to this disclosure are preferably unmodified, i.e., preferably natural granular starches.

[0044] Generally, granular starch is also available. This granular starch is insoluble in water and can be recovered by dissolving the granules according to this disclosure in water at room temperature.

[0045] The granules according to this disclosure can typically be obtained by agglomerating microcrystalline mannitol and granular starch. Thus, the granules according to this disclosure contain or consist of co-processed (or "co-aggregated") microcrystalline mannitol and granular starch. They can be obtained by spraying a liquid containing solubilized 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 and drying, the granular starch being introduced into the fluidized bed in powder form. During the drying step, the liquid containing solubilized mannitol evaporates, thus leading to the formation of microcrystals of mannitol that agglomerate with the granular starch.

[0046] Aggregation may be achieved by multi-stage spray drying or by fluidized bed granulation. Typically, these processes involve recycling of particulate matter.

[0047] In this regard, the inventors have observed that granules of the present disclosure prepared from a process including a spray-drying step performed in a fluidized bed exhibit advantageous characteristics, particularly a larger volume-average diameter and improved fluidity, compared to those obtained from the same process including spray-drying but not performed in a fluidized bed. Therefore, granules prepared from a process including a spray-drying step performed in a fluidized bed can be suitably used, for example, in equipment used for tableting or filling sachets, stick packs, or hard capsules.

[0048] The granules according to this disclosure have a water activity of 0.30 or less, preferably lower than 0.30, preferably 0.20 or less, preferably lower than 0.20. It is preferably 0.10 or higher.

[0049] The term "water activity," also referred to as "Aw," is thought to represent 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. Pure distilled water has a water activity of exactly 1. Water activity is temperature-dependent; that is, it changes with temperature. In this disclosure, water activity is measured at 25°C.

[0050] The water activity of a product can be determined by measuring the relative humidity of the air surrounding the sample at equilibrium. Therefore, the measurement of water activity in a sample is typically performed in a sealed (usually adiabatic) space where this equilibrium state can occur. At equilibrium, the water activity of the sample and the relative humidity of the air are equal, and therefore, measuring the equilibrium relative humidity (ERH) of the air in the chamber provides a measure of the water activity of the sample. At least two different types of water activity meters are commercially available. One type of water activity meter uses the cooled mirror dew point technique (e.g., the AquaLab® water activity meter available from Decagon Devices, Inc.), while the other measures relative humidity with a sensor that changes electrical resistance or capacitance (e.g., the water activity meter available from Rotronic®).

[0051] This water activity can be determined by those skilled in the art, for example, by a capacitive hygrometer and a dew point hygrometer, preferably by a dew point hygrometer, according to the methods described in Section 1.2 of the subsequent examples herein.

[0052] Preferably, the dry weight ratio of mannitol to granular starch in the granules according to this disclosure is 50:50 or higher, preferably 55:45 or higher, preferably 60:40 or higher, preferably 65:35 or higher, more preferably higher than 65:35, preferably 70:30 or higher, preferably 75:25 or higher, more preferably higher than 75:25. It is preferably 95:5 or lower, preferably 90:10 or lower, preferably 85:15 or lower, more preferably 85:15. It is, for example, equal to about 80:20.

[0053] This weight ratio is understood to refer to the dry weights of mannitol and granular starch used to produce the granules. This dry weight ratio may differ slightly from the amounts of mannitol and granular starch measured in the final granules. For example, as will be evident from the following examples herein, a dry weight ratio of 80:20 mannitol / granular starch results in a mannitol content of 75–84%, and this percentage is found to be the weight percentage of mannitol relative to the total weight of the granules.

[0054] The amount of mannitol may be determined by those skilled in the art by high-performance liquid chromatography on a calcium-type ion exchange resin, and quantification is carried out using an external calibration method, for example, according to the method described in Section 1.2 of the Examples hereafter in this specification. Preferably, this measured amount of mannitol in the granules according to this disclosure is 50% by weight or more, preferably 55% by weight or more, preferably 60% by weight or more, preferably 65% ​​by weight or more, more preferably 66% by weight or more, preferably 70% by weight or more, more preferably 70% by weight or more, preferably 75% by weight or more. Preferably it is 95% by weight or less, preferably 90% by weight or less, preferably 85% by weight or less. It is, for example, equal to about 75% to about 85%.

[0055] Preferably, the granules according to this disclosure have a moisture content (also referred to as "loss on drying") of 5.0% by weight or less, preferably 4.0% by weight or less, preferably 3.0% by weight or less, preferably 1.4% by weight or less, preferably 2.0% by weight or less, preferably 1.5% by weight or less, preferably 1.3% by weight or less, and preferably 1.2% by weight or less. This is generally higher than 0.1% and even higher than 0.2%. This moisture content can be determined by those skilled in the art, for example, by a halogen hygrometer according to the method described in Section 1.2 of the Examples later in this specification, or most preferably by drying a test portion in an electric heating oven at a temperature in the range of 130-133°C under air pressure for 1 hour and 30 minutes.

[0056] Preferably, the granules according to this disclosure have a bulk density of 350 g / L or more, preferably 400 g / L or more, and preferably 450 g / L or more. Generally, it is 750 g / L or less, more preferably 700 g / L or less, and more preferably 650 g / L or less.

[0057] This bulk density may be determined by those skilled in the art by the following methods: flowing the sample through a determined funnel into a test tube of known volume; determining the volume of the test tube by measuring the mass of a certain volume of the product in the test tube at a specified temperature and measuring the mass of an equal volume of water at the same temperature; and calculating the specific gravity of the product by dividing the mass of the product by the volume of the test tube. It may be determined, for example, by the method described in Section 1.2 of the Examples hereafter in this Spec.

[0058] Preferably, the granules according to this disclosure have a tap density of 400 g / L or more, preferably 450 g / L or more, and preferably 500 g / L or more. Generally, it is 800 g / L or less, and more preferably 750 g / L or less.

[0059] This tap density may be determined by a person skilled in the art by the following method. Measuring the mass of a certain volume of the product after consolidation and an equal volume of distilled water at the same temperature. Calculating the specific gravity by dividing the mass of the volume of the product by the volume of the product itself. It is determined, for example, according to the method described in Section 1.2 of the Examples later in this specification.

[0060] The Hausner ratio can be calculated from these densities as follows.

[0061] [Number]

[0062] The flow characteristics can be determined from this Hausner ratio according to Table 1 below.

