Porous carrier for the delivery of poorly water-soluble substances

Abstract

The invention relates to water-soluble porous particles comprising a polysaccharide, said particles having a BET specific surface area equal to or higher than 40 m2 / g and a particle hardness equal to or higher than 5 MPa. The inventions also relate to a method for making thereof. The invention also relates to the use thereof as a carrier, in particular for the delivery of poorly water-soluble substance.

Description

BR927 - Porous carrier for the delivery- WO1DescriptionTitle: Porous carrier for the delivery of poorly water- soluble substancesTechnical Field

[0001] The present invention pertains to the field of carriers for the delivery of poorly water- soluble drugs, and to methods for producing said carriers.Background Art

[0002] Oral drug administration has been most convenient and popular successfully used route for drug delivery because of ease of administration, greater flexibility in dosage form design, ease and low cost of production. Major challenge in design of oral dosage form is bioavailability. The oral bioavailability depends on several factors including aqueous solubility, drug permeability, dissolution rate and presystemic metabolism or first pass metabolism. Frequently poor bioavailability is due to low solubility and low permeability. Solubility plays a major role to reach desired drug concentration in systemic circulation for pharmacological response. The poor solubility and low dissolution rate cause insufficient bioavailability. Particularly for BCS class II and IV drugs the bioavailability can be enhanced by increasing solubility and dissolution rate.

[0003] The adsorption of poorly soluble drug on high surface carriers such as porous material is a technique used to enhance the dissolution rate of drug. To this end, the use of mesoporous silica has been widely reported.

[0004] Patent literature WO 2005 / 000740, for example, discloses a crystalline mesoporous silica material that has a zeolite-type micropore framework (expressed in nanometer-sized structural units) and that does not give rise to Bragg type diffraction in powder X-ray diffraction patterns, as well as to the use of the material for drug delivery purposes. This document discloses that the use of the zeolite material results in a drug release rate of less than 80%.

[0005] The specific surface area of porous materials that are formed from inorganic compounds like silica can be readily increased, but inorganic compounds are not soluble in water and cannot dissolve in the body accordingly. As a result, not all the active ingredient supported on the carrier is released, preventing the desired dose from being delivered to its target site.

[0006] Interestingly, patent literature WO 2024 / 029516 (WO’516) describes porous carrier particles with high specific surface area which are water-soluble. They can thus be used as a carrier to further improve bioavailability of poorly water-soluble drugs.BR927 - Porous carrier for the delivery- WO2

[0007] For making those carriers, a solution containing a water-soluble polymer is spray-dried to obtain precursor particles, and the resulting precursor particles are then mixed with an organic solvent. When the solvent is removed, some of the oligosaccharides (such as maltose and maltotriose) contained in the three-dimensional network structure of the precursor particles are extracted, resulting in micropores where the extracted material used to exist, and thus in the formation of carrier particles.

[0008] The specific surface area of these carrier particles is higher that than of conventional water-soluble porous particles. They can therefore support greater amounts of functional ingredients than conventional water-soluble porous particles can.

[0009] However, there was still a need to further improve this technology, for example for making it easier to handle at industrial scale.Technical Problem

[0010] An object of the present invention was to provide improved solid carrier particles, in particular for oily or poorly water-soluble substances.

[0011] It was an object of the present invention to provide carrier particles that can support a great amount of a substance, in particular of an oily or poorly water-soluble substance.

[0012] It was an object of the present invention to provide carrier particles that are easy to handle at industrial scale, for example which are free-flowing and have sufficient mechanical strength.

[0013] It was an object of the present invention to provide carrier particles that can efficiently deliver a substance, in particular an oily or poorly water-soluble substance. In particular, it was an object of the present invention to provide carrier particles that can improve the bioavailability of oily drugs or of poorly water-soluble drugs.Presentation of the Invention

[0014] The inventors successfully developed carrier particles that are easier to handle. They have improved flowability and particle strength as compared to the ones described in WO’516 mentioned above.

[0015] These carrier particles can better flow in the equipments used for the formulation and manufacture of the final product (e.g., final medicament). They can further facilitate and improve the process for making the final product (including steps such as blending, impregnation with a substance of interest, coating etc.). For example, the carrier particles according to the invention allow obtaining more homogenous impregnation of the substance. Also, the particles can better resist to the mechanical stress induced by the final product manufacturing steps and by transportation.BR927 - Porous carrier for the delivery- WO3

[0016] Such improved carrier particles can be obtained from precursor particles prepared by spray-granulation, instead of spray-drying like used in WO’516.

[0017] The carrier particles according to the invention can quickly and completely dissolve into the body thus allowing all of the supported ingredient to be released, making them suitable for use as a support for active ingredients, in particular of ingredients which are poorly soluble or not miscible in water.Brief Description of the Invention

[0018] The invention first relates to water-soluble porous particles comprising a polysaccharide, said particles having a BET specific surface area equal to or higher than 40 m2 / g and a particle hardness equal to or higher than 5 MPa.

[0019] Preferably, said polysaccharide is selected from a dextrin, a maltodextrin, a dextran, agarose, pullulan, or from a mixture thereof. Preferably, said polysaccharide is a glucose polymer. Preferably, said polysaccharide is selected from a dextrin, a maltodextrin, or from a mixture thereof. Preferably, said particles have a D50 in volume higher than 70 pm. Preferably, said particles have an angle of repose equal to or lower than 45°.

[0020] The invention also relates to the use of the water-soluble porous particles according to the disclosure, as a carrier for one or more substances. Preferably, said one or more substances comprises a substance that is poorly water-soluble or not miscible with water.

[0021] The invention also relates to a composition comprising the water-soluble porous particles according to the disclosure and one or more substances supported by said particles. Preferably, said one or more substances comprise a substance that is poorly water-soluble or not miscible with water.

[0022] The invention also relates to a composition comprising the water-soluble porous particles according to the disclosure and one or more substances supported by said particles, for use as a medicament, wherein said one or more substances comprise a pharmaceutical or veterinary active ingredient. Preferably, said one or more substances comprise a substance that is poorly water-soluble or not miscible with water.

[0023] The invention also relates to a method for making water-soluble porous particles, said water-soluble porous particles comprising a polysaccharide, and said particles having a BET specific surface area equal to or higher than 40 m2 / g, said method comprising:(a) preparing precursor particles by fluidized bed spray-granulation of a saccharide solution, said saccharide comprising a polysaccharide;(b) obtaining the carrier particles by exposing the precursor particles to an organic solvent.

[0024] Preferably, said saccharide contains at least 10% of disaccharides, as dry weight with respect to the total dry weight of carrier particles. Preferably, said saccharide contains at leastBR927 - Porous carrier for the delivery- WO420% of polysaccharides, as dry weight with respect to the total dry weight of carrier particles. Preferably, said saccharide contains at least 1% of trisaccharides, as dry weight with respect to the total dry weight of carrier particles.Brief Description of Drawings

[0025] Other features, details and advantages will be shown in the following detailed description and on the figures, on which:Fig. 1

[0026] [Fig. 1] is a simplified scheme of a process for making the precursor particles according to the disclosure.Fig. 2

[0027] [Fig. 2] are Scanning Electron Microscope (SEM) photographs of carrier particles according to the disclosure.Description of EmbodimentsPorous particles

[0028] The invention first relates to water-soluble porous particles comprising a polysaccharide, said particles having a BET specific surface area equal to orhigherthan 40 m2 / g and a particle hardness equal to or higher than 5 MPa.

