Tablets, medicines, and their manufacturing methods and kits

Abstract

The present invention addresses the problem of providing a tablet or the like having excellent permeability and retainability of a pharmaceutically active ingredient. The problem can be solved by a tablet which contains a monosaccharide and / or a disaccharide, and is for impregnating a pharmaceutically active ingredient.

Description

[Technical Field]

[0001] The present invention relates to a tablet, a medicine, a method for producing the same, and a kit. [Background technology]

[0002] Conventional methods for producing tablets include mixing pharmaceutically active ingredients, excipients, binders, etc., and compressing the mixture into tablets. In such methods, the tablets produced contain all of the desired pharmaceutically active ingredients.

[0003] As a new tablet manufacturing method, for example, Non-Patent Document 1 discloses a method in which a liquid-fillable tablet (LLT) containing magnesium aluminometasilicate, crospovidone, and magnesium stearate and a cyclosporine-containing self-microemulsifying drug delivery system (CyA-SMEDDS) are prepared, and the LLT is immersed in an excess amount of CyA-SMEDDS. In this method, the initially prepared LLT does not contain the active pharmaceutical ingredient (cyclosporine), and cyclosporine is added to the LLT later. [Prior art documents] [Patent documents]

[0004] [Non-Patent Document 1] AAPS PharmSciTech,Vol.10,No.4,pp.1388-1395(2009) Summary of the Invention [Problem to be solved by the invention]

[0005] The method of adding a pharmaceutically active ingredient to a tablet later has various advantages over conventional tablet manufacturing methods. However, the porous inorganic particles, silica, used in the prior art have silanol groups on their surface, which may interact with the pharmaceutically active ingredient and other compounded ingredients. Furthermore, the carrier itself is insoluble. Therefore, the pharmaceutically active ingredient adsorbed inside the carrier is released only by natural diffusion in liquid, resulting in inferior release properties compared to conventional tablets, which are released by tablet disintegration or dissolution of ingredients. Therefore, it is desirable to develop a new tablet for use in this method without using porous inorganic silica particles, which have various problems. Such a tablet preferably has the properties of a conventional tablet and, in addition, is easily permeable to the pharmaceutically active ingredient and has high retention properties for the permeated pharmaceutically active ingredient.

[0006] Therefore, an object of the present invention is to provide a tablet having excellent permeability and retention of a pharmaceutically active ingredient, a medicine using the same, methods for producing the tablet and the medicine, and a kit. [Means for solving the problem]

[0007] As a result of extensive research, the present inventors have found that tablets containing monosaccharides and / or disaccharides are excellent in permeability and retention of pharmaceutically active ingredients.

[0008] The present invention includes the following embodiments. [1] A tablet for impregnation with a pharmaceutical active ingredient, comprising mono- and / or disaccharides. [1-1] The tablet according to [1], wherein the content of the monosaccharide and / or disaccharide is 60 to 100% by mass based on the mass of the tablet. [1-2] The tablet according to [1], wherein the content of the monosaccharide and / or disaccharide is 70 to 98% by mass based on the mass of the tablet. [1-3] The tablet according to [1], wherein the content of the monosaccharide and / or disaccharide is 80 to 96% by mass based on the mass of the tablet. [1-4] The tablet according to [1], wherein the content of the monosaccharide and / or disaccharide is 90 to 94% by mass based on the mass of the tablet. [2] The tablet according to any one of [1] to [1-4], wherein the monosaccharide and / or disaccharide comprises at least one selected from the group consisting of lactose, sucrose, trehalose, maltose, mannitol, erythritol, xylitol, sorbitol, and maltitol. [2-1] The tablet according to [2], wherein the monosaccharide and / or disaccharide comprises at least one selected from the group consisting of lactose, mannitol, and sorbitol. [2-2] The tablet according to [2] or [2-1], wherein the monosaccharide and / or disaccharide comprises mannitol. [3] The tablet according to any one of [1] to [2-2], wherein the monosaccharide and / or disaccharide is mannitol, and the mannitol includes δ-D-mannitol. [4] The tablet according to any one of [1] to [3], wherein the theoretical porosity is 20 to 50%. [4-1] The tablet according to any one of [1] to [3], wherein the theoretical porosity is 25 to 45%. [4-2] The tablet according to any one of [1] to [3], wherein the theoretical porosity is 30 to 40%. [5] The tablet according to any one of [1] to [4-2], further comprising a water-insoluble polymer. [6] The tablet according to [5], wherein the water-insoluble polymer comprises at least one selected from the group consisting of croscarmellose sodium, carmellose, crospovidone, crystalline cellulose, and low-substituted hydroxypropyl cellulose. [7] The tablet according to [5] or [6], wherein the content of the water-insoluble polymer is 0.1 to 30% by mass based on the mass of the tablet. [7-1] The tablet according to [5] or [6], wherein the content of the water-insoluble polymer is 0.5 to 20% by mass based on the mass of the tablet. [7-2] The tablet according to [5] or [6], wherein the content of the water-insoluble polymer is 1 to 15% by mass based on the mass of the tablet. [8] The tablet according to any one of [1] to [7-2], further comprising a binder. [9] The tablet according to [8], wherein the binder comprises at least one selected from the group consisting of organic solvent-insoluble binders, organic solvent-slightly soluble binders, and polyvinylpyrrolidone.