[0063] [Table 1]

[0064] Preferably, the granules 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).

[0065] Preferably, the granules according to the present disclosure have a specific surface area of 0.30 m 2 / g or more, preferably 0.40 m 2 / g or more, preferably 0.50 m 2 / g or more, preferably 0.80 m 2 / g or more, preferably 1.00 m 2 / g or more, preferably 1.20 m 2 / g or more, preferably 1.40 m 2 / g or more, preferably 1.50 m 2 / g or more. Generally, it is 2.50 m 2 / g or less, further 2.00 m 2The specific surface area is less than or equal to / g. This specific surface area can be determined by those skilled in the art, for example, by using the BET method, according to the method described in Section 1.2 of the Examples hereafter in this specification.

[0066] Preferably, the volume-average diameter of the granules according to this disclosure is 90 μm or more and 400 μm or less. Preferably it is 100 μm or more, preferably 110 μm or more. Preferably it is 350 μm or less, preferably 300 μm or less, preferably 250 μm or less, preferably 200 μm or less, and preferably 150 μm or less.

[0067] Preferably, the granules according to this disclosure have a D10 in volume of 100 μm or less, preferably 80 μm or less, preferably 60 μm or less, and preferably 50 μm or less. Generally, it is 10 μm or more, more preferably 20 μm or more, more preferably 30 μm or more, and more preferably 40 μm or more.

[0068] Preferably, the granules according to this disclosure have a D50 in volume of 50-180 μm, preferably 70-160 μm, preferably 90-140 μm, preferably 100-130 μm, and preferably 110-120 μm.

[0069] Preferably, the granules according to this disclosure have a D90 in volume of 250 μm or less, preferably 230 μm or less, preferably 210 μm or less, and preferably 200 μm or less. Generally, this is 120 μm or more, more preferably 140 μm or more, more preferably 150 μm or more, more preferably 160 μm or more, and more preferably 170 μm or more.

[0070] It should be noted that the D10, D50, and D90 values ​​in volume correspond to the sizes in micrometers where 10%, 50%, and 90% of the particles have a lower particle size distribution, respectively.

[0071] The volume-average diameter and particle size distribution by volume can be determined, for example, by determining the particle size distribution on the powder product by laser diffraction according to the method described in Section 1.2 of the Examples later in this specification.

[0072] The granules according to this disclosure can also be characterized in that they are “granules for direct compression” or “granules that can be directly compressed.” They are also conventionally referred to as “direct compression excipients.” Thus, the granules according to this disclosure can be compressed directly, i.e., without any pretexturing treatment or physical transformation, such as a pre-dry or wet granulation step. This typically means that the granules can form tablets of sufficient hardness by direct compression only in the presence of an efficient amount of lubricant. This “efficient amount” is such that tablet formation is effectively possible, i.e., typically, there is no adhesion or bonding, and the force of ejecting the tablets from the press is less than 1000 Newtons, for example, in the production of 10 tablets. This efficient amount of lubricant generally does not exceed 3% by weight of the total weight of the powder being compressed. “Bonding” corresponds to the adhesion of some material to the matrix, which is thought to persist after the tablets are ejected. Bonding is visible on the tablet, with vertical longitudinal stripes, corresponding to the locations where the product adhered to the die.

[0073] The ability to form satisfactory tablets can be determined by the direct compression of a powdered composition consisting of the excipient and lubricant to be tested, for example, magnesium stearate, to form a round, flat-faced tablet having 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 consolidation simulator that simulates compression on an industrial rotary press, such as the one used in Section 1.2 of the Examples. The press speed can be set to 25 revolutions per minute. A pre-compression force of 1.0 to 1.3 kN can be applied. When using a consolidation simulator (STYL'One Evolution, Medelpharm) simulated on a FETTE 2090 (EU-B) rotary tablet press, this speed corresponds to 54,000 tablets per hour on an industrial scale.

[0074] The tablets thus obtained are subjected to hardness testing using a tablet hardness tester, such as the one used in the following examples section. The hardness of tablets prepared from excipients, expressed in Newtons (N) and tested only in the presence of a lubricant, specifies what is commonly referred to as the "tableting capacity" of the excipient.

[0075] According to “Test A” in this disclosure, the tableting capacity of the excipient being tested is evaluated as follows: A round, flat-faced tablet having a diameter of 11.28 mm and a tablet weight of approximately 400 ± 5 mg is prepared on a single-point unfolding press simulating compression on an industrial rotary press, simulated at a speed of 25 rpm on a FETTE 2090 (EU-B) rotary press, corresponding to 54,000 tablets / hour, using a pre-compression force of 1.0–1.3 kN and a compression force of 3–15 kN. The hardness of the tablet is then measured. According to this test, the tableting capacity is the maximum hardness obtained within this compression force range, and the tablet does not exhibit breakage, sticking, or bonding in the production of, for example, 3–10 tablets, preferably 3 or 10 tablets.

[0076] According to this test A, the granules according to this disclosure preferably have a tableting capacity of 40N or more, preferably 50N or more, more preferably higher than 50N, preferably 60N or more, preferably 70N or more, more preferably higher than 70N, preferably 80N or more, preferably 90N or more, preferably 100N or more, preferably 110N or more, and preferably 120N or more. The tableting capacity is preferably 300N or less, preferably 250N or less, preferably 200N or less, preferably 150N or less, preferably 140N or less, preferably 130N or less, and preferably 120N or less.

[0077] The granules according to this disclosure are granules of microcrystalline mannitol and granular starch, which may contain other components in small amounts, provided that they do not interfere with the desired properties, particularly with respect to efficacy and safety. Examples of such other components include binders, such as hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), carboxymethylcellulose (CMC), cellulosic derivatives, acacia gum, gelatin, starch derivatives such as maltodextrin, tragacanth gum, minerals, sugars and sugar alcohols other than mannitol, food additives, colorants, pharmaceuticals, nutritional supplements, veterinary or cosmetic active ingredients, preservatives, and stabilizers. Preferably, the amount of other components in the granules according to this 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), and preferably less than 0.5% (w / w).

[0078] More preferably, the granules of mannitol and granular starch according to this disclosure do not contain other components. In the latter case, it means that the granules consist only of mannitol and granular starch and contain their moisture and impurities.

