Absorption-promoting granulated material, method for producing same, pharmaceutical composition, and combined preparation

Abstract

Provided are a granulated material and others which can provide novel application methods for absorption promoters.　This absorption-promoting granulated material includes a core particle A that contains an absorption promoter and a coating particle layer A that coats the core particle.

Description

Absorption-enhancing granules, their manufacturing method, pharmaceutical compositions, and combinations

[0001] The present invention relates to an absorption-enhancing granule, a method for producing the same, a pharmaceutical composition, a combination drug, and the like.

[0002] There are a wide variety of routes of administration for pharmaceuticals, including oral administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, cutaneous administration, pulmonary administration, enteral administration, etc. Among these, oral administration is the most commonly used because it allows pharmaceuticals to be administered safely and easily.

[0003] However, in the case of oral administration, the active ingredients of pharmaceuticals are usually absorbed in the small intestine via the oral cavity, esophagus, and stomach, and therefore the applicable active ingredients tend to be limited due to, for example, limitations on membrane permeability in the small intestine.

[0004] In recent years, for medicinal ingredients for which oral administration is limited, techniques that utilize absorption enhancers to enable absorption of medicinal ingredients in the small intestine and the like have been attracting attention.

[0005] For example, Patent Document 1 describes an invention relating to a solid composition containing a GLP-1 peptide and an enhancer for use as a pharmaceutical for oral administration. Patent Document 1 describes that the enhancer (absorption enhancer) is a compound that increases the bioavailability of the GLP-1 peptide, and that specific examples of absorption enhancers include sodium caprate and SNAC. In addition, an example of Patent Document 1 describes that a tablet composition was prepared by mixing a GLP-1 peptide, an enhancer (absorption enhancer), and an additive, and roller compacting the mixture.

[0006] Special table 2016-519128 publication

[0007] According to the technology described in Patent Document 1, a medicinal ingredient and an absorption enhancer are mixed together with additives (such as excipients). In such cases, for example, the medicinal ingredient and the absorption enhancer may interact within the formulation, potentially reducing the stability of the formulation. Furthermore, the need to incorporate the two ingredients together may limit the formulation techniques that can be applied. Furthermore, optimizing the blending ratio of the two ingredients can be time-consuming, requiring the preparation of formulations with different content ratios. Therefore, the present invention provides a new method for applying an absorption enhancer.

[0008] The present invention includes, for example, the following aspects.

[0009] [1-1] An absorption-enhancing granule comprising a core particle A containing an absorption enhancer and a coated particle layer A coating the core particle A. [1-2] The absorption-enhancing granule according to [1-1] above, which does not contain an active ingredient. [1-3] The absorption-enhancing granule according to [1-1] or [1-2] above, wherein the core particle A further contains a thickener. [1-4] The absorption-enhancing granule according to any of [1-1] to [1-3] above, wherein the core particle A further contains a hydrophobic thickener. [1-5] The absorption-enhancing granule according to [1-3] or [1-4] above, wherein the thickener comprises at least one selected from the group consisting of carrageenan, gelatin, glycerin monostearate, agar, polyethylene glycol, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, aminoalkyl methacrylate copolymer, and ammonioalkyl methacrylate copolymer. [1-6] The absorption-enhancing granule according to any one of [1-1] to [1-5] above, wherein the coated particle layer A contains at least one selected from the group consisting of bentonite, ethyl cellulose, corn starch, rice starch, wheat starch, potato starch, calcium stearate, magnesium carbonate, low-substituted sodium carboxymethyl starch, sodium starch glycolate, anhydrous silicic acid, magnesium silicate, diatomaceous earth, zeolite, silicon dioxide, powdered agar, croscarmellose sodium, crospovidone, and talc. [1-7] The absorption-enhancing granule according to any one of [1-1] to [1-6] above, wherein the core particle A further contains an enteric polymer. [1-8] A pharmaceutical composition comprising the absorption-enhancing granule according to any one of [1-1] to [1-7] above, and a first granule containing an active ingredient. [1-9] The pharmaceutical composition according to [1-8] above, wherein the first granule is a medicinal ingredient-containing granule comprising a core particle B containing a medicinal ingredient and a coated particle layer B coating the core particle B. [1-10] The pharmaceutical composition according to [1-9] above, wherein the medicinal ingredient-containing granule does not contain an absorption enhancer. [1-11] The pharmaceutical composition according to any of [1-8] to [1-10] above, wherein the medicinal ingredient is a polymer component.[1-12] A pharmaceutical composition comprising: a second granule containing an absorption enhancer; and a medicinal ingredient-containing granule containing core particles B containing a medicinal ingredient and a coated particle layer B coating the core particles B. [1-13] The pharmaceutical composition according to [1-12] above, wherein the medicinal ingredient-containing granule does not contain an absorption enhancer. [1-14] The pharmaceutical composition according to [1-12] above, wherein the absorption enhancer comprises at least one selected from the group consisting of sodium caprate, sodium caprylate, SNAC, a cell membrane-permeable peptide, C-CPE, Angubindin-1, polyoxyethylene alkyl ethers, sodium lauryl sulfate, saponin, chitosan, cyclodextrin, alkyl saccharides, sucrose fatty acid esters, N-acyl amino acids, N-acyltaurines, glycocholic acid, taurocholic acid, deoxycholic acid, ethylenediaminetetraacetic acid (EDTA), sodium salicylate, sodium laurate, tryptophan, arginine, and fatty acids having 8 to 30 carbon atoms. [1-15] The pharmaceutical composition according to any one of [1-12] to [1-14] above, wherein the active ingredient is a polymer component. [1-16] A combination comprising the absorption-enhancing granules according to any one of [1-1] to [1-7] above, and a first granule containing a medicinal ingredient. [1-17] The combination according to [1-16] above, wherein the first granules is a medicinal ingredient-containing granule containing core particles B containing a medicinal ingredient and a coated particle layer B coating the core particles B. [1-18] The combination according to [1-17] above, wherein the medicinal ingredient-containing granules does not contain an absorption enhancer. [1-19] The combination according to any one of [1-16] to [1-18] above, wherein the first granules are administered simultaneously with the absorption-enhancing granules. [1-20] A combination comprising a second granule containing an absorption enhancer, and a medicinal ingredient-containing granule containing core particles B containing a medicinal ingredient and a coated particle layer B coating the core particles B. [1-21] The combination according to the above [1-20], wherein the medicinal ingredient-containing granules do not contain an absorption enhancer.[1-22] The combination according to [1-20] or [1-21] above, wherein the absorption enhancer comprises at least one selected from the group consisting of sodium caprate, sodium caprylate, SNAC, a cell membrane-permeable peptide, C-CPE, Angubindin-1, polyoxyethylene alkyl ethers, sodium lauryl sulfate, saponin, chitosan, cyclodextrin, alkyl saccharides, sucrose fatty acid esters, N-acyl amino acids, N-acyltaurines, glycocholic acid, taurocholic acid, deoxycholic acid, ethylenediaminetetraacetic acid (EDTA), sodium salicylate, sodium laurate, tryptophan, arginine, and fatty acids having 8 to 30 carbon atoms. [1-23] The combination according to any of [1-20] to [1-22] above, wherein the medicinal ingredient-containing granules are administered simultaneously with the second granules. [1-24] A method for producing the absorption-enhancing granules according to any one of [1-1] to [1-7] above, comprising a granulation step of introducing droplets of a granulating solution containing an absorption enhancer into a fluidized bed in which coated particles are flowing, thereby causing the coated particles to adhere to the surfaces of the droplets and forming granules. [2-1] A pharmaceutical composition comprising: a second granule containing an absorption enhancer; and an active ingredient-containing granule, comprising core particles B containing an active ingredient and a coated particle layer B coating the core particles B. [2-2] The pharmaceutical composition according to [2-1] above, wherein the active ingredient-containing granules does not contain an absorption enhancer. [2-3] The pharmaceutical composition according to [2-1] or [2-2] above, wherein the absorption enhancer comprises at least one selected from the group consisting of sodium caprate, sodium caprylate, SNAC, a cell membrane-permeable peptide, C-CPE, Angubindin-1, polyoxyethylene alkyl ethers, sodium lauryl sulfate, saponin, chitosan, cyclodextrin, alkyl saccharides, sucrose fatty acid esters, N-acyl amino acids, N-acyltaurines, glycocholic acid, taurocholic acid, deoxycholic acid, ethylenediaminetetraacetic acid (EDTA), sodium salicylate, sodium laurate, tryptophan, arginine, and fatty acids having 8 to 30 carbon atoms. [2-4] The pharmaceutical composition according to any one of [2-1] to [2-3] above, wherein the active ingredient is a polymer component.[2-5] A combination comprising: a second granule containing an absorption enhancer; and a medicinal ingredient-containing granule comprising core particles B containing a medicinal ingredient and a coated particle layer B coating the core particles B. [2-6] The combination according to the above [2-5], wherein the medicinal ingredient-containing granule does not contain an absorption enhancer. [2-7] The combination according to [2-5] or [2-6] above, wherein the absorption enhancer comprises at least one selected from the group consisting of sodium caprate, sodium caprylate, SNAC, a cell membrane-permeable peptide, C-CPE, Angubindin-1, polyoxyethylene alkyl ethers, sodium lauryl sulfate, saponin, chitosan, cyclodextrin, alkyl saccharides, sucrose fatty acid esters, N-acyl amino acids, N-acyltaurines, glycocholic acid, taurocholic acid, deoxycholic acid, ethylenediaminetetraacetic acid (EDTA), sodium salicylate, sodium laurate, tryptophan, arginine, and fatty acids having 8 to 30 carbon atoms. [2-8] The combination according to any of [2-5] to [2-7] above, wherein the medicinal ingredient-containing granules are administered simultaneously with the second granules. [2-9] An absorption-enhancing granule comprising a core particle A containing an absorption enhancer and a coated particle layer A coating the core particle A. [2-10] The absorption-enhancing granule according to [2-9] above, which does not contain an active ingredient. [2-11] The absorption-enhancing granule according to [2-9] or [2-10] above, wherein the core particle A further contains a thickener. [2-12] The absorption-enhancing granule according to any of [2-9] to [2-11] above, wherein the core particle A further contains a hydrophobic thickener. [2-13] The absorption-enhancing granule according to [2-11] or [2-12] above, wherein the thickener comprises at least one selected from the group consisting of carrageenan, gelatin, glycerin monostearate, agar, polyethylene glycol, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, aminoalkyl methacrylate copolymer, and ammonioalkyl methacrylate copolymer.[2-14] The absorption-enhancing granule according to any one of [2-9] to [2-13] above, wherein the coated particle layer A contains at least one selected from the group consisting of bentonite, ethyl cellulose, corn starch, rice starch, wheat starch, potato starch, calcium stearate, magnesium carbonate, low-substituted sodium carboxymethyl starch, sodium starch glycolate, silicic anhydride, magnesium silicate, diatomaceous earth, zeolite, silicon dioxide, powdered agar, croscarmellose sodium, crospovidone, and talc. [2-15] The absorption-enhancing granule according to any one of [2-9] to [2-14] above, wherein the core particle A further contains an enteric polymer. [2-16] A pharmaceutical composition comprising the absorption-enhancing granule according to any one of [2-9] to [2-15] above, and a first granule containing an active ingredient. [2-17] The pharmaceutical composition according to the above [2-16], wherein the first granule is a medicinal ingredient-containing granule comprising core particles B containing a medicinal ingredient and a coated particle layer B coating the core particles B. [2-18] The pharmaceutical composition according to the above [2-17], wherein the medicinal ingredient-containing granule does not comprise an absorption enhancer. [2-19] The pharmaceutical composition according to any of the above [2-16] to [2-18], wherein the medicinal ingredient is a polymer component. [2-20] A combination comprising the absorption-enhancing granule according to any of the above [2-9] to [2-15] and a first granule containing a medicinal ingredient. [2-21] The combination according to the above [2-20], wherein the first granule is a medicinal ingredient-containing granule comprising core particles B containing a medicinal ingredient and a coated particle layer B coating the core particles B. [2-22] The combination according to [2-21] above, wherein the active ingredient-containing granules do not contain an absorption enhancer. [2-23] The combination according to any of [2-20] to [2-22] above, wherein the first granules are administered simultaneously with the absorption-enhancing granules. [2-24] A method for producing the absorption-enhancing granules according to any of [2-9] to [2-15] above, comprising a granulation step of introducing droplets of a granulating solution containing an absorption enhancer into a fluidized bed in which coated particles are flowing, thereby causing the coated particles to adhere to the surfaces of the droplets and forming granules.