[10] The tablet according to [9], wherein the organic solvent is ethanol or isopropyl alcohol.

[11] The tablet according to [8], wherein the binder comprises at least one selected from the group consisting of polyvinyl alcohol, pullulan, xanthan gum, and hypromellose.

[12] The tablet according to any one of [8] to

[11] , wherein the content of the binder is 0.1 to 10% by mass based on the mass of the tablet. [12-1] The tablet according to any one of [8] to

[11] , wherein the content of the binder is 0.3 to 8% by mass based on the mass of the tablet. [12-2] The tablet according to any one of [8] to

[11] , wherein the content of the binder is 0.6 to 6% by mass based on the mass of the tablet.

[13] a mixing step of mixing monosaccharides and / or disaccharides with a solvent to obtain a mixture; and a tableting step of compressing the mixture into tablets; A method for producing a tablet for impregnating a pharmaceutically active ingredient, comprising: [13-1] The method according to

[13] , wherein the amount of the solvent used is 1 to 40% by mass based on the total mass of the components (excluding the solvent) of the tablet. [13-2] The method according to

[13] , wherein the amount of the solvent used is 10 to 30% by mass based on the total mass of the components of the tablet (excluding the solvent). [13-3] The method according to

[13] , wherein the amount of the solvent used is 15 to 25% by mass based on the total mass of the components of the tablet (excluding the solvent).

[14] The method according to any one of

[13] to [13-3], wherein the tableting step is carried out on the mixture in a wet state.

[15] The method according to any one of

[13] to

[14] , wherein the solvent contains at least water.

[16] The method according to

[15] , wherein the solvent further contains an organic solvent. [16-1]

[16] The method according to

[16] , wherein the organic solvent is ethanol.

[17] The production method according to

[16] or [16-1], wherein the mass ratio of water to organic solvent in the solvent is 1:0.1 to 1:10. [17-1] The production method according to

[16] or [16-1], wherein the mass ratio of water to organic solvent in the solvent is 1:0.3 to 1:5. [17-2] The production method according to

[16] or [16-1], wherein the mass ratio of water to organic solvent in the solvent is 1:0.6 to 1:3.

[18] The method according to any one of

[13] to [17-2], wherein the mixture further contains a water-insoluble polymer.

[19] The method according to any one of

[13] to

[18] , wherein the mixture further contains a binder.

[20] A method for producing a pharmaceutical, comprising an impregnation step of impregnating the tablet according to any one of [1] to [12-2] with a pharmaceutically active ingredient. [twenty one] The manufacturing method according to

[20] , wherein the impregnation step comprises dropping the pharmaceutically active ingredient onto the tablet. [twenty two] A medicine comprising the tablet according to any one of [1] to [12-2] impregnated with a pharmaceutically active ingredient. [twenty three] [1] to [12-2], and a tablet according to any one of [1] to [12-2]. a pharmaceutically active ingredient present in the tablet; Including, A pharmaceutical product, wherein the pharmaceutically active ingredient is present non-uniformly in the tablet. [twenty four] [1] to [12-2], and a tablet according to any one of [1] to [12-2]. A pharmaceutical active ingredient; Kit including: [Effects of the Invention]

[0009] According to the present invention, it is possible to provide a tablet having excellent permeability and retention of a pharmaceutically active ingredient, a medicine using the same, methods for producing the tablet and the medicine, and a kit. [Brief explanation of the drawings]