[0079] Process for producing granules of mannitol and granular starch The present invention also relates to a process for producing granules according to the present disclosure, comprising the steps of: (a) agglomerating microcrystalline mannitol and granular starch by spraying solubilized mannitol onto granular starch and drying it; (b) drying the granules obtained in step (a); and (c) cooling the granules obtained in step (b), wherein steps (b) and (c) are carried out using dry air and cooling air, respectively, and both the dry air and the cooling air have a water content of 3.0 g or less per 1 kg of dry air.

[0080] Preferably, the process according to this disclosure is a continuous process.

[0081] Step (a) In the first embodiment, step (a) is carried out by spraying a liquid, typically an aqueous composition, containing solubilized mannitol and granular starch into a fluid bed. The granular starch is insoluble in water, and the starch is suspended in the aqueous mannitol solution.

[0082] In a second, more preferred embodiment, step (a) is carried out by introducing powdered granular starch into a fluidized bed while spraying a mannitol solution, particularly an aqueous mannitol solution, into the fluidized bed.

[0083] Aggregation can be carried out by multi-stage spray drying or by fluidized bed granulation. Step (a) is typically carried out in the chamber of either a spray dryer or a fluidized bed granulator, respectively. Both spraying and drying in step (a) are carried out in this unit.

[0084] Preferably, step (a) is carried out by multi-stage spray drying.

[0085] This can be implemented in a multi-stage spray dryer equipped with a high-pressure drying nozzle, in particular, while recycling the fine particles at the top of the spray dryer (e.g., an MSD® type spray dryer).

[0086] While the moisture content of the air in drying step (b) must be carefully controlled, the moisture content of the dry air in step (a) does not require such control.

[0087] The temperature of the dry air in step a) can be easily adjusted by those skilled in the art, depending on the equipment used. This temperature will typically be higher than 100°C.

[0088] Preferably, the dry weight ratio of mannitol to granular starch used to carry out step (a) is as described above for the granules according to this disclosure. Thus, the dry weight ratio of mannitol to granular starch used to prepare the liquid sprayed in step (a) may be in the range of 50 / 50 to 95 / 5, among other things.

[0089] Preferably, the liquid or solution sprayed in step (a) contains 30-50%, preferably 35-45%, for example, about 40% solid, where the percentage is expressed as the dry weight of the solid relative to the total weight of the liquid or solution.

[0090] Steps (b) and (c) In the process according to this disclosure, the drying and cooling air in steps (b) and (c) has a water content of 3.0 g or less per kg of dry air. Preferably, the drying and cooling air in steps (b) and (c) has a water content of 2.5 g or less per kg of dry air, preferably 2.0 g or less per kg of dry air, preferably 1.5 g or less per kg of dry air, and preferably 1.0 g or less per kg of dry air. This is generally dry air with a water content of 0 g / kg or more, and more specifically, dry air with a water content of 0.5 g / kg or more. This is, for example, equivalent to dry air with a water content of about 0.6 g / kg.

[0091] The drying and cooling steps (b) and (c) may be carried out in a unit separated from the fluidized bed granulator or spray drying chamber, especially when a continuous process is used.

[0092] Preferably, the drying step (b) is carried out in a fluidized bed selected from a static fluidized bed and / or a vibrating fluidized bed. It is more preferably carried out in a static fluidized bed, and then preferably in a vibrating fluidized bed.

[0093] Preferably, the cooling step (c) is carried out in a vibrating fluidized bed, preferably the same vibrating fluidized bed used in the drying step (b).

[0094] The temperature of the drying and cooling air in step (b) can be easily adjusted by those skilled in the art, depending on the equipment used and based on the detailed processes described in the examples later herein.

[0095] For example, the temperature of the dry air in step (b) can be selected from 50°C to 130°C, preferably 60°C to 120°C, preferably 70°C to 110°C, for example, about 75°C to about 100°C. When a static fluidized bed and a vibrating fluidized bed are used in drying step (b), the air temperature of the static fluidized bed may 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 vibrating fluidized bed are used in drying step (b), the air temperature of the vibrating fluidized bed may be 70°C to 130°C, preferably 80°C to 120°C, preferably 90°C to 110°C, for example, about 100°C.

[0096] The temperature of the cooling air in step (c) may be 5 to 30°C, preferably 10 to 25°C, for example, about 20°C.

[0097] Preferably, the process includes recycling of fine particles. They can be recycled in powder form or by solubilization in a mannitol solution that is sprayed. Preferably, they are recycled in powder form. The recycling step can be easily performed by those skilled in the art. Recycling can be carried out by extracting the fine particles at the top of the chamber. After extraction, the fine particles can then be separated from the coarse particles that are ultimately present by a cyclone, for example, at the top of the chamber before being reintroduced into the chamber.

[0098] When granular starch is introduced into a powder form, it can be advantageously introduced through an inlet used for recycling powdered fine particles.

[0099] Preferably, the process according to the present disclosure further includes step (d) of recovering the granules thus obtained.

[0100] Other process parameters can be readily adjusted by those skilled in the art depending on the equipment used and based on the detailed processes described in the examples later herein. Examples of such other process features include the spray pressure, the type and number of nozzles used, the flow rate of the sprayed solution or liquid in step (a), and the flow rate of granular starch if it is introduced in powder form.

[0101] If the granules according to this disclosure contain other components, such other components are typically introduced during step (a). They may be introduced via a sprayed liquid or solution, via an inlet for recycling the particulate matter, via an inlet used to introduce the granular starch, or via an additional inlet.

[0102] Figure 1 shows a scheme of a preferred device for carrying out the process according to the present disclosure. In this device, a mannitol solution (1) is sprayed into a drying chamber (2) of a multi-stage spray dryer (3) via a spray nozzle. Granular starch is introduced into a powder state via an inlet (4), which is also used to recycle powdered particles. Dry air (5) is introduced into the chamber (2) to carry out the drying of step (a). The drying step (b) is carried out in a static fluidized bed (6) supplied with dry air (7) having a water content of 3.0 g or less per 1 kg of dry air, and then in a vibrating fluidized bed (8) supplied with dry air (9) having a water content of 3.0 g or less per 1 kg of dry air. The cooling step (c) is carried out in a vibrating fluidized bed (8) supplied with cooling air (10) having a water content of 3.0 g or less per 1 kg of dry air. The particles are recycled via the inlet (4).