[0010] According to the present invention, there are provided granulated materials and the like which can provide a new method for applying absorption enhancers.

[0011] FIG. 1 is a schematic diagram of an absorption-enhancing granulation material according to one embodiment of the present invention.

[0012] Hereinafter, embodiments of the present invention will be described in detail.

[0013] 1. Absorption-Enhancing Granules The absorption-enhancing granules of one embodiment of the present invention comprise core particles A containing an absorption enhancer and a coated particle layer A that coats the core particles A.

[0014] The absorption-enhancing granules of one embodiment of the present invention preferably do not contain a medicinal ingredient. This can achieve at least one of the following effects: for example, it is possible to avoid interactions between the medicinal ingredient and the absorption enhancer within the formulation; it is possible to prepare granules containing additives suitable for the absorption enhancer; and it is possible to apply various formulation techniques to the absorption enhancer, such as providing sustained release properties. Furthermore, when optimizing the blending ratio of the medicinal ingredient and the absorption enhancer, it is possible to reduce the effort required to prepare formulations with different content ratios. Note that, as used herein, "granules" refers to a granular or particulate form in which one or more powdered components have been aggregated, bound, complexed, or the like to improve handleability.

[0015] The present invention will be described below with reference to the drawings. Note that the drawings may be exaggerated for the purpose of explanation and may differ from the actual dimensions.

[0016] 1 is a schematic diagram of an absorption-enhancing granulation according to one embodiment of the present invention. The absorption-enhancing granulation 10 comprises a core particle A1 containing an absorption enhancer and a coated particle layer A2 that coats the core particle A1. The presence of the coated particle layer A2 formed by the coated particles adhering to the surface of the core particle A1 allows the core particle A1 to be granulated into the shape of the absorption-enhancing granulation 10.

[0017] In one embodiment of the present invention, the absorption-enhancing granules 10 are formulated into a pharmaceutical composition (e.g., capsules) together with a separately prepared granule containing a medicinal ingredient. When such a pharmaceutical composition is ingested, the absorption-enhancing granules 10 are formulated to optimize the stability and pharmacokinetics of the absorption enhancer and the absorption-enhancing effect on the medicinal ingredient used, which may enhance the absorption of the medicinal ingredient in the pharmaceutical composition in the small intestine and reduce side effects.

[0018] The average particle size of the absorption-enhancing granules is preferably 10 to 1,000 μm, and more preferably 100 to 500 μm. An average particle size of 10 μm or more of the absorption-enhancing granules is preferable because sufficient hardness is obtained and the shape can be maintained during formulation processes such as tableting. On the other hand, an average particle size of 1,000 μm or less of the absorption-enhancing granules is preferable because the resulting tablets and the like can be easily ingested. In this specification, "particle size" refers to the maximum distance between two points on the outline of an object. Furthermore, "average particle size" refers to the average particle size of any 50 objects contained in one field of view of a scanning electron microscope (SEM).

[0019] Each component of the composition of the present invention will be described in detail below.

[0020] [Core particle A] Core particle A contains an absorption enhancer. Core particle A may further contain a thickener, an enteric polymer, an antacid, a pH adjuster, a solvent, an additive, etc. It is preferable that core particle A does not contain a medicinal ingredient.