[0010] [Figure 1] 1 shows a Raman chemical imaging image of a cross section of an acetaminophen tablet. DETAILED DESCRIPTION OF THE INVENTION

[0011] <Impregnated tablets> One embodiment of the present invention relates to a tablet for impregnation with a pharmaceutically active ingredient (hereinafter referred to as a "tablet for impregnation"), which contains a monosaccharide and / or a disaccharide. The use of a monosaccharide and / or a disaccharide makes it easier for the pharmaceutically active ingredient to permeate the tablet for impregnation, and also makes it easier for the permeated pharmaceutically active ingredient to be retained in the tablet for impregnation.

[0012] As used herein, "tablets for impregnation" refers to tablets for later impregnation with a pharmaceutically active ingredient. The tablets for impregnation may contain no pharmaceutically active ingredient, may already contain a portion of the pharmaceutically active ingredient to be impregnated later, or, if the final pharmaceutical product contains two or more pharmaceutically active ingredients, may contain only some of the pharmaceutically active ingredients. Adding a pharmaceutically active ingredient to a pre-manufactured tablet for impregnation enables its use as a pharmaceutical. Advantages of adding a pharmaceutically active ingredient to a tablet for impregnation include, for example, ease of changing the content of the pharmaceutically active ingredient, the ability to reliably blend a trace amount of a highly active pharmaceutically active ingredient in each tablet for impregnation in the desired amount, the ease of blending multiple pharmaceutically active ingredients, the low risk of heat-labile pharmaceutically active ingredients being destroyed during the manufacturing process, the ability to avoid interactions between the pharmaceutically active ingredient and other ingredients, the lack of scale effects of manufacturing, and the ability to manufacture the minimum amount of pharmaceuticals, such as rare disease drugs and investigational drugs, by preparing tablets for impregnation in advance.

[0013] The tablet for impregnation is used to produce a tablet (medicine) containing a pharmaceutically active ingredient. After contacting the tablet for impregnation with a drug solution containing the pharmaceutically active ingredient, the solvent of the drug solution is removed by drying to produce a tablet (medicine) containing the pharmaceutically active ingredient. When the tablet for impregnation comes into contact with a medicinal solution, it can absorb a certain amount of the medicinal solution and can retain all or part of the absorbed medicinal solution in the tablet for impregnation for a certain period of time. The tablet for impregnation that comes into contact with the drug solution containing the pharmaceutically active ingredient absorbs a certain amount of the drug solution without appearing to disintegrate (while maintaining its external shape), and can retain the drug solution until the drying process is completed. In order to incorporate a predetermined amount of a pharmaceutically active ingredient into the tablet for impregnation, the concentration and amount of the drug solution to be brought into contact with the tablet for impregnation can be determined so that the drug solution containing the predetermined amount of the pharmaceutically active ingredient does not leak from the tablet for impregnation. Alternatively, the amount of drug solution absorbed by the tablet for impregnation (the amount of drug in the drug after drying) can be adjusted by immersing the tablet for impregnation in a drug solution of a certain concentration for a certain period of time. The tablet for impregnation can also be used to produce rapidly disintegrating tablets that have the strength (hardness, abrasion) of ordinary pharmaceuticals and can be rapidly disintegrated by contact with water, or orally disintegrating tablets containing a pharmaceutically active ingredient.

[0014] Monosaccharides and disaccharides can improve the permeability, retention, strength, and disintegrability of the tablet to be impregnated. From the viewpoint of ensuring excellent permeability, retention, strength, and disintegrability, the content of monosaccharides and / or disaccharides is preferably 60% by mass or more, more preferably 70% by mass or more, even more preferably 80% by mass or more, and particularly preferably 90% by mass or more, based on the mass of the tablet to be impregnated. The upper limit of the content of monosaccharides and / or disaccharides is not particularly limited, and may be, for example, 100% by mass, 98% by mass, 96% by mass, or 94% by mass.

[0015] The monosaccharides and disaccharides are concepts that also include their respective sugar alcohols, and for example, lactose, sucrose, trehalose, maltose, mannitol, erythritol, xylitol, sorbitol, and maltitol are preferred, with δ-D-mannitol being more preferred.