[0103] Once prepared, the granules of the present disclosure are preferably stored under conditions that allow them to maintain a water activity of 0.3 or less over time, particularly to preserve the granules from environmental moisture, taking into consideration potential combinations with hygroscopic components. For example, the granules may be stored at room temperature, i.e., 18–25°C, or in a refrigerator. Preferably, the granules of the present disclosure are stored in aluminum foil packaging.

[0104] The present invention also relates to microcrystalline mannitol and granular starch granules obtained or obtainable by the process described herein.

[0105] Products containing mannitol and granular starch granules. The present invention also relates to a product comprising granules according to this disclosure and another component, preferably a moisture-sensitive active ingredient.

[0106] Preferably, the product is selected from a powder composition and / or tablets.

[0107] Preferably, the product contains a moisture-sensitive active ingredient. Active ingredients as disclosed herein include non-pharmaceuticals and pharmaceuticals. The term “active ingredient” classically refers to any substance that is the subject of a pharmaceutical, veterinary, food, dietary supplement, or cosmetic product. Preferably, active ingredients as disclosed herein are dietary supplements or pharmacoactive ingredients. Active ingredients may be selected from so-called small molecules, particularly when they are pharmacoactive ingredients, but may also be selected from so-called “biopharmaceuticals,” such as active substances based on or derived from proteins, nucleic acids (e.g., DNA or RNA), cells, or viruses.

[0108] The term "hygroscopic active ingredient" is well understood in this field. It typically refers to an active ingredient that undergoes undesirable changes when exposed to moisture from various sources, such as excipients, manufacturing processes, or environmental conditions. A common consequence of contact between a hygroscopic active ingredient and moisture is the formation of one or more different chemical species. This can result in hydration of the drug molecule, leading to changes in its physical properties (e.g., different solubility profiles), or the production of different compounds or degradation products, leading to loss of potency. For probiotics, it is known that moisture exposure must be limited to minimize the reduction in cell viability caused by harmful chemical reactions.

[0109] In some cases, drug stability is demonstrated by the slow rate of degradation compound formation over time. The period during which a drug must remain stable, i.e., the period during which its potency and / or impurity content in the formulation must be maintained, varies according to the commercial specifications set by the manufacturer. For example, certain products may be required to maintain a specific potency specification for a period of 6 months, 1 year, 2 years, or some other time after manufacture. The established shelf life of a product assumes maintenance in its original packaging under specified temperature and humidity conditions.

[0110] Non-limiting examples of hygroscopic active ingredients include probiotics, for example, bacteria or yeasts preferably derived from the genus Lactobacillus or Bifidobacterium, and drug molecules such as dabigatran, enalapril, ranitidine, omeprazole, aspirin, and ascorbic acid. It is preferably selected from probiotics, preferably from bacteria, and more preferably from lactic acid bacteria, for example, Lb. rhamnosus.

[0111] Preferably, in the product according to the present disclosure, the weight ratio of granules to hygroscopic active ingredient according to the present disclosure is 1:1 to 10:1, preferably 1:1 to 8:1, preferably 1:1 to 5:1, preferably 1:1 to 4:1, and preferably 2:1 to 4:1. This is, for example, equal to about 3:1.

[0112] Preferably, the product according to this disclosure has a water activity of 0.50 or less, preferably 0.45 or less, preferably 0.40 or less, preferably 0.35 or less, preferably 0.30 or less, preferably 0.25 or less, and preferably 0.20 or less. It is preferably 0.01 or more, preferably 0.05 or more.

[0113] This water activity can be determined by a person skilled in the art, for example, by a capacitive hygrometer and a dew point hygrometer, preferably by a dew point hygrometer, according to the method described in Section 1.3 of the subsequent examples herein.

[0114] Preferably, the products according to this disclosure have a moisture content (also referred to as "loss on drying") of 5.0% by weight or less, preferably 4.0% by weight or less, preferably 3.0% by weight or less, and preferably 2.0% by weight or less. This is generally higher than 0.5% and more preferably higher than 1.0%. This moisture content can be determined by those skilled in the art, for example, by a halogen hygrometer or a water oven at 130°C, most preferably a halogen hygrometer, according to the method described in section 1.3 of the Examples later in this specification.

[0115] In a first preferred embodiment, the product according to the present disclosure is a tablet, preferably a chewable tablet. It is understood that some of the characteristics of the granules (e.g., their diameter or density) may not be found in the final tablet when it is tabletized. Therefore, alternatively, the tablets according to the present disclosure may be defined by the fact that they are obtained or can be obtained from a powdered composition containing the granules according to the present disclosure.

[0116] Preferably, the tablets according to this disclosure are biconvex caplets having a width of 9.5 mm and a length of 19 mm.

[0117] Preferably, the tablets according to this disclosure have a weight of about 1 g.

[0118] Preferably, the tablets according to this disclosure have a hardness of 40 N or more, preferably 50 N or more, preferably 60 N or more, and preferably 70 N or more. Preferably, the tablets according to this disclosure have a hardness of 250 N or less, preferably 200 N or less, preferably 150 N or less, preferably 140 N or less, preferably 130 N or less, and preferably 120 N or less. It is selected, for example, from 60 to 130 N or 70 to 120 N.

[0119] In a second preferred embodiment, the product according to the disclosure is a powdered composition. The powdered composition may be a powdered composition suitable for making another product (e.g., a premix for making tablets). The powdered composition may be a filler for hard capsules, sachets, or stick packs.

[0120] In a first preferred embodiment, the granules or product according to the present disclosure are stored in a refrigerator, i.e., at a temperature of 4 to 8°C.

[0121] In a second preferred embodiment, the granules or product according to the present disclosure are stored at a temperature of 15 to 30°C, preferably 20 to 30°C, more preferably 20 to 25°C, and more preferably about 25°C, at a relative humidity of 60% or less. This relative humidity is preferably as low as possible, for example, about 20 to 30%.

[0122] Preferably, the products of this disclosure are in aluminum foil packaging. The products of this disclosure may be packaged in bags, bottles, blisters, sachets, or stick packs. Preferably, the tablets of this disclosure are packaged in bags, bottles, or blisters, more preferably in blisters, and preferably in aluminum blisters. Preferably, the powdered compositions of this disclosure are packaged in bags, sachets, or stick packs, more preferably in aluminum sachets or aluminum stick packs. The powdered compositions may be used as fillers for hard capsules. In this case, the hard capsules are preferably packaged in bags, bottles, or blisters, more preferably in blisters, and preferably in aluminum blisters.