[0029] Such porous particles are particularly useful for use as a carrier for one or more substances, in particular as a carrier for poorly water-soluble substances or substances which are not miscible with water. The terms “porous particles”, “carrier particles”, “porous carrier particles” can be used interchangeably throughout the disclosure.

[0030] The term “porous” means the state of having a large number of pores which notably results into a high BET specific surface area of 1 m2 / g or more.

[0031] The term “polysaccharide” includes both oligosaccharides and polysaccharides and thus refers to saccharides having at least 3 saccharide units.

[0032] In an embodiment, polysaccharide includes a glucose-based helical structure.

[0033] The following method may be used to determine whether the particles comprise a polysaccharide having a glucose-based helical structure: as per the dextrin identification method disclosed in the Japanese Pharmacopoeia, Eighteenth Edition, page 1150, add 100 mL of water to 0.1 g of carrier particles, and add 1 drop of iodine test solution. The development of a light red-brown or light red-purple color after the addition of the iodine solution will confirm that the carrier particles comprise a polymer having a glucose-based helical structure.BR927 - Porous carrier for the delivery- WO5

[0034] Preferably, the polysaccharide according to the disclosure is selected from a dextrin, a maltodextrin, a dextran, agarose, pullulan, or from a mixture thereof.

[0035] In a preferred embodiment, the polysaccharide according to the disclosure is a glucose polymer, preferably selected from a dextrin, a maltodextrin, a dextran, pullulan, orfrom a mixture thereof.

[0036] In a preferred embodiment, the polysaccharide according to the disclosure is selected from a dextrin, a maltodextrin, or from a mixture thereof.

[0037] The term “maltodextrin” refers to glucose polymers obtained by acid and / or enzymatic hydrolysis of starch, having a dextrose equivalent (DE) lower than 20. Preferably, the maltodextrins according to the disclosure have a DE higher than 3.

[0038] The term “dextrin” (sometimes also referred to as “pyrodextrin”) refers to a glucose polymer obtained by dry heating of starch under acidic conditions, which results hydrolysis of the starch followed by reconnection via a-1 ,6 bonds. In general, these dextrins are classified in “white dextrins”, “yellow dextrins”, or “British gum”, depending on the temperature, acidity and humidity conditions used.

[0039] Preferably, the terms “dextrin” and “maltodextrin” excludes cyclic forms thereof e.g., cyclodextrins.

[0040] In a preferred embodiment, the polysaccharide is obtained from partial hydrolysis of starch.

[0041] The term “starch” classically refers to starch isolated from any suitable botanical source, by any technique well known to those skilled in the art. Isolated starch typically contains no more than 3% of impurities; said percentage being expressed a dry weight with respect to the total dry weight of isolated starch. These impurities typically comprise proteins, colloidal matters and fibrous residues. Suitable botanical source includes for instance legumes, cereals, and tubers.

[0042] The polysaccharide according to the disclosure can thus be selected from legume (e.g., pea, fava bean) polysaccharide, cereal (maize, rice, wheat, oat) polysaccharide, and tuber (e.g., potato, tapioca) polysaccharide. Preferably, the polysaccharide according to the disclosure is a maize polysaccharide, more preferably a maize dextrin, a maize maltodextrin, or a mixture thereof.

[0043] Preferably, the carrier particles according to the disclosure, or the polysaccharide included in said particles, have a weight average molecular weight (Mw), determined by size exclusion chromatography with detection by differential refractometer, equal to or higher than 1 000 Da, preferably equal to or higher than 2 000 Da, preferably equal to or higher than3 000 Da, preferably equal to or higher than 3 000 Da, preferably equal to or higher than4 000 Da, preferably equal to or higher than 5 000 Da. This Mw is preferably equal to or lowerBR927 - Porous carrier for the delivery- WO6 than 200 000 Da, preferably equal to or lower than 100 000 Da, preferably equal to or lower than 50 000 Da, preferably equal to or lower than 10 000 Da, preferably equal to or lower than9 000 Da, preferably equal to or lower than 8 000 Da.

[0044] Preferably, the carrier particles according to the disclosure, or the polysaccharide included in said particles, have a number average molecular weight (Mn), determined by size exclusion chromatography with detection by differential refractometer, equal to or higher than 500 Da, preferably equal to or higher than 1 000 Da, preferably equal to or higher than 1 500 Da. This Mn is preferably equal to or lower than 50 000 Da, preferably equal to or lower than10 000 Da, preferably equal to or lower than 5 000 Da, preferably equal to or lower than 4 000 Da.

[0045] The Mw and Mn may be determined by the person skilled in the art by high pressure size-exclusion chromatography (HPSEC), for example according to the protocol given in the example section A-ll, 1.

[0046] The carrier particles according to the disclosure are water-soluble. The term “water- soluble” refers to substances which are from soluble to very soluble in water at 20°C. This solubility is also sometimes referred to as “cold water-solubility”. This solubility in water is well defined for instance in 11th edition of The International Pharmacopeia (2011), Section “General Notice, Solubility”: a substance is soluble in water if 1g of said substance requires 10 to 30 mL of water at 20°C to dissolve. A substance is freely soluble in water if 1 g of said substance requires 1 to 10 mL of water at 20°C to dissolve. A substance is very soluble in water if 1 g of said substance requires less than 1 mL of water at 20°C to dissolve.

[0047] Products like those derived from starch may comprise a water-soluble fraction and a water-insoluble fraction. Indeed, native starch granules are water insoluble. Therefore, depending on the level of hydrolysis, a fraction of the polysaccharide obtained therefrom might have retained its insoluble structure. In that case, the definition above applies to the water- soluble fraction. That being said, preferably, the water-insoluble fraction represents less than 30% as dry weight with respect to the total dry weight of carrier particles, preferably less than 20%, preferably less than 15%, preferably less than 10%, preferably less than 5%, preferably less than 1%, preferably 0%. The amount of water-soluble fraction may be determined by the person skilled in the art by putting 5 grams of the polysaccharide to be tested in 200 mL distilled water. The dry weight dissolved can be determined after centrifugation, and desiccation of the supernatant.

[0048] The carrier particles according to the disclosure have a BET specific surface area equal to or higher than 40 m2 / g. Preferably, this BET specific surface area is equal to or higher than 50 m2 / g, preferably equal to or higher than 60 m2 / g, preferably equal to or higher than 70 m2 / g, preferably equal to or higher than 80 m2 / g, preferably equal to or higher than 90 m2 / g, preferably equal to or higher than 100 m2 / g, preferably equal to or higher than 110 m2 / g, preferably equalBR927 - Porous carrier for the delivery- WO7 to or higher than 120 m2 / g, preferably equal to or higher than 130 m2 / g, preferably equal to or higher than 140 m2 / g, preferably equal to or higher than 150 m2 / g, preferably equal to or higher than 160 m2 / g, preferably equal to or higher than 170 m2 / g, preferably equal to or higher than 180 m2 / g. It is further preferably equal to or lower than 1000 m2 / g, preferably equal to or lower than 900 m2 / g, preferably equal to or lower than 800 m2 / g, even equal to or lower than 700 m2 / g, even equal to or lower than 600 m2 / g, even equal to or lower than 500 m2 / g, even equal to or lowerthan 400 m2 / g, even equal to orlowerthan 300 m2 / g, even equal to orlowerthan 250 m2 / g, even equal to or lower than 200 m2 / g.

