dosage form

Abstract

The present invention relates to dosage forms comprising at least one functionalized calcium carbonate-containing material (FCC) and at least one hot melt extruded polymeric resin; methods for producing the dosage forms; pharmaceutical, nutraceutical, cosmetic, home and personal care products comprising the dosage forms and uses thereof.

Description

Technical Field

[0001] This invention relates to dosage forms comprising at least one functionalized calcium carbonate (FCC) material and at least one hot melt extruded polymer resin; methods for producing the dosage form; pharmaceuticals, nutrients, cosmetics, household and personal care products comprising the dosage form, and their uses. Background Technology

[0002] In many products such as pharmaceuticals, nutrients, cosmetics, and household and personal care products, dosage forms such as tablets, mini tablets, granules, pills, or capsules are used to provide active and / or inactive reagents. These dosage forms are primarily manufactured from powders. Depending on the end use, the carrier material or matrix of these dosage forms is typically mixed with the desired active and / or inactive reagents, and additional compatible disintegrants need to be identified to enable the production of the dosage form. A common problem arising from this type of dosage form is that they typically do not allow for high ratios of active and / or inactive reagents to the carrier material or matrix, thus resulting in relatively heavy and bulky dosage forms with low loadings of active and / or inactive reagents.

[0003] Numerous carriers have been used in these dosage forms, including waxes, oils, fats, soluble polymers, and the like. Another approach involves dispersing the active and / or inactive reagents throughout a solid matrix material, through which the active and / or inactive reagents are released by diffusion. Yet another approach involves encapsulating the dosage form within a capsule with polymer walls through which the active and / or inactive reagents can diffuse.

[0004] For example, Pawar et al. (Gastroretentive dosage forms: A review with specialemphasis on floating drug delivery systems. Drug Delivery. Feb 2011;18(2):97-110) viewed floating drug delivery systems (FDDS) as an easy and logical approach to the development of GRDDS in terms of formulation and technology.

[0005] US 3,976,764 discloses an instant floating tablet having a gelatin-based hollow sphere coated with several undercoatings, wherein a therapeutically active ingredient is contained in one of the undercoatings.

[0006] DE 35 27 852 A1 discloses a pharmaceutical formulation with a specific density less than 1, wherein a substance that will form a gel in water is mixed with a pharmaceutically active agent and a fat / oil that is solid at room temperature. The gel-forming substance is a derivative of cellulose, dextran, or starch.

[0007] EP 0 338 861 A2 relates to an antacid composition having a prolonged gastric retention time. An antacid such as hydrotalcite or amalgate forms a solid core surrounded by a solid outer phase containing hydrophobic substances, such as esters of glycerol with palmitic or stearic acid, hydroxylated polyolefins, and nonionic emulsifiers.

[0008] EP 0 717 988 A1 relates to an expanded molding part having an expanded structure with a mesh-like cross-section and an apparent density of less than 1. This structure is primarily an acid-resistant polymer compound and also contains at least one auxiliary foaming agent and a pharmaceutical ingredient. Due to the mesh-like structure in its cross-section, the expanded molding part of this invention has a large number of continuous or discontinuous micropores. The acid-resistant polymer compound is selected, for example, from succinic acid acetate or hydroxypropyl methylcellulose phthalate.

[0009] US 4,451,260 relates to a multilayer structure containing a pharmaceutically active ingredient, wherein air is embedded within the multilayer structure, thereby promoting levitation.

[0010] US 4,814,179 relates to a floating sustained-release therapeutic composition. The uncompressed sustained-release tablet comprises a hydrocolloid gelling agent, a therapeutically acceptable inert oil, a selected therapeutic agent, and water.

[0011] EP 2 719 376 A1 relates to a gastric retention drug formulation and delivery system using functionalized calcium carbonate, and methods for preparing the same.

[0012] In this regard, calcium carbonate appears promising for the preparation of drug delivery systems because it exhibits a highly porous network structure with a lamellar surface structure that strongly binds particles together, see, for example, EP 2719 373 A1. This thus offers the possibility of formulating them into granules, pills, capsules, or compressing them into tablets or mini-tablets.

[0013] In 1998, a new type of surface-reacted calcium carbonate was first described in FR 2787802 B1, and subsequently in WO 00 / 39222 A1 and US 2004 / 0020410 A1, based on naturally ground calcium carbonate with gaseous CO2 and one or more medium to strong H3O. + The reaction of ion donors. The resulting product is porous calcium carbonate with a special surface structure, porosity and specific surface area. When used as a pigment or coating filler for paper, it contributes to a reduction in paper weight without loss of physical properties for a constant surface area.

[0014] WO 2004 / 083316 A1 describes another advantageous modification in the preparation of such surface-reacted calcium carbonate, involving aluminum silicate, synthetic silica, calcium silicate, silicates and / or monovalent salts, and is also applicable to papermaking applications. Furthermore, WO 2005 / 121257 A2 relates to the addition of advantageous additives in the manufacture of said surface-reacted calcium carbonate, wherein one or more compounds of formula RX are added, for example selected from fatty acids, fatty amines, or fatty alcohols. WO 2009 / 074492 A1 relates particularly to the optimization of known methods for precipitating calcium carbonate, as it demonstrates that methods applicable to naturally ground calcium carbonate, due to the specific conditions in calcium carbonate precipitation, cannot provide the same favorable results for the surface reaction of synthesizing precipitated calcium carbonate. Several further optimizations and modifications to the method for preparing surface-reacted calcium carbonate follow those described in EP 2264 108 A1 (WO 2010 / 146530 A1) and EP 2 264 109 A1 (WO 2010 / 146531 A1), which involve the use of a weak acid in the preparation of surface-reacted calcium carbonate.

[0015] WO2014 / 001063 discloses a high-solids aqueous mineral filler suspension that maintains its mechanical properties under low-temperature and acidic conditions.

[0016] The applicant's European patent application EP 3 034 070 A1 relates to roller compaction of a mixture comprising functionalized natural or synthetic calcium carbonate, an active pharmaceutical ingredient and / or an inactive precursor and one or more formulation aids, and compacting the resulting roller-compacted mixture into a drug delivery system. Unpublished European patent application EP 16 175 590.5 relates to a method for manufacturing a dosage form, comprising the steps of: a) providing surface-reacted calcium carbonate, wherein the surface-reacted calcium carbonate is naturally milled or precipitated calcium carbonate with carbon dioxide and one or more H3O. + The reaction products of the ion donor in an aqueous medium, wherein the carbon dioxide passes through H3O +The process involves: a) in-situ formation and / or supply of an ion donor from an external source; b) providing at least one active ingredient and / or its inactive precursor; c) loading the surface-reacted calcium carbonate of step a) with at least one active ingredient and / or its inactive precursor from step b); d) compacting the loaded surface-reacted calcium carbonate obtained in step c) into a compacted form using a roller compactor at a compaction pressure in the range of 1-30 kN / cm; and e) grinding the compacted form of step d) into granules; provided that the compacted form of the loaded surface-reacted calcium carbonate obtained in step d) consists of the surface-reacted calcium carbonate of step a) and at least one active ingredient and / or its inactive precursor from step b). Unpublished European patent application 16,175,595.4 relates to a method for producing granules comprising surface-reacted calcium carbonate, the method comprising the steps of: a) providing surface-reacted calcium carbonate, wherein the surface-reacted calcium carbonate is naturally ground or precipitated calcium carbonate with carbon dioxide and one or more H3O. + The reaction products of the ion donor in an aqueous medium, wherein the carbon dioxide passes through H3O + Ion donor treatment is formed in situ and / or supplied from an external source; b) the surface-reacted calcium carbonate of step a) is compacted into a compacted form by means of a roller compactor at a compaction pressure in the range of 1-30 kN / cm; c) the compacted form of step b) is ground into granules; wherein the compacted form obtained in step b) consists of the surface-reacted calcium carbonate of step a).

[0017] The applicant's unpublished European patent application EP 15 160 194.5 relates to a method for producing a dispersible formulation in an aqueous environment, comprising the following steps: a) providing a functionalized material containing natural and / or synthetic calcium carbonate, which is the product of the reaction of naturally ground or precipitated calcium carbonate with carbon dioxide and one or more acids in an aqueous medium, wherein the carbon dioxide is formed in situ by acid treatment and / or supplied from an external source; b) providing at least one disintegrant; c) optionally, providing at least one other formulation aid; d) mixing the at least one functionalized material containing natural and / or synthetic calcium carbonate from step a), the at least one disintegrant from step b), and the optional at least one other formulation aid from step c); e) compacting the mixture obtained in step d) into a strip using a roller compactor at a compaction pressure in the range of 2-20 bar; f) grinding the strip from step e) into granules; and g) sieving the granules from step f) through at least one sieve mesh size.

[0018] Throughout this invention and in view of the prior art cited, surface-reacted (natural or synthetic) calcium carbonate is equivalent to functionalized (natural and / or synthetic) calcium carbonate-containing materials.

[0019] However, there is a continuous demand for dosage forms that offer better performance than existing formulations, and particularly for dosage forms that are lighter and smaller in volume under higher active and / or inactive reagent loads compared to conventional dosage forms containing functionalized calcium carbonate materials. There is also a continuous demand for methods for producing dosage forms, and particularly for methods that allow for the production of dosage forms that are lighter and smaller in volume under higher active and / or inactive reagent loads compared to conventional dosage forms containing functionalized calcium carbonate materials. Furthermore, it is desirable to provide methods for producing dosage forms that are efficient and allow for direct compression of the formulation without the use of binders and / or compaction aids. Summary of the Invention

[0020] The object of the present invention is therefore to provide a dosage form. Another object is to provide a dosage form that is lighter and smaller in volume, particularly compared to conventional dosage forms containing functionalized calcium carbonate materials, under higher active and / or inactive reagent loadings. A further object is to provide a method for producing the dosage form. Another object is to provide a method for producing a dosage form that is lighter and smaller in volume, particularly compared to conventional dosage forms containing functionalized calcium carbonate materials, under higher active and / or inactive reagent loadings. Yet another object is to provide an efficient pressing method for the dosage form without the use of binders and / or compaction aids.

[0021] One or more of the foregoing and other problems are addressed by means of the subject matter as defined herein in the independent claims. Advantageous embodiments of the invention are defined in the respective dependent claims.

[0022] The first aspect of the present invention relates to a dosage form comprising

[0023] a) At least one functionalized calcium carbonate-containing material (FCC), which is natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more H3O + The reaction product of the ion donor, wherein the carbon dioxide passes through H3O + Ion donor treatments are formed in situ and / or supplied from external sources.

[0024] b) At least one hot melt extrusion polymer resin,

[0025] The at least one functionalized calcium carbonate-containing material is dispersed in the at least one hot melt extruded polymer resin, and the weight ratio (FCC / polymer) of the functionalized calcium carbonate-containing material to the hot melt extruded polymer resin is in the range of 95:5 to 5:95.

[0026] According to another aspect of the invention, the use of dosage forms as defined herein in pharmaceuticals, nutrients, cosmetics, and household and personal care products is provided. According to another aspect of the invention, pharmaceuticals, nutrients, cosmetics, and household and personal care products comprising the dosage forms as defined herein are provided.

[0027] According to another aspect of the present invention, a method for producing a dosage form is provided. The method includes the following steps:

[0028] a) Provide at least one functionalized calcium carbonate-containing material (FCC) as defined herein, which is natural milled calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more H3O + The reaction product of the ion donor, wherein the carbon dioxide passes through H3O + Ion donors are formed in situ and / or supplied from external sources;

[0029] b) Provide at least one polymer resin as defined herein;

[0030] c) Mix the at least one functionalized calcium carbonate-containing material from step a) with the at least one polymer resin from step b);

[0031] d) The mixture obtained in hot melt extrusion step c); and

[0032] e) The hot melt extruded product obtained in step d) is milled or granulated to obtain the dosage form.

[0033] According to one embodiment of the method of the present invention, the method further includes: step b1) providing at least one active reagent and / or inactive reagent, preferably, the at least one active reagent and / or inactive reagent is selected from pharmaceutical active reagents, active or inactive prodrugs, nutrients, food additives, cosmetic additives, and mixtures thereof; and / or step b2) providing at least one excipient, preferably, the at least one excipient is selected from disintegrants, especially modified cellulose gum, insoluble cross-linked polyvinylpyrrolidone, glycolic acid starch (starch). Glycolates, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, homopolymers of N-vinyl-2-pyrrolidone, alkyl cellulose esters, hydroxyalkyl cellulose esters, carboxyalkyl cellulose esters, alginate, microcrystalline cellulose and its polymorphs, ion exchange resins, gums, chitin, chitosan, clay, gellan gum, crosslinked polacrillin copolymers, agar, gelatin, dextrin, acrylic polymers, sodium / calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose phthalate, shellac or mixtures thereof, lubricants, in-phase lubricants, out-of-phase lubricants, impact modifiers, plasticizers, waxes, stabilizers, pigments, colorants, flavorings, taste maskers, flavorings, sweeteners, mouthfeel modifiers, binders, diluents, film-forming agents, adhesives, buffers, adsorbents, odor maskers and mixtures thereof.

[0034] According to another embodiment of the method of the present invention, the at least one active reagent and / or inactive reagent in step b1) and / or the at least one excipient in step b2)

[0035] a) Loaded onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC) prior to mixing step c), and / or

[0036] b) Mixing the at least one functionalized calcium carbonate material from step a) and the at least one polymer resin from step b) in mixing step c) prior to hot melt extrusion step d), and / or

[0037] c) Apply one or more layers onto the dosage form obtained in step e).

[0038] According to another embodiment of the method of the present invention, the method includes one or more steps f): compacting the dosage form obtained in step e).

[0039] According to one embodiment of the method of the present invention, the at least one active reagent and / or inactive reagent and / or the at least one excipient in step b1) and step b2) are mixed and compacted in compaction step f1) to form a core tablet.

[0040] According to another embodiment of the method of the present invention, it further includes step g): covering at least partially the core tablet formed in step f1) with the dosage form obtained in step e), and compacting the resulting product.

[0041] According to another embodiment of the method of the present invention, at least one active reagent and / or inactive reagent and / or at least one excipient in step b1) of the same or different steps and / or step b2)

[0042] a) Loaded onto the at least one functionalized calcium carbonate (FCC) material prior to mixing step c), and / or

[0043] b) Mixing the at least one functionalized calcium carbonate material from step a) and the at least one polymer resin from step b) in mixing step c) prior to hot melt extrusion step d).

[0044] According to an even further aspect of the invention, the use of a functionalized calcium carbonate-containing material (FCC) as defined herein is provided in a method for producing dosage forms. According to yet another aspect of the invention, the use of a functionalized calcium carbonate-containing material (FCC) as defined herein is provided in dosage forms such as tablets, mini tablets, pellets, capsules, granules, and / or tablet-in-cup.

[0045] According to one embodiment of the dosage form of the present invention, the naturally ground calcium carbonate is selected from calcium carbonate-containing minerals, which are selected from marble, chalk, dolomite, limestone and mixtures thereof; or the precipitated calcium carbonate is selected from precipitated calcium carbonate and mixtures thereof having aragonite, aragonite or calcite mineralogical crystal forms.

[0046] According to another embodiment of the dosage form of the present invention, the at least one functionalized calcium carbonate-containing material

[0047] a) Possesses a 20m measurement according to ISO 9277 using nitrogen and the BET method. 2 / g-450m 2 / g, preferably 20m 2 / g-250m 2 / g, more preferably 30m 2 / g-160m 2 / g, optimal choice 40m 2 / g-150m 2 / g, even more preferably 50m 2 / g-140m 2 / g of BET specific surface area; and / or

[0048] b) Containing particles with a median volume diameter d of 1µm-50µm, preferably 1-45µm, more preferably 2-30µm, even more preferably 3-15µm, and most preferably 4-12µm. 50 (Volume) particles; and / or

[0049] c) Porosity calculated from the mercury intrusion porosity determination method is between 0.15 and 1.35 cm. 3 / g, preferably 0.30-1.30cm 3 / g, more preferably 0.40-1.25cm 3 In-particle pore volume within the range of / g.

[0050] According to another embodiment of the dosage form of the present invention, the at least one hot melt extruded polymer resin is selected from polyethylene, polystyrene, polyvinyl chloride, polyamide 66 (nylon), polycaprolactam, polycaprolactone, acrylic polymers, acrylonitrile butadiene styrene, polybenzimidazole, polycarbonate, polyphenylene ether / polyphenylene sulfide, polypropylene, Teflon, polylactic acid, polylactic acid-based polymers, aliphatic polyesters such as polyhydroxybutyrate, poly-3-hydroxybutyrate (P3HB), polyhydroxyvalerate, polyhydroxybutyrate-polyhydroxyvalerate copolymer, poly(3-hydroxybutyrate-co-3-hydroxyvalerate), polygluconate, poly(di(hydroxybutyrate-co-3-hydroxyvalerate)), and poly(di(hydroxybutyrate-co-3-hydroxyvalerate)). Dioxanone and mixtures thereof, preferably, the at least one polymer resin is selected from polycaprolactone, polylactic acid, polylactic acid-based polymers and mixtures thereof.

[0051] According to one embodiment of the dosage form of the present invention, the dosage form further comprises at least one active reagent and / or an inactive reagent.

[0052] According to another embodiment of the dosage form of the present invention, the at least one active reagent and / or inactive reagent is selected from pharmaceutical active reagents, active or inactive prodrugs, nutrients, food additives, cosmetic additives and mixtures thereof.

[0053] According to another embodiment of the dosage form of the present invention, the at least one active reagent and / or inactive reagent

[0054] a) being loaded onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC), and / or

[0055] b) dispersed in at least one hot melt extruded polymer resin comprising at least one functionalized calcium carbonate (FCC) material, and / or

[0056] c) In the form of a core, preferably in the form of a compacted tablet, which is at least partially covered by at least one hot-melt extruded polymer resin comprising at least one functionalized calcium carbonate material (FCC), or

[0057] d) In the form of a layer, which at least partially covers a core made of at least one hot-melt extruded polymer resin comprising at least one functionalized calcium carbonate material (FCC), preferably a compacted tablet, or

[0058] e) It is in the form of a layered structure with at least two layers, wherein at least one layer is made of at least one hot melt extruded polymer resin containing at least one functionalized calcium carbonate material (FCC).