[0123] The products according to this disclosure may be packaged together with a desiccant pack, for example, a pack containing silica beads. This may be particularly interesting for protecting the product from environmental moisture caused by multiple openings of the packaging by the user. Such a desiccant pack can typically be added inside the bottle.

[0124] Use of microcrystalline mannitol and granular starch granules The present invention also relates to the use of granules according to this disclosure for formulating or stabilizing a moisture-sensitive active ingredient.

[0125] Preferably, the granules are as described above. Preferably, the hygroscopic active ingredient is as described above. In particular, it is preferably selected from bacteria or yeast, preferably from the genus Lactobacillus or Bifidobacterium, or from drug molecules such as dabigatran, enalapril, ranitidine, omeprazole, aspirin, and ascorbic acid. It is preferably selected from probiotics, preferably from bacteria, more preferably from lactic acid bacteria, such as Lb. rhamnosus.

[0126] Preferably, granules are used to formulate a product which is preferably as described above. In particular, the product is preferably selected from tablets or powder compositions.

[0127] Preferably, the granules are used as a filler and / or a binder and / or a direct compression excipient.

[0128] The ability to stabilize a hygroscopic active ingredient can be determined, for example, by subjecting a formulation consisting of a hygroscopic active ingredient and 1-3% by weight of a lubricant in granules to storage at a temperature of 30°C and a relative humidity of 65% for a given period, for example, at least 3 months, or 3-12 months, or 3-6 months, for example, 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 formulation is less than that of the active ingredient alone, the active ingredient can be considered stabilized. For probiotics, this can be done, for example, by measuring cell viability according to the method described in Section 1.4 of the Examples.

[0129] Preferably, the granules and products containing them according to the present disclosure, in particular the tablets according to the present disclosure, are for individuals with difficulty swallowing, and / or for children, and / or for the elderly, and / or for pediatric patients, and / or for elderly patients, and / or for patients suffering from dysphagia.

[0130] In this disclosure, the amounts of components are generally expressed as weight percentages. Unless otherwise specified, these weights are the raw amounts of the components in powder or oil form. Powdered components generally contain small amounts of water (also referred to as moisture % or "loss on drying") and / or small amounts of impurities.

[0131] Other features and advantages of the present invention will be clearly understood by reading the examples provided later in this specification, which illustrate but do not limit the present invention. [Examples]

[0132] 1. Prototype of mannitol and starch granules 1.1. Preparation of mannitol and starch granules in batch mode using a fluidized air bed granulator. Different compositions consisting of mannitol and granular starch were prepared by agglomeration and drying according to the present disclosure, in dry weight ratios of 85:15, 80:20, 75:25, and 65:35, respectively.

[0133] Solutions of mannitol and granular starch with the desired solid content were prepared by dissolving mannitol (PEARLITOL® 50C, ROQUETTE) in desalinated water at 55°C and by suspending extra white corn starch. The mixture was stirred to obtain a homogeneous, fluid solution free of lumps.

[0134] The operating conditions for producing these granules in the AGT 150 batch fluidized air bed granulator sold by Glatt are shown in Table 2 below. The spray nozzle was in the "bottom spray" position.

[0135] [Table 2]

[0136] To carry out drying step (b), the obtained granules were placed in a ventilated oven and dried at a temperature of 80°C for 48 hours using air with controlled humidity (less than 3.0 g per 1 kg of dry air). To carry out drying step (c), the granules were cooled to room temperature using air with controlled humidity (less than 3.0 g per 1 kg of dry air) for 24 hours.

[0137] 1.2. Characterization of Granules The granules obtained in this manner were characterized according to the following method.

[0138] 1. Water activity (Aw). Aw was measured using the Waterlab STEROGLASS® device. The analysis was performed at 25°C. The analysis was carried out according to the instrument recommendations (WATERLAB_MU_ENG_Rev2_2020).

[0139] 2. Mannitol content. Mannitol content was determined by high-performance liquid chromatography on a calcium-type ion exchange resin. Quantification was performed using an external calibration method. The following materials and parameters were used: Eluent: water, flow rate: 0.5 ml / min, column temperature: 85°C, injected volume: 20 μL, calcium-type ion exchange resin column: Ca++ type BIORAD HPX87C (300 × 7.8 mm) (e.g., ref. 125-0095), detector: differential refractometer.

[0140] 3. Moisture content. The moisture content was determined by drying the test portion in an electric heating oven under air pressure at a temperature in the range of 130-133°C for 1.5 hours, following the protocol below. Approximately 5g of the accurately weighed test portion of the test sample was introduced. It was dispersed in a uniform thin layer at the bottom of the capsule. The uncovered capsule was placed in the oven for 1 hour and 30 minutes, leaving the lid nearby, from the moment the oven was readjusted to the specified temperature range. The oven was not opened during drying.

[0141] 4. Bulk density, tap density, and Hausner ratio. The bulk density was determined by the following methods: Fluidizing the sample into a test tube of known volume through a determined funnel. Determining the volume of the test tube by measuring the mass of a certain volume of the product in the test tube at a specified temperature, and measuring the mass of an equal volume of water at the same temperature. Calculating 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 were used: Temperature: 20°C, Stainless steel funnel: Top diameter 12 cm, bottom diameter 12 mm, cone height 9 cm, tube length 2 cm. This funnel was placed on a stand so that the distance between the funnel and the test tube was 10 cm.

[0142] The tap density was determined by the following method: measurement of the mass of a certain volume of the product after compaction and an equal volume of distilled water at the same temperature. The tap density was calculated by dividing the mass of the product volume by the volume of the product itself. The protocol was as follows: weigh 20 g of powder into a test tube. place the test tube on the tap density tester (STAV 2003 tap density tester) and turn on the power with 50 strokes. read the volume in the test tube.

[0143] 5. Specific surface area. The specific surface area of ​​powdered granules was measured based on the three-point Brunauer, Emmett, and Teller (BET) theory. The physical principle used to determine the specific surface area is based on low-temperature gas adsorption. Apparatus: Beckman-Coulter SA3100.

[0144] 6. Crystalline Polymorphism. Crystalline polymorphism was determined by X-ray diffraction on the powder. A powder X-ray diffraction spectrometer (Bruker) equipped with a copper anode tube (wavelength: 1.54 Å) was used to determine and quantify the crystal forms of mannitol. The analysis was performed continuously at 5–60° in reflection using a rotating sample holder. The sample was manually compacted and deposited in a flat layer on the sample holder. The crystal forms of mannitol were determined by comparing the positions of the diffraction lines of the sample to the alpha, beta, and delta forms of mannitol using a basic parameter approach from structural files available in the COD (Crystallography Open Database) and CSD (Cambridge Structural Database) databases. References: Alpha ref CSD1142501 / Beta ref CSD1142500 / Delta ref CSD 662815.