[0049] It may for example be selected from 1 m2 / g to 1000 m2 / g, or from 40 m2 / g to 1000 m2 / g, or from 50 m2 / g to 1000 m2 / g, or from 100 m2 / g to 900 m2 / g, or from 150 m2 / g to 800 m2 / g.

[0050] The BET specific surface area of the carrier particles may be determined by the person skilled in the art by the nitrogen adsorption BET (Brunauer, Emmett, Teller) method using a specific surface area analyzer. An example of a specific surface area analyzer that can be used is the analyzer Macsorb® (Mountech).

[0051] In a preferred embodiment, the carrier particles according to the disclosure have a Dv10 equal to or higher than 50 pm, preferably equal to or higher than 60 pm, preferably equal to or higher than 70 pm, preferably equal to or higher than 80 pm, preferably equal to or higher than 90 pm, preferably equal to or higher than 100 pm. it is in general equal to or lower than 300 pm, even equal to or lower than 250 pm, even equal to or lower than 200 pm, even equal to or lower than 150 pm. In a preferred embodiment, the carrier particles according to the disclosure have a Dn10 equal to or higher than 50 pm, preferably equal to or higher than 60 pm, preferably equal to or higher than 70 pm, preferably equal to or higher than 80 pm, preferably equal to or higher than 90 pm, preferably equal to or higher than 100 pm. it is in general equal to or lowerthan 300 pm, even equal to orlowerthan 250 pm, even equal to orlowerthan 200 pm, even equal to or lower than 150 pm.

[0052] In a preferred embodiment, the carrier particles according to the disclosure have a Dv50 higher than 100 pm, preferably equal to or higher than 110 pm, preferably equal to or higher than 120 pm, preferably equal to or higher than 130 pm, preferably equal to or higher than 140 pm, preferably equal to or higher than 150 pm. it is in general equal to or lower than 2000 pm, even equal to or lower than 1000 pm, even equal to or lower than 500 pm, even equal to or lowerthan 400 pm, even equal to orlowerthan 350 pm, even equal to orlowerthan 300 pm, even equal to or lower than 250 pm, even equal to or lower than 200 pm. In a preferred embodiment, the carrier particles according to the disclosure have a Dn50 higher than 100 pm, preferably equal to or higher than 110 pm, preferably equal to or higher than 120 pm, preferably equal to or higher than 130 pm, preferably equal to or higher than 140 pm. it is in general equal to or lower than 2000 pm, even equal to or lower than 1000 pm, even equal to or lower thanBR927 - Porous carrier for the delivery- WO8500 pm, even equal to or lower than 400 pm, even equal to or lower than 350 pm, even equal to or lowerthan 300 pm, even equal to orlowerthan 250 pm, even equal to orlowerthan 200 pm.

[0053] In a preferred embodiment, the carrier particles according to the disclosure have a Dv90 equal to or higher than 100 pm, preferably equal to or higher than 150 pm, preferably equal to or higher than 200 pm. it is in general equal to or lower than 2500 pm, even equal to or lower than 1500 pm, even equal to or lower than 1000 pm, even equal to or lower than 500 pm, even equal to or lower than 400 pm, even equal to or lower than 450 pm, even equal to or lower than 400 pm, even equal to or lower than 350 pm, even equal to or lower than 300 pm, even equal to or lower than 250 pm. In a preferred embodiment, the carrier particles according to the disclosure have a Dn90 equal to or higher than 100 pm, preferably equal to or higher than 150 pm, preferably equal to or higher than 190 pm. it is in general equal to or lower than 2500 pm, even equal to or lower than 1500 pm, even equal to or lower than 1000 pm, even equal to or lower than 500 pm, even equal to or lower than 400 pm, even equal to or lower than 450 pm, even equal to or lower than 400 pm, even equal to or lower than 350 pm, even equal to or lower than 300 pm, even equal to or lower than 250 pm.

[0054] It is reminded that the Dv10, Dv50 and Dv90 values in volume are the sizes, in pm, for which 10%, 50% and 90% respectively of particles, in volume, have a lower granulometry. The Dn10, Dn50 and Dn90 values in number are the sizes, in pm, for which 10%, 50% and 90% respectively of particles, in number, have a lower granulometry.

[0055] Preferably, the arithmetic mean volume diameter D(4;3) of the carrier particles is selected from 100 pm to 2000 pm, preferably from 100 pm to 1500 pm, preferably from 100 pm to 1000 pm, preferably from 100 pm to 500 pm, preferably from 100 pm to 400 pm, preferably from 100 pm to 300 pm, more preferably from 100 pm to 200 pm. In a preferred embodiment, in particular where the carrier particles are for use as sugar spheres (sometimes also referred to as “non-pareil”) substitute, this average particle size is from 100 pm to 1400 pm, or from 250 pm to 1400 pm.

[0056] The arithmetic mean volume diameter D(4;3) of the carrier particles may be determined by the person skilled in the art by laser diffraction or laser scattering for example according to the protocol given in the example section A-l 1 , 1 .

[0057] In an embodiment, smaller particle size may be desirable, for example where the carrier particles are intended to be inhaled, for the nasal delivery of a substance.

[0058] In general, the polysaccharide of the carrier particles are obtained from hydrolysis of a larger polysaccharide e.g., starch. They can accordingly contain a certain amount of mono or disaccharides.

[0059] Preferably, the carrier particles according to the disclosure have a disaccharide (e.g., maltose) content equal to or lower than 40% as dry weight with respect to the total dry weightBR927 - Porous carrier for the delivery- WO9 of the carrier particles, preferably equal to or lower than 30%, preferably equal to or lower than 20%, preferably equal to or lower than 10%, preferably equal to or lower than 5%, preferably equal to or lower than 1%, preferably equal to 0%.

[0060] Preferably, the carrier particles according to the disclosure have a trisaccharide (e.g., maltotriose) content equal to or lower than 40% as dry weight with respect to the total dry weight of the carrier particles, preferably equal to or lower than 30%, preferably equal to or lower than 20%, preferably equal to or lower than 10%, preferably equal to or lower than 5%, preferably equal to or lower than 4%, preferably equal to or lower than 3%, preferably equal to or lower than 2%. In a preferred embodiment, it is equal to or lower than 1%, preferably equal to 0%. In another embodiment, it may be equal to or higher than 0.1 %, even equal to or higher than 0.5%, equal to or higher than 1 .0%, even equal to or higher than 1 %.

[0061] These trisaccharide (e.g., maltotriose) and disaccharide (e.g., maltose) contents may be determined by the person skilled in the art by HPLC according with Rl detector to USP-NF Method (USP-NF 2024, Issue 1).

[0062] Preferably, the porous material according to the disclosure is a mesoporous material i.e. , a material having pores mainly between 2 and 50 nm.

[0063] Preferably, the carrier particles according to the disclosure have an average pore size equal to or higher than 3 nm, preferably equal to or higher than 5 nm, preferably equal to or higher than 6 nm, preferably equal to or higher than 7 nm, preferably equal to or higher than8 nm, preferably equal to or higher than 9 nm, preferably equal to or higher than 10 nm. It is preferably equal to or lower than 20 nm.

[0064] This average pore size may be determined by the person skilled in the art by Tris star with nitrogen adsorption method, for example using the TriStar II Plus apparatus (Micromeritics®).

[0065] Preferably, the carrier particles according to the disclosure are spherical.