[0021] (Absorption enhancer) The absorption enhancer is not particularly limited as long as it is a component that has the function of promoting the absorption of a medicinal ingredient, but for example, it has the function of acting on cell membranes, intercellular spaces, etc. in the small intestine, etc., to promote the absorption of a medicinal ingredient.

[0022] The absorption enhancer is not particularly limited, but preferably includes at least one selected from the group consisting of sodium caprate, sodium caprylate, SNAC, cell membrane-permeable peptides, C-CPE, Angubindin-1, polyoxyethylene alkyl ethers, sodium lauryl sulfate, saponin, chitosan, cyclodextrin, alkyl saccharides, sucrose fatty acid esters, N-acyl amino acids, N-acyltaurine, glycocholic acid, taurocholic acid, deoxycholic acid, ethylenediaminetetraacetic acid (EDTA), sodium salicylate, sodium laurate, tryptophan, arginine, and fatty acids having 8 to 30 carbon atoms; more preferably includes at least one selected from the group consisting of sodium caprate, sodium caprylate, SNAC, cell membrane-permeable peptides, C-CPE, Angubindin-1, and tryptophan; and even more preferably includes at least one selected from the group consisting of sodium caprate, SNAC, and tryptophan.

[0023] "SNAC," also known as sodium sulcaprozate, has the following structure:

[0024]

[0025] "C-CPE" includes the C-terminal fragment of Clostridium perfringens enterotoxin and mutants thereof, such as C-CPE184-319, C-CPE194-319, and C-CPE Y306W / S313H.

[0026] "Angubindin-1" is the amino acid region from positions 421 to 644 of the Ib component, one of two proteins (Ia component and Ib component) that constitute the iota toxin produced by Clostridium perfringens.

[0027] Examples of polyoxyethylene alkyl ethers include polyoxyethylene capryl ether, polyoxyethylene lauryl ether, polyoxyethylene myristyl ether, and polyoxyethylene stearyl ether.

[0028] Examples of alkyl saccharides include β-octylglucoside, β-decylglucoside, β-decylgalactoside, β-octylmannoside, β-dodecylmaltoside, β-dodecylisomaltoside, β-dodecylmaltotrioside, β-stearylglucoside, β-stearylgalactoside, β-stearylmannoside, β-stearylmaltoside, β-stearylisomaltoside, decyloligoglucoside, and dodecyloligoglucoside.

[0029] Examples of N-acyl amino acids include amino acids N-acylated with fatty acids having 8 to 30 carbon atoms, as described below. The amino acids are not particularly limited, but are preferably glutamic acid, aspartic acid, glycine, or alanine. The fatty acids are not particularly limited, but are preferably caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, or stearic acid, with lauric acid being more preferred.

[0030] Examples of sucrose fatty acid esters include those in which the hydroxy group of sucrose is esterified with a fatty acid having 8 to 30 carbon atoms, as described below. In this case, the fatty acid is not particularly limited, but is preferably caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, or stearic acid, and more preferably lauric acid. The sucrose fatty acid may be a monoester, diester, triester, tetraester, or a mixture thereof. The HLB (hydrophilic-lipophilic balance) of the sucrose fatty acid ester is preferably 1 to 18, more preferably 3 to 15.

[0031] Examples of fatty acids having 8 to 30 carbon atoms include saturated fatty acids having 8 to 30 carbon atoms and unsaturated fatty acids having 8 to 30 carbon atoms. Examples of saturated fatty acids having 8 to 30 carbon atoms include, but are not limited to, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, and behenic acid. Examples of unsaturated fatty acids having 8 to 30 carbon atoms include, but are not limited to, oleic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, arachidonic acid, docosahexaenoic acid, and eicosapentaenoic acid.

[0032] The above absorption enhancers may be used alone or in combination of two or more.

[0033] In one embodiment, the content of the absorption enhancer is preferably 0.01 to 80% by mass, 0.01 to 70% by mass, 0.01 to 60% by mass, 0.01 to 50% by mass, 0.01 to 30% by mass, 0.01 to 20% by mass, 0.01 to 15% by mass, 0.01 to 10% by mass, 0.1 to 70% by mass, 0.1 to 60% by mass, 0.1 to 50% by mass, 0.1 to 30% by mass, 0.1 to 20% by mass, 0.1 to 15% by mass, 0.1 to 10% by mass, 0.3 to 70% by mass, 0.3 to 60% by mass, 0.3 to 50% by mass, 0.3 to 30% by mass, 0.3 to 20% by mass, 0.3 to 15% by mass, 0.3 to 10% by mass, 1 to 70% by mass, 1 to 60 mass%, 1 to 50 mass%, 1 to 30 mass%, 1 to 20 mass%, 1 to 10 mass%, 3 to 70 mass%, 3 to 60 mass%, 3 to 50 mass%, 3 to 30 mass% %, 3-20% by mass, 3-10% by mass, 5-70% by mass, 5-60% by mass, 5-50% by mass, 5-30% by mass, 5-20% by mass, 5-10% by mass, 10-50 Mass%, 10-70% by mass, 10-60% by mass, 10-50% by mass, 10-30% by mass, 10-20% by mass, 15-70% by mass, 15-60% by mass, 15-5 More preferably, it is 0% by mass, 20-70% by mass, 20-60% by mass, 20-50% by mass, 30-70% by mass, 30-60% by mass, and 30-50% by mass. According to the absorption-enhancing granules of the present invention, the content of the absorption enhancer can be set over a wide range due to the shape-retaining function of the coated particle layer A, and for example, the shape of the absorption-enhancing granules can be suitably maintained even when a large amount of absorption enhancer is contained.

[0034] Furthermore, the absorption-enhancing granules of the present invention allow the content (proportion) of the absorption enhancer to be increased, and the absorption of the drug can be enhanced as the content (proportion) of the absorption enhancer increases (see, for example, Buckley et al., Sci. Transl. Med. 10, eaar7047 (2018) 14).

[0035] (Thickener) According to one embodiment of the present invention, the core particle A further contains a thickener. The thickener can have, for example, a function of stabilizing the shape of the core particle A, a function of adjusting the physical properties (hardness, etc.) of the absorption-enhancing granules, a function of promoting membrane permeation of the medicinal ingredient in the small intestine, etc. in the body, and the like.

[0036] Examples of thickeners include hydrophobic thickeners and hydrophilic thickeners. In this specification, the term "hydrophobic thickener" refers to a thickener whose solubility when 1 g of the thickener is added to 25 mL of water at 25° C. is less than 100 mg / mL. The term "hydrophilic thickener" refers to a thickener whose solubility when 1 g of the thickener is added to 25 mL of water at 25° C. is 100 mg / mL or more.

[0037] The hydrophobic thickener is not particularly limited, but examples thereof include glycerin monostearate, aminoalkyl methacrylate copolymer, ammonioalkyl methacrylate copolymer, and the like.

[0038] The hydrophilic thickener is not particularly limited, but examples thereof include carrageenan, gelatin, agar, polyethylene glycol, methyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropyl cellulose.

[0039] In one embodiment, the thickener preferably includes a hydrophobic thickener, more preferably glyceryl monostearate, which can improve bioavailability by promoting membrane permeation of the medicinal ingredient in the small intestine or the like in vivo.

[0040] In one embodiment, the thickener preferably includes carrageenan. Carrageenan can swell at least partially upon contact with water in the oral cavity, esophagus, stomach, and small intestine. As a result, for example, the carrageenan can inhibit the degradation of the absorption enhancer by digestive enzymes, gastric acid, etc., and can sustain the release of the absorption enhancer in the small intestine, thereby improving the absorption-enhancing effect of the medicinal ingredient.