[0016] It is preferable that the tablet for impregnation further contains a water-insoluble polymer. As used herein, "insoluble" means "almost insoluble" as defined in the General Rules of the Japanese Pharmacopoeia, 17th Edition (i.e., "the amount of solvent required to dissolve 1 g or 1 mL of solute" is "10,000 mL or more"). By including a water-insoluble polymer, the tablet for impregnation can improve its permeability and disintegration properties while maintaining its retention and strength. Examples of water-insoluble polymers include croscarmellose sodium, carmellose, crospovidone, crystalline cellulose, low-substituted hydroxypropyl cellulose, carmellose calcium, partially pregelatinized starch, and sodium starch glycolate. These are also commonly used as disintegrants. The water-insoluble polymer may be used alone or in combination.

[0017] The water-insoluble polymer is preferably insoluble or poorly soluble in an organic solvent such as ethanol, from the viewpoint of maintaining the shape of the tablet to be impregnated when the tablet to be impregnated is impregnated with a pharmaceutically active ingredient dissolved or dispersed in the organic solvent. In this specification, "poorly soluble" means "extremely poorly soluble" (i.e., "the amount of solvent required to dissolve 1 g or 1 mL of solute" is "1,000 mL or more but less than 10,000 mL"), "slightly soluble" (i.e., "the amount of solvent required to dissolve 1 g or 1 mL of solute" is "100 mL or more but less than 1,000 mL"), or "slightly soluble" (i.e., "the amount of solvent required to dissolve 1 g or 1 mL of solute" is "30 mL or more but less than 100 mL") as defined in the General Rules of the Japanese Pharmacopoeia, 17th Edition. The organic solvents referred to here include, in addition to ethanol, isopropyl alcohol, 1-propanol, methanol, DMF, and the like.

[0018] The content of the water-insoluble polymer is preferably 0.1 to 30% by mass, more preferably 0.5 to 20% by mass, and even more preferably 1 to 15% by mass, based on the mass of the tablet to be impregnated, from the viewpoint of ensuring excellent permeability, retention ability, strength, and disintegrability.

[0019] The tablet for impregnation preferably further contains a binder, and more preferably contains a binder together with a water-insoluble polymer. The binder can improve the permeability and disintegration property of the tablet for impregnation while maintaining its retention ability and strength. Examples of binders include polyvinyl alcohol (including partially saponified products), polyvinylpyrrolidone (povidone), hypromellose, pullulan, xanthan gum, guar gum, gelatin, carrageenan, agar, etc. One type of binder may be used alone, or multiple types may be used in combination. For example, the binder is preferably insoluble or poorly soluble in an organic solvent such as ethanol, from the viewpoint of maintaining the shape of the tablet for impregnation when the tablet for impregnation is impregnated with a pharmaceutically active ingredient dissolved or dispersed in the organic solvent. Although polyvinylpyrrolidone and hypromellose are soluble in ethanol, they can also be used preferably. The organic solvents referred to here include, in addition to ethanol, isopropyl alcohol, 1-propanol, methanol, DMF, and the like.

[0020] The content of the binder is preferably 0.1 to 10% by mass, more preferably 0.3 to 8% by mass, and even more preferably 0.6 to 6% by mass, based on the mass of the tablet to be impregnated, from the viewpoint of ensuring excellent permeability, retention ability, strength, and disintegrability.

[0021] The tablet to be impregnated may further contain optional ingredients within the range that does not adversely affect the effect of the tablet, such as excipients, lubricants, fluidizing agents, colorants, etc.

[0022] Examples of excipients include corn starch, calcium carbonate, anhydrous calcium hydrogen phosphate, and the like.

[0023] Examples of lubricants include magnesium stearate, calcium stearate, talc, hydrogenated vegetable oil, sucrose fatty acid ester, polyethylene glycol, sodium lauryl sulfate, and the like.

[0024] Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, titanium oxide, synthetic aluminum silicate, and magnesium aluminometasilicate.

[0025] Examples of colorants include tar dyes and natural dyes.

[0026] The properties of the tablet for impregnation can be changed by adjusting its theoretical porosity. For example, from the viewpoint of further improving the permeability, retention ability, strength, and disintegrability of the tablet for impregnation, the theoretical porosity is preferably 20 to 50%, more preferably 25 to 45%, and even more preferably 30 to 40%.