[0066] The particle configuration can be confirmed by static image analysis. Static image analysis may be performed by the person skilled in the art by using an automated static image analyzer (e.g., Morphologi 4 (Morphological Image Analyzer) by Malvern Panalytical).

[0067] The carrier particles according to the disclosure have particle hardness equal to or higher than 5MPa. Preferably, the carrier particles according to the disclosure have a particle hardness higher than 5 MPa, preferably equal to or higher than 6 MPa, preferably equal to or higher than 7 MPa, preferably equal to or higher than 8 MPa, preferably equal to or higher than9 MPa, preferably equal to or higher than 10 MPa. It is in general equal to or lower than 50 MPa, even equal to or lower than 40 MPa, even equal to or lower than 30 MPa, even equal to or lower than 20 MPa, even equal to or lower than 15 MPa.BR927 - Porous carrier for the delivery- WO10

[0068] This particle hardness may be determined by the person skilled in the art by Micro Compression Tester (MCT), for example using MCT series apparatus marketed by Shimadzu.

[0069] In a preferred embodiment, the carrier particles according to the disclosure have a flowability equal to or lower than 15 seconds, preferably equal to or lower than 14 seconds, equal to or lower than 13 seconds, equal to or lower than 12 seconds, equal to or lower than 11 seconds, equal to or lower than 10 seconds. It is preferably equal to or higher than 3 seconds.

[0070] This flowability may be determined by a person skilled in the art according to the method recommended by the European Pharmacopoeia, for example the reference method described in European Pharmacopoeia 7.0, 2.9.16, “Flowability”, using equipment according to figure 2.9.16. -2

[0071] In a preferred embodiment, the carrier particles according to the disclosure have an angle of repose equal to or lower than 45°, preferably equal to or lower than 40°, preferably equal to or lower than 35°, preferably equal to or lower than 30°. It also preferably of at least 20°, preferably of at least 21 °, preferably of at least 22°, preferably of at least 23°.

[0072] A definition of the angle of repose is given in the US Pharmacopeia, 30(6) Harmonization; <1174> POWDER FLOW; 11 / 22 / 2016. According to this definition, the carrier particles according to the disclosure preferably have excellent flow property, or good flow property, or fair flow property, or passable flow property. More preferably, the carrier particles according to the disclosure have excellent, good, or fair flow property. More preferably, the carrier particles according to the disclosure have excellent or good flow property. More preferably, the carrier particles according to the disclosure have excellent flow property. The angle of repose may be determined for example by using a Multiple Powder Characteristics Analyzer (Multi Tester) MT-02 apparatus marketed by Seishin Enterprise Co., LTD.

[0073] Preferably, the carrier particles according to the disclosure have a bulk density equal to or higher than 0.1 g / mL, preferably equal to or higher than 0.2 g / mL, preferably equal to or higher than 0.3 g / mL, preferably equal to or higher than 0.4 g / mL. It is preferably equal to or lower than 0.8 g / mL, preferably equal to or lower than 0.7 g / mL, preferably equal to or lower than 0.6 g / mL, preferably equal to or lower than 0.5 g / mL.

[0074] This bulk density may be determined by the person skilled in the art by the method described in Japanese pharmacopeia 3.01 Determination of Bulk and Tapped Densities, Method 3.

[0075] The carrier particles according to the disclosure may comprise substances other than the polysaccharide (and eventual other substances coming from its manufacturing process) according to the disclosure, to the extent that it does not compromise their safety and function, notably for use as a carrier. Examples of such other ingredients are: granulation binders, e.g., hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), carboxymethylcelluloseBR927 - Porous carrier for the delivery- WO11(CMC), cellulose derivatives, starches and starch derivatives, acacia gum, gelatin, tragacanth gum; minerals; added carbohydrates like sugars and sugar alcohols other than mannitol; food additives, colorants; pharmaceutical, nutraceutical, veterinary or cosmetic active ingredients; preservatives; stabilizers; organic acids.

[0076] The expression "does not compromise their safety and function" means, for example, that the amount of the supported substance is not significantly lowered or that the particles can for example be safely administered to an organism when used in the form of a pharmaceutical.

[0077] As it will be explained in the section dedicated to the process for making the carrier particles, organic acid may be used to prepare the carrier particles. Preferably, however, the carrier particles according to the disclosure are free of organic acid. The expression " free of organic acids" means that, when the organic acid content of the carrier particles is measured, the content is below the detection limit.

[0078] Organic acids may or may not be used during the carrier particle production process, but must ultimately be removed, if used. Depending on the method of removal, trace amounts of organic acids might possibly remain in the carrier particles. If that happens, the organic acid content in the carrier particles should be no more than 1 % as dry weight with respect to the total dry weigh of carrier particles. Organic acids can be detected by high-performance liquid chromatography (HPLC) analysis after carrier particles have been dissolved in an aqueous phosphoric acid solution.

[0079] More generally, the amount of other ingredients in the carrier particles according to the disclosure is preferably lower than 15 % (w / w), preferably lower than 10 % (w / w), preferably lower than 5 % (w / w), preferably lower than 2 % (w / w), preferably lower than 1 % (w / w), preferably lower than 0.5 % (w / w). More preferably, the carrier particles according to the disclosure essentially consists of the polysaccharide according to the disclosure (and eventual other substances coming from its manufacturing process like mono or disaccharides). The expression "essentially consisting of' means configurations in which the carrier particles consist only of a water-soluble polysaccharide according to the disclosure, and configurations in which the carrier particles include small amounts of other ingredients. Specifically, this means that the content ratio of other ingredients is no more than 1% (w / w), and preferably no more than 0.1% (w / w).

[0080] In the interests of safe administration, the carrier particles are preferably free of metal elements.Use of the porous particles as a carrier

[0081] The carrier particles according to the disclosure are suitable for use as a carrier for one or more substances, in particular as a carrier for substances that are poorly soluble in water or not miscible with water.BR927 - Porous carrier for the delivery- WO12

[0082] Therefore, the instant disclosure also relates to the use of the carrier particles according to the invention, as a carrier for one or more substances.

[0083] The term “carrier” refers to a solid that is able to support one or more substances. The term "support" is intended to mean that the one or more substances is associated with the particles, whether inside the matrix formed by the carrier particles, and / or on its surface.

[0084] Preferably, the one or more substances according to the invention are selected from poorly water-soluble substances and / or substance that are not miscible with water. Typical example of substances that are not miscible with water are oily substances.

[0085] The term “poorly water-soluble” refers to substances which are from sparingly soluble to practically insoluble in water at 20°C. This solubility in water is well defined for instance in 11th edition of The International Pharmacopeia (2011), Section “General Notice, Solubility”: a substance is sparingly soluble in water if 1 g of said substance requires 30 to 100 mL of water at 20°C to dissolve. A substance is slightly soluble in water if 1 g of said substance requires 100 to 1 000 mL of water at 20°C to dissolve. A substance is very slightly soluble in water if 1g of said substance requires 1 000 to 10 000 mL of water at 20°C to dissolve. A substance is practically insoluble in water if 1 g of said substance requires more than 10 000 mL of water at 20°C to dissolve.

[0086] Preferably, the one or more substances according to the disclosure comprises an active ingredient.

[0087] Preferably, the carrier particles according to the disclosure is for the oral delivery of an active ingredient. It may also find applications in other epithelial routes such as cutaneous route, mucosal route (e.g., vaginal route, sublingual route, buccal route), transdermal route, ophthalmic route, nasal route, transnasal route, or bronchopulmonary route. For example, the carrier particles according to the disclosure may be used for nasal delivery of an active ingredient.