[0145] 7. Volume-average diameter and particle size distribution in volume. The volume-average diameter and particle size distribution in volume were determined by laser diffraction on the powder product. Measurement of the diffraction of the laser beam by the particles of the sample being analyzed. These particles diffract individually. The resulting diffracted light intensity is a function of particle size. Computer processing of these light intensities provides access to the particle size distribution. Equipment: SYMPATEC HELOS KR brand laser diffraction particle size analyzer equipped with R5 and R7 lenses. RODOS M system associated with a 6mm gun and VIBRI system. Nilfisk IBVI5 vacuum cleaner.

[0146] 8. Tablet Compression Capability. The excipient to be tested was mixed with 1% magnesium stearate. Using a preliminary compression force of 1.0–1.3 kN, round, flat-faced tablets with a diameter of 11.28 mm and a weight of approximately 400 mg were prepared on a single-punch compaction simulator (STYL'One Evolution, Medelpharm) simulated at a speed of 25 rpm on a FETTE 2090 (EU-B) rotary press, corresponding to 54,000 tablets / hour. Different compression forces of approximately 3–20 kN were tested. The hardness of the tablets thus obtained was measured using a tablet hardness tester (ERWEKA TBH 425, ERWEKA GmBH).

[0147] The results are shown in Figures 2 and 3.

[0148] All granules according to this disclosure had a low water activity of less than 0.3. Water activity and tableting ability increased with the dry weight ratio of mannitol to granular starch (Figures 2 and 3).

[0149] The granules according to this disclosure have satisfactory tableting ability (Figure 3). Therefore, they are suitable for producing tablets with sufficient hardness, i.e., tablets that do not break during storage and transport. On the other hand, because the hardness is not too high, the tablets can be easily chewed. Therefore, the granules according to this disclosure are particularly suitable for producing chewable tablets.

[0150] Because it depends on the size and shape of the tablet, there is no ideal hardness value for a tablet to be chewable. However, generally, the hardness is preferably at least 60-70 N. Therefore, granules having a mannitol-to-granular starch dry weight ratio greater than 65:35 are preferred for making tablets due to their higher tableting ability. Granules having a mannitol-to-granular starch dry weight ratio of at least 75:25 are even more preferred.

[0151] The granules according to this disclosure typically exhibit a volume-average diameter and size distribution that makes them suitable for use in tableting or for filling, for example, hard capsules, sachets, or stick packs. This allows them to be properly fed into devices used to prepare and package formulations containing them. It also allows for homogeneous mixing with the majority of the active ingredient.

[0152] 1.3. Stability of granules and probiotic-containing formulations Lactobacillus rhamnosus was selected as a model strain because it is a well-known and well-studied probiotic strain and is found in many commercially available probiotic formulations for multiple age groups.

[0153] Two types of formulations, namely tablets and powdered compositions, were tested.

[0154] The formulation used after optimization was as follows by weight: 1% magnesium stearate, 74.25% prototype, and 24.75% Lb. rhamnosus. The same formulation was used in tablet and powder compositions.

[0155] The tablets were prepared as follows: Using a pre-compression force of 1.0–1.3 kN and a compression force of 15–20 kN (selected after optimization), biconvex caplets with a length of 19 mm, a width of 9.5 mm, and a weight of approximately 1 g were prepared on a single-punch compaction simulator (STYL'One Evolution, Medelpharm) simulated at a speed of 25 rpm on a FETTE 2090 (EU-B) rotary press, corresponding to 54,000 tablets / hour.

[0156] For stability studies, the tablets and powder compositions were packaged in aluminum foil bags with low headspace to minimize the amount of air in contact with the granules.

[0157] The stability was evaluated by measuring Aw and moisture content during storage at 65%RH / 30℃ according to the following method.

[0158] 1. Water activity. Water activity was measured at 25°C using a water activity meter (Aqualab 4TE Duo, Meter Group, USA). Powdered composition samples were measured using a sample weight of 1 g (±0.05 g) immediately after opening the package, while tablets (1 g (±0.05 g) sample weight) were crushed before analysis to shorten the equilibrium time in the water activity chamber.

[0159] 2. Moisture content. Loss on drying (LOD) was measured using a halogen hygrometer (Mettler Toledo, HC103) at a drying temperature of 105°C. Powdered composition samples were measured using a sample weight of 1 g (±0.05 g) immediately after opening the package, while tablets (sample weight of 1 g (±0.05 g)) were crushed before analysis.

[0160] For tablets, storage hardness and disintegration time were also assayed. Disintegration time was measured using a disintegration tester (PTZ Auto, Pharma Test Apparatebau AG, Germany) in accordance with the European Pharmacopoeia disintegration test (EP 5.0 2.9.1.) for tablets and capsules.

[0161] The results are shown in Figures 4 to 8.

[0162] These results demonstrate that the tablets and powder compositions obtained from the granules according to this disclosure have good stability.

[0163] After 3 months of storage at 65% RH / 30°C, the increase in water activity for Lb. rhamnosus was 0.27. An increase in water activity was observed for both the powdered composition and the tablets. The increase in water activity ranged from 0.18 to 0.26 for the powdered composition and from 0.26 to 0.34 for the tablets. Generally, the incorporation of granules into the formulation did not result in increased free water uptake during storage, as long as the final water activity after 3 months was equivalent to that of Lb. rhamnosus alone. Therefore, unexpectedly, these results indicate that the granules do not introduce any additional free water into the formulation.

[0164] As a further unexpected effect, subsequent data in this specification comparing the cell viability of Lb. rhamnosus alone and mixed with granules surprisingly demonstrate that not only is cell viability not negatively impaired over time by the granules, but on the contrary, the presence of granules improves cell viability over time and thus even makes it possible to protect Lb. rhamnosus from moisture.

[0165] The hardness and disintegration time of the tablets remain stable over time, which indicates the physical stability of the tablets.

[0166] Prototypes containing 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 capacity data shown in Section 1.2. Disintegration time increased with tablet hardness.