[0027] The theoretical porosity can be increased by using a composition with a high true density and compressing it at low pressure to increase the tablet volume, but at the same time, the molded product must also meet the properties that a tablet should have, such as hardness and abrasion resistance.

[0028] The theoretical porosity can be calculated by the following formula (1).

number

[0029] The solid volume can be calculated based on the following formula (2).

number

[0030] The tablet volume can be measured using a known body side measuring device such as a 3D scanner (VL series manufactured by Keyence Corporation). The tablet volume may also be simply calculated based on the following formula (3).

number

[0031] The above formula (3) is a simple calculation method assuming that the tablet for impregnation is a perfect cylinder. If the tablet for impregnation is a cylinder with corners and the volume of the corners needs to be calculated in detail, calculation and correction can be performed using the Pappus-Guldin theorem. If the tablet for impregnation is not cylindrical, a different formula can be used for simplified calculation.

[0032] The shape of the tablet for impregnation is not particularly limited, but it is preferable that the tablet has a recess on its surface. By dripping a solution or dispersion containing a pharmaceutically active ingredient into the recess, problems such as the solution or dispersion spilling out of the tablet for impregnation can be avoided.

[0033] <Method of manufacturing tablets for impregnation> One embodiment of the present invention relates to a method for producing tablets for impregnation, which includes a mixing step and a tableting step.

[0034] The mixing step is a step of mixing monosaccharides and / or disaccharides with a solvent to obtain a mixture. In the mixing step, it is preferable to further mix a water-insoluble polymer and / or a binder, and it is more preferable to further mix a water-insoluble polymer and a binder. Details of the monosaccharides and disaccharides, water-insoluble polymer, and binder are as explained above in the section "Tablets for impregnation." Furthermore, in the mixing step, it is preferable to granulate the mixture.

[0035] Examples of solvents used in the mixing step include water, ethanol, isopropyl alcohol, 1-propanol, methanol, DMF, etc. Although not particularly limited, from the viewpoint of improving retention ability and strength, a solvent containing at least water is preferred, and a mixed solvent of water and ethanol is more preferred. When a mixed solvent of water and ethanol is used, the mass ratio of water to ethanol is preferably 1:0.1 to 1:10, more preferably 1:0.3 to 1:5, and even more preferably 1:0.6 to 1:3.

[0036] The amount of the solvent used is preferably 1 to 40% by mass, more preferably 10 to 30% by mass, and even more preferably 15 to 25% by mass, based on the total mass of the components of the tablet to be impregnated (excluding the solvent).

[0037] In the mixing step, optional ingredients may be further used within the range that does not adversely affect the effects of the tablet to be impregnated. Details of the optional ingredients are as explained above in the section <Tablet to be impregnated>.

[0038] Examples of the mixing method include wet granulation, dry granulation, etc. Although not particularly limited, it is preferable to employ wet granulation in order to ensure that the tablet to be impregnated has a high porosity and satisfies the properties that a tablet should have.

[0039] As a method of wet granulation, commonly used equipment and techniques such as stirring and mixing granulation (Kawata Corporation, SMV-20A) and fluidized bed granulation can be used.

[0040] The tableting step is a step of tableting the mixture obtained in the mixing step. The tableting step is preferably performed on the mixture in a wet state.

[0041] As a tableting method, for example, commonly used devices and techniques such as a single punch tableting machine (AUTOGRAPH, manufactured by Shimadzu Corporation), a rotary tableting machine, or a rapid disintegrating tablet molding machine (EMT type molding machine: Sankyo Seisakusho) can be used.

[0042] The production method according to this embodiment may further include a drying step following the tableting step. The drying step is a step of removing the solvent remaining in the produced tablet to be impregnated.

[0043] Drying methods include, for example, natural drying, drying by ventilation or hot air using a shelf dryer, a ventilation dryer, or a conveyor dryer (EDT type dryer: Sankyo Seisakusho), freeze drying, vacuum drying, and microwave drying.

[0044] <Pharmaceuticals> One embodiment of the present invention relates to a pharmaceutical in which a pharmaceutical active ingredient is impregnated (preferably dropped) into a tablet for impregnation. In a pharmaceutical in which the pharmaceutical active ingredient is added to the tablet for impregnation later, the pharmaceutical active ingredient is distributed unevenly throughout the tablet for impregnation. Therefore, the pharmaceutical can be described as a pharmaceutical in which the tablet for impregnation and the pharmaceutical active ingredient are present in the tablet for impregnation, and the pharmaceutical active ingredient is distributed unevenly throughout the tablet for impregnation.