[0059] According to one embodiment of the dosage form of the present invention, the dosage form further comprises at least one excipient, preferably selected from disintegrants, particularly modified cellulose gum, insoluble cross-linked polyvinylpyrrolidone, glycolic acid starch, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, homopolymers of N-vinyl-2-pyrrolidone, alkyl cellulose esters, hydroxyalkyl cellulose esters, carboxyalkyl cellulose esters, alginate, microcrystalline cellulose and its polymorphs, ion exchange resins, gums, and chitosan. Chitosan, clay, gellan gum, crosslinked polacrillin copolymer, agar, gelatin, dextrin, acrylic polymers, sodium / calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose phthalate, shellac or mixtures thereof, lubricants, in-phase lubricants, out-of-phase lubricants, impact modifiers, plasticizers, waxes, stabilizers, pigments, colorants, flavorings, taste maskers, flavorings, sweeteners, mouthfeel modifiers, binders, diluents, film-forming agents, adhesives, buffers, adsorbents, odor maskers and mixtures thereof.

[0060] According to another embodiment of the dosage form of the invention, the dosage form is in the form of powder, tablets such as multilayer tablets, tablets with modified geometry or matrix tablets, mini tablets, pills, capsules, granules and / or cup tablets.

[0061] It should be understood that, for the purposes of this invention, the following terms have the following meanings.

[0062] For the purposes of this invention, "acid" is defined as Brønsted-Lowryacid, i.e., its form is H3O. + Ion provider. "Acidic salt" is defined as H3O. + Ion providers, such as hydrogen-containing salts partially neutralized by positively charged elements. A "salt" is defined as an electrically neutral ionic compound formed by anion and cation. A "partially crystalline salt" is defined as a salt that exhibits a substantially discrete diffraction pattern during XRD analysis.

[0063] According to the present invention, pK a pK is a symbol representing the acid dissociation constant associated with a given ionizable hydrogen atom in a given acid, and indicating the degree of spontaneous dissociation of this hydrogen atom from the acid at equilibrium in water at a given temperature. a The value can be found in the following reference materials, such as: Harris, DC, “Quantitative Chemical Analysis: 3rd Edition”, 1991, WH Freeman & Co. (USA), ISBN 0-7167-2170-8.

[0064] "Functionalized calcium carbonate-comprising material" is a material comprising calcium carbonate and, preferably, a water-insoluble, at least partially crystalline non-calcium carbonate salt extending from at least a portion of the surface of the calcium carbonate. The calcium ions forming the at least partially crystalline non-calcium carbonate salt are primarily derived from the starting calcium carbonate material, which is also used to form at least one functionalized calcium carbonate-containing core material of natural and / or synthetic calcium carbonate. This salt may include OH-. - Anions and / or water of crystallization.

[0065] In the context of this invention, a "water-insoluble" material is defined as a material in which, when mixed with deionized water and filtered at 20°C through a filter having a pore size of 0.2 µm to recover the liquid filtrate, 100 g of the liquid filtrate, after evaporation at 95-100°C, provides less than or equal to 0.1 g of recovered solid material. A "water-soluble" material is defined as a material in which 100 g of the liquid filtrate, after evaporation at 95-100°C, results in the recovery of more than 0.1 g of recovered solid material.

[0066] In the context of this invention, "naturally ground calcium carbonate" (GCC) refers to calcium carbonate obtained from natural sources (e.g., limestone, marble, dolomite, or chalk) and processed by wet and / or dry methods such as grinding, screening, and / or grading (e.g., by means of a cyclone or classifier). The naturally ground calcium carbonate is the base material for this functionalized natural calcium carbonate.

[0067] In this invention, "precipitated calcium carbonate" (PCC) refers to a synthetic substance obtained by precipitation after the reaction of carbon dioxide and lime in an aqueous, semi-dry, or humid environment, or by precipitation in water using a calcium and carbonate ion source. PCC can be in the form of aragonite, calcite, or spheroidite. The precipitated calcium carbonate is the base material for this functionalized synthetic calcium carbonate.

[0068] Throughout this document, the "particle size" of calcium carbonate and other materials is described by their particle size distribution. d x This refers to a diameter such that, relative to this diameter, x% of the weight of particles have a smaller than [a certain value]. d x The diameter. This means d 20 The value is the particle size that is less than 20% of the weight of all the particles, and d 75 The value is the particle size that is less than 75% of the weight of all the particles. d 50 The value is therefore the weight-median particle size, which is defined as the particle size at which 50% of the total weight of all particles is greater than this particle size and the remaining 50% of the total weight of particles is smaller than this particle size. For the purposes of this invention, unless otherwise specified, the particle size is defined as the weight-median particle size. d 50 To determine the median particle size by weight d 50 Values ​​can be obtained using Sedigraph. For the purposes of this invention, the "particle size" of the functionalized calcium carbonate-containing material is described as a volume-determined particle size distribution. To determine the volume-determined particle size distribution of the functionalized calcium carbonate-containing material, a volume median particle diameter (VMC) is used. d 50 ) or volume determines the top cut particle size ( d 98 Malvern Mastersizer 2000 can be used. If all particles have the same density, then the weight-determined particle size distribution corresponds to the volume-determined particle size.

[0069] In the context of this invention, the "specific surface area (SSA)" of calcium carbonate is defined as the surface area of ​​calcium carbonate divided by its mass. As used herein, the specific surface area is measured using a BET isotherm by nitrogen adsorption (ISO 9277:2010) and expressed in m³. 2 / g regulations.

[0070] In the context of this invention, the term "pore" is understood to describe the space found between and / or within particles, i.e., the space formed by particles when they are packed together in the nearest adjacent contact (interparticle pore), such as in powders or compacts, and / or the void space within porous particles (intraparticle pore), which, when saturated with liquid, allows liquid to pass through under pressure and / or supports the absorption of surface-wetting liquid.

[0071] The "intraparticle-intruded specific pore volume" according to the present invention can be calculated from the results of mercury intrusion porosimetry and describes the measured pore volume per unit mass of particle-containing sample found inside pigment particles. The intruded total specific pore volume represents the sum of all individual pore volumes per unit mass of sample that can be intruded by mercury, which can be measured by mercury intrusion porosimetry using a Micrometrics Autopore IV mercury porosimeter. An illustrative mercury intrusion porosimetry experiment requires purging the porous sample to remove trapped gas, after which the sample is surrounded by mercury. The amount of mercury displaced by the sample allows for the calculation of the bulk volume of the sample. V bulk Then, pressure is applied to the mercury to allow it to penetrate into the sample through pores connected to the outer surface. The maximum applied pressure to the mercury is 414 MPa, equivalent to a Laplace throat diameter of 0.004 μm. Data correction can be performed using Pore-Comp (PACGane et al., “Void Space Structure of Compressible Polymer Spheres and Consolidated Calcium Carbonate Paper-Coating Formulations”, Industrial and Engineering Chemistry Research 1996, 35(5): 1753-1764) (for mercury and translucency effects, and also for sample compression). By obtaining the first derivative of the cumulative penetration curve, the pore size distribution based on the equivalent Laplace diameter is revealed, which necessarily includes the effect of pore shielding (if present). The total specific void volume of the penetration corresponds to the void volume per unit mass of sample determined by the mercury porosimetry.

[0072] In the context of this invention, the term "polymer resin" refers to a polymer material that is solid or liquid, preferably solid, prior to being processed into a hot melt extruded polymer resin.

[0073] The term "hot melt extrusion" refers to polymer resins that have been processed through the hot melt extrusion process.

[0074] When the term "comprising" is used in this specification and claims, it does not exclude other elements. For the purposes of this invention, the term "consisting of" is considered a preferred embodiment of the term "comprising of". If a group is defined below as including at least a certain number of embodiments, this is also understood to disclose a group that preferably consists only of these embodiments.

[0075] When discussing singular nouns, the use of indefinite or definite articles such as "a," "an," or "the" includes the plural form of the noun, unless otherwise specified in some cases.

[0076] Terms such as “obtainable” or “definable” and “obtained” or “defined” are used interchangeably. This means, for example, that unless the context explicitly indicates otherwise, the term “obtainable” does not imply that an embodiment must be obtained through, for example, a sequence of steps following the term “obtainable”, although the terms “obtainable” or “defined” always include such limiting understanding as a preferred embodiment.

[0077] According to the present invention, it has been found that dosage forms comprising a functionalized calcium carbonate material dispersed in at least one hot melt extrusion polymer resin and wherein the weight ratio (FCC / polymer) of the functionalized calcium carbonate material to the hot melt extrusion polymer resin is in the range of 95:5 to 5:95 are lighter and smaller in volume at higher drug loadings, especially compared with conventional dosage forms comprising a functionalized calcium carbonate material without using at least one hot melt extrusion polymer resin.

[0078] Further details of the invention will be described below, particularly the aforementioned dosage forms.

[0079] One requirement of this invention is that the dosage form comprises at least one functionalized calcium carbonate-containing material, which is naturally ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more H3O. + The reaction product of the ion donor, wherein the carbon dioxide passes through H3O + The ion donor treatment is formed in situ and / or supplied from an external source. In other words, the dosage form comprises at least one functionalized material containing natural and / or synthetic calcium carbonate, which is naturally ground or precipitated calcium carbonate with carbon dioxide and one or more H3O. + The reaction product of the ion donor, wherein the carbon dioxide passes through H3O + Ion donor treatment is formed in situ and / or supplied by an external source.

[0080] The statement "at least one" functionalized calcium carbonate-containing (natural and / or synthetic) material means that one or more types of functionalized calcium carbonate-containing (natural and / or synthetic) materials may be present in the dosage forms of this invention.

[0081] Therefore, the at least one functionalized calcium carbonate-containing (natural and / or synthetic) material can be one type of functionalized calcium carbonate-containing (natural or synthetic) material. Alternatively, the at least one functionalized calcium carbonate-containing (natural and / or synthetic) material can be a mixture of two or more types of functionalized calcium carbonate-containing (natural and / or synthetic) materials. For example, the at least one functionalized calcium carbonate-containing (natural and / or synthetic) material can be a mixture of two or three types of functionalized calcium carbonate-containing (natural and / or synthetic) materials. Preferably, the at least one functionalized calcium carbonate-containing (natural and / or synthetic) material is one type of functionalized calcium carbonate-containing (natural or synthetic) material.

[0082] Therefore, the at least one functionalized calcium carbonate-containing material according to the present invention (i.e., the at least one functionalized material containing natural and / or synthetic calcium carbonate) is natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more H3O. + The reaction product of the ion donor, wherein the carbon dioxide passes through H3O + Ion donor treatment is formed in situ and / or supplied by an external source.

[0083] In the context of this invention, H3O + The ion donors are Brønsted acids and / or acid salts.

[0084] In a preferred embodiment of the present invention, the at least one functionalized calcium carbonate-containing material (i.e., the at least one functionalized material containing natural and / or synthetic calcium carbonate) is obtained by a method comprising the following steps: (a) providing a suspension of natural or precipitated calcium carbonate, and (b) adding to the suspension of step (a) at least one material having a pK of 0 or less at 20°C. a The value or pK value at 20℃ is 0-2.5. aThe acid of value, and (c) treating the suspension of step (a) with carbon dioxide before, during or after step (b). According to another embodiment, the at least one functionalized calcium carbonate-containing material (i.e., the at least one functionalized material containing natural and / or synthetic calcium carbonate) is obtained by a method comprising the following steps: (A) providing natural or precipitated calcium carbonate, (B) providing at least one water-soluble acid, (C) providing gaseous CO2, (D) contacting the natural or precipitated calcium carbonate of step (A) with the at least one acid of step (B) and the CO2 of step (C), characterized in that: (i) the at least one acid of step (B) has a pK value greater than 2.5 and less than or equal to 7 at 20°C. a The pK a Related to the ionization of its first available hydrogen, and the formation of a corresponding anion capable of forming a water-soluble calcium salt upon the loss of this first available hydrogen, and (ii) after contacting the at least one acid with native or precipitated calcium carbonate, providing an additional at least one water-soluble salt having a pK greater than 7 at 20°C in the case of a hydrogen-containing salt. a (The pK) a (related to the ionization of the first available hydrogen), and its salt anion is capable of forming a water-insoluble calcium salt.

[0085] "Naturally ground calcium carbonate (GCC)" is preferably selected from calcium carbonate-containing minerals, such as marble, chalk, limestone, and mixtures thereof. Natural calcium carbonate may further contain naturally occurring components such as magnesium carbonate, aluminosilicates, etc.

[0086] Typically, the grinding of naturally ground calcium carbonate can be a dry or wet grinding process and can be carried out, for example, with any conventional grinding apparatus under conditions where the pulverization is primarily achieved by the impact of an auxiliary body, i.e., in one or more of the following: ball mill, rod mill, vibratory mill, crusher, centrifugal impact mill, vertical bead mill, grinder, pin mill, hammer mill, powder mill, shredder, de-lumping machine, knife cutter, or other such equipment known to those skilled in the art. In cases where the calcium carbonate-containing mineral material comprises a wet-ground calcium carbonate-containing mineral material, the grinding process can be carried out under conditions that allow self-grinding to occur and / or by horizontal ball milling and / or other such methods known to those skilled in the art. The resulting wet-processed ground calcium carbonate-containing mineral material can be washed and dehydrated by well-known methods, such as by flocculation, filtration, or forced evaporation (before drying). Subsequent drying steps (if necessary) can be carried out in a single step (e.g., spray drying) or in at least two steps. It is also common for such mineral materials to undergo beneficiation steps (e.g., flotation, bleaching, or magnetic separation steps) to remove impurities.

[0087] In the context of this invention, "precipitated calcium carbonate" (PCC) refers to a synthetic substance, typically obtained by precipitation following the reaction of carbon dioxide with calcium hydroxide in an aqueous environment, or by precipitating calcium and carbonate ions (e.g., CaCl2 and Na2CO3) from solution. Other possible methods for producing PCC include the lime-soda process or the Solvay process, where PCC is a byproduct of ammonia production. Precipitated calcium carbonate exists in three primary crystalline forms: calcite, aragonite, and aragonite, and for each of these forms, there are many different polymorphs (crystal inertia). Calcite has a triangular structure, which exhibits typical crystal inertia such as subtrigonal (S-PCC), orthorhombic (R-PCC), hexagonal prism, axial, colloidal (C-PCC), cubic, and prismatic (P-PCC). Aragonite has an orthorhombic crystal structure, which exhibits typical crystal inertia of paired hexagonal prisms, as well as various classifications including slender prisms, curved leaf-like crystals, steep cone-shaped crystals, chisel-shaped crystals, branched trees, and coral or worm-like forms. Spherulite belongs to the hexagonal crystal system. The obtained PCC slurry can be mechanically dehydrated and dried.

[0088] According to one embodiment of the present invention, the precipitated calcium carbonate is preferably precipitated calcium carbonate containing aragonite, aragonite or calcite mineral crystals or mixtures thereof.

[0089] Precipitate calcium carbonate using carbon dioxide and at least one H3O. + Prior to ion donor treatment, the material is ground in the same manner as natural calcium carbonate as described above.

[0090] According to one embodiment of the invention, natural or precipitated calcium carbonate is in the form of particles having a median weight particle size. d 50 The particle size is 0.05-10.0 μm, preferably 0.2-5.0 μm, more preferably 0.4-3.0 μm, most preferably 0.6-1.2 μm, and especially 0.7 μm. According to another embodiment of the invention, natural or precipitated calcium carbonate is in the form of particles having a top-cut particle size. d 98 The value is 0.15-55μm, preferably 1-40μm, more preferably 2-25μm, most preferably 3-15μm, and especially 4μm.

[0091] The natural and / or precipitated calcium carbonate can be used dried or suspended in water. Preferably, the corresponding slurry has a content of natural or precipitated calcium carbonate ranging from 1% to 90% by weight, more preferably 3% to 60% by weight, even more preferably 5% to 40% by weight, and most preferably 10% to 25% by weight, based on the weight of the slurry.

[0092] One or more H3Os used to prepare at least one functionalized calcium carbonate-containing material (i.e., at least one functionalized material containing natural and / or synthetic calcium carbonate). + Ion donors can generate H3O under the preparation conditions. + Any strong, moderately strong, or weak acid, or mixture thereof, containing ions. According to the present invention, at least one H3O + Ion donors can also generate H3O under the preparation conditions. + Acidic salts of ions.

[0093] According to one embodiment, the at least one H3O + The ion donor is one with a pK value of 0 or less at 20 °C. a A strong acid of high value.

[0094] According to another embodiment, the at least one H3O + The ion donor has a pK value of 0-2.5 at 20 °C. a A moderately strong acid. If pK at 20℃... a If the pK value is 0 or less, the acid is preferably selected from sulfuric acid, hydrochloric acid, or a mixture thereof. If the pK value at 20°C is... a If the value is 0-2.5, then the H3O + The ion donor is preferably selected from H₂SO₃, H₃PO₄, oxalic acid, or mixtures thereof. At least one H₂SO₄ ion donor is preferred. + Ion donors can also be acid salts, such as HSO4. - or H2PO4 - It is through corresponding cations such as Li + Na + or K + At least partially neutralized, or HPO4 2- It is through corresponding cations such as Li + Na + K + Mg 2+ or Ca 2+ At least partially neutralized. This at least one H3O + Ion donors can also be a mixture of one or more acids and one or more acid salts.

[0095] According to yet another embodiment, the at least one H3O + The ion donor is a weak acid with a pK value greater than 2.5 and less than or equal to 7 when measured at 20°C. a The value (related to the ionization of the first available hydrogen) and having a corresponding anion capable of forming a water-soluble calcium salt. Then, at least one additional water-soluble salt is added, which, in the case of a hydrogen-containing salt, has a pK value greater than 7 when measured at 20°C. a(Related to the ionization of the first available hydrogen) and its salt anion is capable of forming a water-insoluble calcium salt. According to a preferred embodiment, the weak acid has a pK of 2.5-5 at 20°C. a The weak acid is selected from acetic acid, formic acid, propionic acid, and mixtures thereof. An exemplary cation of the water-soluble salt is selected from potassium, sodium, lithium, and mixtures thereof. In a more preferred embodiment, the cation is sodium or potassium. An exemplary anion of the water-soluble salt is selected from phosphate, dihydrogen phosphate, monohydrogen phosphate, oxalate, silicate, mixtures thereof, and their hydrates. In a more preferred embodiment, the anion is selected from phosphate, dihydrogen phosphate, monohydrogen phosphate, mixtures thereof, and their hydrates. In a most preferred embodiment, the anion is selected from dihydrogen phosphate, monohydrogen phosphate, mixtures thereof, and their hydrates. The water-soluble salt can be added dropwise or in one step. In the case of dropwise addition, this addition preferably occurs within a 10-minute time period. More preferably, the salt is added in one step.