[0088] The expression "active ingredient" classically refers to any substance of pharmaceutical, veterinary, food, nutraceutical, cosmetic or agrochemical interest. Preferably, the active ingredient according to the disclosure is a pharmaceutical, nutraceutical, cosmetic or veterinary active ingredient, preferably a pharmaceutical, nutraceutical, or veterinary active ingredient, preferably a pharmaceutical or veterinary active ingredient. Preferably, the active ingredient according to the disclosure is intended to be administered to a mammal, preferably a human.

[0089] Examples of pharmaceutical active ingredients that can be supported include one or more components selected from antipyretics / analgesics / anti-inflammatories, psychotropics, anxiolytics, antidepressants, hypnotics / sedatives, anticonvulsants, CNS agents, brain metabolic stimulants, cerebral circulation activators, antiepileptics, sympathomimetics, gastrointestinal agents, antacids, anti-ulcerogenics, antitussive expectorants, antiemetics, respiratoryBR927 - Porous carrier for the delivery- WO13 stimulants, bronchodilators, allergy medications, agents for dental and oral use, antihistamins, cardiotonics, antiarrhythmics, diuretics, antihypertensives, vasoconstrictors, coronary vasodilators, peripheral vasodilators, anti-hyperlipidemia agents, cholagogues, antibiotics, chemotherapeutic agents, antidiabetic agents, osteoporosis medications, antirheumatics, antispasmodics, hormones, alkaloid narcotics, sulfonamides, gout medications, anticoagulants, antineoplastics, and revitalizers.

[0090] Examples of food active ingredient (also sometimes referred to as “functional food ingredients”) include vitamins such as vitamin A, vitamin D, and vitamin E, and higher unsaturated fatty acids such as DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid), and liver oil.

[0091] The carrier particles in the present embodiment may also be used as a catalyst or as a catalyst support. Examples of supported catalysts include platinum-, palladium-, or iridium- based catalysts, as well as titanium oxide.Composition comprising the porous particles and one or more substances

[0092] The instant invention also relates to a composition comprising the carrier particles according to the disclosure and one or more substances supported by said carrier particles.

[0093] Preferably, said supported one or more substances is as described in the claims and embodiments included in the present specification.

[0094] The one or more substances is preferably supported on the carrier particles by impregnating the carrier particles with the desired one or more substances. The method disclosed in US 10,004,682 B2, for example, can be used as such a method.

[0095] Where the one or more substances is an oil, the carrier particles may be impregnated with said oil.

[0096] The following is another example of a method for supporting the one or more substances in the carrier particles.

[0097] The one or more substances is first suspended or dissolved in a suitable liquid to obtain a suspension or a solution (preferably a solution). Typically, suitable solvent is an organic solvent in which the carrier particles are not soluble. Example of suitable organic solvent include ethanol. At this time, a small amount of water (around 1 % relative to the total amount of solution) may be added to the organic solvent in order to enhance the solubility of the one or more substances, especially if the latter is a highly water-soluble substance.

[0098] The carrier particles are then mixed with the solution or suspension.

[0099] Examples of methods for mixing the carrier particles with the solution or suspension include methods in which the resulting solution or suspension is dribbled or sprayed onto the carrier particles.BR927 - Porous carrier for the delivery- WO14

[0100] After the prescribed amount of the solution or suspension and carrier particles have been mixed, the resulting mixture is heated for example at a temperature of 20°C to 60°C under reduced pressure, thereby giving carrier particles on which one or more substances is supported.

[0101] The invention also relates to the use of the composition according to the disclosure as a medicament. In that case, the one or more substance comprises a pharmaceutical or veterinary active ingredient. The invention also relates to a method for treating an organism in need thereof, comprising administering a composition according to the invention.

[0102] Preferably, the medicament or the method is for a mammal, preferably a human.Method for makina the porous particles

[0103] The instant invention also relates to a method particularly useful for making the carrier particles according to the disclosure, said method comprising:(a) preparing precursor particles by fluidized bed spray-granulation of a saccharide solution, said saccharide comprising a polysaccharide;(b) obtaining the carrier particles by exposing the precursor particles to an organic solvent.

[0104] Preferably, in particular for the carrier particles to be water-soluble, the saccharide used as a raw material in the process according to the disclosure is also water-soluble.

[0105] Typically, the saccharide comprises polysaccharides, monosaccharides, and disaccharides. Typically, the polysaccharides include trisaccharides.

[0106] In an embodiment, the saccharide includes a saccharide having a glucose-based helical structure. In a preferred embodiment, the saccharide is obtained from a starch, said starch being preferably as described before.

[0107] Preferably, the saccharide is a dried glucose syrup. The term “dried glucose syrup” refers to a solid product obtained by acid and / or enzymatic hydrolysis of starch, and then drying, having a DE equal to orhigherthan 20, and equal to or lowerthan 60. In a preferred embodiment, the saccharide is a dried glucose syrup having a DE equal to or higher than 25, preferably equal to or higher than 30, preferably equal to or higher than 35, preferably equal to or higher than 40. It is preferably equal to or lower than 55.

[0108] Preferably, the saccharide used for making the carrier particles contains at least 20% of polysaccharide as dry weight with respect to the total dry weight of saccharide, preferably at least 30%, preferably at least 40%, preferably at least 45%, preferably at least 50%. Preferably, this amount is further equal to or lower than 80%, even equal to or lower than 70%, even equal to or lower than 60.

[0109] Preferably, the saccharide used for making the carrier particles contains at least 10 % of disaccharides (e.g., maltose) as dry weight with respect to the total dry weight of saccharide, preferably at least 20%, preferably at least 30%, preferably at least 40%. Preferably, this amountBR927 - Porous carrier for the delivery- WO15 is further equal to or lower than 80%, even equal to or lower than 70%, even equal to or lower than 60%.

[0110] Preferably, the saccharide used for making the carrier particles contains at least 1 % of trisaccharides (e.g., maltotriose) as dry weight with respect to the total dry weight of saccharide, preferably at least 5%, preferably at least 10%, preferably at least 15%. Preferably, this amount is further equal to or lower than 40%, even equal to or lower than 30%, even equal to or lower than 25%, even equal to or lower than 20%.

[0111] Preferably, the saccharide used for making the carrier particles contains less than 10% of monosaccharides (e.g., glucose) as dry weight with respect to the total dry weight of saccharide, preferably less than 5%, preferably less than 4%, preferably less than 3%.

[0112] These polysaccharide, trisaccharide, disaccharide and monosaccharide amounts may be determined by the person skilled in the art by HPLC according with Rl detector to USP-NF Method (USP-NF 2024, Issue 1).

[0113] In a particular embodiment, a template (mold agent) is added to the saccharide solution to be sprayed. Organic acids, sugars, or sugar alcohols can be used as the template.

[0114] This embodiment is preferably carried out where a saccharide having a low monosaccharide (e.g., glucose), disaccharide (e.g., maltose) or trisaccharide (e.g., maltotriose) content is used as the raw material. Carrier particles having a high BET specific surface can be readily obtained by creating pores through the removal of the added template rather than the disaccharide or trisaccharide of the saccharide used as the starting material.

[0115] The organic acid is preferably citric acid, malic acid, tartaric acid, succinic acid, or adipic acid, and more preferably citric acid, malic acid, or tartaric acid.