[0167] 1.4. Cell viability in probiotic-containing formulations The inventors investigated the effect of compression on cell viability. Cell viability was assayed using the 3M Petrifilm Lactic Acid Bacteria Count Plate method. A sterile sample (equivalent to 1.0 ± 0.1 g) was weighed and added to 9 mL of 3M peptone aqueous solution. The suspension was mixed for 5 minutes using a Turbula blender (Turbula T2F, Glen Mills), and homogeneity was visually confirmed. If the sample was not sufficiently dispersed, the suspension was mixed for another 5 minutes. After 5 minutes of mixing, the suspension was left at room temperature for 25 minutes, for a total of 30 minutes for sample hydration. The total time for mixing and sample standing is 30 minutes. If the mixing step took 10 minutes, the standing time would be 20 minutes accordingly. After a homogeneous suspension was obtained, the suspension was diluted to achieve a theoretical concentration that would yield a count of 20-300 colonies. Before the dilution and plating steps for each sample, the sample was vortexed for 30 seconds. Appropriately diluted samples were plated onto 3M Petrifilm Lactic Acid Bacteria Count plates according to the manufacturer's instructions and incubated at 28–37°C for 48±3 hours.

[0168] The 3M Petrifilm Lactic Acid Bacteria Count Plate method was validated using the ISO 15214 pour plate method, and no significant difference was observed between the two test methods based on the mean of sample replication determined by a paired t-test (p=0.43).

[0169] The tablets were prepared as described in Section 1.3.

[0170] The results are shown in Figure 9(a).

[0171] The effect of compressive force on cell viability was observed to be secondary to the effect of the mannitol-to-granular starch ratio. Regardless of the mannitol-to-granular starch ratio, tablets compressed at 20 kN consistently had a 13% lower cell viability compared to tablets compressed at 15 kN. The lowest cell viability was obtained using a compressive force of 20 kN with granules having a dry weight ratio of 85:15 mannitol-to-granular starch (56% cell viability). The highest cell viability was obtained using a compressive force of 15 kN with granules having a dry weight ratio of 75:25 mannitol-to-granular starch (94% cell viability).

[0172] For comparison, commercially available excipients for probiotic tableting (made from different materials) showed cell viability of 30-40% using a compressive force of 15 kN and approximately 20% using a compressive force of 20 kN.

[0173] These results also indicate that higher granular starch content is associated with higher cell viability. In this regard, therefore, when granules are used to make tablets, a dry weight ratio of mannitol to granular starch lower than 85:15 is preferable.

[0174] Next, cell viability was evaluated for the tablet and powder compositions prepared as described in Section 1.3 and stored at 30°C / 65%RH for two weeks. Granules with a dry weight ratio of mannitol to granular starch of 85:15 were selected for this evaluation. Indeed, these granules had the highest water activity and the lowest cell viability after compression, leading to the hypothesis that other granules with higher starch content would perform at least as well, if not better. For tablets, a compressive force of 20 kN was selected for similar reasons, namely, because the use of this compressive force resulted in the lowest cell viability.

[0175] The results are shown in Figure 9(b).

[0176] After two weeks of storage, both the tablet and powder formulations showed higher cell viability compared to probiotics alone. These results demonstrate the protective effect of granules according to this disclosure. Even if cell viability was impaired by tableting, this loss was quickly balanced by the fact that cell viability decreased much more slowly in tablets compared to untabletized probiotics.

[0177] 2. Pilot batch of starch and mannitol granules For scaling purposes, a dry weight ratio of 80:20 mannitol to granular starch was selected because it was identified as a preferred ratio in a previous set of experiments for producing chewable tablets. In fact, granules with a dry weight ratio of mannitol to granular starch greater than 75:25 and lower than 85:15 represent the best compromise between Aw, tableting capacity, and cell viability.

[0178] 2.1. Preparation of starch and mannitol granules in continuous mode using a multi-stage spray-drier (MSD) Granules consisting of mannitol and granular starch in a dry weight ratio of 80:20 were prepared by multi-stage spray drying. Crystalline mannitol, marketed by the applicant under the name PEARLITOL® 50C, exhibiting a laser volume-average diameter of approximately 50 μm, and "Extra White" corn starch were used. A mannitol solution with the desired solid content was prepared by dissolving the crystalline mannitol in demineralized water at 80°C. Granular starch was introduced in powder form into a system for recycling fine particles via a weight-powder dispensing device. The operating conditions for producing these granules in an MSD-type spray dryer marketed by Niro with an evaporation capacity of 400 kg / hour are shown in Table 3 below. Fine particles are recycled at the top of the chamber.

[0179] [Table 3]

[0180] 2.2. Characterization of Granules The granules obtained in this manner were characterized according to the method described in Section 1.2.

[0181] They were also examined using scanning electron microscopy (Quanta 200F, FEI).

[0182] The results are shown in Figures 10, 11, and 12.

[0183] These results confirm the good tableting ability of the granules according to this disclosure, as well as the robustness of the process used.

[0184] The granules according to this disclosure have excellent fluidity (Figure 10).

[0185] Furthermore, the taste and sensory characteristics of the obtained tablets were evaluated during chewing. Experts found that the overall taste and texture were good. The tablets were slightly sweet, had no unpleasant aftertaste, and did not have a sandy or chalky texture.

[0186] For further characterization and evaluation, pilot batch G-MS-lowAw-80 / 20_#22 was selected. In fact, if this batch has the highest Aw and the inventors can demonstrate that it is good for formulating probiotics, it means that other batches can be expected to be at least as effective, if not more so.

[0187] 2.3. Stability of granules and probiotic-containing formulations Probiotic formulations (powdered compositions and tablets) were prepared as described in Section 1.3, except that the tablets were packaged in aluminum blisters. To prepare the tablets, compressive forces of 15 kN and 20 kN were selected to match the hardness previously obtained with prototype G-MS-lowAw-80 / 20_#1. Such compressive forces were 12.5 kN and 16.5 kN, respectively.

[0188] The abrasion of the tablets prepared in this manner was measured as follows. A sample of the entire tablet, corresponding to a minimum of 6.5 g, was used for evaluation. The tablet samples were weighed, and before placing them in the drum of the abrasion tester (PTF 20E, Pharma Test Apparatebau AG), the tablets were carefully sieved to remove dust. The drum was rotated 100 times, after which the tablets were removed. The dust released from the tablets was removed as before, and the tablets were weighed. The mass loss rate as a function of the initial mass was determined.

[0189] Stability was assayed as described in Section 1.3.