[0096] According to one embodiment of the present invention, the at least one H3O + The ion donor is selected from hydrochloric acid, sulfuric acid, sulfurous acid, phosphoric acid, citric acid, oxalic acid, acetic acid, formic acid, and mixtures thereof. Preferably, at least one H3O + Ion donors are selected from hydrochloric acid, sulfuric acid, sulfurous acid, phosphoric acid, oxalic acid, and H2PO4. - (It is through corresponding cations such as Li) + Na + or K + (at least partially neutralized), HPO4 2- (It is through corresponding cations such as Li) + Na + K + Mg 2+ or Ca 2+ (at least partially neutralized), and mixtures thereof, more preferably, the at least one acid is selected from hydrochloric acid, sulfuric acid, sulfurous acid, phosphoric acid, oxalic acid, or mixtures thereof, and most preferably, the at least one H3O + Phosphoric acid is the ion donor.

[0097] One or more H3O + The ion donor can be added to the suspension as a concentrated solution or a more diluted solution. Preferably, the H3O + The molar ratio of the ion donor to the natural or precipitated calcium carbonate is 0.01 to 4, more preferably 0.02 to 2, even more preferably 0.05 to 1, and most preferably 0.1 to 0.58.

[0098] As an alternative, the H3O can also be added before suspending or precipitating the natural or precipitated calcium carbonate. +Ion donors are added to water.

[0099] In the next step, carbon dioxide is used to treat either natural or precipitated calcium carbonate. If a strong acid such as sulfuric acid or hydrochloric acid is used, H₃O is produced for either natural or precipitated calcium carbonate. + When treated with an ion donor, carbon dioxide is automatically formed. Alternatively or additionally, carbon dioxide can be supplied from an external source.

[0100] H3O + Ion donor treatment and carbon dioxide utilization can be carried out simultaneously, especially when using strong or moderately strong acids. Alternatively, H₃O can be processed first. + Ion donor treatment, for example, utilizing ion donors with a pK value in the range of 0 to 2.5 at 20°C. a The process is carried out using a moderately strong acid, in which carbon dioxide is formed in situ, and therefore, the carbon dioxide treatment will automatically react with H3O. + Ion donor processing is carried out simultaneously, followed by additional processing using carbon dioxide supplied from an external source.

[0101] Preferably, the concentration of gaseous carbon dioxide in the suspension is such that the ratio (volume of suspension) : (volume of gaseous CO2) is 1:0.05 to 1:20, or even more preferably 1:0.05 to 1:5.

[0102] In a preferred embodiment, H3O + The ion donor treatment step and / or carbon dioxide treatment step are repeated at least once, more preferably multiple times. According to one embodiment, the at least one H3O is added over a time period of at least about 5 minutes, preferably at least about 10 minutes, typically about 10 to about 20 minutes, more preferably about 30 minutes, even more preferably about 45 minutes, and sometimes about 1 hour or longer. + ion donor.

[0103] In H3O + After ion donor treatment and carbon dioxide treatment, the pH value of the aqueous suspension measured at 20°C naturally reaches a value greater than 6.0, preferably greater than 6.5, more preferably greater than 7.0, and even more preferably greater than 7.5, thereby preparing the at least one functionalized calcium carbonate-containing material (i.e., the at least one functionalized material containing natural and / or synthetic calcium carbonate) into an aqueous suspension having a pH value greater than 6.0, preferably greater than 6.5, more preferably greater than 7.0, and even more preferably greater than 7.5.

[0104] Further details regarding the preparation of at least one functionalized natural calcium carbonate-containing material are disclosed in the following documents: WO 00 / 39222A1, WO 2004 / 083316A1, WO 2005 / 121257A2, WO 2009 / 074492 A1, EP 2264 108 A1, EP 2 264 109 A1 and US 2004 / 0020410 A1, the contents of which are incorporated herein by reference.

[0105] Similarly, functionalized synthetic calcium carbonate-containing materials are obtained. As detailed in WO 2009 / 074492 A1, functionalized synthetic calcium carbonate is obtained by reacting precipitated calcium carbonate with H3O. + Ions and anions that are dissolved in an aqueous medium and capable of forming water-insoluble calcium salts are contacted in an aqueous medium to form a slurry of functionalized synthetic calcium carbonate, wherein the functionalized synthetic calcium carbonate comprises at least partially crystalline calcium salts of the anions formed on the surface of at least a portion of the precipitated calcium carbonate.

[0106] The dissolved calcium ions correspond to the calcium carbonate being dissolved by H3O relative to the precipitated calcium carbonate. + Excessive dissolved calcium ions, specifically H3O, are naturally occurring dissolved calcium ions. + The ions are provided only as counterions to the anion, i.e., via the addition of an acid or non-calcic acid salts, and there are no other sources of calcium ions or calcium ion generation.

[0107] The excess dissolved calcium ions are preferably provided by adding a soluble neutral or acidic calcium salt, or by adding an acid or neutral or acidic non-calcium salt that produces a soluble neutral or acidic calcium salt in situ.

[0108] The H3O + The ions can be provided by adding an acid or an acidic salt of the anion, or by adding an acid or an acidic salt that simultaneously provides all or part of the excess dissolved calcium ions.

[0109] In preparing the at least one functionalized calcium carbonate-containing material (i.e., the at least one functionalized material containing natural and / or synthetic calcium carbonate), milled or precipitated calcium carbonate is reacted with one or more H3O compounds in the presence of at least one compound selected from the group consisting of... + Ion donor and / or carbon dioxide reaction: silicates, silicon dioxide, aluminum hydroxide, alkaline earth aluminates such as sodium aluminate or potassium aluminate, magnesium oxide, or mixtures thereof. Preferably, the at least one silicate is selected from aluminum silicate, calcium silicate, or alkaline earth metal silicates. These components may be added with one or more H3O. +Ion donors and / or carbon dioxide are added to aqueous suspensions containing natural or precipitated calcium carbonate.

[0110] Alternatively, silicate and / or silica and / or aluminum hydroxide and / or alkaline earth aluminate and / or magnesium oxide components may be incorporated into natural or precipitated calcium carbonate with one or more H3O. + The ion donor and carbon dioxide are added to an aqueous suspension of naturally ground or precipitated calcium carbonate once the reaction has begun. Further details regarding the preparation of the at least one functionalized calcium carbonate-containing material (i.e., the at least one functionalized natural and / or synthetic calcium carbonate-containing material) in the presence of at least one silicate and / or silica and / or aluminum hydroxide and / or alkaline earth aluminate component are disclosed in WO 2004 / 083316 A1, the contents of which are incorporated herein by reference.

[0111] The at least one functionalized calcium carbonate-containing material (i.e., the at least one functionalized material containing natural and / or synthetic calcium carbonate) can be kept in a suspension state, optionally further stabilized by a dispersant. Conventional dispersants known to those skilled in the art can be used. Preferred dispersants include polyacrylic acid and / or carboxymethyl cellulose.

[0112] Alternatively, the aqueous suspension can be dried to obtain at least one functionalized calcium carbonate material (i.e., at least one functionalized material containing natural and / or synthetic calcium carbonate) in the form of granules or powder (i.e., dried or containing very little water that is not in a fluid form).

[0113] The at least one functionalized calcium carbonate-containing material (i.e., the at least one functionalized material containing natural and / or synthetic calcium carbonate) may have different particle shapes, such as the shape of a rose, a golf ball, and / or a brain.

[0114] Furthermore, in a preferred embodiment, the at least one functionalized calcium carbonate-containing material (i.e., the at least one functionalized material containing natural and / or synthetic calcium carbonate) has a molecular weight of 20.0 m, as measured using the nitrogen and BET methods according to ISO 9277 77. 2 / g – 450.0 m 2 / g, preferably 20.0 m 2 / g – 250.0 m 2 / g, more preferably 30.0 m 2 / g – 160.0 m 2 / g, or even more preferably 40.0 m 2 / g – 150.0 m 2 / g and the optimal value is 50.0 m 2 / g – 140.0 m 2Specific surface area per g. In the context of this invention, BET specific surface area is defined as the surface area of ​​a particle divided by the mass of the particle. As used herein, specific surface area is measured using BET isotherms via adsorption (ISO 9277:2010) and expressed in m³. 2 / g regulations.

[0115] According to one embodiment, the at least one functionalized calcium carbonate-containing material (i.e., the at least one functionalized natural and / or synthetic calcium carbonate-containing material) comprises a volumetric particle diameter d having a median particle diameter d of 1-50 µm, preferably 1-45 µm, more preferably 2-30 µm, even more preferably 3-15 µm, and most preferably 4-12 µm. 50 (Volume) of particles.

[0116] Additionally or alternatively, the at least one functionalized calcium carbonate-containing material (i.e., the at least one functionalized material containing natural and / or synthetic calcium carbonate) comprises a particle diameter d having a particle diameter d of less than or equal to 40.0 µm, preferably less than or equal to 30.0 µm, more preferably less than or equal to 25.0 µm, further more preferably less than or equal to 20.0 µm, and more preferably less than or equal to 19.0 µm. 98 (Volume) particles. Preferably, the at least one functionalized calcium carbonate-containing material (i.e., the at least one functionalized material containing natural and / or synthetic calcium carbonate) comprises particles with a particle diameter d in the range of 5.0-40 µm, preferably 6-30 µm, more preferably 7.0-25.0 µm, further more preferably 10.0-20.0 µm, and more preferably 11.0-19.0 µm. 98 (Volume) of particles.

[0117] value d x This represents a diameter such that x% of the particles have a diameter smaller than [a certain value]. d x The diameter. This means d 98 The value refers to a particle size such that 98% of all particles are smaller than that particle size. d 98 The value is also called "top cut". d x The value can be given as a percentage of volume or weight. d 50 The (weight) value is therefore the median particle size by weight, meaning that 50% of all particles weigh less than this particle size. d 50 The (volume) value is the median particle size, which is the particle size at which 50% of the volume of all particles is smaller than this particle size.

[0118] Evaluation of volume median particle size using a Malvern Mastersizer 2000 laser diffraction system d 50 Measured using a Malvern Mastersizer 2000 laser diffraction system. d 50 or d 98 The value indicates a diameter smaller than this value for particles representing 50% or 98% of their volume, respectively. The raw data obtained through measurement were analyzed using Mie theory, with a particle refractive index of 1.57 and an absorption index of 0.005.

[0119] The median weight particle size was measured by a sedimentation method, which is an analysis of sedimentation behavior in a gravitational field. A Sedigraph from Micromeritics Instrument Corporation was used. TM Measurements were performed at 5100 or 5120. The methods and instruments are known to those skilled in the art and are commonly used to determine the particle size of fillers and pigments. Measurements were performed in an aqueous solution of 0.1% by weight Na₄P₂O₇. The sample was dispersed using a high-speed stirrer and ultrasonication.

[0120] The methods and instruments are known to those skilled in the art and are commonly used to determine the particle size of fillers and pigments.

[0121] Specific pore volume was measured using a Micromeritics Autopore V 9620 mercury porosimeter via mercury intrusion porosimetry. This mercury porosimeter has a maximum applied mercury pressure of 414 MPa (60,000 psi) and is equivalent to a Laplace throat diameter of 0.004 μm (~nm). The equilibration time used for each pressure step was 20 seconds. The sample material was sealed in a 5 cm... 3 The powder transilluminator in the laboratory was used for analysis. The data were corrected for mercury compression, transilluminator expansion, and sample material compression using the software Pore-Comp (Gane, PAC, Kettle, JP, Matthews, GP and Ridgway, CJ, “Void Space Structure of Compressible Polymer Spheres and Consolidated Calcium Carbonate Paper-Coating Formulations”, Industrial and Engineering Chemistry Research, 35(5), 1996, pp. 1753-1764).

[0122] The total pore volume seen in the cumulative intrusion data can be divided into two regions, where intrusion data from 214 μm down to approximately 1–4 μm show coarse filling between any agglomerated structures in the sample, contributing strongly. Below these diameters is fine interparticle filling of the particles themselves. This region exhibits a bimodal distribution if they also have intraparticle pores, and the specific intraparticle pore volume is defined by obtaining the specific pore volume of pores finer than the peak inflection point (i.e., finer than the bimodal inflection point) caused by mercury intrusion. The sum of these three regions gives the total pore volume of the powder, but is strongly dependent on the compaction of the original sample / settling of the powder at the ends of the distributed coarse pores.

[0123] By obtaining the first derivative of the cumulative intrusion curve, the pore size distribution based on the equivalent Laplace diameter is revealed, which necessarily includes pore shielding. The differential curve clearly shows the coarse agglomeration pore structure region, the interparticle pore region, and the intraparticle pore region (if any). Knowing the range of intraparticle pore diameters, the remaining interparticle and interagglomerate pore volumes can be subtracted from the total pore volume to give the desired pore volume of the individual intrapores in terms of pore volume per unit mass (specific pore volume). Of course, the same subtraction principle also applies to separating any other pore size regions of interest.

[0124] Preferably, the at least one functionalized calcium carbonate-containing material (i.e., the at least one functionalized material containing natural and / or synthetic calcium carbonate) has a porosity of 0.15-1.35 cm⁻¹ calculated by mercury intrusion porosity determination. 3 / g, preferably 0.30-1.30 cm 3 / g, with the optimal value being 0.40-1.25 cm. 3 In-particle pore volume within the range of / g.

[0125] The pore diameter of the at least one functionalized calcium carbonate-containing material (i.e., the at least one functionalized material containing natural and / or synthetic calcium carbonate) determined by the mercury porosity determination method is preferably in the range of 4-500 nm, more preferably 20-80 nm, especially 30-70 nm, for example 50 nm.

[0126] The particle pore size of the surface-reacted calcium carbonate, as determined by the mercury porosity determination method, is preferably in the range of 0.004-1.6 µm, more preferably in the range of 0.005-1.3 µm, particularly preferably in the range of 0.006-1.15 µm, and most preferably in the range of 0.007-1.0 µm.

[0127] According to a preferred embodiment, the intraparticle and / or interparticle pores of the at least one functionalized calcium carbonate-containing material (i.e., the at least one functionalized natural and / or synthetic calcium carbonate-containing material) are hollow, and therefore the at least one functionalized calcium carbonate-containing material (i.e., the at least one functionalized natural and / or synthetic calcium carbonate-containing material) is unloaded. In other words, the at least one functionalized calcium carbonate-containing material (i.e., the at least one functionalized natural and / or synthetic calcium carbonate-containing material) is not used as a carrying agent.

[0128] The at least one functionalized calcium carbonate-containing material (i.e., the at least one functionalized material containing natural and / or synthetic calcium carbonate) may be in dust or powder form, and preferably in powder form.

[0129] A further requirement of the present invention is that the formulation comprises at least one hot melt extrusion polymer resin.

[0130] The statement "at least one" hot melt extruded polymer resin means that one or more types of hot melt extruded polymer resins may be present in the formulations of this invention.

[0131] Therefore, the at least one hot melt extruded polymer resin may be one type of hot melt extruded polymer resin. Alternatively, the at least one hot melt extruded polymer resin may be a mixture of two or more types of hot melt extruded polymer resins. For example, the at least one hot melt extruded polymer resin may be a mixture of two or three types of hot melt extruded polymer resins. Preferably, the at least one hot melt extruded polymer resin is one type of hot melt extruded polymer resin.

[0132] It should be understood that the at least one hot-melt extruded polymer resin according to the present invention is not limited to a specific resin material, as long as the polymer resin is hot-melt extruded, that is, the unprocessed polymer resin must be suitable for processing by hot-melt extrusion. Furthermore, preferably, the at least one hot-melt extruded polymer resin is suitable for the desired end use, for example, approved for human and / or animal consumption. For example, the at least one hot-melt extruded polymer resin is a resin approved for medical use.

[0133] In one embodiment, the at least one hot-melt extruded polymer resin is selected from polyethylene, polystyrene, polyvinyl chloride, polyamide 66 (nylon), polycaprolactam, polycaprolactone, acrylic polymers, acrylonitrile butadiene styrene, polybenzimidazole, polycarbonate, polyphenylene ether / polyphenylene sulfide, polypropylene, Teflon, polylactic acid, polylactic acid-based polymers, aliphatic polyesters such as polyhydroxybutyrate, poly-3-hydroxybutyrate (P3HB), polyhydroxyvalerate, polyhydroxybutyrate-polyhydroxyvalerate copolymer, poly(3-hydroxybutyrate-co-3-hydroxyvalerate), polygluconate, poly(di(hydroxybutyrate-co-3-hydroxyvalerate)), and poly(di(hydroxybutyrate-co-3-hydroxyvalerate)). Alkyl ketones and their mixtures.

[0134] In one embodiment, the formulation may be intended for consumption by animals or humans. Therefore, the hot melt extruded polymer resin may advantageously be selected from polymer resins known to be intended for such use.

[0135] In one embodiment, the at least one hot melt extruded polymer resin is therefore preferably a hot melt extruded biodegradable and / or biocompatible polymer resin.

[0136] The term "biodegradable" polymer resin refers to a polymer resin that can be broken down by bodily fluids, bacteria or other living organisms (such as the gastrointestinal tract) without producing harmful or toxic decomposition products.

[0137] As used in this application, the term "biocompatible" polymer resin means a polymer resin that does not cause or provoke a reaction in a human or animal, for example, no toxic or allergic reaction to the biocompatible polymer resin is observed.

[0138] In one embodiment, the at least one hot melt extruded polymer resin is a hot melt extruded biodegradable and biocompatible polymer resin. Alternatively, the at least one hot melt extruded polymer resin may be a hot melt extruded biodegradable or biocompatible polymer resin.

[0139] If the at least one hot-melt extruded polymer resin is a hot-melt extruded biodegradable and / or biocompatible polymer resin, then the hot-melt extruded polymer resin is preferably selected from polycaprolactone, polylactic acid, polylactic acid-based polymers, aliphatic polyesters such as polyhydroxybutyrate, poly-3-hydroxybutyrate (P3HB), polyhydroxyvalerate, polyhydroxybutyrate-polyhydroxyvalerate copolymer, poly(3-hydroxybutyrate-co-3-hydroxyvalerate), polygluconate, poly(dihydroxybutyrate-co-3-hydroxyvalerate), etc. Alkyl ketones and their mixtures.

[0140] Preferably, the at least one hot melt extruded polymer resin, more preferably the at least one hot melt extruded biodegradable and / or biocompatible polymer resin, is selected from polycaprolactone, polylactic acid, polylactic acid-based polymers, and mixtures thereof.

[0141] For example, the at least one hot melt extruded polymer resin, preferably the at least one hot melt extruded biodegradable and / or biocompatible polymer resin, is polycaprolactone.

[0142] At least one hot-melt extruded polymer resin can be prepared using well-known methods and is commercially available from various manufacturers. For example, medical-grade polycaprolactone can be obtained from Perstorp in Sweden via Capa TM 6506 was obtained.