[0116] Examples of sugars include monosaccharides and disaccharides. Glucose, fructose, and galactose can be used as the monosaccharide. Examples of disaccharides that can be used include sucrose, lactose, maltose, trehalose, and cellobiose. Preferably, the disaccharide is maltose, trehalose, or a mixture thereof, trehalose being in particular preferred. Examples of sugar alcohols include mannitol, erythritol, and xylitol.

[0117] Preferably, the saccharides used for making the carrier particles according to the disclosure are free of metal elements.

[0118] Examples of suitable saccharides are commercially available. Mention can be made for example of maltodextrin and dried glucose syrups range GLUCIDEX® (Roquette Freres), in particular of maize dried glucose syrups GLUCIDEX® IT47 and GLUCIDEX® 39 (Roquette Freres).BR927 - Porous carrier for the delivery- WO16Step (a): preparation of the precursor particles

[0119] Step (a) is a fluidized spray-granulation process. Contrary to so-called “agglomeration” processes, the material to be granulated is in the liquid form, and not in the powdery form. In the instant disclosure, this liquid is a saccharide solution. Fluidized spray-granulation process is a continuous process. Particles are formed from the drying of the solution on a seed obtained from the recycling of a fraction of granulated particles obtained during the process. As it is a continuous process, the prepared precursor particles are collected as long as the system is fed with the saccharide solution.

[0120] Figure 1 provides a scheme of a preferred process for making the precursor particles.

[0121] Preferably, the process according to the disclosure does not use exogenous saccharide powder i.e., other than the one formed by the drying of the saccharide solution; except for the neglectable amount of saccharide powder that may be use in the beginning of the process for the initial seeding.

[0122] Preferably, the fluidized bed temperature is selected from 50°C to 100°C, more preferably from 60°C to 80°C.

[0123] The fluidized air temperature is typically selected to control the fluidized bed temperature. It may for example be selected from 80°C to 150°C, preferably from 100°C to 150°C.

[0124] The fluidized air flow rate is typically selected to have a linear speed in the fluidized bed of from 0.5 to 2.5 m / s, preferably from 1 .0 to 2.0m / s.

[0125] Preferably, the fluidized bed used is a circulating fluidized bed.

[0126] Preferably, the sprayed saccharide solution as a dry matter content selected from 20 to 50%, preferably from 30 to 40%; as dry weight with respect to the total weight of said solution.

[0127] Preferably, the saccharide solution is maintained at a temperature (“feeding temperature”) which allow the saccharides to stay solubilized. Preferably, this temperature is equal to or higher than 50°C, preferably equal to or higher than 60°C, preferably equal to or higher than 70°C. It is preferably lower than 95°C, even equal to or lower than 90°C, even equal to or lower than 80°C.

[0128] Preferably, the spraying is performed by way of bi-fluid nozzles. Their number will be classically adapted to the size of the fluidized bed. They are preferably placed in the bottom position (“bottom spray”) of the fluidized bed.

[0129] Preferably, the feeding flow rate of the saccharide solution is equal to or higher than 10 kg / h / m2of fluidized bed, preferably equal to or higher than 20 kg / h / m2of fluidized bed. It is preferably equal to or lower than 300 kg / h / m2of fluidized bed, preferably lower than 100 kg / h / m2of fluidized bed.BR927 - Porous carrier for the delivery- WO17

[0130] Preferably, the spraying pressure is selected from 0.5 to 5 bars, preferably from 1 to 4 bars.

[0131] Preferably, the spraying air temperature is equal to or higher than 10°C and equal to or lower than 95°C. it is preferably equal to or higher than 15°C, even equal to or higher than 20°C. it is preferably equal to or lower than 80°C, preferably equal to or lower than 50°C, preferably equal to or lower than 40°C, preferably equal to or lower than 30°C.

[0132] The process is a continuous process involving the recycling of saccharide particles. Therefore, a fraction of saccharide particles is continuously extracted from the granulator.

[0133] Preferably, particles having a particle size equal to or higher than 50 pm, preferably equal to or higher than 80 pm are extracted; being understood that some particles with lower size might be extracted as well, as the means for performing the extraction (e.g., classifier) do not allow in general to perform a clean cut.

[0134] Preferably, this extraction is performed byway of an air classifier discharging tube. The classification cut-off is set by the flow rate of the classifying air.

[0135] Preferably, the step (a) according to the disclosure comprises a cooling step, performed after the extraction from the granulator. This step is preferably performed by way of a vibrated fluidized air bed.

[0136] The step (a) according to the disclosure comprises the recycling of granulated saccharide particles, in particular or small particles (often referred to as “fines”). The recycled fraction is recycled into the dry state, that is to say that the saccharide particles are not resolubilized but directly injected into the granulator bed. They may be recycled as is, or after grinding. The few fines transported by the exiting air flow may also be reintroduced into the recycling system and are in general in small quantities in comparison with the particles extracted for example by mean of the classifier.

[0137] Preferably, the particles extracted from the granulator are subjected to a step of separation of the undersized particles (“fines”) and / or a step of separation of the oversized particles, preferably both. The terms “undersized” and “oversized” mean respectively “below” and “above” the final target size for the precursor particles. Typically, the fines will feed the recycling system without the need of a grinding step. Oversized particles will feed the recycling system after a grinding step. Preferably, this separation is performed after a cooling step, notably as described before.

[0138] Preferably, this separation is ensured by means of one or more sieving(s). Preferably, the cut-off threshold used for fines is selected from 50 pm to 150 pm, preferably from 80 pm to 150 pm. This cut-off threshold is for example equal to 100 pm. The fraction which passes through the sieve is typically and preferably introduced as is (without undergoing grinding) into the recycling system. Preferably, the cut-off threshold used for oversized particles is selectedBR927 - Porous carrier for the delivery- WO18 from 200 m to 800 pm, preferably from 315 pm to 500 pm, or from 400 pm to 800 pm. This cut-off threshold is for example equal to 315 pm. The retained fraction may then be introduced into the recycling system after grinding. Preferably, these sievings are carried out in series.

[0139] The particles remaining after the separation of the oversized and fine particles are collected and can be packaged.

[0140] For performing the grinding, the size of the ground particles is typically smaller than the desired final precursor particle size.

[0141] Preferably, the process includes an initial seeding step, to allow granulation to start. For this step, powdered saccharide is introduced into the fluidized bed. Typically, the quantity of powdery saccharide used for initial seeding is less than or equal to 25% relative to the weight of precursor particles produced and will tend towards 0% after several days of continuous production.

[0142] Where the carrier particles according to the disclosure comprise other ingredients, the granulation process according to the disclosure may include the use of these other ingredients, which can be introduced in dry form into the chamber of the granulator, for example via the recycling system or via an additional inlet, and / or in the form of suspension or solution, for example via the sprayed saccharide solution.

[0143] In a preferred embodiment, step (a) thus includes the following steps:(a.1) preparing a saccharide solution;(a.2) spraying the saccharide solution obtained in step (a.1) into a fluidized air bed granulator;(a.3) optionally cooling the saccharide particles obtained in step (a.2);(a.4) sieving the saccharide particles obtained in step (a.2) or (a.3) so as to obtain:- fines,- oversized particles,- particles having a diameter higher than the fines, and lower than the oversized particles (precursor particles);(a.5) recycling fines and oversized particles obtained in step (a.4) toward the fluidized air granulator, said oversized particles being ground before entering said fluidized air granulator; collecting precursor particles obtained in step (a.4).Step (b): obtaining the carrier particles

[0144] The precursor particles are then exposed to an organic solvent. Exposure is typically performed by blending the precursor particles with the organic solvent.