[0041] In one embodiment, the thickener preferably comprises at least one selected from the group consisting of carrageenan, gelatin, glycerin monostearate, agar, polyethylene glycol, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, aminoalkyl methacrylate copolymer, and ammonioalkyl methacrylate copolymer, more preferably comprises at least one selected from the group consisting of carrageenan, gelatin, glycerin monostearate, agar, and polyethylene glycol, and even more preferably comprises at least one selected from the group consisting of carrageenan, gelatin, and glycerin monostearate.

[0042] The above-mentioned thickeners may be used alone or in combination of two or more kinds.

[0043] The content of the thickener is preferably 1 to 85% by mass, more preferably 1 to 75% by mass, and even more preferably 5 to 65% by mass, based on the total mass of the absorption-enhancing granulation product. A thickener content of 1% by mass or more is preferred because it makes it easier to maintain the shape after injection until granulation. On the other hand, a thickener content of 85% by mass or less is preferred because it makes it possible to adjust the viscosity of the granulation solution to a level suitable for injection.

[0044] (Enteric polymer) According to one embodiment of the present invention, the core particle A further contains an enteric polymer. The enteric polymer can have the function of suppressing the release and / or decomposition of the absorption enhancer in the stomach, for example, by encapsulating at least a portion of the absorption enhancer within the core particle A. In this specification, the term "enteric polymer" refers to a polymer that does not dissolve in the stomach but dissolves in the intestine. Furthermore, the term "enteric" refers to small intestinal enteric and / or large intestinal enteric, preferably small intestinal enteric.

[0045] The enteric polymer is not particularly limited, but includes methacrylic acid copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinyl acetate phthalate, cellulose acetate phthalate (ceracephate), ethyl acrylate-methyl methacrylate copolymer, carboxymethyl ethyl cellulose (CMEC), cellulose acetate phthalate (CAP), polyvinyl alcohol phthalate (PVAP), etc. Among these, the enteric polymer preferably contains at least one selected from the group consisting of methacrylic acid copolymer, HPMCP, and CMEC, and more preferably contains a methacrylic acid copolymer. The above-mentioned enteric polymers may be used alone or in combination of two or more.

[0046] The content of the enteric polymer is preferably 20% by mass or less, more preferably 15% by mass or less, and even more preferably 0.1 to 10% by mass, based on the total mass of the absorption-enhancing granules.

[0047] (Antacid) The core particle A may further contain an antacid. The antacid neutralizes gastric acid to increase the intragastric pH, thereby preventing the decomposition of the medicinal ingredient and the absorption enhancer, increasing the solubility of the absorption enhancer, etc.

[0048] Antacids are not particularly limited, but include sodium compounds, calcium compounds, magnesium compounds, aluminum compounds, and the like.

[0049] The sodium compound is sodium bicarbonate (NaHCO ３ ), sodium alginate, etc. Examples of the calcium compounds include calcium carbonate, etc. Examples of the magnesium compounds include magnesium oxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, etc. Examples of the aluminum compounds include aluminum hydroxide, aluminum silicate, etc.

[0050] Among these, the antacid preferably contains a sodium compound, such as sodium bicarbonate (NaHCO ３ The above-mentioned antacids may be used alone or in combination of two or more.

[0051] The content of the antacid is preferably 60% by mass or less, more preferably 0.01 to 50% by mass, and even more preferably 0.01 to 40% by mass, based on the total mass of the absorption-enhancing granules.

[0052] (pH Adjusting Agent) The core particle A may further contain a pH adjusting agent. The pH adjusting agent has the function of improving the stability of the absorption enhancer by controlling the pH inside the core particle A.

[0053] The pH adjuster is not particularly limited, but examples thereof include lactic acid, acetic acid, acetates (such as sodium acetate), citric acid, citrates (such as sodium citrate), phosphoric acid, phosphates (such as sodium phosphate), diisopropanolamine, triisopropanolamine, triethanolamine, potassium hydroxide, sodium hydroxide, L-arginine, etc. These pH adjusters may be used alone or in combination of two or more.

[0054] (Solvent) The core particles A may contain a solvent. The solvent has the function of adjusting the dispersibility of the absorption enhancer, the hardness of the absorption-enhancing granules, and the like.

[0055] The solvent may be water or an organic solvent.

[0056] The organic solvent is not particularly limited, but examples thereof include propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol dicaprate, propylene glycol monolaurate, propylene glycol monooleate, benzyl benzoate, octyldecyl triglyceride, oleic acid, triethyl citrate, dimethylpolysiloxane, cinnamaldehyde, medium-chain mono- and diglycerides, medium-chain fatty acid triglycerides, triacetin, piperonyl butoxide, diethyl phthalate, dibutyl phthalate, butylphthalyl butyl glycolate, octyldodecyl myristate, ethyl butyrate, ethanol, and isopropanol.

[0057] Of these, the solvent preferably contains water. The above-mentioned solvents may be used alone or in combination of two or more.

[0058] The content of the solvent is preferably 20% by mass or less, more preferably 0.01 to 15% by mass, and even more preferably 0.1 to 10% by mass, based on the total mass of the absorption-enhancing granules.

[0059] (Additives) The core particles A may contain additives.

[0060] The additives are not particularly limited, and examples thereof include colorants, masking agents, sweeteners, antioxidants, preservatives, lubricants, flavorings, etc. These additives may be used alone or in combination of two or more.

[0061] The average particle size of the core particles A is preferably 5 to 1000 μm, more preferably 10 to 800 μm, and even more preferably 100 to 500 μm. When the average particle size of the core particles is 5 μm or more, the proportion of the core particles can be increased, which is preferable. On the other hand, when the average particle size of the core particles is 1000 μm or less, the resulting tablets and the like can be of a size that is easy to take.

[0062] The core particles A preferably account for 90% by mass or less, and more preferably 10 to 90% by mass, of the total mass of the absorption-enhancing granules. When the core particles A account for 90% by mass or less, the shape stability of the absorption-enhancing granules can be improved, which is preferable.

[0063] [Coated particle layer A] The coated particle layer A of the absorption-enhancing granule of the present invention coats the core particles A. The coated particle layer A contains coated particles. The coated particles adhere to the surface of the core particles A to form a layer, thereby forming the coated particle layer A. The coated particle layer A of the present invention is layered, and includes a form in which the core particles A are completely coated and a form in which only a portion of the core particles A is coated. In a form in which only a portion of the core particles A is coated, the portion of the core particles A that is not coated with the coated particle layer A is exposed.

[0064] The coated particles are not particularly limited, but are usually water-insoluble particles. Specific examples of the coated particles include divalent or higher metal salts, inorganic substances, polysaccharides or derivatives thereof, and organic polymers.

[0065] Examples of the divalent or higher metal salts include calcium chloride, calcium carbonate, calcium oxide, calcium sulfate, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium stearate, magnesium chloride, magnesium carbonate, magnesium oxide, magnesium silicate, aluminum chloride, aluminum hydroxide, aluminum phosphate, aluminum sulfate, aluminum silicate, potassium alum, iron chloride alum, ammonium alum, ferric sulfate, iron citrate, zinc oxide, zinc sulfate, and hydrates thereof.

[0066] Examples of the inorganic substances include silicic anhydride, silicon dioxide, titanium oxide, kaolin, diatomaceous earth, bentonite, zeolite, and talc.

[0067] Examples of the polysaccharides or derivatives thereof include corn starch, rice starch, wheat starch, potato starch, powdered agar, crystalline cellulose, ethyl cellulose, croscarmellose sodium, low-substituted sodium carboxymethyl starch, sodium starch glycolate, and the like.

[0068] Examples of the organic polymer include crospovidone, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer S, and ammonioalkyl methacrylate copolymer.