[0143] In one embodiment of the invention, the at least one hot melt extruded polymer resin has a melting temperature T m The temperature is above 40°C, more preferably in the range of 40 to 200°C, and most preferably in the range of 40 to 170°C.

[0144] Furthermore, it should be understood that the at least one hot melt extrusion polymer resin may be selected from polymer resins having a wide range of melt flow rates. Typically, preferably, the at least one hot melt extrusion polymer resin has a melt flow rate (MFR) (160°C, 2.16 kg) measured according to ISO 1133 of 1.0 to 120.0 g / 10 min, more preferably 2.0 to 100.0 g / 10 min. For example, the melt flow rate (MFR) (160°C, 2.16 kg) of the at least one hot melt extrusion polymer resin measured according to ISO 1133 is 2.1 to 40.0 g / 10 min or 2.3 to 35.0 g / 10 min.

[0145] For example, the melt flow rate (MFR) (160°C, 2.16 kg) of the at least one hot melt extruded biodegradable and / or biocompatible polymer resin, preferably polycaprolactone, is measured according to ISO 1133 to be 2.0 to 100.0 g / 10 min, preferably 2.3 to 35.0 g / 10 min, and most preferably 2.3 to 15.0 g / 10 min.

[0146] There is no specific limitation on the molecular weight of the at least one hot-melt extruded polymer resin used in this invention. However, the weight-average molecular weight of the at least one hot-melt extruded polymer resin is preferably in the range of 20,000 to 5,000,000 g / mol, more preferably in the range of 20,000 to 1,000,000 g / mol, and most preferably in the range of 20,000 to 500,000 g / mol, for example in the range of 20,000 to 400,000 g / mol or in the range of 30,000 to 250,000 g / mol. If the weight-average molecular weight is less than the above range, the mechanical strength (tensile strength, impact strength) of the polymer composition is too low. Polymer resins with a weight-average molecular weight of up to 5,000,000 g / mol are described, for example, in EP 2 272 536, the disclosure of which is therefore incorporated herein by reference.

[0147] The weight-average molecular weight of the at least one hot-melt extruded biodegradable and / or biocompatible polymer resin, preferably polycaprolactone, is preferably in the range of 20,000 to 400,000 g / mol, more preferably in the range of 30,000 to 300,000 g / mol, and most preferably in the range of 30,000 to 250,000 g / mol, for example in the range of 40,000 to 100,000 g / mol.

[0148] Examples of polylactic acid-based resins include copolymers of lactic acid and blends of polylactic acid.

[0149] If the polylactic acid-based resin is a copolymer, then the polylactic acid-based resin may contain other copolymer components besides lactic acid. Examples of such other copolymer components include hydroxybutyric acid, 3-hydroxybutyric acid, hydroxyvalerate, 3-hydroxyvalerate, and citric acid.

[0150] The weight-average molecular weight of the polylactic acid-based resin is preferably in the range of 20,000 g / mol to 400,000 g / mol, more preferably in the range of 30,000 g / mol to 300,000 g / mol, and most preferably in the range of 30,000 g / mol to 250,000 g / mol. Additionally or alternatively, the melt flow rate (MFR) of the polylactic acid-based resin, measured according to ISO 1133, is 1.0 to 120.0 g / 10 min, preferably 2.0 to 100.0 g / 10 min, more preferably 2.3 to 35.0 g / 10 min, and most preferably 2.5 to 15.0 g / 10 min.

[0151] In one embodiment of the present invention, the at least one hot melt extruded polymer resin, preferably the at least one hot melt extruded biodegradable and / or biocompatible polymer resin, is an aliphatic polyester selected from polyhydroxybutyrate, poly-3-hydroxybutyrate (P3HB), polyhydroxyvalerate, polyhydroxybutyrate-polyhydroxyvalerate copolymer, poly(3-hydroxybutyrate-co-3-hydroxyvalerate) and mixtures thereof.

[0152] The weight-average molecular weight of the aliphatic polyester is preferably in the range of 20,000 to 400,000 g / mol, more preferably in the range of 30,000 to 300,000 g / mol, and most preferably in the range of 30,000 to 250,000 g / mol. Additionally or alternatively, the melt flow rate (MFR) of the aliphatic polyester, measured according to ISO 1133, is 1.0 to 120.0 g / 10 min, preferably 2.0 to 100.0 g / 10 min, more preferably 2.3 to 35.0 g / 10 min, and most preferably 2.5 to 15.0 g / 10 min.

[0153] In one embodiment of the present invention, the at least one hot-melt extruded polymer resin, preferably the at least one hot-melt extruded biodegradable and / or biocompatible polymer resin, is polyglucopyranoester, poly(di(glucopyranoester)) Alkyl ketones and their mixtures.

[0154] The polygluconate and / or poly(di) The weight-average molecular weight of the poly(alkyl ketone) is preferably in the range of 20,000 to 400,000 g / mol, more preferably in the range of 30,000 to 300,000 g / mol, and most preferably in the range of 30,000 to 250,000 g / mol. Additionally or alternatively, the polyglucopyranoester and / or poly(di(alkyl ketone)) The melt flow rate (MFR) of the alkane (210°C, 2.16 kg) is measured according to ISO 1133 as 1.0 to 120.0 g / 10 min, preferably 2.0 to 100.0 g / 10 min, more preferably 2.3 to 35.0 g / 10 min, and most preferably 2.5 to 15.0 g / 10 min.

[0155] This formulation comprises at least 5% by weight (i.e., 5-95% by weight) of the at least one hot-melt extruded polymer resin, preferably the at least one hot-melt extruded biodegradable and / or biocompatible polymer resin, based on the total weight of the formulation. Preferably, the formulation comprises 20-80% by weight of the at least one hot-melt extruded polymer resin, preferably the at least one hot-melt extruded biodegradable and / or biocompatible polymer resin, based on the total weight of the formulation. More preferably, the formulation comprises 30-70% by weight of the at least one hot-melt extruded polymer resin, preferably the at least one hot-melt extruded biodegradable and / or biocompatible polymer resin, based on the total weight of the formulation.

[0156] A further requirement of the present invention is that the dosage form comprises at least one functionalized calcium carbonate-containing material and at least one hot-melt extruded polymer resin, preferably at least one hot-melt extruded biodegradable and / or biocompatible polymer resin, such that the weight ratio (FCC / polymer) of the functionalized calcium carbonate-containing material to the hot-melt extruded polymer resin is in the range of 95:5 to 5:95. Preferably, the weight ratio (FCC / polymer) of the functionalized calcium carbonate-containing material to the hot-melt extruded polymer resin is in the range of 80:20 to 20:80, more preferably in the range of 70:30 to 30:70, and most preferably in the range of 60:40 to 40:60. For example, the weight ratio (FCC / polymer) of the functionalized calcium carbonate-containing material to the hot-melt extruded polymer resin is about 50:50.

[0157] A further requirement is that the at least one functionalized calcium carbonate-containing material is dispersed in the at least one hot-melt extruded polymer resin, preferably the at least one hot-melt extruded biodegradable and / or biocompatible polymer resin. For example, the at least one functionalized calcium carbonate-containing material is uniformly dispersed in the at least one hot-melt extruded polymer resin, preferably the at least one hot-melt extruded biodegradable and / or biocompatible polymer resin.

[0158] Therefore, it should be understood that this dosage form contains

[0159] a) At least one functionalized calcium carbonate-containing material (FCC), preferably at least one functionalized natural and / or synthetic calcium carbonate-containing material (FCC), which is natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more H3O. + The reaction product of the ion donor, wherein the carbon dioxide passes through H3O + Ion donor treatment is formed in situ and / or supplied by an external source.

[0160] b) At least one hot-melt extruded polymer resin, preferably at least one hot-melt extruded biodegradable and / or biocompatible polymer resin.

[0161] The at least one functionalized calcium carbonate-containing material is dispersed in the at least one hot melt extruded polymer resin, and the weight ratio (FCC / polymer) of the functionalized calcium carbonate-containing material to the hot melt extruded polymer resin is in the range of 95:5 to 5:95.

[0162] In one embodiment, the dosage form comprises the following substances:

[0163] a) At least one functionalized calcium carbonate-containing material (FCC), preferably at least one functionalized natural and / or synthetic calcium carbonate-containing material (FCC), which is natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more H3O. +The reaction product of the ion donor, wherein the carbon dioxide passes through H3O + Ion donor treatment is formed in situ and / or supplied by an external source, and

[0164] b) At least one hot-melt extruded polymer resin, preferably at least one hot-melt extruded biodegradable and / or biocompatible polymer resin.

[0165] The at least one functionalized calcium carbonate-containing material is dispersed in the at least one hot melt extruded polymer resin, and the weight ratio (FCC / polymer) of the functionalized calcium carbonate-containing material to the hot melt extruded polymer resin is in the range of 95:5 to 5:95.

[0166] Preferably, the dosage form further comprises at least one active reagent and / or an inactive reagent.

[0167] Therefore, in one embodiment, the dosage form comprises, preferably, the following substances:

[0168] a) At least one functionalized calcium carbonate-containing material (FCC), preferably at least one functionalized natural and / or synthetic calcium carbonate-containing material (FCC), which is natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more H3O. + The reaction product of the ion donor, wherein the carbon dioxide passes through H3O + Ion donor treatment is formed in situ and / or supplied by an external source.

[0169] b) at least one hot-melt extruded polymer resin, preferably at least one hot-melt extruded biodegradable and / or biocompatible polymer resin, and

[0170] c) At least one active reagent and / or an inactive reagent,

[0171] The at least one functionalized calcium carbonate-containing material is dispersed in the at least one hot melt extruded polymer resin, and the weight ratio (FCC / polymer) of the functionalized calcium carbonate-containing material to the hot melt extruded polymer resin is in the range of 95:5 to 5:95.

[0172] The statement "at least one" active reagent and / or inactive reagent means that the dosage form contains one or more active reagents and / or inactive reagents.

[0173] According to one embodiment of the invention, the dosage form contains only one active or inactive reagent. According to another embodiment of the invention, the dosage form contains a mixture of two or more active and / or inactive reagents. For example, the dosage form contains a mixture of two or three active and / or inactive reagents.

[0174] Preferably, the dosage form contains only one active reagent or an inactive reagent.

[0175] The active and / or inactive reagents are preferably selected from pharmaceutical active reagents, active or inactive prodrugs, nutrients, food additives, cosmetic additives and mixtures thereof.

[0176] It should be noted that the at least one active reagent and / or inactive reagent may be any such compound known to those skilled in the art.

[0177] The at least one pharmaceutically active agent, active or inactive prodrug is preferably selected from pharmaceutically active agents or pharmaceutically active or inactive prodrugs of synthetic, semi-synthetic, natural, or combined sources.

[0178] Therefore, the active pharmaceutical ingredient (API) encompasses APIs of synthetic, semi-synthetic, natural, and combinations thereof. Furthermore, the active pharmaceutical ingredient (API) also includes prodrugs of synthetic, semi-synthetic, natural, and combinations thereof, which will be converted into the corresponding API in a subsequent stage. Additionally, the inactive API also includes inactive prodrugs of synthetic, semi-synthetic, natural, and combinations thereof, which will be activated into the corresponding API in a subsequent stage.

[0179] The conversion or activation of such active or inactive prodrugs is known to those skilled in the art and is commonly used in, for example, conversion and activation in the gastric and / or gastrointestinal pathways, such as via pH-mediated or enzyme-mediated activation.

[0180] To the best of the knowledge of those skilled in the art, the mentioned transformation and activation methods are illustrative in nature and are not intended to be limiting.

[0181] It should be noted that the at least one active pharmaceutical agent, or its active or inactive prodrug, may be any such compound known to those skilled in the art.

[0182] When administered to humans and / or animals, a pharmaceutically active agent, and its active or inactive prodrug, therefore includes any compound that provides preventative and / or therapeutic properties. Examples include, but are not limited to, pharmaceutically active agents, therapeutically active agents, veterinary active agents, nutrients and growth regulators, and their corresponding active or inactive prodrugs.

[0183] For example, the at least one active and / or inactive reagent, preferably the at least one pharmaceutically active reagent, or its active or inactive prodrug, is an anti-tartar agent. Anti-tartar agents suitable for this document include phosphates. Phosphates include pyrophosphates, polyphosphates, polyphosphonates, and mixtures thereof. Pyrophosphates are among the most well-known phosphates used in dental care products. Pyrophosphate ions delivered to the teeth originate from pyrophosphates. Pyrophosphates suitable for this formulation include dialkali metal pyrophosphates, tetraalkali metal pyrophosphates, and mixtures thereof. Preferred are non-hydrated and hydrated forms of disodium dihydrogen pyrophosphate (Na₂H₂P₂O₇), tetrasodium pyrophosphate (Na₄P₂O₇), and tetrapotassium pyrophosphate (K₄P₂O₇). Anti-tartar phosphates include potassium pyrophosphate and sodium pyrophosphate; sodium tripolyphosphate; bisphosphonates, such as ethane-1-hydroxy-1,1-bisphosphonate; 1-azacycloheptane-1,1-bisphosphonate; and linear alkyl bisphosphonates; linear carboxylic acids and sodium citrate and zinc.

[0184] Alternatives to or in combination with the aforementioned pyrophosphates include materials such as synthetic anionic polymers, including copolymers of polyacrylates and maleic anhydride or acids and methyl vinyl ethers, such as Gantrez, as described, for example, in U.S. Patent No. 4,627,977 to Gaffar et al., which describes such reagents and is incorporated herein by reference in its entirety, and, for example, polyaminopropane sulfonic acid (AMPS), zinc citrate trihydrate, polyphosphates such as tripolyphosphate and hexametaphosphate, bisphosphonates such as EHDP and AMP, polypeptides such as polyaspartic acid and polyglutamic acid, and mixtures thereof.

[0185] Antimicrobial agents can also be used as at least one active and / or inactive agent. These agents may include, but are not limited to, 5-chloro-2-(2,4-dichlorophenoxy)-phenol, commonly known as triclosan, chiorhexidine, Alexidine, hexetidine, sanguinarine, benzalkonium chloride, salicylamide, domiphenbromide, and hexadecylpyridine chloride. (CPC), tetradecylpyridine chloride (TPC); N-Tetradecyl-4-ethylpyridine chloride (TDEPC); octenidine; delmopinol, octapinol and other piperidinyl derivatives; nicotinic acid preparations; zinc / stannous ion reagents; antibiotics such as AUGMENTIN, amoxycillin, tetracycline, doxycyline, minocycline and metronidazole; and analogues, derivatives and salts of the above antimicrobial agents, and mixtures thereof.

[0186] Anti-inflammatory agents may also be used as the at least one active agent and / or inactive agent, preferably the at least one pharmaceutically active agent, or its active or inactive prodrug. Such agents may include, but are not limited to, nonsteroidal anti-inflammatory agents or NSAIDs, such as propionic acid derivatives; acetic acid derivatives; fenamic acid derivatives; biphenyl carboxylic acid derivatives; and oxicams. All of these NSAIDs are fully described in U.S. Patent No. 4,985,459 to Sunshine et al., the entire description of which is incorporated herein by reference. Examples of available NSAIDs include acetylsalicylic acid, ibuprofen, naproxen, and benzyl alcohol. Benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, microprofen, sulfur Tioxaprofen, suprafen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, and mixtures thereof.

[0187] Also available are steroidal anti-inflammatory drugs such as hydrocortisone, and COX-2 inhibitors such as meloxicam, celecoxib, rofecoxib, valdecoxib, etoricoxib, or mixtures thereof. Mixtures of any of the above anti-inflammatory agents may be used.

[0188] Other materials that can be used as the at least one active reagent and / or inactive reagent, preferably the at least one pharmaceutically active reagent, or its active or inactive prodrug, include commonly known oral and pharyngeal products. These products include, but are not limited to, upper respiratory tract reagents such as phenylephrine, diphenhydramine, dextromethorphan, bromhexine, and chiorpheniramine; gastrointestinal reagents such as famotidine, loperamide, and polydimethylsiloxane; antifungal agents such as miconazole nitrate; and antibiotics and analgesics such as ketoprofen and fluribuprofen.

[0189] The at least one active and / or inactive reagent may also be selected from vitamin E (i.e., tocopherol), vitamin C (i.e., ascorbic acid and its salts), sodium metabisulfite, butylated hydroxytoluene, butylated hydroxyanisole; and preservatives, including parabens, benzalkonium chloride, chlorobutanol, benzyl alcohol, β-phenylethanol, and hexadecylpyridine chloride. Citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid and sorbic acid and their salts; as well as chelating agents such as EDTA; and gallic esters such as propyl gallate.

[0190] The at least one active and / or inactive reagent may also be selected from vitamins such as vitamins B, C and E; minerals such as fluorides, especially sodium fluoride, sodium monofluorophosphate and stannous fluoride; deodorizing agents such as zinc and cyclodextrin; propellants such as 1,1,2,2-tetrafluoroethane (HFC-134a) (optionally liquefied) and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227) (optionally liquefied).