[0145] The precursor particles must not be soluble into this organic solvent. Indeed, the purpose of this solvent treatment is to remove some saccharides (e.g., disaccharides and trisaccharides) from the particle structure to create pores. But for doing to, the overall structure of the particles must be retained.BR927 - Porous carrier for the delivery- WO19

[0146] Typically, the precursor particles are mixed with an organic solvent, and the liquid is removed from the mixture. Known organic solvents can be used as the organic solvent. In the present embodiment, hydrophilic organic solvents are preferable, where ethanol and methanol are preferred examples.

[0147] The precursor particles can be mixed with the organic solvent by suspending the precursor particles in a heated organic solvent and maintaining the particles in that state for at least a prescribed period of time. The heating temperature and time can be suitably adjusted, as befits the organic solvent that is being used; for example, the heating temperature can be maintained at 0°C to 70°C for 10 minutes to 120 minutes.

[0148] Porous carrier particles are then obtained by removing the liquid from the mixture. The liquid to be removed is an organic solvent containing a fraction of the saccharide chain that constitutes the saccharide raw material. The liquid to be removed may also be an organic solvent containing a template that was added to the saccharide for the purpose of forming pores.

[0149] Known methods can be used to remove the liquid from the mixture, such as filtration and decantation.

[0150] The process of exposing the particles to an organic solvent and removing the liquid from the mixture can be repeated in order to increase the specific surface area of the carrier particles that are obtained.

[0151] The invention also relates to water-soluble porous particles comprising a polysaccharide, said particles having a BET specific surface area equal to orhigherthan 40 m2 / g and said particles being obtainable by a process comprising:- (a) preparing precursor particles by fluidized bed spray-granulation of a saccharide solution, said saccharide comprising a polysaccharide;- (b) obtaining the carrier particles by exposing the precursor particles to an organic solvent.

[0152] Preferably, the carrier particles are described in the claims and embodiments included in the present specification. Preferably, the process for making the carrier particles is as described in the claims and embodiments included in the present specification.Remarks

[0153] The amounts of ingredients may be expressed in percentages by weight. These weights are amounts of ingredients as such, in their typical powdery or oily form (or liquid form for solvents). All compounds may include small amounts of impurities. Powdery ingredients may also include small amount of water (also referred to as %moisture or as “loss on drying”).

[0154] However, if the amounts are expressed as “dry weights”, this refers to amounts of anhydrous ingredients i.e., without the water. Similarly, “dry matters” referto anhydrous matters.BR927 - Porous carrier for the delivery- WO20

[0155] Where an amount of ingredient in a product is selected in a range of from 0 to X% or expressed as being “less than X%” or “lower than X%”, it is understood that an embodiment where said product is free of said ingredient is included.

[0156] Also, where a material is defined in generic terms (e.g., polysaccharide), in embodiments where the latter are selected among a list (from 1 to n species), said list can be used interchangeably with said generic term.

[0157] Still where a material is selected among a list, it is considered that embodiments where said material comprises or consist of said list are also disclosed.

[0158] Where a product or composition comprises “other ingredient(s)” it classically means any ingredient that doesn’t meet the definition of the ingredients otherwise listed in the considered embodiment. In otherwords, where a generic composition Y comprises a compound A which can be selected from A’, A”, or from a mixture thereof: in the embodiment where the generic term Y is substituted by the species A’, compound A” is considered to be an “other ingredient”.

[0159] It is reminded that, as used in the specification and in the claims, the term “comprising” may include the embodiments “consisting of’ and “consisting essentially of’. The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, are intended to be open-ended transitional phrases that require the presence of the named feature(s) / element(s) / step(s) / unit operation(s) and permit the presence of other feature(s) / element(s) / step(s) / unit operation(s). However, such description should be construed as also describing products or methods “consisting of’ and “consisting essentially of’ the enumerated feature(s) / element(s) / step(s) / unit operation(s), which allows the presence of only the named feature(s) / element(s) / step(s) / unit operation(s), along with any impurities or moisture that might result therefrom, and excludes other feature(s) / element(s) / step(s) / unit operation(s).

[0160] It is reminded that, as used in the specification and in the claims, for describing in a method the order of steps / unit operations with one another, the terms “prior to”, “before”, “after”, “followed by”, “preceded by”, may include “immediately before”, or “immediately after”. The terms “prior to”, “before”, “after”, “followed by”, “preceded by”, and variants thereof, are intended to be open-ended transitional phrases that allow the presence of one or more other step(s) / unit operation(s) in between. However, such description should be construed as also describing steps / unit operations performed “immediately after” or “immediately before” one another, which does not allow the presence of any other step(s) / unit operation(s) in between.

[0161] It is reminded that, as used in the specification and the appended claims, the singular form "a," "an," and "the" comprise plural referents unless the context clearly indicates otherwise, and means “at least one” or “one or more”. For example, reference to a component in theBR927 - Porous carrier for the delivery- WO21 singular is intended to comprise a plurality of components. Thus, for example, “an” active ingredient” means “one or more” active ingredients.

[0162] It is reminded that, where the specification discloses more than one upper and lower limits for a value, any combination of said upper and lower limits are also disclosed.

[0163] Other characteristics and advantages of the present invention will emerge clearly on reading the examples given hereinafter, which illustrate the invention without however limiting it.ExamplesA- Section AA-l Preparation of porous carriers (comparative and according to the invention)A- 1, 1. Production of precursor spray-dried particles according to WO 2024 / 29516

[0164] Aqueous solution was obtained by dissolving 2.0 kg of dried glucose syrup (GLUCIDEX® IT47) in 3.0 kg of water heated to 70°C. Note that the DE value of the dextrin used was 47.Aqueous solution was sprayed with a spray dryer under the following conditions to obtain the precursor spray dried particles.Spraying conditions were the following:- Inlet temperature: 140°C;- Outlet temperature: 96-100°C;- Disc rotation speed: 5000 rpm;- Aqueous solution supply rate: Liquid rate 7kg / hour.

[0165] As a raw material dried glucose syrup comprising approx. 2% glucose, 43% maltose, 20% maltotriose, and 35% polysaccharides otherthan maltotriose was used (GLUCIDEX® IT47, Roquette Freres).A-l, 2. Production of precursor granulated particles according to the disclosure

[0166] Granulation was performed using a Glatt ProCell® LabSystem equipped with an AGT2 insert and zig-zag sifter product discharge system.

[0167] Granulation settings were the followings: fluidized air temperature about 100°C; fluidized air flow rate about 105 Nm3 / h dehumidified to approx. 6 g / kg dry air.

[0168] Solution of GLUCIDEX® IT47 was prepared with demineralized water at 40% dry substance at a temperature of 70°C.

[0169] 250 g of ground particles of GLUCIDEX® IT47 (D(4;3) of about 65 pm) obtained by grinding with Retsch grinder ZM200 (Conditions: 10000 tr / min; Grid 0,75mm) were introduced in the fluid bed.BR927 - Porous carrier for the delivery- WO22

[0170] Then solution of GLUCIDEX® IT47 was continuously spray with a bi-fluid nozzle in bottom spray position at a flow rate of 15 g / min. The spraying air temperature and pressure were of 25°C and 4 bars respectively.