[0069] Among these, the coated particle layer A preferably contains at least one coated particle selected from the group consisting of bentonite, ethyl cellulose, corn starch, rice starch, wheat starch, potato starch, calcium stearate, magnesium carbonate, low-substituted sodium carboxymethyl starch, sodium starch glycolate, silicic anhydride, magnesium silicate, diatomaceous earth, zeolite, silicon dioxide, powdered agar, croscarmellose sodium, crospovidone, and talc, and preferably contains bentonite and / or corn starch. Bentonite can, for example, act on the carrageenan thickener present in the core particle A to promote swelling of the carrageenan. This allows the absorption-enhancing granules to preferably exhibit enteric properties, more preferably small intestinal enteric properties. In one embodiment, the absorption-enhancing granules preferably contain core particle A containing an absorption enhancer and carrageenan, and a coated particle layer A containing bentonite that coats the core particle A. The above-mentioned coated particles may be used alone or in combination of two or more kinds.

[0070] The average particle size of the coated particles is preferably 1 to 100 μm, more preferably 2 to 50 μm, and even more preferably 3 to 30 μm. An average particle size of 1 μm or more is preferable because the fluidity of the coated particles can be increased. On the other hand, an average particle size of 100 μm or less is preferable because the surface area is small and the bonding strength with the core particles A can be increased. In one embodiment, the average particle size of the coated particles is preferably 30 to 100 μm, more preferably 30 to 80 μm, even more preferably 30 to 70 μm, and particularly preferably 40 to 60 μm, from the viewpoint that the increased voids between the particles allow the core particles A to favorably come into contact with digestive fluids (saliva, gastric acid, intestinal juice, pancreatic juice, etc.), thereby improving absorbability.

[0071] The coated particle layer A preferably accounts for 90% by mass or less, more preferably 10 to 85% by mass, even more preferably 15 to 70% by mass, and particularly preferably 20 to 70% by mass of the total mass of the absorption-enhancing granules. When the coated particle layer A accounts for 90% by mass or less, the shape stability of the absorption-enhancing granules can be improved, which is preferable.

[0072] 2. Method for Producing Absorption-Enhancing Granules According to one embodiment of the present invention, there is provided a method for producing absorption-enhancing granules. The production method of the present invention includes a granulation step of introducing droplets of a granulating solution containing an absorption enhancer into a fluidized bed in which coated particles are flowing, and adhering the coated particles to the surfaces of the droplets to form granules. When the coated particles are adhering to the surfaces of the droplets of the granulating solution, components of the granulating solution (thickener, solvent, etc.) are absorbed by the coated particles, thereby forming granules.

[0073] [Granulation step] The granulation step can be performed using, for example, the granulation method described in JP 2019-073459 A. Specifically, the granulation step is a step of introducing droplets of a granulation solution containing an absorption enhancer into a fluidized bed in which coated particles are flowing, and adhering the coated particles to the surfaces of the droplets to form granules. More specifically, a predetermined amount of the granulation solution is intermittently injected, and droplets of the granulation solution are introduced into a fluidized bed of coated particles, and the coated particles are allowed to adhere to the surfaces of the droplets, allowing components (thickener, solvent, etc.) to be absorbed by the coated particles.

[0074] (Granulation solution) The granulation solution contains an absorption enhancer. The granulation solution may further contain a thickener, an enteric polymer, an antacid, a pH adjuster, a solvent, an additive, etc. It is preferable that the granulation solution does not contain an active ingredient. The granulation solution may be contained in core particles A of the absorption-enhancing granules.

[0075] The components such as the absorption enhancer, thickener, enteric polymer, antacid, pH adjuster, solvent, and additives are as described above.

[0076] The content of each component, such as the absorption enhancer, thickener, enteric polymer, antacid, pH adjuster, solvent, and additive, is preferably adjusted so that the content of each component in the core particle A of the absorption-enhancing granule falls within the above-mentioned range. The content of the core particle A in the absorption-enhancing granule and the average particle size of the core particle A can be adjusted by adjusting the content of the solids in the granulation solution (the total content of components other than the solvent in the granulation solution).

[0077] In one embodiment, the granulating solution preferably contains water. In this case, the water content is preferably 60 to 98% by mass, more preferably 70 to 95% by mass, and even more preferably 80 to 90% by mass, based on the total mass of the granulating solution. When the water content is within the above range, the absorption-enhancing granules can be suitably formed when droplets of the granulating solution are introduced into a fluidized bed of coated particles, as described below.

[0078] The viscosity of the granulating solution is not particularly limited, but is preferably 0.5 to 20,000 mPa, and more preferably 1 to 10,000 mPa. A viscosity of 0.5 mPa or more is preferred because the shape of the injected droplets of the granulating solution is easily maintained when they are introduced into a fluidized bed. A viscosity of 20,000 mPa or less is preferred because productivity is excellent.

[0079] (Injection of Granulation Solution) The granulation solution is preferably injected intermittently in a predetermined amount. At this time, the injected granulation solution is in the form of droplets. The injection of the granulation solution can be performed, for example, by a liquid formulation constant amount ejection device equipped with an ejection nozzle.

[0080] The amount of the granulating solution ejected per injection can usually be controlled by the nozzle diameter and ejection pressure of the ejection nozzle of the liquid formulation metered ejection device. The average particle size of the core particles A can be controlled by adjusting the amount of the granulating solution ejected.

[0081] The nozzle diameter of the discharge nozzle is not particularly limited, but is preferably 0.1 to 1.0 mm, and more preferably 0.2 to 0.5 mm. A discharge nozzle diameter of 0.1 mm or more is preferred from the viewpoints of being able to discharge even a highly viscous granulation solution and of achieving excellent productivity. On the other hand, a discharge nozzle diameter of 1.0 mm or less is preferred because the shape of the droplets can be maintained when they come into contact with the fluidized bed.

[0082] The discharge pressure is not particularly limited, but is preferably 0.1 to 5.0 MPa, and more preferably 0.1 to 2.0 MPa. A discharge pressure of 0.1 MPa or more is preferred from the viewpoints of being able to discharge even a highly viscous granulation solution and of being excellent in productivity. On the other hand, a discharge pressure of 5.0 MPa or less is preferred because the shape of the droplets can be maintained when they come into contact with the fluidized bed.

[0083] The time interval between injections of the granulating solution (intermittent time) is usually controlled by the intermittent injection rate of the liquid dosage form dispenser. There are no particular limitations on the intermittent injection rate, but it is preferably 500 to 50,000 rpm, and more preferably 1,000 to 20,000 rpm. An intermittent injection rate of 500 rpm or more is preferred because it can increase productivity. On the other hand, an intermittent injection rate of 50,000 rpm or less is preferred because it can suppress heat generation in the device due to friction. In this specification, "intermittent injection rate" means the number of injections per minute.

[0084] (Addition to fluidized bed) The injected droplets of the granulation solution are added to the fluidized bed. Coated particles are contained in the fluidized bed, and when the droplets come into contact with the coated particles in the fluidized bed, the coated particles adhere to the surface of the droplets. Next, the attached coated particles absorb the components in the droplets (thickener, solvent, etc.), reducing the fluidity of the droplets and turning into core particles A. Furthermore, the coated particles attached to core particles A form a layer structure, turning into coated particle layer A. This allows the production of an absorption-enhancing granulation product. The coated particles are as described above.

[0085] A fluidized bed can be, for example, a pan granulator containing coated particles and tumbling them. The rotating pan (dish) provides a rolling motion to the coated particles, allowing the coated particles to form a layered structure when droplets come into contact with the coated particles. This also prevents or suppresses collisions with subsequent droplets.

[0086] The vibration applied to the coated particles in the fluidized bed is not particularly limited, but is preferably 10 to 500 rpm, more preferably 20 to 200 rpm. A vibration of 10 rpm or more is preferred because it can prevent or suppress collisions with subsequent droplets. On the other hand, a vibration of 500 rpm or less is preferred because it can suppress deviation of the coated particles due to centrifugal force.

[0087] 3 Pharmaceutical Composition One aspect of the present invention provides a pharmaceutical composition. The pharmaceutical composition comprises a granulated material containing an absorption enhancer and a granulated material containing a medicinal ingredient. In this specification, the term "pharmaceutical composition" refers to a product prepared by combining granulated material, additives, etc., and molding, filling, packaging, etc. into a single formulation suitable for administration by a patient. Examples of the pharmaceutical composition include solid formulations such as tablets, capsules, powders, and fine granules, and liquid formulations such as suspensions. The pharmaceutical composition is preferably a solid formulation, more preferably a tablet, capsule, or powder, and even more preferably a tablet or capsule.