[0191] The at least one active reagent and / or inactive reagent, preferably the at least one pharmaceutically active reagent, and its active or inactive prodrug may also be selected from, such as magnesium aluminum, sildenafil, lidocaine, and benzalkonium chloride. Chloride, caffeine, phenylephrine, amfepramone, orlistat, acetaminophen, aspirin, aluminum glycate, aluminum glycate in combination with magnesium oxide, aluminum oxide hydrate in combination with magnesium oxide, calcium carbonate in combination with magnesium hydroxide, calcium carbonate, sodium aluminum dihydroxycarbonate, magnesium oxide, glitazones, metformin such as metformin hydrochloride, chlorpromazine, dimenhydrinate, domperidone, meclozine, metoclopramide, odansetron, prednisolone, promethazine cetirizine, cinnarizine, clemastine, cyclizine, desloratadine, dexchlorpheniramine, dimenhydrinate, ebastine, fexofenadine, ibuprofen, levolevoproricin, loratadine, meclozine, mizolastine, promethazine, miconazole, vitamin B12, folic acid, iron compounds, vitamin C, chlorhexidine diacetate. diacetate, fluoride, decapeptide KSL, aluminum fluoride, aminochelated calcium, ammonium fluoride, ammonium fluorosilicate, ammonium monofluorophosphate, calcium fluoride, calcium gluconate, calcium glycerophosphate, calcium lactate, calcium monofluorophosphate, calcium carbonate, urea, hexadecylpyridine chloride Chlorhexidine, chlorhexidine digluconate, chlorhexidine chloride, chlorhexidine diacetate, CPP caseine phospho peptide, hexetedine, octadecentyl ammonium fluoride Ammonium fluoride, potassium fluorosilicate, potassium chloride, potassium monofluorophosphate, sodium bicarbonate, sodium carbonate, sodium fluoride, sodium fluorosilicate, sodium monofluorophosphate, sodium tripolyphosphate, stannous fluoride, stearoyl triethylpropylene diamine dihydrofluoride, strontium chloride, tetrapotassium pyrophosphate, tetrasodium pyrophosphate, tripotassium orthophosphate, trisodium orthophosphate, alginate, aluminum hydroxide, sodium bicarbonate, sildenafil, tadalafil, vardenafil, yohimbine, cimetidine, nizatidine, ranitidine e), acetylsalicylic acid, clopidogrel, acetylcysteine, bromhexine, codeine, dextromethorphan, diphenhydramine, noscapine, phenylpropanolamine, vitamin D, simvastatin, bisacodyl, lactitol, lactulose, magnesium oxide, sodium picosulfate, senna Glycosides, benzocaine, lidocaine, tetracaine, amotriptan, eletriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan, calcium, chromium, copper, iodine, iron, magnesium, manganese, molybdenum, phosphorus, selenium, zinc, chloramine, hydroperoxide, metronidazole, triamcinolone acetonide, benzyl chloride, cetyl pyridinium chloride, chlorhexidine, fluoride, lidocaine, amphotericin B, miconazole.Nystatin, fish oil, ginkgo biloba, ginseng, ginger, purple coneflower, saw palmetto, cetirizine, levocetirizine, loratadine, diclofenac, flurbiprofen, glucosamine, hyaluronic acid, decapeptide KSL-W, decapeptide KSL, resveratrol, misoprostol, bupropion, ondansetron hydrochloride HCl), esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, bacteria, etc., loperamide, simethicone, acetylsalicylic acid, etc., sucralfate, vitamin A, vitamin B1, vitamin B12, vitamin B2, vitamin B6, biotin, vitamin C, vitamin D, vitamin E, folinic acid, vitamin K, niacin, Q10, clotrimazole, fluconazole, itraconazole, ketoconazole, terbinafine, allopurinol, probenecid, atorvastatin, fluvastatin, lovastatin, niacin. acid, pravastatin, rosuvastatin, simvastatin, pirocarpine, naproxen, alendronate, etidronate, raloxifene, risedronate, benzodiazepines, disulfiram, naltrexone, buprenorphine, codeine, dextropropoxyphene, fentanyl.Hydromorphone, ketobemidone, ketoprofen, methadone, morphine, naproxen, nicomorphine, oxycodone, pethidine, tramadol, amoxicillin, ampicillin, azithromycin, ciprofloxacin, clarithromycin arithromycin, doxycycline, erythromycin, fusidic acid, lymecycline, metronidazole, moxifloxacin, ofloxacin, oxytetracycline, phenoxymethylpenicillin, rifamycins, roxithromycin, sulfathiazole thizole, tetracycline, trimethoprim, vancomycin, acarbose, glibenclamide, gliclazide, glimepiride, glipizide, insulin, repaglinide, tolbutamide, oseltamivir, acyclovir, famciclovir Clavivir, penciclovir, valganciclovir, amlopidine, diltiazem, felodipine, nifedipine, verapamil, finasteride, minoxidil, buphrenorphin, clonidine, methadone, naltrexone, calcium antagonists, clonidine.Ergotamine, β-blockers, aceclofenac, celecoxib, dexiprofen, etodolac, indometacin, ketoprofen, ketorolac, lornoxicam, meloxicam, nabumetone, oiroxicam, parecoxib, phenylbutazone, piroxicam, tiaprofenic acid, tolfenamic acid acid), aripiprazole, chlorpromazine, chlorprothixene, clozapine, flupentixol, fluphenazine, haloperidol, lithium carbonate, lithium citrate, melperone, penfluridol, periciazine, perphenazine, pimozide, pipamperone, prochlorperazine, risperidone, thioridizine, fluconazole, itraconazole Ketoconazole, voriconazole, benzodiazepines, hydroxine, meprobamate, phenothiazine, aluminum aminoacetate, esomeprazole, famotidine, magnesium oxide, nizatide, omeprazole, pantoprazole, fluconazole, itraconazole, ketoconazole, metronidazole, amphetamine, atenolol.Bisoprolol fumarate, metoprolol, metoprolol, pindolol, propranolol, auranofen, and bendazac.

[0192] Other examples of available at least one active and / or inactive reagent, preferably the at least one pharmaceutically active reagent, or its active or inactive prodrug may include reagents selected from the following therapeutic agents: analgesics, anesthetics, antipyretics, antihistamines, antiarrhythmics, appetite suppressants, antifungals, anti-inflammatory agents, bronchodilators, cardiovascular drugs, coronary artery dilators, cerebral dilators, peripheral vasodilators, anti-infectives, psychotropic drugs, antimanic agents, antihistamines, laxatives, decongestants, gastrointestinal sedatives, sexual dysfunction agents, disinfectants, antidiarrheal agents, antianginal agents, vasodilators, antihypertensive agents, vasoconstrictors, migraine treatment agents, antibiotics, sedatives, antipsychotics, antitumor drugs, anticoagulants, antithrombotic agents, hypnotics, sedatives, antiemetics, antinausea agents, anti- Convulsants, neuromuscular agents, hyperglycemic and hypoglycemic agents, thyroid and antithyroid agents, diuretics, antispasmodics, uterine relaxants, antiobesity agents, anorexia nervosa, antispasmodics, anabolic agents, erythropoietin, antiasthmatics, expectorants, cough suppressants, mucolytics, antiuremic agents, dental excipients, breath fresheners, antacids, antidiuretics, antiflatulents, beta-blockers, teeth whitening agents, enzymes, coenzymes, proteins, energy enhancers, fiber, probiotics, prebiotics, antimicrobial agents, NSAIDs, cough suppressants, alkaloid decongestants, antihistamines, expectorants, antidiarrheals, hydrogen ion antagonists, proton pump inhibitors, general nonselective CNS inhibitors, selective CNS modifiers, anti-Parkinson's drugs, narcotic analgesics, analgesics, psychopharmacological drugs, and sexual dysfunction agents.

[0193] Examples of at least one active and / or inactive reagent that may be used may also include: casein glycosyl macropeptide (CGMP), triclosan, hexadecylpyridine chloride. Domiphen bromide, quaternary ammonium salts, zinc components, sanguinarine, fluoride, Alexidine, Octonidine, EDTA, aspirin, acetaminophen, ibuprofen, ketoprofen, diflunisal, fenoprofen calcium, naproxen, tometidine sodium, indomethacin, benzonatate, caramiphen edisylate, menthol, dextromethorphan hydrobromide, theobromine hydrochloride, chlorphendianol hydrochloride, phenylephrine, phenylpropanolamine, brompheniramine maleate, chlorpheniramine maleate, carbinoxamine maleate, cleemastine fumarate fumarate, Dexchlorpheniramine maleate, Dephenhydramine hydrochloride, Diphenylamine hydrochloride, Azatadine maleate, Diphenhydramine citrate, Doxylamine succinate, Promethazine hydrochloride, Pyrilamine maleate, Tripellenamine citrate, Triprolidine hydrochloride, Acrivastine, Loratadine, Brompheniramine, Dexbrompheniamine, Guaifenesin, Ipecac, Potassium iodide, Terpin hydrate), loperamide, famotidine, ranitidine, omeprazole, lansoprazole, aliphatic alcohol, barbiturate, caffeine, ctrychnine, picrotoxin, pentylenetetrazol, phenylhydantoin,Phenobarbital, Primidone, Carbamazapine, Ethosuccinylamine, Methosuccinylamine, Phensuximide, Trimethadione, Diazepam, Benzodiazepine, Phenylacetylurea, Chlorbutyrylurea, Acetazolamide, Sulthiame, Bromide, Levodopa, Amantadine, Morphine, Hydromorphone, Metopon, Oxymorphone, Levophanol, Codeine, Hydrocodone ydrocodone, oxycodone, nalorphine, naloxone, naltrexone, salicylates, phenylbutazone, indomethacin, phenacetin, chlorpromazine, levomethimeprazine, haloperidol, clozapine, reserpine, imipramine, tranylcypromine, phenelzine, lithium, sildenafil citrate, tadalafil, and vardenafil CL.

[0194] Examples of at least one available active and / or inactive reagent may include active ingredients selected from: ACE inhibitors, antianginal drugs, antiarrhythmic agents, antiasthmatic agents, anticholesterol agents, analgesics, anesthetics, anticonvulsants, antidepressants, antidiabetic agents, antidiabetic agents, antidiabetic agents, antidiabetic agents, antidiabetic agents, antidiabetic agents, antitoxins, antihistamines, antihypertensive drugs, anti-inflammatory agents, antilipidemic agents, anti-irritant agents, antinausea agents, anti-stroke agents, antithyroid agents, antitumor drugs, antiviral agents, acne drugs, alkaloids, amino acid preparations, antitussives, antidiuretics. Toxic agents, antiviral drugs, anabolic agents, systemic and nonsystemic anti-infective agents, antitumor drugs, anti-Parkinson's agents, antirheumatic agents, appetite stimulants, biological response modifiers, blood modifiers, bone metabolism modifiers, cardiovascular agents, central nervous system stimulants, cholinesterase inhibitors, contraceptives, alkaloid decongestants, dietary supplements, dopamine receptor agonists, endometriosis treatments, enzymes, erectile dysfunction therapies (e.g., sildenafil citrate currently sold as Viagra™). Citrates, fertility agents, gastrointestinal medications, homeopathic remedies, hormones, treatments for hypercalcemia and hypocalcemia, immunomodulators, immunosuppressants, migraine preparations, motion sickness treatments, muscle relaxants, obesity management agents, osteoporosis preparations, oxytocin, parasympathetic blockers, parasympathetic drugs, prostaglandins, psychotropic agents, respiratory agents, sedatives, smoking cessation aids (e.g., bromoergotamine), sympathetic agents, tremor preparations, urinary tract medications, vasodilators, laxatives, antacids, ion exchange resins, antipyretics, appetite suppressants, expectorants. Anti-anxiety agents, anti-ulcer agents, anti-inflammatory substances, coronary artery dilators, cerebral dilators, peripheral vasodilators, psychotropic drugs, antihypertensive drugs, vasoconstrictors, migraine treatments, antibiotics, sedatives, antipsychotics, antitumor drugs, anticoagulants, antithrombotic drugs, hypnotics, antiemetics, antinausea drugs, anticonvulsants, neuromuscular drugs, hyperglycemic and hypoglycemic agents, thyroid and antithyroid preparations, diuretics, anticonvulsants, uterine relaxants, antiobesity drugs, erythropoietin-stimulating agents, antiasthmatics, antitussives, mucolytics, DNA and genetic modification drugs, and combinations thereof.

[0195] Examples of at least one available active and / or inactive reagent intended for use in this dosage form may include antacids, H2-antagonists, and analgesics. For example, antacids may be prepared using calcium carbonate alone or in combination with magnesium hydroxide and / or aluminum hydroxide. Furthermore, antacids may be used in combination with H2-antagonists.

[0196] Analgesics include ibuprofen, aspirin, acetaminophen, and combinations thereof that may optionally include caffeine.

[0197] Examples of other available active and / or inactive agents used in the implementation scheme may include antidiarrheal agents such as Immodium™ AD, antihistamines, cough suppressants, alkali decongestants, vitamins, and breath fresheners. It is also expected that the following medications will be used in this article: anxiolytics such as Xanax™; antipsychotics such as Clozalaril™ and Haldol™; nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen sodium, Voltaren™ and Lodine™; antihistamines such as Claritin™, Hismanal™, Relaxon™ and Tavist™; antiemetics such as Kytril™ and Cemesamet™; bronchodilators such as Bentolin™ and Proventil™; antidepressants such as Prozac™, Zoloft™ and Paxil™; antimigraines such as Imigra™; ACE inhibitors such as Vasotec™, Capoten™ and Zestril™; anti-Alzheimer's drugs such as Nicergoline™; and CaH antagonists such as Procardia™, Adalat™ and Calan™.

[0198] Common H2-antagonists intended for use in this invention include cimetidine, ranitidine hydrochloride, famotidine, nizatidien, ebrotidine, mifentidine, roxatidine, pisatidine, and aceroxatidine.

[0199] Active anti-acid ingredients may include, but are not limited to, the following substances: aluminum hydroxide, aluminum dihydroxyacetate, glycine, aluminum phosphate, sodium dihydroxyacetate, bicarbonate, bismuth aluminate, bismuth carbonate, basic bismuth carbonate, basic bismuth gallate, bismuth subnitrate, bismuth subsilysilate, calcium phosphate, citrate ions (acid or salt), glycine, hydrated magnesium aluminum sulfate, magnesium plus aluminum, magnesium aluminum silicate, magnesium carbonate, magnesium glycine, magnesium hydroxide, magnesium oxide, magnesium trisilicate, milk solids, di- or dihydrogen calcium aluminum phosphate, tricalcium phosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate, magnesium aluminum silicate, tartaric acid and salts.

[0200] Various nutrients may also be used as at least one active and / or inactive agent, including virtually any vitamin or mineral. For example, vitamins A, C, D, E, K, B6, B12, thiamine, riboflavin, biotin, folic acid, niacin, pantothenic acid, sodium, potassium, calcium, magnesium, phosphorus, sulfur, chlorine, iron, copper, iodine, zinc, selenium, manganese, choline, chromium, molybdenum, fluorine, cobalt, and combinations thereof may be used. Examples of nutrients that may be used as at least one active and / or inactive agent are illustrated in U.S. Patent Application Publications Nos. 2003 / 0157213A1, 2003 / 0206993, and 2003 / 0099741A1, the entire contents of which are incorporated herein by reference for all purposes. Various herbal preparations may also be used as at least one active and / or inactive agent, such as those possessing various medicinal or dietary supplement properties. Herbs are typically aromatic plants or plant parts and their extracts that are medicinal or flavoring. Suitable herbs can be used alone or in various mixtures. Commonly used herbs include echinacea, goldensedge, calendula, rosemary, thyme, kava, aloe, blood root, grapefruit seed extract, black cohosh, ginseng, guarana, cranberry, ginkgo biloba, St. John's Wort, evening primrose oil, yohimbe bark, green tea, ephedra, maca, raspberry, lutein, and combinations thereof.

[0201] In some embodiments, the at least one active and / or inactive reagent may include, but is not limited to, L-carnitine, choline, coenzyme Q10, α-lipoic acid, ω-3 fatty acids, pepsin, phytase, trypsin, lipase, protease, cellulase, and combinations thereof.

[0202] The at least one active and / or inactive reagent may also include ascorbic acid, citric acid, rosemary oil, vitamin A, vitamin E, vitamin E phosphate, tocopherol, di-α-tocopherol phosphate, tocotrienol, α-lipoic acid, dihydrolipoic acid, lutein, β-cryptoxanthin, lycopene, lutein, zeaxanthin, astaxanthin, β-carotene, carotene, mixed carotenoids, polyphenols, flavonoids, and combinations thereof.

[0203] In some embodiments, the at least one active and / or inactive reagent may be selected from phytochemicals, such as carotenoids, chlorophyll, chlorophyll, fiber, flavonoids, anthocyanins, cyaniding, taraxerin, mallow pigment, geranium pigment, peony pigment, petunia pigment, flavanols, catechins, epicatechin, epigallocatechin, epigallocatechin gallate, theaflavins, thearubigins, proanthocyanidins, flavonols, quercetin, calciferol, myricetin, isorhamnetin, flavononeshesperetin, naringenin, sagelin, hesperidin, flavonoids, apigenin, luteolin, lignans, phytoestrogens, resveratrol, isoflavones, daidzein, genistein, soybean isoflavones, and combinations thereof.

[0204] In some embodiments, the at least one active and / or inactive agent may be selected from analgesics / anesthetics, such as menthol, phenol, hexylresorcinol, benzocaine, dapoxetine hydrochloride, benzyl alcohol, salicylol, and combinations thereof. In some embodiments, the at least one active and / or inactive agent may be selected from a soothing agent, such as slippery elm bark, pectin, gelatin, and combinations thereof. In some embodiments, the at least one active and / or inactive agent may be selected from an antiseptic component, such as hexadecylpyridine chloride. Domiphen bromide, dequalinium chloride, and combinations thereof.

[0205] In some embodiments, the at least one active and / or inactive reagent may be selected from antitussive ingredients, such as chlorpheniramine hydrochloride, codeine, codeine phosphate, codeine sulfate, dextromethorphan, dextromethorphan hydrobromide, diphenhydramine citrate, and diphenhydramine hydrochloride, and combinations thereof.

[0206] In some embodiments, the at least one active and / or inactive agent may be selected from throat soothing agents, such as honey, propolis, aloe vera, glycerol, menthol, and combinations thereof. In other embodiments, the at least one active and / or inactive agent may be selected from cough suppressants. Such cough suppressants may be divided into two groups: those that alter the texture or production of sputum, such as mucolytics and expectorants; and those that suppress the cough reflex, such as codeine (a narcotic cough suppressant), antihistamines, dextromethorphan, and isoproterenol (non-narcotic cough suppressants). In some embodiments, components from any one or both groups may be included.

[0207] In other embodiments, the at least one active and / or inactive agent may be selected from the following antitussives: codeine, dextromethorphan, dextromethorphan, diphenhydramine, hydrocodone, noscapine, oxycodone, pentoxyverine, and combinations thereof. In some embodiments, the at least one active and / or inactive agent may be selected from antihistamines, such as acetaminophen, atazatidine, bromophenamine, chlorpheniramine, etc. The following are listed: fenamistatin, clomastine, cyproheptadine, dextrobromin, dimenhydrinate, diphenhydramine, phenpipramine, acetyl, meclizine, indoleamine, bentoxamin, promirtine, pyrazinamide, tripinamine, triprolidine, and combinations thereof. In some embodiments, the at least one active agent and / or inactive agent may be selected from non-sedating antihistamines, such as astemizole, cetirizine, ebastine, fexofenadine, loratadine, terfenadine, and combinations thereof.