[0045] The non-uniform presence of the pharmaceutically active ingredient is due to the subsequent addition of the pharmaceutically active ingredient to the tablet for impregnation. For example, in the case of a medicine to which the pharmaceutically active ingredient has been dropped, the amount of the pharmaceutically active ingredient is likely to be greater in the surface portion (drop portion) of the tablet to which the pharmaceutically active ingredient has been dropped. Therefore, the amount of the pharmaceutically active ingredient in the drop portion is greater than that in the portion corresponding to the drop portion of a tablet in which the same amount of the pharmaceutically active ingredient is uniformly distributed, and the amount of the pharmaceutically active ingredient is less in the portion away from the drop portion. Therefore, confirming the distribution of the pharmaceutically active ingredient can be one method for confirming the manufacturing method of a medicine.

[0046] An example of "unevenly present" is a situation in which, in a tablet for impregnation impregnated with a pharmaceutically active ingredient by immersion, the amount of the pharmaceutically active ingredient present on the surface of the tablet for impregnation (hereinafter referred to as "surface ingredient") differs from the amount of the pharmaceutically active ingredient present in the center of the tablet for impregnation (hereinafter referred to as "center ingredient"), and the pharmaceutically active ingredient is unevenly present near the surface. Alternatively, for example, in a tablet to be impregnated that has been impregnated with a pharmaceutically active ingredient by dropping, there may be a difference in the amount of the pharmaceutically active ingredient present in the dropped portion (hereinafter referred to as "dropped portion component") and the amount of the pharmaceutically active ingredient present on the surface opposite to the dropped portion (hereinafter referred to as "dropped opposite portion component"), and the pharmaceutically active ingredient may be unevenly present in the dropped portion.

[0047] Spectral analysis using Raman spectroscopy can be used to confirm the uneven distribution of surface and central components, or components in the dropped portion and components in the dropped opposite portion. By superimposing the distribution of the pharmaceutically active ingredient detected by spectral analysis using Raman spectroscopy on an image of a cross section (a cross section perpendicular to the surface onto which the drug solution has been dropped) of a tablet for impregnation in which the pharmaceutically active ingredient has been impregnated, it can be confirmed that the pharmaceutically active ingredient is unevenly distributed near the surface.

[0048] The type of pharmaceutically active ingredient is not particularly limited, but examples include pharmaceutically active ingredients whose prescribed dosage varies depending on the patient's weight, and pharmaceutically active ingredients taken by elderly patients who suffer from multiple illnesses and are prescribed various medications. Advantages include the ability to dispense an appropriate dosage on the spot based on the patient's weight, and the ability to take multiple medications in a single tablet, which reduces the hassle of taking multiple tablets and contributes to medication compliance. Therefore, the pharmaceutically active ingredient may be one or more types. The pharmaceutically active ingredient may be an active ingredient used in quasi-drugs, in which case, the medicament of this embodiment also includes quasi-drugs. The medicament of this embodiment may also be a component or nutritional ingredient of a health claim food, in which case, the medicament of this embodiment also includes health claim foods containing these components. The content of the medicament active ingredient is appropriately adjusted according to the dosage and administration method.

[0049] From the viewpoint of improving the rapid disintegration property of the medicine, the theoretical porosity of the medicine is preferably 20 to 50%, more preferably 25 to 45%, and even more preferably 30 to 40%. Since the theoretical porosity of the medicine depends on the theoretical porosity of the tablet to be impregnated, the theoretical porosity of the medicine can be adjusted by adjusting the theoretical porosity of the tablet to be impregnated. The theoretical porosity of the medicine can be determined in the same manner as the theoretical porosity of the tablet to be impregnated.

[0050] The medicine may have a coating layer on its surface, such as a sugar coating layer or a film coating layer.

[0051] <Medicinal manufacturing method> One embodiment of the present invention relates to a method for manufacturing a pharmaceutical, comprising an impregnation step.