[0088] As described above, the pharmaceutical composition may be formulated using a "granulation containing an absorption enhancer" and a "granulation containing a medicinal component" that are separately prepared. Therefore, the granulation containing an absorption enhancer and the granulation containing a medicinal component are not particularly limited, and known materials may be used. For example, the pharmaceutical composition may contain the above-described absorption-enhancing granulation as the "granulation containing an absorption enhancer," and any granulation as the "granulation containing a medicinal component" (first embodiment). Furthermore, the pharmaceutical composition may contain any granulation as the "granulation containing an absorption enhancer," and a medicinal component-containing granulation as the "granulation containing a medicinal component" (the absorption-enhancing granulation described above contains a medicinal component instead of the absorption enhancer, as described in detail below) (second embodiment).

[0089] 3-1 First embodiment (form containing absorption-enhancing granules and granules containing an optional medicinal ingredient) In the first embodiment, the pharmaceutical composition contains the absorption-enhancing granules described above and a first granule containing a medicinal ingredient. That is, the first embodiment is a pharmaceutical composition containing the absorption-enhancing granules described above.

[0090] <Absorption-promoting granules> The absorption-promoting granules described above can be used. In this case, the absorption-promoting granules may be used alone or in combination of two or more kinds.

[0091] The content of the absorption enhancer is preferably 0.01 to 90% by mass, more preferably 0.01 to 80% by mass, relative to the total mass of the absorption-enhancing granules and the first granules. The content of the absorption enhancer is preferably 1 to 500 parts by mass, more preferably 1 to 300 parts by mass, and even more preferably 1 to 200 parts by mass, 1 to 100 parts by mass, 1 to 70 parts by mass, 1 to 60 parts by mass, 1 to 50 parts by mass, 1 to 20 parts by mass, 1 to 10 parts by mass, 1 to 5 parts by mass, 10 to 100 parts by mass, 20 to 100 parts by mass, 50 to 200 parts by mass, 60 to 200 parts by mass, 70 to 200 parts by mass, or 100 to 200 parts by mass.

[0092] <First Granulated Material> The first granulated material contains a medicinal ingredient.

[0093] The form of the first granules is not limited and may be any form. Examples of the first granules include agglomerated granules in which the medicinal ingredient is aggregated via a binder or the like, layered granules containing excipient core particles and a coating layer containing the medicinal ingredient that coats the excipient core particles, and granules containing core particles B containing the medicinal ingredient and a coating particle layer B that coats the core particles B (hereinafter also referred to as "medicinal ingredient-containing granules"). These first granules may be used alone or in combination of two or more types.

[0094] Of these, the first granule is preferably a medicinal ingredient-containing granule comprising core particles B containing a medicinal ingredient and a coated particle layer B coating the core particles B. That is, in a preferred embodiment, the pharmaceutical composition comprises the absorption-enhancing granule described above, and the first granule is a medicinal ingredient-containing granule comprising core particles B containing a medicinal ingredient and a coated particle layer B coating the core particles B.

[0095] Hereinafter, the case where the first granules are granules containing a medicinal ingredient will be described in detail.

[0096] The medicinal ingredient-containing granules have a configuration in which a medicinal ingredient is used instead of the absorption enhancer contained in the absorption-enhancing composition. That is, the medicinal ingredient-containing granules preferably do not contain an absorption-enhancing composition. It is preferable to appropriately adjust the configuration of the medicinal ingredient-containing granules depending on the type of medicinal ingredient, etc.

[0097] [Core particle B] Core particle B contains a medicinal ingredient. Core particle B may further contain a thickener, an enteric polymer, an antacid, a pH adjuster, a solvent, an additive, etc. It is preferable that core particle B does not contain an absorption enhancer.

[0098] (Medicinally Active Ingredient) The medicinally active ingredient is not particularly limited, but is preferably a polymeric ingredient. In this specification, the term "polymeric" means a molecular weight of 500 or more, preferably 500 to 1,000,000, more preferably 500 to 200,000, and even more preferably 500 to 10,000.

[0099] Examples of the polymer component include antibodies, peptides, proteins, polymerized substances, nucleic acids, and biosimilars thereof.

[0100] Specific examples of the polymer component include insulin, calcitonin, angiotensin, vasopressin, desmopressin, LH-RH (luteinizing hormone-releasing hormone), somatostatin, glucagon, oxytocin, gastrin, cyclosporine, somatomedin, secretin, h-ANP (human atrial natriuretic peptide), ACTH (adrenocorticotropic hormone), MSH (melanophore-stimulating hormone), β-endorphin, muramyl dipeptide, enkephalin, and the like. Examples of such hormones include phospholipids, neurotensin, bombesin, VIP (vasoactive intestinal peptide), CCK-8 (cholecystokinin-8), PTH (parathyroid hormone), CGRP (calcitonin gene-related peptide), TRH (thyrotropin-releasing hormone), endothelin, hGH (human growth hormone), cytokines such as interleukins, interferons, colony-stimulating factors, and tumor necrosis factors, GLP-1 receptor agonists (semaglutide), and cyanocobalamin.

[0101] These medicinal ingredients may be used alone or in combination of two or more.

[0102] In one embodiment, the content of the medicinal ingredient is preferably 0.01 to 10% by mass, more preferably 0.01 to 5% by mass, more preferably 0.03 to 3% by mass, even more preferably 0.05 to 1% by mass, and particularly preferably 0.15 to 0.8% by mass, relative to the total mass of the medicinal ingredient-containing granulated product. In another embodiment, the content of the medicinal ingredient is preferably 0.1 to 10% by mass, more preferably 0.4 to 10% by mass, even more preferably 0.4 to 5% by mass, even more preferably 1 to 10% by mass, particularly preferably 1 to 5% by mass, and most preferably 1.5 to 4% by mass, relative to the total mass of the medicinal ingredient-containing granulated product.

[0103] (Thickener, enteric polymer, antacid, pH adjuster, solvent, additive) The core particle B may further contain at least one of a thickener, an enteric polymer, an antacid, a pH adjuster, a solvent, an additive, and the like.

[0104] The thickener, enteric polymer, antacid, pH adjuster, solvent, and additives that can be used are the same as those used in the core particles A of the absorption-enhancing granules.

[0105] [Coated Particle Layer B] The coated particle layer B coats the core particles B. The coated particle layer B can have the same configuration as the coated particle layer A of the absorption-enhancing granules.

[0106] [Content of First Granules, etc.] The content of the first granules is preferably 0.01 to 80% by mass, more preferably 0.01 to 50% by mass, based on the total mass of the absorption-enhancing granules and the first granules. The content of the medicinal ingredient is preferably 0.01 to 20% by mass, more preferably 0.01 to 10% by mass, based on the total mass of the absorption-enhancing granules and the first granules.

[0107] <Additives> The pharmaceutical composition may further contain an additive. Note that the additive is usually different from the additives that may be contained in the absorption-enhancing granules and the first granules, and is an additive that is used during the production (formulation) of the pharmaceutical composition.

[0108] As the additives, known additives can be used, and examples thereof include excipients, binders, disintegrants, lubricants, coating agents, preservatives, emulsifiers, solvents, solubilizers, buffers, isotonicity agents, soothing agents, flavoring agents, coloring agents, etc.

[0109] 3-2 Second embodiment (form including granules containing any absorption enhancer and medicinal ingredient-containing granules) In the second embodiment, the pharmaceutical composition includes a second granule containing an absorption enhancer, and a medicinal ingredient-containing granule including core particles B containing an active ingredient and a coated particle layer B coating the core particles B. That is, the second embodiment is a pharmaceutical composition including the medicinal ingredient-containing granules described in the first embodiment above.