[0208] In some embodiments, the at least one active and / or inactive agent may be selected from expectorants such as ammonium chloride, guaifenesin, ipecac fluid extract, potassium iodide, and combinations thereof. In some embodiments, the at least one active and / or inactive agent may be selected from mucolytics such as acetylcysteine, ambroxol, bromhexine, and combinations thereof. In some embodiments, the at least one active and / or inactive agent may be selected from analgesics, antipyretics, and anti-inflammatory agents, such as acetaminophen, aspirin, diclofenac, diflunisal, etodoxacin, fenprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, nabumetone, naproxen, piroxicam, caffeine, and mixtures thereof. In some embodiments, the at least one active and / or inactive agent may be selected from local anesthetics such as lidocaine, benzocaine, phenol, dyclonine, benzonatate, and mixtures thereof. In some embodiments, the at least one active and / or inactive agent may be selected from nasal decongestants and ingredients that provide a nasal cleansing sensation. In some embodiments, nasal decongestants may include, for example, phenylpropanolamine, phenylephrine, oxymetazoline, and combinations thereof. In some embodiments, the at least one active and / or inactive agent may be selected from ingredients that provide a nasal cleansing sensation such as menthol, camphor, borneol, eucalyptus oil, peppermint oil, methyl salicylate, borneol acetate, lavender oil, wasabi extract, horseradish extract, and combinations thereof. In some embodiments, the nasal cleansing sensation may be provided by scented essential oils, extracts from wood, gums, flowers, and other botanicals, resins, animal secretions, and synthetic aromatic materials.

[0209] For example, the at least one active reagent and / or inactive reagent is metformin hydrochloride.

[0210] It should be understood that the at least one active reagent and / or inactive reagent is preferably loaded onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC). In other words, the at least one functionalized calcium carbonate-containing material preferably contains the at least one active reagent and / or inactive reagent on its accessible surface area. The term "accessible" surface area of ​​the material refers to the portion of the material surface that comes into contact with the at least one active reagent and / or inactive reagent during loading or mixing.

[0211] Additionally or alternatively, the at least one active and / or inactive reagent is preferably dispersed in at least one hot-melt extrusion polymer resin comprising the at least one functionalized calcium carbonate-containing material (FCC). That is, the at least one active and / or inactive reagent is dispersed in the at least one hot-melt extrusion polymer resin independently of the at least one functionalized calcium carbonate-containing material. For example, the at least one active and / or inactive reagent is preferably uniformly dispersed in at least one hot-melt extrusion polymer resin comprising the at least one functionalized calcium carbonate-containing material (FCC).

[0212] In one embodiment, the at least one active reagent and / or inactive reagent is loaded onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC), and the at least one active reagent and / or inactive reagent is dispersed in at least one hot melt extruded polymer resin comprising the at least one functionalized calcium carbonate-containing material (FCC). It should be understood that the at least one active reagent and / or inactive reagent loaded onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC) and dispersed in the at least one hot melt extruded polymer resin may be the same or different.

[0213] Additionally or alternatively, the at least one active agent and / or inactive agent is in the form of a core, which is at least partially covered by at least one hot-melt extruded polymer resin comprising the at least one functionalized calcium carbonate (FCC) material. In this embodiment, the at least one active agent and / or inactive agent is preferably in the form of a compacted tablet. It should be understood that this configuration is particularly preferred if cup-sized tablets are being prepared.

[0214] In one embodiment, the at least one active and / or inactive reagent is in the form of a core, which is at least partially covered by at least one hot-melt extruded polymer resin comprising the at least one functionalized calcium carbonate-containing material (FCC), and the at least one active and / or inactive reagent is loaded onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC). It should be understood that the at least one active and / or inactive reagent loaded onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC) and in the form of a core may be the same or different.

[0215] Additionally or alternatively, the at least one active and / or inactive reagent is in the form of a layer that at least partially covers a core made of the at least one hot-melt extruded polymer resin comprising the at least one functionalized calcium carbonate material (FCC). In this embodiment, the core is preferably a compacted tablet.

[0216] In one embodiment, the at least one active and / or inactive reagent is in the form of a layer that at least partially covers a core made of at least one hot-melt extruded polymer resin comprising the at least one functionalized calcium carbonate-containing material (FCC), and the at least one active and / or inactive reagent is loaded onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC). It should be understood that the at least one active and / or inactive reagent, loaded onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC) and in the form of a layer that at least partially covers the core, may be the same or different.

[0217] Alternatively or additionally, the at least one active reagent and / or inactive reagent is in the form of a layered structure of at least two layers, wherein at least one layer is made of the at least one hot melt extruded polymer resin comprising the at least one functionalized calcium carbonate material (FCC).

[0218] In one embodiment, the at least one active reagent and / or inactive reagent is in the form of a layered structure of at least two layers, wherein at least one layer is made of the at least one hot-melt extruded polymer resin comprising the at least one functionalized calcium carbonate-containing material (FCC), and the at least one active reagent and / or inactive reagent is loaded onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC). It should be understood that the at least one active reagent and / or inactive reagent loaded onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC) and in the form of a layered structure may be the same or different.

[0219] Preferably, the dosage form further comprises at least one excipient.

[0220] Therefore, in one embodiment, the dosage form comprises, preferably, the following substances:

[0221] a) At least one functionalized calcium carbonate-containing material (FCC), preferably at least one functionalized natural and / or synthetic calcium carbonate-containing material (FCC), which is natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more H3O. +The reaction product of the ion donor, wherein the carbon dioxide passes through H3O + Ion donor treatment is formed in situ and / or supplied by an external source.

[0222] b) at least one hot-melt extruded polymer resin, preferably at least one hot-melt extruded biodegradable and / or biocompatible polymer resin, and

[0223] c) At least one excipient,

[0224] The at least one functionalized calcium carbonate-containing material is dispersed in the at least one hot melt extruded polymer resin, and the weight ratio (FCC / polymer) of the functionalized calcium carbonate-containing material to the hot melt extruded polymer resin is in the range of 95:5 to 5:95.

[0225] For example, this dosage form contains, and preferably consists of, the following substances:

[0226] a) At least one functionalized calcium carbonate-containing material (FCC), preferably at least one functionalized natural and / or synthetic calcium carbonate-containing material (FCC), which is natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more H3O. + The reaction product of the ion donor, wherein the carbon dioxide passes through H3O + Ion donor treatment is formed in situ and / or supplied by an external source.

[0227] b) At least one hot-melt extruded polymer resin, preferably at least one hot-melt extruded biodegradable and / or biocompatible polymer resin.

[0228] c) At least one active reagent and / or an inactive reagent, and

[0229] d) At least one excipient,

[0230] The at least one functionalized calcium carbonate-containing material is dispersed in the at least one hot melt extruded polymer resin, and the weight ratio (FCC / polymer) of the functionalized calcium carbonate-containing material to the hot melt extruded polymer resin is in the range of 95:5 to 5:95.

[0231] The statement "at least one" excipient means that the dosage form contains one or more excipients.

[0232] According to one embodiment of the invention, the dosage form contains only one excipient. According to another embodiment of the invention, the dosage form contains a mixture of two or more excipients. For example, the dosage form contains a mixture of two or three excipients.

[0233] Preferably, the dosage form contains only one excipient.

[0234] For example, the at least one excipient is selected from disintegrants, lubricants, intraphase lubricants, extraphase lubricants, impact modifiers, plasticizers, waxes, stabilizers, pigments, colorants, flavorings, taste maskers, flavorings, sweeteners, texture modifiers, binders, diluents, film-forming agents, adhesives, buffers, adsorbents, odor maskers, and mixtures thereof.

[0235] Those skilled in the art will understand that the excipients mentioned are illustrative only and are not intended to be limiting.

[0236] Preferably, the dosage form according to the invention comprises at least one disintegrant selected from modified cellulose gum, insoluble cross-linked polyvinylpyrrolidone, glycolic acid starch, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, homopolymers of N-vinyl-2-pyrrolidone, alkyl cellulose esters, hydroxyalkyl cellulose esters, carboxyalkyl cellulose esters, alginate, microcrystalline cellulose and its polymorphs, ion exchange resins, gums, chitin, chitosan, clay, gellan gum, cross-linked prelactam copolymers, agar, gelatin, dextrin, acrylic polymers, sodium / calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose phthalate, shellac, or mixtures thereof.

[0237] An example of a suitable disintegrant is Ac-Di-Sol from FMC in the United States. ® It is a modified cellulose gum; Kollidon from BASF in Germany ® CL, which is insoluble cross-linked polyvinylpyrrolidone; Vivastar from JRS Germany. ® It is sodium glycolate starch; MCC polymorph II (MCC SANAQ Burst) from Pharmatrans Sanaq AG, Switzerland. ® ), which is a type II polymorph of stable crystals of microcrystalline cellulose, and is the standard microcrystalline cellulose (MCC) MCC SANAQ 102.

[0238] In one embodiment, the at least one excipient is a lubricant, preferably an intraphase lubricant and / or an external lubricant, more preferably at least one intraphase lubricant. Alternatively, the at least one excipient may be at least one intraphase lubricant and at least one external lubricant.

[0239] The at least one intraphase lubricant may be selected from dehydrated sorbitol esters of fatty acids and polyoxyethylated hydrogenated castor oil (e.g., under the trademark name CREMOPHOR). ® Products sold), block copolymers of ethylene oxide and propylene oxide (e.g., under the trademark PLURONIC) ® and POLOXAMER ®Products for sale), polyoxyethylene fatty alcohol ethers, polyoxyethylene dehydrated sorbitol fatty acid esters, fatty acid dehydrated sorbitol esters and polyoxyethylene stearate, stearyl alcohol, disorbitol Glyceryl ester, sodium stearoyl fumarate, glycerol distearate, and combinations thereof. Preferably, the at least one intraphase lubricant is sodium stearoyl fumarate.

[0240] The at least one external lubricant may be selected from lecithin, polyoxyethylene stearate, polyoxyethylene dehydrated sorbitol fatty acid ester, fatty acid salts, monoacetyl and diacetyl tartrates of monoglycerides and diglycerides of edible fatty acids, citrates of monoglycerides and diglycerides of edible fatty acids, sucrose esters of fatty acids, polyglycerides of fatty acids, polyglycerides of transesterified ricinoleic acid (E476), sodium stearoyl lactylate, magnesium stearate and / or calcium stearate, hydrogenated vegetable oil, stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silica, talc, and combinations thereof. Preferably, the at least one external lubricant is magnesium stearate and / or calcium stearate, more preferably magnesium stearate.

[0241] In one embodiment, the at least one excipient is a plasticizer. It should be understood that, for hot melt extrusion processes, plasticizers lower the melting point of the polymer and are therefore advantageously used in the preparation of hot melt extruded polymer resins. For example, the plasticizer can be a citrate-based plasticizer selected from triethyl citrate (TEC), tributyl citrate (TBC), acetyl tributyl citrate (ATBC), acetyl triethyl citrate (ATEC), monoglycerides, acetylated monoglycerides, and acetyl tri-2-ethylhexyl citrate (ATEHC).

[0242] According to further embodiments of this dosage form, the at least one excipient may be further selected from binders, diluents, film-forming agents, adhesives, buffers, adsorbents, natural or synthetic flavoring agents, natural or synthetic flavoring agents, natural or synthetic coloring agents, natural or synthetic sweeteners, natural or synthetic odor masking agents, natural or synthetic taste or flavor masking agents, natural and / or synthetic mouthfeel modifiers, and mixtures thereof.

[0243] Suitable natural or synthetic fragrances include one or more volatile compounds that humans or other animals typically perceive through their sense of smell at very low concentrations.

[0244] Suitable natural or synthetic flavorings include, but are not limited to, peppermint such as peppermint, menthol, vanilla, cinnamon, various fruit flavorings (alone or in combination), essential oils such as thymol, eucalyptol, menthol and methyl salicylate, allyl pyrazine, methoxypyrazine, 2-isobutyl-3-methoxypyrazine, acetyl-L-pyrazine, 2-acetoxypyrazine, aldehydes, alcohols, esters, ketones, pyrazines, phenolic resins, terpenes and mixtures thereof.

[0245] The flavoring agent is typically used in an amount that will vary according to individual taste, and may be used, for example, in the range of about 0.5% to about 4% of the final dosage form by weight.

[0246] Suitable natural or synthetic colorants include, but are not limited to, titanium dioxide, flavonoid dyes, isoquinoline dyes, polyene colorants, piperan colorants, naphthoquinone dyes, quinone and anthraquinone dyes, benzopyran dyes, benzopyranone dyes, as well as indigo dyes and indole colorants. Examples include caramel coloring, annatto, chlorophyll, cochineal, betaine, turmeric, saffron, paprika, lycopene, pandanus, and butterfly pea.

[0247] Suitable natural or synthetic sweeteners include, but are not limited to, xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, sugar, maltose, partially hydrolyzed starch or corn syrup solids, and sugar alcohols such as sorbitol, xylitol, mannitol and mixtures thereof; water-soluble artificial sweeteners such as soluble saccharin salts (i.e., sodium or calcium saccharin salts), cyclohexylsulfamic acid salts, butanyl sulfadiazine-K, etc., as well as saccharin in free acid form and aspartame-based sweeteners such as L-aspartic acid-phenylalanine methyl ester, alitame, etc. ® Or Neotame ® .

[0248] Typically, the amount of sweetener will vary depending on the desired amount of sweetener selected for a particular dosage form composition.

[0249] Suitable natural and / or synthetic taste modifiers include, but are not limited to, polyethylene oxide (PEO-1NF), Lot. L20141017A from Sumitomo Seika, Osaka; hydroxypropyl cellulose (L-HPC LH-11), Lot. 505200 from Shin-Etsu, Japan; hydroxypropyl ethyl cellulose (Methocel E15LV Premium EP), Lot. LD250012N23, Lot. 024208213 from Gummi arabicum Pheur, Germany; or Instant gum AA (Nexira, France), or combinations thereof.

[0250] The total amount of the at least one excipient in the dosage form is preferably about 0.1% to about 10.0% by weight, more preferably about 0.3% to about 5.0% by weight, and more preferably about 0.5% to about 2.5% by weight, based on the total weight of the dosage form.

[0251] The at least one excipient is preferably dispersed in at least one hot melt extrusion polymer resin comprising the at least one functionalized calcium carbonate-containing material (FCC). In other words, the at least one excipient is preferably dispersed in the at least one hot melt extrusion polymer resin independently of the at least one functionalized calcium carbonate-containing material. For example, the at least one excipient is uniformly dispersed in at least one hot melt extrusion polymer resin comprising the at least one functionalized calcium carbonate-containing material (FCC).

[0252] Additionally or alternatively, the at least one excipient is present in a core, preferably a compacted tablet, at least partially covered by a hot-melt extrusion polymer resin comprising the at least one functionalized calcium carbonate (FCC) material. In one embodiment, the layer at least partially covering the core also comprises at least one excipient. It should be understood that the at least one excipient in the core and the layer at least partially covering the core may be the same or different.

[0253] Alternatively, the at least one excipient may be present in a layer of a core, preferably a compacted tablet, that at least partially covers a core made of at least one hot-melt extruded polymer resin containing the at least one functionalized calcium carbonate material (FCC). In one embodiment, the core made of at least one hot-melt extruded polymer resin also contains at least one excipient. It should be understood that the core and the at least one excipient in the layer at least partially covering the core may be the same or different.

[0254] Alternatively, the at least one excipient may be present in a layered structure of at least two layers, wherein at least one layer contains the at least one excipient.

[0255] The dosage forms of the present invention are in the form of powder, tablets such as multilayer tablets, tablets or matrix tablets with modified geometry, mini tablets, pills, capsules, granules and / or cup tablets.

[0256] These dosage forms and their configurations are well known in the art, for example, Kovanya Moodley et al., “Oraldrug delivery systems comprising altered geometric configurations for controlled drug delivery”; Int. J. Mol. Sci. 2012, 13, 18-43, which is therefore incorporated herein by reference in its entirety.

[0257] The inventors have unexpectedly discovered that, in particular, compared to conventional dosage forms containing functionalized calcium carbonate materials, the dosage forms of the present invention are lighter and smaller in volume at higher drug loadings.

[0258] This invention further relates to the use of this dosage form in pharmaceuticals, nutrients, cosmetics, and household and personal care products. Particularly, it relates to the use of this dosage form in pharmaceuticals, nutrients, cosmetics, and household and personal care products, in the form of powders, tablets such as multilayer tablets, tablets or matrix tablets with modified geometry, mini tablets, pills, capsules, granules, and / or cup tablets.

[0259] The present invention further relates to pharmaceuticals, nutrients, cosmetics, and household and personal care products comprising this dosage form. In particular, the dosage form is in the form of powders, tablets such as multilayer tablets, tablets or matrix tablets with modified geometry, mini tablets, pills, capsules, granules, and / or cup-formed tablets.

[0260] According to one aspect of the invention, a cup-shaped tablet is provided, comprising...

[0261] a) At least one functionalized calcium carbonate-containing material (FCC), which is natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more H3O + The reaction product of the ion donor, wherein the carbon dioxide passes through H3O + Ion donor treatments are formed in situ and / or supplied from external sources.

[0262] b) At least one hot melt extrusion polymer resin,

[0263] The at least one functionalized calcium carbonate-containing material is dispersed in the at least one hot melt extruded polymer resin, and the weight ratio (FCC / polymer) of the functionalized calcium carbonate-containing material to the hot melt extruded polymer resin is in the range of 95:5 to 5:95.

[0264] In one embodiment, the dosage form comprises, preferably, the following substances:

[0265] a) At least one functionalized calcium carbonate-containing material (FCC), preferably at least one functionalized natural and / or synthetic calcium carbonate-containing material (FCC), which is natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more H3O. + The reaction product of the ion donor, wherein the carbon dioxide passes through H3O + Ion donor treatment is formed in situ and / or supplied by an external source.

[0266] b) at least one hot-melt extruded polymer resin, preferably at least one hot-melt extruded biodegradable and / or biocompatible polymer resin, and

[0267] c) At least one active reagent and / or an inactive reagent,

[0268] d) Optionally, at least one excipient,

[0269] The at least one functionalized calcium carbonate-containing material is dispersed in the at least one hot melt extruded polymer resin, and the weight ratio (FCC / polymer) of the functionalized calcium carbonate-containing material to the hot melt extruded polymer resin is in the range of 95:5 to 5:95.

[0270] For example, the at least one active and / or inactive reagent is in the form of a core, said core being at least partially covered by at least one hot-melt extruded polymer resin comprising the at least one functionalized calcium carbonate (FCC) material. In this embodiment, the at least one active and / or inactive reagent is preferably in the form of a compacted tablet.

[0271] In one embodiment, the at least one active and / or inactive reagent is in the form of a core, said core being at least partially covered by at least one hot-melt extruded polymer resin comprising the at least one functionalized calcium carbonate-containing material (FCC), and the at least one active and / or inactive reagent is loaded onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC). It should be understood that the at least one active and / or inactive reagent loaded onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC) and in the form of a core may be the same or different.