[0190] The results are shown in Figures 13 to 17.

[0191] Considering 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 Lb. rhamnosus. This further highlights the need for excipients with low Aw and moisture content to maintain the overall acceptable Aw and moisture content of the final formulation.

[0192] For the powdered composition, a slight increase in water activity and water content was observed. For the refrigerated sample, water activity was maintained throughout the entire 3-month storage period. The room-temperature sample showed an increase in water activity of 0.2.

[0193] The results obtained for the tablets were remarkably good. Both water activity and moisture content were maintained throughout the entire 3-month period under both storage conditions. Furthermore, increases in hardness and disintegration time were minimal under both storage conditions and compressive forces, which demonstrates the good stability of tablets obtained from granules according to this disclosure.

[0194] Furthermore, it can be seen that compressive force significantly affects hardness and abrasion, with lower compressive force resulting in lower hardness and higher abrasion.

[0195] 2.4. Cell viability in preparations containing probiotics To evaluate whether the granules according to this disclosure are suitable for formulating probiotics, more generally, hygroscopic components, cell viability was assayed in the formulations. Cell viability was assayed as described in Section 1.4.

[0196] The results are shown in Figures 18 and 19. In Figure 19, the inventors plotted cell viability along with water activity under storage conditions of 25°C / 60%RH.

[0197] Figure 18 shows that refrigeration was able to maintain the viability of Lb. rhamnosus in all formulations. Unlike standard excipients, this indicates that the granules according to this disclosure do not destabilize the probiotics. At room temperature, the granules according to this disclosure even have a protective effect, and the decrease in cell viability is less pronounced in formulations containing the granules according to this disclosure and Lb. rhamnosus compared to Lb. rhamnosus alone. When formulated into tablets, there was almost no decrease in cell viability.

[0198] Figure 19 shows that increased water activity dramatically reduced the cell viability of Lb. rhamnosus alone. In contrast, when combined with the granules according to this disclosure, the cell viability of Lb. rhamnosus improved. This further highlights the ability of the granules according to this disclosure to limit the increase of free water in the probiotic formulation and thus protect the probiotics from water.

[0199] 3. Comparison with starch and mannitol granules (not provided for) having a higher Aw, and with mannitol and starch blends (not provided for).

[0200] To confirm the importance of having mannitol and granular starch in the same granules (i.e., by simultaneous processing) and the importance of having low water activity, the inventors compared the granules according to this disclosure with the following comparative samples. A mixture of directly compressible mannitol (PEARLITOL® 200SD) and granular starch (corn starch) having a dry weight ratio of -80:20 mannitol to granular starch, an Aw of 0.276, and a moisture content of 1.81% (hereinafter referred to as "low Aw mannitol and granular starch blend"), the Aw and moisture content being determined according to the methods listed in Section 1.3. Co-processed mannitol and starch according to U.S. Patent No. 9,839,610 (hereinafter referred to as "high Aw mannitol and granular starch granules," PEARLITOL® Flash), having a dry weight ratio of -80:20 mannitol to granular starch, an Aw of 0.545, and a moisture content of 2.32%, the Aw and moisture content being determined according to the methods listed in Section 1.3.

[0201] To obtain a blend with the lowest possible moisture and Aw, a comparative blend of mannitol and granular starch with low Aw was obtained by using a grade of granular starch with particularly low moisture content.

[0202] 3.1. Stability of granules or blends and preparations containing probiotics Tablets containing probiotics were prepared as described in Section 2.3. To prepare the tablets, a compressive force of 16.5 kN was selected to match the thickness obtained in the sample according to this disclosure (pilot batch G-MS-lowAw-80 / 20_#22), which was 6.9 mm.

[0203] Stability was assayed as described in Section 1.3.

[0204] The results are shown in Figures 20 to 23.

[0205] When compressed to a similar thickness, the tablets containing granules according to this disclosure were harder, while surprisingly exhibiting the shortest disintegration time.

[0206] The hardness and disintegration time of the tablets under both conditions (refrigeration and 25°C / 60%RH) remained stable over time, which is an indicator of the physical stability of the tablets for all three formulations.

[0207] The lowest water activity was obtained under both conditions when using the granules according to this disclosure. For these tablets, the water activity of the tablets was maintained within the ideal range of 0.2–0.3 for 3 months.

[0208] 3.2. Cell viability in probiotic-containing formulations Cell viability was assayed as described in Section 1.4.

[0209] The results are shown in Figure 24.

[0210] The granules according to this disclosure showed a remarkable probiotic protective effect. After 3 months of storage at 25°C / 60%RH, the cell viability of tablets containing the granules according to this disclosure was significantly higher than that obtained with comparative tablets containing granules with an Aw greater than 0.3 or a blend of mannitol and granular starch with a low Aw.

[0211] These results indicate that it is essential for both mannitol and granular starch to be present in the same granules (i.e., processed simultaneously) while exhibiting a low Aw.

Claims

1. Microcrystalline mannitol and granular starch granules having a water activity of 0.3 or less, measured at 25°C.

2. The granules according to claim 1, having a water activity of 0.2 or less.

3. The granules according to claim 1 or 2, wherein the dry weight ratio of mannitol to granular starch is 50:50 or more.

4. Granules according to any one of claims 1 to 3, having a moisture content of 5.0% by weight or less.

5. Granules according to any one of claims 1 to 4, having a bulk density of 350 g / L or more.

6. Granules according to any one of claims 1 to 5, having a tap density of 400 g / L or more.

7. Granules according to any one of claims 1 to 6, having a specific surface area of ​​0.30 m² / g or more.

8. The granules according to any one of claims 1 to 7, wherein the mannitol comprises α and β polymorphs.

9. Granules according to any one of claims 1 to 8, having a volume average diameter of 90 μm or more and 400 μm or less.

10. A process for producing granules according to any one of claims 1 to 9, comprising the steps of: (a) agglomerating microcrystalline mannitol and granular starch by spraying solubilized mannitol onto granular starch and drying it; (b) drying the granules obtained in step (a); and (c) cooling the granules obtained in step (b), wherein steps (b) and (c) are carried out using dry air and cooling air, respectively, and both the dry air and the cooling air have a water content of 3.0 g or less per 1 kg of dry air.

11. A product comprising the granules described in any one of claims 1 to 9 and another component.

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

13. The product according to claim 11 or 12, wherein the other component is a probiotic.

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

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

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