[0052] The impregnation step is a step of impregnating a tablet to be impregnated with a pharmaceutically active ingredient. In this specification, "impregnation" means impregnating a tablet to be impregnated with a pharmaceutically active ingredient. The impregnation method is not particularly limited, and examples include a method of dropping a solution or dispersion containing the pharmaceutically active ingredient onto a tablet to be impregnated (hereinafter referred to as the "dropping method"), and a method of immersing a tablet to be impregnated in the solution or dispersion (hereinafter referred to as the "immersion method"). From the viewpoint of accurately impregnating a specified amount of the pharmaceutically active ingredient, it is preferable to adopt the dropping method.

[0053] The solvent for the solution or dispersion containing a pharmaceutically active ingredient is not particularly limited as long as it is a pharmaceutically acceptable solvent (i.e., a solvent with low toxicity). Examples of pharmaceutically acceptable solvents include ethanol, isopropanol, 1-propanol, methanol, DMF, etc. From the viewpoint of ensuring high safety, it is preferable to use ethanol.

[0054] The tablets for impregnation used in the impregnation step have certain permeability and retention capacity. The concentration and amount of the solution or dispersion containing the pharmaceutically active ingredient can be appropriately adjusted depending on the permeability and retention capacity so that the desired pharmaceutically active ingredient is incorporated into the medicine. In the case of the dropping method, production control is easy if the concentration and amount are such that the dropped solution or dispersion quickly penetrates the tablet for impregnation, does not ooze out from the tablet for impregnation, and is retained in the tablet for impregnation for a certain period of time (for example, the time from after dropping to before the start of the drying step).

[0055] As used herein, "permeability" refers to the ease with which a solution or dispersion containing a pharmaceutically active ingredient permeates into a tablet to be impregnated. From the viewpoint of production efficiency, it is desirable that the solution or dispersion containing the pharmaceutically active ingredient can be rapidly permeated into the tablet to be impregnated. The permeation time described in the following examples can be used as an indicator of permeability. The shorter the permeation time, the more advantageous it is. However, it is sufficient that the solution or dispersion permeates into the tablet to be impregnated before it is transferred to the drying step, and a time of 120 seconds or less can be used as a guideline. On the other hand, even if the permeation time is as short as about 10 seconds, if the tablet lacks retention capacity and leaks out immediately, it becomes difficult to control the manufacturing process conditions.

[0056] As used herein, "retention ability" refers to the ability of a tablet to be impregnated to retain a solution or dispersion containing a pharmaceutically active ingredient without leaking from the tablet. The retention ability of a tablet to be impregnated can be qualitatively evaluated by confirming the presence or absence and degree of retention of the solution or dispersion when a certain amount of solution or dispersion is dropped onto the tablet, as in the following examples. A tablet to be impregnated that easily retains a certain amount of solution or dispersion is advantageous in that it allows for a wider range of adjustment of the manufacturing conditions for the pharmaceutical according to this embodiment. When setting manufacturing conditions, the concentration or amount of the solution or dispersion may be adjusted to be suitable for the confirmed retention ability, or a viscosity modifier may be used to adjust the viscosity of the solution or dispersion, or other process conditions may be adjusted. The retention ability of a tablet to be impregnated can also be quantitatively evaluated by changing the amount of solution or dispersion dropped onto the tablet to be impregnated and defining the amount of liquid at which seepage begins as the retention amount (the upper limit of the amount of liquid that can be retained). The larger the amount of the tablet to be impregnated that can be retained, the more advantageous it is for pharmaceutical production. However, since the amount of the pharmaceutically active ingredient can be controlled by the conditions of the solution or dispersion, it is sufficient for the tablet to have a certain level of retention capacity.

[0057] The tablet to be impregnated may have a hardness sufficient to withstand the impregnation step and subsequent steps, or a hardness sufficient to withstand the impacts that the medicine produced through the steps will sustain during distribution.

[0058] The manufacturing method according to this embodiment may further include a drying step following the impregnation step, in which the solvent remaining in the manufactured pharmaceutical is removed.

[0059] Drying methods include, for example, natural drying, drying using ventilation or hot air using a shelf dryer, a ventilation dryer, or a conveyor dryer (EDT type dryer: Sankyo Seisakusho), freeze drying, vacuum drying, etc.

[0060] The production method according to this embodiment may further include a coating step following the drying step. The coating step is a step of forming a coating layer on the surface of the pharmaceutical. Details of the coating layer are as described above in the section entitled "Pharmaceuticals."