[0110] <Second Granulated Material> The second granulated material contains an absorption enhancer.

[0111] The form of the second granules is not particularly limited as long as it is a form other than the absorption-enhancing granules described above, and any form may be used. Examples of the second granules include agglomerated granules in which the absorption enhancer is agglomerated via a binder or the like, and layered granules containing excipient core particles and a coating layer containing an absorption enhancer that coats the excipient core particles. These second granules may be used alone or in combination of two or more. The second granules may further contain an antacid.

[0112] The absorption enhancer used in the second granule is the same as that used in the absorption enhancing granule.

[0113] In one embodiment, the content of the absorption enhancer is preferably 0.01 to 80% by mass, more preferably 0.01 to 70% by mass, based on the total mass of the second granules.

[0114] The second granules can be prepared by a known method.

[0115] The content of the second granules is preferably 0.01 to 90% by mass, and more preferably 0.01 to 80% by mass, relative to the total mass of the second granules and the medicinal ingredient-containing granules. The content of the absorption enhancer is preferably 1 to 500 parts by mass, more preferably 1 to 300 parts by mass, and even more preferably 1 to 200 parts by mass, 1 to 100 parts by mass, 1 to 70 parts by mass, 1 to 60 parts by mass, 1 to 50 parts by mass, 1 to 20 parts by mass, 1 to 10 parts by mass, 1 to 5 parts by mass, 10 to 100 parts by mass, 20 to 100 parts by mass, 50 to 200 parts by mass, 60 to 200 parts by mass, 70 to 200 parts by mass, or 100 to 200 parts by mass.

[0116] <Medicinally Active Ingredient-Containing Granules> The medicinally active ingredient-containing granules described above can be used. In this case, the medicinally active ingredient-containing granules may be used alone or in combination of two or more. The content of the medicinally active ingredient-containing granules is preferably 0.01 to 80% by mass, more preferably 0.01 to 50% by mass, based on the total mass of the second granules and the medicinally active ingredient-containing granules. Furthermore, the content of the medicinally active ingredient is preferably 0.01 to 20% by mass, more preferably 0.01 to 10% by mass, based on the total mass of the second granules and the medicinally active ingredient-containing granules.

[0117] <Additives> The pharmaceutical composition may further contain an additive. Note that the additive is usually different from the additives that may be contained in the second granules and the medicinal ingredient-containing granules, and is an additive that is used during the production (formulation) of the pharmaceutical composition.

[0118] As the additives, known additives can be used, and examples thereof include excipients, binders, disintegrants, lubricants, coating agents, preservatives, emulsifiers, solvents, solubilizers, buffers, isotonicity agents, soothing agents, flavoring agents, coloring agents, etc.

[0119] Furthermore, in the second embodiment, the pharmaceutical composition may further contain an antacid. When an antacid is used in the second embodiment, the antacid may be the same as that used in core particle A, and the preferred antacid is also the same as that used in core particle A. In the second embodiment, the content of the antacid is preferably 60% by mass or less, more preferably 0.01 to 50% by mass, and even more preferably 0.01 to 40% by mass, based on the total content of the antacid and the absorption enhancer.

[0120] 4. Combination According to one aspect of the present invention, a combination is provided. The combination comprises a granule containing an absorption enhancer and a granule containing a medicinal ingredient. In this specification, the term "combination" refers to a combination of two or more granules or pharmaceutical compositions that are each prepared separately and taken separately.

[0121] 4-1 First Embodiment In the first embodiment, the combination drug contains the absorption-enhancing granules described above and a first granule containing an active ingredient. That is, in the first embodiment, the absorption-enhancing granules and the first granule are each taken separately.

[0122] The absorption-promoting granules and the first granules can be those described above. In this case, the absorption-promoting granules and the first granules can be used alone or in combination of two or more.

[0123] In one embodiment, the combination drug comprises an absorption-enhancing granule, which includes a core particle A containing an absorption enhancer and a coated particle layer A that coats the core particle A, and a medicinal ingredient-containing granule, which includes a core particle B containing an active ingredient and a coated particle layer B that coats the core particle A. Because the absorption-enhancing granule and the medicinal ingredient-containing granule have similar structures, they can be adjusted to have a composition suitable for absorption of the active ingredient when taken.

[0124] The first granule may be administered before, simultaneously with, or after the absorption-enhancing granule. In a preferred embodiment, the first granule is administered simultaneously with the absorption-enhancing granule. Simultaneous administration can facilitate formulation design, improve compliance, and other effects.

[0125] 4-2 Second Embodiment In a second embodiment, the combination drug comprises a second granule containing an absorption enhancer, and a medicinal ingredient-containing granule containing core particles B containing an active ingredient and a coated particle layer B coating the core particles.

[0126] The second granules and the medicinal ingredient-containing granules can be those described above. In this case, the second granules and the medicinal ingredient-containing granules can be used alone or in combination of two or more.

[0127] The active ingredient-containing granules may be administered before, simultaneously with, or after the second granules. In a preferred embodiment, the first granules are administered simultaneously with the absorption-enhancing granules. Simultaneous administration can facilitate formulation design, improve compliance, and other effects.

[0128] The absorption-promoting granules and the first granules used in the first embodiment, and the second granules and the medicinal ingredient-containing granules used in the second embodiment are granules, and therefore may be difficult to take. Therefore, from the viewpoint of making them easier to take, at least one of the absorption-promoting granules, the first granules, the second granules, and the medicinal ingredient-containing granules can be made into a pharmaceutical composition form (tablets, capsules, etc.) using an additive.

[0129] The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

[0130] Preparation Example 1 A medicinal ingredient-containing granulated product was prepared, which included core particles B containing insulin as the medicinal ingredient and coated particle layer B coating the core particles B.

[0131] Specifically, gelatin as a thickener and water were heated to 90°C to dissolve, and then the temperature was lowered to 70°C, after which insulin was added to prepare a granulation solution.

[0132] The prepared granulation solution was heated to 80° C. and charged into a liquid formulation constant-amount discharge device (discharge nozzle diameter: 0.3 mm), and the discharge pressure was set to 0.5 MPa and the intermittent injection rate to 10,000 rpm.

[0133] An open-pan granulator (pan diameter: 300 mm) was placed 70 cm below the discharge nozzle, and corn starch (average particle size: 50 μm) was placed in the open-pan granulator. The open-pan granulator was orbitally vibrated at 90 rpm to form a fluidized bed in which the corn starch tumbled and flowed.

[0134] The granulating solution was intermittently injected from a liquid dosage unit, and droplets of the granulating solution were introduced into the fluidized bed. Corn starch adhered to the surface of the droplets, producing a medicinal ingredient-containing granule having core particles derived from the granulating solution and a corn starch coating particle layer. The medicinal ingredient-containing granules and corn starch from the open-pan granulator were classified, and the medicinal ingredient-containing granules in the fraction that fell under a 500 μm sieve and over a 180 μm sieve were collected. The composition of the medicinal ingredient-containing granules prepared is shown in Table 1.

[0135] Example 1-1 An absorption-enhancing granulated product was prepared, which included core particles A containing L-tryptophan as an absorption enhancer and a coated particle layer A coating the core particles A.

[0136] Specifically, an absorption-enhancing granule was prepared in the same manner as in Preparation Example 1, except that L-tryptophan was used instead of insulin and the composition was adjusted to be as shown in Table 1.

[0137]

[0138] Example 2-1 A pharmaceutical composition was prepared by suspending 46.2 parts of the medicinal ingredient-containing granules of Preparation Example 1 and 53.8 parts of the absorption-enhancing granules of Example 1-1 in 5720.8 parts of water.

[0139] Example 2-2 A pharmaceutical composition was produced by suspending 16.6 parts of the active ingredient-containing granules of Preparation Example 1, 19.3 parts of the absorption-enhancing granules of Example 1-1, and 64.1 parts of the absorption enhancer sulcaprozate sodium (SNAC) in 2054.2 parts of water.