[0272] If present, the at least one excipient is present in a core, preferably a compacted tablet, at least partially covered by a hot-melt extrusion polymer resin comprising at least one functionalized calcium carbonate (FCC) material. In one embodiment, the layer at least partially covering the core also comprises at least one excipient. It should be understood that the core and the at least one excipient in the layer at least partially covering the core may be the same or different.

[0273] According to one aspect of this application, a method for producing a dosage form is provided. The method is characterized by the following steps:

[0274] a) Provide at least one functionalized calcium carbonate-containing material (FCC) as defined herein, which is natural milled calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more H3O + The reaction product of the ion donor, wherein the carbon dioxide passes through H3O + Ion donors are formed in situ and / or supplied from external sources;

[0275] b) Provide at least one polymer resin;

[0276] c) Mix the at least one functionalized calcium carbonate-containing material from step a) with the at least one polymer resin from step b);

[0277] d) The mixture obtained in hot melt extrusion step c); and

[0278] e) Grind or granulate the hot melt extruded product obtained in step d) to obtain the dosage form.

[0279] The definitions of the at least one functionalized calcium carbonate-containing material, the at least one polymer resin, and their preferred embodiments are given in reference to the statements provided above in the discussion of the technical details of the dosage forms of the present invention.

[0280] Regarding the at least one polymer resin, it should be noted that the material provided in step b) corresponds to the polymer resin prior to hot melt extrusion and thus the formation of the hot melt extruded polymer resin.

[0281] In one embodiment, the method further includes step b1): providing at least one active reagent and / or an inactive reagent, and / or step b2): providing at least one excipient.

[0282] For definitions of the active and / or inactive reagents, at least one excipient, and their preferred embodiments, refer to the statements provided above in the discussion of the technical details of the dosage forms of the present invention.

[0283] If the dosage form contains at least one active agent and / or inactive agent and / or at least one excipient loaded onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC), it should be understood that the method further includes the step of loading or mixing the at least one active agent and / or inactive agent and / or at least one excipient onto the at least one functionalized calcium carbonate-containing material (FCC) prior to mixing step c). This loading or mixing can be achieved by any conventional method known to those skilled in the art. For example, the step of loading the at least one active agent and / or inactive agent and / or at least one excipient onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC) is carried out under mixing conditions. Those skilled in the art will adapt these mixing conditions and the configuration of the mixing apparatus according to their needs, such as a mixer and / or blender, preferably a mixer like a rolling mixer, or any other apparatus suitable for this operation. However, the listed apparatus should not be considered as having limiting characteristics.

[0284] According to step c) of the method of the present invention, the at least one functionalized calcium carbonate-containing material of step a) and the at least one polymer resin of step b) are mixed.

[0285] If the formulation contains at least one active agent and / or inactive agent and / or at least one excipient dispersed in at least one hot melt extruded polymer resin containing at least one functionalized calcium carbonate material (FCC), it should be understood that the at least one active agent and / or inactive agent of step b1) and / or the at least one excipient of step b2) are preferably mixed with the at least one functionalized calcium carbonate material of step a) and the at least one polymer resin of step b) in mixing step c) prior to hot melt extrusion step d).

[0286] The mixing of the at least one functionalized calcium carbonate-containing material in step a), the at least one polymer resin in step b), and optionally the at least one active reagent and / or inactive reagent in step b1) and / or the at least one excipient in step b2) may be carried out simultaneously or separately in any order to form a mixture.

[0287] The components provided in steps a), b), and optionally b1) and b2) can be mixed by any conventional method known to those skilled in the art. However, mixing step c) is preferably carried out in a mixer and / or blending machine, preferably a mixer such as a rolling mixer.

[0288] In one embodiment of the invention, step c) is performed, wherein the at least one functionalized calcium carbonate-containing material of step a) and the at least one active and / or inactive reagent of step b1) and / or the at least one excipient of step b2) are simultaneously combined with the at least one polymer resin of step b). For example, step c) is performed, wherein the at least one polymer resin of step b) is combined with a blend of the at least one functionalized calcium carbonate-containing material of step a) and the at least one active and / or inactive reagent of step b1) and / or the at least one excipient of step b2). In other words, the at least one functionalized calcium carbonate-containing material of step a) and the at least one active and / or inactive reagent of step b1) and / or the at least one excipient of step b2) may be premixed before being added to the at least one polymer resin of step b).

[0289] Preferably, the mixing step c) is performed, wherein the at least one functionalized calcium carbonate-containing material of step a) and the at least one active reagent and / or inactive reagent and / or the at least one excipient of step b2) are added independently to the at least one polymer resin of step b).

[0290] According to step d) of the method of the present invention, the mixture obtained by hot melt extrusion in step c) is used.

[0291] Hot melt extrusion can be performed using any conventional hot melt extruder known to those skilled in the art. For example, hot melt extrusion can be performed using a twin-screw hot melt extruder with a perforated die (e.g., Three-Tec, ZE9 20602, Switzerland). Those skilled in the art will adapt the extrusion conditions and configuration of the hot melt extruder to their needs.

[0292] The hot-melt extruded product obtained in steps e) and d) of the method according to the invention is ground or granulated to obtain the dosage form. This grinding or granulation can be performed using any conventional grinding or granulation method known to those skilled in the art. For example, grinding can be performed using IKA A11 from IKA, Germany.

[0293] In the context of this invention, the term "grinding" refers to the process of reducing the size of the dosage form obtained in step d), preferably resulting in a free-flowing dosage form that provides little or no dust generation. For example, the dosage form has a Hausner ratio in the range of 1.0-1.34. In the context of this invention, the term "granulation" refers to the process of compacting or molding the dosage form obtained in step d) into the shape of pellets or granules.

[0294] For example, the dosage form is obtained from the hot melt extruded product obtained in the cryogenic milling step d). In this embodiment, the hot melt extruded product obtained in the step d) is obtained, for example, by using liquid nitrogen to freeze it, and then milling the product.

[0295] In one embodiment of the method of the present invention, the method includes one or more steps f): compacting the dosage form obtained in step e). In compaction step f), tablets or granules are preferably obtained.

[0296] Additionally or alternatively, the hot melt extruded product obtained in step d) may be compacted in step d1 prior to the grinding or granulation step e).

[0297] Preferably, optional method steps f) and / or d1) are performed under a compressive force in the range of 5 to 500 kN. It should be noted that the compressive force used in steps f) and / or d1) depends on the specific functionalized calcium carbonate-containing material provided in step a) and the at least one polymer resin provided in step b). Those skilled in the art will therefore adjust the compressive force accordingly. Preferably, optional compaction steps f) and / or d1) are performed under a compressive force in the range of 6 to 300 kN, and most preferably in the range of 8 to 200 kN. For example, optional compaction steps f) and / or d1) are performed under a compressive force in the range of 8 to 100 kN, and most preferably in the range of 8 to 50 kN or 8 to 28 kN.

[0298] It should be understood that the dosage form obtained in step e) may be sieved after step e) and before step f) if present. This sieving can be performed using any conventional sieving method known to those skilled in the art. Sieving can be performed using one or more sieve sizes. Suitable sieve sizes are (but are not limited to) about 180 µm, 250 µm, 355 µm, 500 µm, and 710 µm.

[0299] If the dosage form comprises at least one active agent and / or inactive agent and / or at least one excipient in the form of a layer, which at least partially covers a core, preferably a compacted tablet, made of at least one hot melt extruded polymer resin containing the at least one functionalized calcium carbonate material (FCC), it should be understood that the at least one active agent and / or inactive agent and / or the at least one excipient in step b1) and step b2) is preferably coated onto the dosage form obtained in step e) in the form of one or more layers.

[0300] According to one embodiment of the present invention, the method described above, including steps a) to e) and further including steps b1) and / or b2), comprises step c): mixing the at least one functionalized calcium carbonate-containing material of step a), the at least one polymer resin of step b), and the at least one active reagent and / or inactive reagent and / or the at least one excipient of step b2), and optionally further including step f): compacting the formulation obtained in step e).

[0301] For example, the method described above, including steps a) to e) and further including steps b1) and b2), includes step c): mixing the at least one functionalized calcium carbonate-containing material of step a), the at least one polymer resin of step b), the at least one active reagent and / or inactive reagent of step b1), and the at least one excipient of step b2), and optionally further includes step f): compacting the formulation obtained in step e).

[0302] If the dosage form further comprises at least one active reagent and / or inactive reagent and / or at least one excipient loaded onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC), the method described above, including steps a) to e) and further including steps b1) and / or b2), comprises loading the at least one active reagent and / or inactive reagent of step b1) and / or the at least one excipient of step b2) onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC) before mixing step c), step c): mixing the at least one functionalized calcium carbonate-containing material of step a) (i.e., the loaded functionalized calcium carbonate-containing material (FCC)), the at least one polymer resin of step b), and the at least one active reagent and / or inactive reagent of step b1) and / or the at least one excipient of step b2), and the method optionally further includes step f): compacting the dosage form obtained in step e).

[0303] For example, the method described above, including steps a) to e) and further including steps b1) and b2), includes loading the at least one active and / or inactive reagent of step b1) onto or mixing with the at least one functionalized calcium carbonate-containing material (FCC) prior to mixing step c), step c): mixing the at least one functionalized calcium carbonate-containing material of step a) (i.e., the loaded functionalized calcium carbonate-containing material (FCC)), the at least one polymer resin of step b), and the same or different at least one active and / or inactive reagent of step b1) and the at least one excipient of step b2), and the method optionally further includes step f): compacting the formulation obtained in step e).

[0304] According to another embodiment of the invention, the method described above, including steps a) to e) and further including steps b1) and / or b2), comprises step c): mixing the at least one functionalized calcium carbonate-containing material of step a), the at least one polymer resin of step b), and the at least one active reagent and / or inactive reagent and / or the at least one excipient of step b2); applying the at least one active reagent and / or inactive reagent and / or the at least one excipient of step b2) in the form of one or more layers onto the dosage form obtained in step e); and optionally further comprising step f): compacting the dosage form obtained after coating.

[0305] For example, the method described above, including steps a) to e) and further including steps b1) and b2), includes step c): mixing the at least one functionalized calcium carbonate-containing material of step a), the at least one polymer resin of step b) and the at least one excipient of step b2); applying the at least one active reagent and / or inactive reagent of step b1) and the same or different excipients of step b2) in the form of one or more layers onto the dosage form obtained in step e); and optionally further including step f): compacting the dosage form obtained after coating.

[0306] If the dosage form further comprises at least one active reagent and / or inactive reagent and / or at least one excipient, the same or different, loaded onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC), then the method described above, including steps a) to e) and further including steps b1) and / or b2), comprises loading the at least one active reagent and / or inactive reagent of step b1) and / or the at least one excipient of step b2) onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC) before mixing step c). Step c): Mixing the at least one functionalized calcium carbonate-containing material (i.e., loaded functionalized calcium carbonate-containing material (FCC)) from step a), the at least one polymer resin from step b), and the at least one active reagent and / or inactive reagent and / or the at least one excipient from step b1) and / or step b2); applying the at least one active reagent and / or inactive reagent and / or the at least one excipient from step b2) in the form of one or more layers onto the dosage form obtained in step e); and optionally further including step f): compacting the dosage form obtained after coating.

[0307] For example, the method described above, including steps a) to e) and further including steps b1) and b2), includes loading the at least one active and / or inactive reagent of step b1) onto or mixing with the at least one functionalized calcium carbonate-containing material (FCC) before mixing step c), step c): mixing the at least one functionalized calcium carbonate-containing material of step a) (i.e., the loaded functionalized calcium carbonate-containing material (FCC)), the at least one polymer resin of step b) and the at least one excipient of step b2); applying the same or different active and / or inactive reagents of step b1) and / or the at least one excipient of step b2) in the form of one or more layers onto the dosage form obtained in step e); and optionally further including step f): compacting the dosage form obtained after coating.

[0308] If the dosage form is in the form of a layered structure with at least two layers, wherein at least one layer is made of the at least one hot melt extruded polymer resin containing the at least one functionalized calcium carbonate material (FCC), then the method described above, including steps a) to e) and further including steps b1) and / or b2), includes step c): mixing the at least one functionalized calcium carbonate material of step a), the at least one polymer resin of step b), and the at least one active agent and / or inactive agent and / or the at least one excipient of step b1) and / or step b2); and further includes step f): compacting the dosage form obtained in step e) into a layered structure.

[0309] In another alternative embodiment, cup-shaped tablets are prepared. In this case, the at least one active agent and / or inactive agent of step b1) and / or the at least one excipient of step b2) are mixed and compacted in compaction step f1) to form a core tablet.

[0310] The at least one active reagent and / or inactive reagent and / or the at least one excipient of step b1) can be mixed by any conventional method known to those skilled in the art. However, the mixing of the at least one active reagent and / or inactive reagent of step b1) and / or the at least one excipient of step b2) is preferably carried out in a mixer and / or blender, preferably a mixer such as a rolling mixer.

[0311] In one embodiment, the at least one active reagent and / or inactive reagent and / or the at least one excipient in step b2) are sieved prior to mixing. This sieving can be performed using any conventional sieving method known to those skilled in the art. One or more sieve sizes can be used for sieving. Suitable sieve sizes are (but are not limited to) about 180 µm, 250 µm, 355 µm, 500 µm, and 710 µm, such as 500 µm.

[0312] The compaction step f1) is performed under a compressive force in the range of 5 to 500 kN. It should be noted that the compressive force used in step f1) depends on the specific active reagent and / or inactive reagent in step b1) and / or the at least one excipient in step b2). Those skilled in the art will therefore adjust the compressive force accordingly. Preferably, the compaction step f1) is performed under a compressive force in the range of 6 to 300 kN, and most preferably in the range of 8 to 200 kN. For example, the compaction step f1) is performed under a compressive force in the range of 8 to 100 kN, and most preferably in the range of 8 to 50 kN or 8 to 28 kN.

[0313] Furthermore, the method further includes step g): covering at least partially the core tablet formed in step f1) with the dosage form obtained in step e), and compacting the resulting product.

[0314] The compaction is preferably carried out under a compressive force in the range of 5 to 500 kN. It should be noted that the compressive force used in step f1) depends on the specific active and / or inactive reagent in step b1) and / or the at least one excipient in step b2) and the at least one hot-melt extruded polymer resin containing the at least one functionalized calcium carbonate (FCC) material. Those skilled in the art will therefore adjust the compressive force accordingly. Preferably, the compaction step f1) is carried out under a compressive force in the range of 6 to 300 kN, and most preferably in the range of 8 to 200 kN. For example, the compaction is carried out under a compressive force in the range of 8 to 100 kN, and most preferably in the range of 8 to 50 kN or 8 to 28 kN.

[0315] It should be understood that this method (i.e., preparation of cup tablets) may include the further step of loading the at least one active reagent and / or inactive reagent and / or at least one excipient of the same or different step b1) onto the at least one functionalized calcium carbonate (FCC) material prior to mixing step c).

[0316] Additionally or alternatively, this method (i.e., preparation of cup tablets) may include the further step of mixing the same or different active and / or inactive reagents of step b1) and / or at least one excipient of step b2) with the at least one functionalized calcium carbonate-containing material of step a) and the at least one polymer resin of step b) in mixing step c) prior to hot melt extrusion step d).

[0317] The inventors have unexpectedly discovered that the method of the present invention for producing dosage forms results in dosage forms that are lighter and smaller in volume at higher drug loadings, especially compared to conventional dosage forms containing functionalized calcium carbonate materials. Furthermore, this dosage form can be prepared using an efficient pressing method without the use of binders and / or compaction aids.

[0318] In view of the favorable results obtained, the present invention relates in another aspect to the use of functionalized calcium carbonate-containing materials (FCC) in methods for producing dosage forms. According to another aspect, the use of functionalized calcium carbonate-containing materials (FCC) in dosage forms such as tablets, mini tablets, pills, capsules, granules, and / or cup tablets is provided.

[0319] The definition of the at least one functionalized calcium carbonate-containing material and its preferred embodiments is given in reference to the statements provided above in the discussion of the technical details of the dosage forms of the present invention. Attached Figure Description

[0320] Figure 1 A schematic diagram involving TIC compaction.

[0321] Figure 2 Scanning electron microscope images involving granules.

[0322] Figure 3 Heckel diagram involving FCC-PCL.

[0323] Figure 4 The modified Heckel diagram involving FCC-PCL.

[0324] Figure 5 Leuenberger diagram involving FCC-PCL.

[0325] Figure 6 Scanning electron microscope images involving cup-sized tablets (TIC). Detailed Implementation

[0326] Example

[0327] 1. Materials

[0328] The core tablet consists of 96% (m / m) metformin hydrochloride (Harman Finochem Limited), 2% (m / m) polyvinyl alcohol (PVA) and 2% (m / m) Carbopol 980 NF (Lubrizol, Advanced Materials, Belgium).

[0329] The formulation used in the cup is made of functionalized calcium carbonate (FCC) (Omya International AG, Switzerland, with a BET specific surface area of ​​62.8 m²). 2 / g, d 50 It is 11.7 µm. d 98 It consists of a 1:1 (m / m) mixture of 26.7 µm and polycaprolactone (Capa 6506, Perstorp UK Limited). Magnesium stearate (Sandoz, Switzerland) is used for lubrication.

[0330] Kombiglyze ® XR 5 mg / 500 mg (Astra Zeneca, USA) was used as a reference.

[0331] 2. Methods

[0332] Scanning electron microscopy (SEM)

[0333] Scanning electron microscopy (SEM) images were prepared using a FEI Nova Nano SEM 230. Samples were sputtered using a LEICA EMACE600 Double Sputter coating machine with gold layers ranging from 20 to 40 nm.

[0334] Preparation of core tablets

[0335] All excipients were sieved (< 500 μm) and blended for 10 minutes at 32 rpm using a Turbula blender (T2C, WA Bachofer, Switzerland). The core formulation was compacted using a Styl`One compaction simulator (Medel'pharm, France) with a 10 mm flat punch. The compaction cycle was defined by the following speed ranges: filling 2 seconds, upper punch approach 1.5 seconds, compaction 70 milliseconds, relaxation 1.0 second, ejection 5 seconds, and tablet selection 70 milliseconds. The compaction force was set at 17 kN.

[0336] Preparation of cup-mixed formulations

[0337] For cup formulations, hot melt granulation was performed on a twin-screw hot melt extruder with a porous die (Three-Tec, ZE9 20602, Switzerland). The five heating units were adjusted to the following temperatures: Unit 1: 10°C, Unit 2: 50°C, and Units 3, 4, and 5: 80°C. The feed rate was set between 3.1 g / min and 4.5 g / min. The twin screw was set to 100 rpm. The extruded product was cryogenically ground using an IKA A11 (IKA, Germany) single-speed manual mill with a cutting tool. The ground product was sieved through a 500 μm sieve. To analyze the cup formulations, deformation characteristic curves were obtained using a 11.28 mm flat Euro D punch with compaction pressures ranging from 50 MPa to 300 MPa.