[0171] The product discharge was regulated by means of air flow in an air sifter at a temperature of 20°C so that at stable operating conditions the same amount of dry material was discharged as dust-free granulates as supplied with the spray. The fine dust of the classifier was recycled to the granulator chamber. Sifter also ensures product cooling.

[0172] During the continuous granulation process, resulting fluid bed temperature was about 70°C and product pressure loss in the fluid bed was about 2 mbars.

[0173] Product after discharge was sieve on 100pm and 315 pm. Particle under 100pm (fines) were directly recycled in the fluid bed while particle over 315 pm (oversized particles) were ground with Retsch grinder ZM200 (Conditions: 10000 tr / min; Grid 0,75mm) before being recycled in the fluid bed.

[0174] The fraction between 100pm and 315pm is the final product.A- 1, 3. Production of the carrier particles

[0175] 60 ml of absolute ethanol was added to 3 g of precursor spray-dried particles or precursor granulated particles, and the mixture was shaken and mixed in a 50° C water bath for 10 minutes. After shaking, the mixture was allowed to stand for 2 minutes, and the supernatant was removed by decantation. To this, 60 ml of absolute ethanol was added again, followed by shaking and decantation in the same manner as above, and this was repeated 10 times in total from the beginning. After the final decantation, it was dried overnight at 40°C and -0.1 MPa, and passed through an 83M sieve to obtain carrier particles.A-ll Characterization of the porous carriersA-ll, 1 . Methods

[0176] Particle size distribution in volume and in number were determined by laser diffraction on powdered products. Measurement of the diffraction of a laser beam by the particles of the sample to be analyzed. These particles diffract individually. The resulting diffraction light intensity is a function of the particle size. The computer processing of these light intensities gives access to particle size distributions. Equipment: LASER diffraction particle size meter Mastersizer 3000, equipped with R5 and R7 lenses. RODOS M system associated with a 6mm gun and a VIBRI system. Vacuum cleaner Nilfisk IBVI5.

[0177] Bulk density was determined according to Japanese Pharmacopeia 18thedition (3.01 Determination of Bulk and Tapped Densities Method 3).

[0178] Particle hardness was determined by the Micro Compression Tester (SHIMADZU).BR927 - Porous carrier for the delivery- WO23

[0179] Specific surface area was determined by the nitrogen adsorption BET method using a Macsorb® (Mountech) specific surface area analyzer.

[0180] Average pore size was determined by Tris star with nitrogen adsorption method, using the TriStar L Plus apparatus (Micromeritics).

[0181] Angle of repose was determined by using a Multiple Powder Characteristics Analyzer (Multi Tester) MT-02 apparatus marketed by Seishin Enterprise Co., LTD.

[0182] Maltose and maltotriose contents were determined by HPLCwith Rl detector according to USP-NF Method (USP-NF 2024, Issue 1).

[0183] Microscope images were captured by Scanning Electron Microscope JSM-IT200 InTouchScope.

[0184] The Mw and Mn were determined by high pressure size-exclusion chromatography (HPSEC). This method allows to separate molecules in solution by their size, which correlates with their molecular weight and are compared to Pullulan standards with known molecular weight. It was determined according to the following protocol: Pullulan standards (Grade P-5, P-10, P-20, P-50, P-100, P-200, P-400 and P-800) were purchased from Showa Denko K.K. (Japan); glycerin, glucose, maltose, maltotriose, maltotetraose, maltopentaose, maltohexose and maltoheptaose were purchased from Sigma Aldrich. 0.5 % standard solutions were prepared by dissolving 50 mg of each standard and 50 mg of glycerin (output marker) in 10.0 mL of eluent solvent and then filtered through a 0.45 micron filter. Samples of the carbohydrate compositions were first de-ashed with 1 .0 g LEWATIT S4228 and PUROLITE C 150 MBH mixed resins and then diluted with Eluent solvent to about 2.5 %. Then, 0.25 % of glycerin (output marker) was added, followed by filtration through a 0.45 micron filter. 100 pL of either the standard solutions or sample solutions were injected into a HPLC system equipped with a refractive index detector and 3 SHODEX SEC columns (OHpak SB-805 HQ, SB-803 HQ, SB- 802 HQ connected in series). The chromatography was performed with following parameters: Injecting volume: 100 pL; Flowrate: 0.5 mL / min; Column temperature: 35°C; Eluent: sodium nitrate 0.1 M + sodium azide 0.02 % filtered on a 0.02 micron filter; Eluting time: 80 min. The resulting chromatograms were analyzed offline using Empower software. The polysaccharides size was determined according to the eluting time comparing to glycerin, glucose, maltose, maltotriose, maltotetraose, maltopentaose, maltohexose, maltoheptaose and Pullulans standard eluting time.

[0185] Results are presented in Table 1 and in Figure 2.A- 11, 2. Results and discussion

[0186] [T able 1 ] - Characterization porous carrier particlesBR927 - Porous carrier for the delivery- WO24

[0187] It can be observed that carrier particles according to the disclosure have higher particle hardness in comparison with the carrier particles of WO’516. Higher particle size may also be obtained if desired, for example to improve the particles flowability. Their specific surface area and loading capacity is as high as the one obtained with the particles of WO’516

Claims

BR927 - Porous carrier for the delivery-WO25Claims

1. Water-soluble porous particles comprising a polysaccharide, said particles having a BET specific surface area equal to or higher than 40 m2 / g and a particle hardness equal to or higher than 5 MPa.

2. The water-soluble porous particles of claim 1 , wherein said polysaccharide is selected from a dextrin, a maltodextrin, a dextran, agarose, pullulan, or from a mixture thereof.

3. The water-soluble porous particles of claim 1 , wherein said polysaccharide is a glucose polymer.

4. The water-soluble porous particles of any of claims 1 to 3, wherein said polysaccharide is selected from a dextrin, a maltodextrin, or from a mixture thereof.

5. The water-soluble porous particles of any of claims 1 to 4, wherein said particles have a D50 in volume (Dv50) higher than 70 pm.

6. The water-soluble porous particles of any of claims 1 to 5, wherein said particles have an angle of repose equal to or lower than 45°.

7. Use of the water-soluble porous particles according to any of claims 1 to 6, as a carrier for one or more substances.

8. The use of claim 7, wherein said one or more substances comprises a substance that is poorly water-soluble or not miscible with water.

9. A composition comprising the water-soluble porous particles of any of claims 1 to 6 and one or more substances supported by said particles.

10. A composition comprising the water-soluble porous particles of any of claims 1 to 6 and one or more substances supported by said particles, for use as a medicament, wherein said one or more substances comprise a pharmaceutical or veterinary active ingredient.

11. The composition of any of claims 9 or 10, wherein said one or more substances comprise a substance that is poorly water-soluble or not miscible with water.

12. A method for making water-soluble porous particles, said water-soluble porous particles comprising a polysaccharide, said particles having a BET specific surface area equal to or higher than 40 m2 / g, said method comprising:(a) preparing precursor particles by fluidized bed spray-granulation of a saccharide solution, said saccharide comprising a polysaccharide;(b) obtaining the carrier particles by exposing the precursor particles to an organic solvent.

13. The method of claim 12, wherein said saccharide contains at least 10% of disaccharides, as dry weight with respect to the total dry weight of carrier particles.BR927 - Porous carrier for the delivery-WO26

14. The method of any of claims 12 or 13, wherein said saccharide contains at least 20% of polysaccharides, as dry weight with respect to the total dry weight of carrier particles.

15. The methods of any of claims 12 to 14, wherein said saccharide contains at least

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