[0140] Example 2-3 A pharmaceutical composition was prepared by suspending 20.6 parts of the active ingredient-containing granules of Preparation Example 1 and 79.4 parts of sulcaprozate sodium (SNAC) as an absorption enhancer in 2545.8 parts of water.

[0141] [Examples 2-4] A pharmaceutical composition was produced by suspending 15.1 parts of the active ingredient-containing granules of Preparation Example 1, 26.5 parts of sodium bicarbonate, and 58.4 parts of the absorption enhancer sulcaprozate sodium (SNAC) in 1,870.6 parts of water.

[0142] Comparative Example 2-1 An aqueous insulin solution (concentration: 0.36% by mass) was used as a control.

[0143] Comparative Example 2-2 A pharmaceutical composition was prepared by suspending 100 parts of the medicinal ingredient-containing granules of Preparation Example 1 in 12,376.2 parts of water.

[0144] The pharmaceutical compositions produced in Examples 2-1 to 2-4 and Comparative Examples 2-1 to 2-2 are shown in Table 2. In Table 2, the mass % value of each component means the content relative to the solid content of the pharmaceutical composition (the content relative to the total mass of the solid content excluding water as a solvent).

[0145]

[0146] [Evaluation] Blood glucose levels and blood insulin concentrations were evaluated.

[0147] Male Sprague-Dawley (SD) rats (Japan LSC Co., Ltd.) were orally administered the pharmaceutical compositions or controls prepared in Examples 2-1 to 2-4 and Comparative Examples 2-1 to 2-2 at an insulin dose of 25 U / kg or 50 U / kg, and an insulin solution (control) was subcutaneously administered via the dorsal neck at an insulin dose of 1 U / kg.

[0148] For both oral and subcutaneous administration, blood was collected from the tail vein immediately before administration and 15, 30, 60, 120, 180, 240, and 300 minutes after administration, and blood glucose levels were measured using a OneTouch UltraView (LifeScan Japan).

[0149] Relative blood glucose levels were calculated by dividing the post-administration blood glucose level by the blood glucose level immediately before administration. AAC (area above the curve) was calculated using the trapezoidal area method from a graph plotting relative blood glucose levels against the time elapsed after administration. Pharmacological availability (PA) was calculated by dividing the AAC after oral administration by the AAC after subcutaneous administration and correcting for the dose ratio.

[0150] (Blood Insulin Concentration) The pharmaceutical compositions prepared in Examples 2-3 to 2-4 and Comparative Example 2-2 were orally administered to male Sprague-Dawley (SD) rats (Japan LSC Co., Ltd.) so that the insulin dose was 50 U / kg.

[0151] Blood was collected from the tail vein immediately after administration and 10, 15, 30, 60, 90, and 120 minutes after administration, and blood insulin concentrations were measured using a Mercodia insulin ELISA kit (Mercodia).

[0152] AUC (area under the curve; area under the blood concentration-time curve) was calculated by the trapezoidal area method from a graph plotting blood insulin concentration against the time elapsed after administration.

[0153]

[0154] The results in Table 3 show that the pharmaceutical compositions of Examples 2-1 to 2-4 enabled insulin to be absorbed in the small intestine.

[0155] 1 Core particle A 2 Coated particle layer A 10 Absorption-promoting granules

Claims

1. A pharmaceutical composition comprising: a second granule containing an absorption enhancer; and a medicinal ingredient-containing granule containing a core particle B containing an active ingredient and a coated particle layer B coating the core particle B.

2. The pharmaceutical composition according to claim 1, wherein the granules containing the active ingredient do not contain an absorption enhancer.

3. The pharmaceutical composition according to claim 1, wherein the absorption enhancer comprises at least one selected from the group consisting of sodium caprate, sodium caprylate, SNAC, cell membrane permeable peptide, C-CPE, Angubindin-1, polyoxyethylene alkyl ethers, sodium lauryl sulfate, saponin, chitosan, cyclodextrin, alkyl saccharide, sucrose fatty acid ester, N-acyl amino acid, N-acyltaurine, glycocholic acid, taurocholic acid, deoxycholic acid, ethylenediaminetetraacetic acid (EDTA), sodium salicylate, sodium laurate, tryptophan, arginine, and fatty acids having 8 to 30 carbon atoms.

4. The pharmaceutical composition according to claim 1, wherein the medicinal ingredient is a polymeric ingredient.

5. A combination agent comprising: a second granule containing an absorption enhancer; and a medicinal ingredient-containing granule containing a core particle B containing an active ingredient and a coated particle layer B coating the core particle B.

6. The combination according to claim 5, wherein the granules containing the active ingredient do not contain an absorption enhancer.

7. The combination according to claim 5, wherein the absorption enhancer comprises at least one selected from the group consisting of sodium caprate, sodium caprylate, SNAC, cell membrane permeable peptide, C-CPE, Angubindin-1, polyoxyethylene alkyl ethers, sodium lauryl sulfate, saponin, chitosan, cyclodextrin, alkyl saccharide, sucrose fatty acid ester, N-acyl amino acid, N-acyltaurine, glycocholic acid, taurocholic acid, deoxycholic acid, ethylenediaminetetraacetic acid (EDTA), sodium salicylate, sodium laurate, tryptophan, arginine, and fatty acid having 8 to 30 carbon atoms.

8. The combination according to claim 5, wherein the active ingredient-containing granule is administered simultaneously with the second granule.

9. An absorption-enhancing granule comprising a core particle A containing an absorption enhancer and a coating particle layer A coating the core particle A.

10. The absorption-enhancing granule according to claim 9, which does not contain any medicinal ingredient.

11. The absorption-promoting granule according to claim 9, wherein the core particle A further contains a thickener.

12. The absorption-promoting granule according to claim 9, wherein the core particle A further contains a hydrophobic thickener.

13. The absorption-promoting granulation of claim 11, wherein the viscosity increasing agent comprises at least one selected from the group consisting of carrageenan, gelatin, glyceryl monostearate, agar, polyethylene glycol, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, aminoalkylmethacrylate copolymer, and ammonioalkylmethacrylate copolymer.

14. The absorption-promoting granule described in claim 9, wherein the coated particle layer A contains at least one selected from the group consisting of bentonite, ethyl cellulose, corn starch, rice starch, wheat starch, potato starch, calcium stearate, magnesium carbonate, low-substituted sodium carboxymethyl starch, sodium starch glycolate, anhydrous silicic acid, magnesium silicate, diatomaceous earth, zeolite, silicon dioxide, powdered agar, croscarmellose sodium, crospovidone, and talc.

15. The absorption-promoting granule according to claim 9, wherein the core particle A further contains an enteric polymer.

16. A pharmaceutical composition comprising: an absorption-promoting granule according to any one of claims 9 to 15; and a first granule containing an active ingredient.

17. The pharmaceutical composition according to claim 16, wherein the first granule is a granule containing an active ingredient, comprising a core particle B containing an active ingredient and a coating particle layer B coating the core particle B.

18. The pharmaceutical composition according to claim 17, wherein the active ingredient-containing granules do not contain an absorption enhancer.

19. The pharmaceutical composition according to claim 16, wherein the medicinal ingredient is a polymeric ingredient.

20. A combination comprising the absorption-promoting granule according to any one of claims 9 to 15 and a first granule containing an active ingredient.

21. The combination according to claim 20, wherein the first granule is a granule containing an active ingredient, comprising core particles B containing an active ingredient and a coating particle layer B coating the core particles B.

22. The combination according to claim 21, wherein the granules containing the active ingredient do not contain an absorption enhancer.

23. The combination of claim 20, wherein said first granulation is co-administered with said absorption enhancing granulation.

24. A method for producing an absorption-enhancing granule according to any one of claims 9 to 15, comprising a granulation step of introducing droplets of a granulation solution containing an absorption enhancer into a fluidized bed in which coated particles are flowing, and adhering the coated particles to the surfaces of the droplets to form granules.

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