[0338] Preparation of TIC (Tip-in-Cup) Tablets

[0339] TIC compaction was performed using a 13 mm angled punch. The cycle time was defined by the following speed ranges: filling 2 seconds, upper punch approximately 10 seconds, compaction 70 milliseconds, relaxation 0.14 seconds, demolding 70 milliseconds, and tablet selection 70 milliseconds. The compaction force was set at 20 kN. The filling height was set at 9.2 mm, with the core placed in the center of the lower punch and the cup-formulated formulation (<500 μm) manually filled into the die; see [link to relevant documentation]. Figure 1 .

[0340] Hardness test

[0341] Empty cups for hardness testing were produced in the same manner as those used with the TIC device (but not the core tablet), with the metal tablet serving as a template. After compaction, the metal tablet was removed. Hardness testing was performed using a Dr. Schleuniger Tablet Tester 8M (Switzerland) (TIC n=6; core n=6, coreless cup n=3).

[0342] Compactability, compactability, solubility, and brittleness

[0343] The compressibility of the FCC-PCL compound was investigated using the Heckel equation (Equation 1) (R. Heckel, “Density-pressure relationships in powder compaction”). Trans. Metall. Soc. AIME Volume 221, pp. 671-675 (1961)

[0344] (Equation 1)

[0345] in k For Heckel parameters (MPa) -1 ), σ To suppress pressure (MPa). ρ The density of the tablet (g / cm³) 3 )and A The pressure is constant. The compressive stress varies between 45 MPa and 295 MPa. The density of the tablet is calculated according to Equation 2 (J. Ilkka and P. Paronen, “Prediction of the compression behavior of powder mixtures by the Heckel equation”). Int. J. Pharm., Volume 94, Issues 1-3, pp. 181-187, June 1993):

[0346] (Equation 2)

[0347] in m The weight (g) of the tablet. r The radius of the tablet (cm) is given. h For tablet height, and ρ 真 The true density of the material (g / cm³) 3The yield pressure is calculated by taking the reciprocal of the Heckel slope (Equation 3) (J. Ilkka and P. Paronen, “Prediction of the compression behavior of powder mixtures by the Heckel equation”). Int. J. Pharm. Volume 94, Issues 1-3, pp. 181-187, June 1993

[0348] ( (Equation 3)

[0349] To investigate the compaction sensitivity of materials, the modified Heckel equation (Equation 4) was used (M. Kuentz and H. Leuenberger, “Pressure susceptibility of polymer tablets as a critical property: A modified heckel equation”). J. Pharm. Sci. (Volume 88, Issue 2, pp. 174-179, February 1999)

[0350] (Equation 4)

[0351] in σ The pressing pressure is (MPa), and C is a constant (MPa). -1 ), Critical density (g / cm³) 3 )and ρ Relative tablet density (g / cm³) 3 ).

[0352] Powder compressibility was investigated by plotting tensile strength as a function of compressive pressure (H. Leuenberger and BD Rohera, “Fundamentals of Powder Compression. I. The Compactibility and Compressibility of Pharmaceutical Powders”). Pharm. Res. Volume 3, Issue 1, pp. 12-22, February 1986. Tensile strength was calculated according to Equation 5 for round tablets and Equation 6 for shaped tablets (available at "The United States Pharmacopoeia" online).

[0353] (http: / / www.drugfuture.com / pharmacopoeia / usp32 / pub / data / v32270 / usp32nf27s0_c1217.html)

[0354] (Equation 5)

[0355] (Equation 6)

[0356] in Tensile strength (MPa) F The breaking force is N. d The diameter (mm) of the round tablet and h This refers to the height (mm) of a round tablet. For shaped tablets, D For tablet width, t For tablet height and W The shaft height is in mm.

[0357] Information regarding the deformation of materials under stress and the bonding properties of materials was evaluated using factors of compressibility and compressibility sensitivity calculated using Leuenberger Equation 7 [H. Leuenberger and BD Rohera, “Fundamentals of Powder Compression. I. The Compactibility and Compressibility of Pharmaceutical Powders”]. Pharm. Res. [Volume 3, Issue 1, pp. 12-22, February 1986]

[0358] (Equation 7)

[0359] in For tensile strength, Let γ be the tensile strength when the compressive pressure (σ) → ∞ and the relative density (ρ) → 1, where γ is the compressive sensitivity and σ is the applied compressive pressure. The calculations include data from 50 MPa to 300 MPa.

[0360] Dissolution test (TIC: n=6; Kombiglyze) ®XR (n=3, core n=6) was performed on a SOTAX AT7 Smart (Sotax, Switzerland) instrument connected to a UV spectrometer (Amersham Biosciences, Ultraspec 3100pro, UK) using a Sotax CY 7-50 pump (Sotax, Switzerland). The XR was performed using a USP device at 2 and 50 rpm for TIC and Kombiglyze, respectively. ® XR dissolution characteristics were measured in water (37°C) for 24 hours and for the core for 3 hours. The spectrometer was set to 250 nm, and the concentration was calculated according to Equation 8 below:

[0361] , (Equation 8)

[0362] Crispness (n=10) was tested using an Erweka TA200 (Erweka, Germany).

[0363] The F2 standard is calculated according to the FDA (US Department of Health and Human Services, Food and Drug Administration, and Center for Drug Evaluation and Research (CDER), "Guidance for Industry, Dissolution Testing of Immediate Release Solid Oral Dosage Forms," ​​August 1997), as described in Equation 9:

[0364] (Equation 9)

[0365] in R t For reference samples at time t Drug release in % (m / m), and T t To test the sample at time t Drug release is expressed as % (m / m), n=146.

[0366] Tensile strength

[0367] Calculate the tensile strength using Equation 10:

[0368] (Equation 10)

[0369] Where σ tRadial tensile strength (MPa). F The breaking force is N. d denoted as tablet diameter (mm) and h as tablet thickness (mm). Crushing force was measured using a tablet hardness tester (8M, Dr. Schleuniger Pharmatron, Switzerland).

[0370] 3. Results

[0371] To produce cup-formulations, such as FCC-PCL complexes, a first FCC and PCL are mixed and then hot-melt granulation is performed. During hot-melt granulation, the torque is kept constant at 3.21 ± 0.04 Nm. The temperatures of units 3, 4, and 5 are 80.12 ± 0.66 °C, 80.02 ± 2.31 °C, and 80.20 ± 3.01 °C, respectively. Because polymer melting occurs only in these units, only the temperatures of units 3 to 5 are considered. The production of the FCC-PCL complex used to form the cups does not present a problem.

[0372] After granulation, the product is frozen, ground, and sieved. Figure 2 SEM images of pellets with a layered structure of FCC embedded in PCL are shown. Only pellets with a size < 500 µm were further used. The results of Heckel, modified Heckel, and Leuenberger analyses are shown in Table 1. Figure 3 , Figure 4 and Figure 5 Display Heckel plots, corrected Heckel plots, and Leuenberger plots.

[0373] Table 1: Results of the FCC-PCL complex

[0374]

[0375] According to Heckel's analysis σ y The value is 377.36 MPa. This value is comparable to the result in a previous study, where the yield pressure of the FCC alone was... σ y=294 MPa (T. Stirnimann, S. Atria, J. Schoelkopf, PAC Gane, R. Alles, J. Huwyler and M. Puchkov, "Compaction of functionalizedcalcium carbonate, a porous and crystalline microparticulate material with alamellar surface", Int. J. Pharm. (Volume 466, Issues 1-2, pp. 266-275, May 2014). These values ​​are higher than those reported in other studies, where the yield stress of plastically deformable materials is shown to be 40-135 MPa (S. Jain, “Mechanical properties of powders for compaction and tableting: an overview”). Pharm. Sci. Technol. Today (Volume 2, Issue 1, pp. 20-31, January 1999). It is shown that FCC-PCL in... ρ Stable compacted material is formed at a relative density of 0.843.

[0376] According to Leuenberger's analysis, the results are as follows: σ tmax The value is 3.44 MPa, which indicates the plastic behavior of the material. For γ The value was found to be 19.43 10. -3 MPa -1 This value is higher than that of the FCC investigated in previous studies and significantly greater than that of the MCC (7.56 × 10⁻⁶). -3 MPa -1 ) (T. Stirnimann, S. Atria, J. Schoelkopf, PAC Gane, R. Alles, J. Huwyler and M. Puchkov, "Compaction of functionalized calciumcarbonate, a porous and crystalline microparticulate material with a lamellarsurface", Int. J. Pharm.(Volume 466, Issues 1-2, pp. 266-275, May 2014). This value indicates the additional bonding effect of the PCL polymer on the FCC layer. A high γ value indicates plastic behavior and the ability to achieve maximum tensile strength under already low compression pressure. γ and σ tmax The values ​​all indicate that the material has good bonding properties.

[0377] The core tablet and cup material are compacted to form the TIC device. The parameters of the core tablet subsequently compacted into the TIC device are shown in Table 2. The parameters obtained from the TIC device (i.e., the core compacted in the cup) are compared with those of the reference product (Kombiglyze). ® The measurement parameters for XR are also shown in Table 2. During the TIC hardness test, the core and cup did not separate. The hardness of the cup was evaluated separately without a core tablet, yielding 90.50 ± 4.68 N.

[0378] Table 2: Parameters of Core, TIC, and Reference

[0379]

[0380] The width of the oval tablet, # Length of oval tablets No quality change detected

[0381] The flow of the cup material under compaction is excellent for both slow (10 seconds) and fast (70 milliseconds) compaction cycles. In both cases, the cup material distribution is uniform, resulting in cup walls of equal size without cracks, bursts, or gaps. An example of a compacted cup is shown below. Figure 6 middle.

[0382] Reference (Kombiglyze ® The release characteristic curves of XR (5 mg / 500 mg) and TIC showed that the release characteristic curve of TIC was slightly lower than that of the reference substance. The linear portion between 200 min and 800 min is shown. The standard deviation was no more than 1.33% (m / m) in the case of the reference substance and no more than 2.58% in the case of TIC. The f2 test yielded a value of 78.60, therefore the dissolution characteristic curves can be considered identical.

[0383] The tablet parameters showed that the TIC was 203 mg lighter than the reference. Therefore, the drug loading in the TIC was 8.5% higher than the reference. (TIC device and reference (985.7 mm)) 3 Compared to its smaller size (754.27±3.82 mm), it has a smaller volume. 3This makes it easier to swallow. The amount of excipient released is 20 mg; this is 2% (m / m) of the total mass of the TIC.

[0384] No change in mass was detected during the brittleness test. The TIC device was stable and showed no breakage or deformation, therefore no coating is required. The cup of the coreless tablet was stable with a hardness of 90.50 N, which was expected given the γ and σ values. tmax The value indicates good adhesion under low compressive stress. For example... Figure 6 As shown, the connection between the core and the cup is tight and no dose burst is expected. Fragility is undetectable. This demonstrates the high stability of the cup and its ability to stabilize the core.

[0385] Furthermore, it should be noted that the FCC-PCL composite material is suitable for human consumption and is biodegradable.

Claims

1. A dosage form comprising a) At least one functionalized calcium carbonate-containing material (FCC), which is natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more H3O + The reaction product of the ion donor, wherein the carbon dioxide passes through H3O + Ion donor treatments are formed in situ and / or supplied from external sources. b) At least one hot-melt extruded polymer resin, wherein the polymer resin is selected from polycaprolactone, polylactic acid, or polylactic acid-based polymers and mixtures thereof. The at least one functionalized calcium carbonate-containing material is dispersed in the at least one hot-melt extrusion polymer resin, and the weight ratio (FCC / polymer) of the functionalized calcium carbonate-containing material to the hot-melt extrusion polymer resin is in the range of 95:5 to 5:

95. This dosage form is available in the form of powder, tablets, capsules, and / or granules. Furthermore, the dosage form further comprises at least one active reagent and / or an inactive reagent.

2. The dosage form of claim 1, wherein the natural ground calcium carbonate is selected from calcium carbonate-containing minerals, which are selected from marble, chalk, dolomite, limestone and mixtures thereof; or the precipitated calcium carbonate is selected from precipitated calcium carbonate and mixtures thereof having aragonite, aragonite or calcite mineralogical crystal forms.

3. The dosage form according to claim 1 or 2, wherein the at least one functionalized calcium carbonate-containing material a) Possesses a 20m measurement according to ISO 9277 using nitrogen and the BET method. 2 / g-450m 2 / g of BET specific surface area; and / or b) Contains particles with a median volumetric particle diameter of d ranging from 1µm to 50µm. 50 particles; and / or c) Porosity calculated from the mercury intrusion porosity determination method is between 0.15 and 1.35 cm. 3 In-particle pore volume within the range of / g.

4. The dosage form according to claim 1, wherein the at least one active reagent and / or inactive reagent is selected from pharmaceutical active reagents, active or inactive prodrugs, nutrients, food additives, cosmetic additives, and mixtures thereof.

5. The dosage form according to claim 1 or 4, wherein the at least one active reagent and / or inactive reagent a) being loaded onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC), and / or b) dispersed in at least one hot melt extruded polymer resin comprising at least one functionalized calcium carbonate (FCC) material, and / or c) In the form of a compacted tablet core, which is at least partially covered by at least one hot-melt extruded polymer resin comprising at least one functionalized calcium carbonate (FCC) material, or d) In the form of a layer, which at least partially covers a core made of at least one hot melt extruded polymer resin comprising at least one functionalized calcium carbonate material (FCC), or e) It takes the form of a layered structure with at least two layers, wherein at least one layer is made of the hot melt extruded polymer resin containing the at least one functionalized calcium carbonate material (FCC).

6. The dosage form according to claim 1 or 2, wherein the dosage form further comprises at least one excipient selected from the group consisting of: disintegrants, lubricants, impact modifiers, plasticizers, waxes, stabilizers, colorants, taste masking agents, binders, diluents, film-forming agents, buffers, adsorbents, odor masking agents, and mixtures thereof.

7. The dosage form of claim 6, wherein the dosage form further comprises at least one disintegrant selected from the group consisting of: modified cellulose gum, insoluble crosslinked polyvinylpyrrolidone, glycolic acid starch, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, homopolymers of N-vinyl-2-pyrrolidone, alkyl cellulose esters, hydroxyalkyl cellulose esters, carboxyalkyl cellulose esters, alginate, ion exchange resins, gums, chitin, chitosan, clay, gellan gum, crosslinked prelactam copolymers, agar, gelatin, dextrin, acrylic polymers, sodium / calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose phthalate, shellac, or mixtures thereof.

8. The dosage form according to claim 1 or 2, wherein the dosage form is in the form of a tablet selected from the group consisting of: multilayer tablets, tablets with modified geometry, matrix tablets, mini tablets and cup tablets.

9. The dosage form according to any one of claims 1-8 in the preparation of a medicament, or in a nutrient, cosmetic, or household and personal care product.

10. Pharmaceuticals, nutrients, cosmetics, and household and personal care products comprising a dosage form according to any one of claims 1-8.

11. A method for producing a dosage form, comprising the following steps: a) Provide at least one functionalized calcium carbonate-containing material (FCC) as defined in any one of claims 1-3, which is natural milled calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more H3O + The reaction product of the ion donor, wherein the carbon dioxide passes through H3O + Ion donors are formed in situ and / or supplied from external sources; b) Provide at least one polymer resin as defined in claim 1; c) Mix the at least one functionalized calcium carbonate-containing material from step a) with the at least one polymer resin from step b); d) The mixture obtained in hot melt extrusion step c); and e) Grind or granulate the hot melt extruded product obtained in step d) to obtain the dosage form; This dosage form is available in the form of powder, tablets, pills, capsules, and / or granules. The method further includes: step b1) providing at least one active reagent and / or an inactive reagent.

12. The method of claim 11, further comprising: Step b1) provides at least one active reagent and / or inactive reagent selected from pharmaceutically active reagents, active or inactive prodrugs, nutrients, food additives, cosmetic additives and mixtures thereof; and / or step b2) provides at least one excipient selected from disintegrants, lubricants, impact modifiers, plasticizers, waxes, stabilizers, colorants, taste maskers, binders, diluents, film-forming agents, buffers, adsorbents, odor maskers and mixtures thereof.

13. The method of claim 11, further comprising: Step b2) provides at least one of the following: modified cellulose gum, insoluble crosslinked polyvinylpyrrolidone, glycolic acid starch, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, homopolymer of N-vinyl-2-pyrrolidone, alkyl cellulose ester, hydroxyalkyl cellulose ester, carboxyalkyl cellulose ester, alginate, ion exchange resin, gum, chitin, chitosan, clay, gellan gum, crosslinked precklin copolymer, agar, gelatin, dextrin, acrylic polymer, sodium / calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose phthalate, shellac, or mixtures thereof.

14. The method of claim 12, wherein the at least one active reagent and / or inactive reagent in step b1) and / or the at least one excipient in step b2) a) Loaded onto or mixed with the at least one functionalized calcium carbonate-containing material (FCC) prior to mixing step c), and / or b) Mixing the at least one functionalized calcium carbonate material from step a) and the at least one polymer resin from step b) in mixing step c) prior to hot melt extrusion step d), and / or c) Apply one or more layers onto the dosage form obtained in step e).

15. The method according to any one of claims 11-13, wherein the method comprises one or more steps f): compacting the dosage form obtained in step e).

16. The method of claim 12, wherein the at least one active agent and / or inactive agent of step b1) and / or the at least one excipient of step b2) are mixed and compacted in compaction step f1) to form a core tablet.

17. The method of claim 16, further comprising step g): at least partially covering the core tablet formed in step f1) with the dosage form obtained in step e), and compacting the resulting product.

18. The method according to claim 16 or 17, wherein at least one active reagent and / or inactive reagent of the same or different step b1) and / or at least one excipient of step b2). a) Loaded onto the at least one functionalized calcium carbonate (FCC) material prior to mixing step c), and / or b) Mixing the at least one functionalized calcium carbonate material from step a) and the at least one polymer resin from step b) in mixing step c) prior to hot melt extrusion step d).

19. Use of the functionalized calcium carbonate-containing material (FCC) as defined in any one of claims 1-3 in a method for producing a dosage form as defined in any one of claims 1-8.

20. Use of the functionalized calcium carbonate-containing material (FCC) as defined in any one of claims 1-3 in a dosage form as defined in any one of claims 1-8, wherein the dosage form is selected from tablets, pills, capsules and / or granules.

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