[0061] Examples of coating methods include pan coating, in which a tablet is placed in a coating pan and rolled to coat the entire tablet evenly, and spray coating, in which a coating agent is applied partially to a stationary tablet using a spray nozzle, etc. The coating layer may cover the entire tablet or only a portion of it.

[0062] Advantages of the production method according to this embodiment include the ease of changing the content of the pharmaceutically active ingredient, the ability to reliably blend a trace amount of a highly active pharmaceutically active ingredient in the desired amount into each tablet for impregnation, the ability to avoid interactions between the pharmaceutically active ingredient and other ingredients, the low risk of pharmaceutically active ingredients that are unstable to heat, etc. being destroyed during the production process, the ability to avoid interactions between the pharmaceutically active ingredient and other ingredients, the lack of scale effects of production, and the ability to produce the minimum amount of medicine such as a drug for a rare disease or an investigational drug by preparing tablets for impregnation in advance.

[0063] <Kit> One embodiment of the present invention relates to a kit comprising a tablet for impregnation and a pharmaceutically active ingredient. The kit may also include a solvent for dissolving or dispersing the pharmaceutically active ingredient. The kit may also include instructions for use. By using the kit, the medicine can be manufactured at the location where the medicine will actually be used. [Example]

[0064] The present invention will be described in more detail below using examples and comparative examples, but the technical scope of the present invention is not limited to these.

[0065] <Evaluation of tablets for impregnation> (permeability) The ethanol permeability (penetration time of dropped ethanol) of the tablets for impregnation produced in the following Examples and Comparative Examples was measured. The permeation time was measured as the time from when 50 μL of ethanol was dropped onto the surface (top) of the tablet until the ethanol droplets completely disappeared from the tablet surface.

[0066] (retention capacity) The ethanol retention capacity of the tablets for impregnation produced in the following Examples and Comparative Examples was measured. The retention capacity was evaluated by dropping 50 μL of ethanol onto the surface (upper part) of the tablet, allowing it to completely penetrate, and then observing the state of ethanol seeping out from the tablet surface (lower part). The results were evaluated on a three-level scale from A to C (A being the most preferable and C being the least preferable).

[0067] (Theoretical porosity) The theoretical porosity of the tablets to be impregnated produced in the following Examples and Comparative Examples was calculated based on the above formulas (1) to (3).

[0068] (hardness) The hardness (N) of the tablets to be impregnated produced in the following Examples and Comparative Examples was measured using a Kiya hardness tester.

[0069] (Collapse time) The disintegration time of the tablets for impregnation produced in the following Examples and Comparative Examples was measured using purified water in accordance with the disintegration test method of the Japanese Pharmacopoeia General Test Method.

[0070] <Production and testing of tablets for impregnation> (Example 1) to (Example 4) 0.6 g of purified water (RO water) and 0.6 g of absolute ethanol (Kanto Chemical) were mixed, and then mixed with 6.0 g of δ-D-mannitol (Merck, Parteck Delta M) placed in a mortar and pestle. The mixture was granulated for 3 minutes using a pestle to obtain a granulated product. The resulting granulated product was wet-milled using a sieve (JP No. 16, 1000 μm mesh) to obtain wet-formed granules. The resulting wet-formed granules were compressed into tablets with a diameter of 8 mm and a tablet mass of 150 mg using a single-punch tablet press (AUTOGRAPH, Shimadzu Corporation). The tablets were then dried at 60°C to obtain tablets for impregnation. During the tableting, the tableting pressure was adjusted to produce tablets with different theoretical porosities, thereby obtaining four types of tablets for impregnation. These tablets for impregnation are designated Examples 1 to 4 in order of decreasing theoretical porosity.

[0071] (Test Examples 1 to 4) The permeability, retention capacity, hardness, and disintegration time were evaluated for Examples 1 to 4. The theoretical porosity was also calculated. The results are shown in Table 1. As a result, all of Examples 1 to 4 showed good permeability and retention (A). In addition, the tablets also had the hardness and disintegration time that are required for tablets. From the viewpoint of theoretical porosity, it can be said that the higher the theoretical porosity, the better the permeability.

[0072] Example 5 5.7 g of δ-D-mannitol (Merck, Parteck Delta M) and 0.3 g of low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical, LH-31) were placed in a mortar and mixed for 3 minutes using a pestle. A mixed solvent of 0.6 g of purified water and 0.6 g of absolute ethanol (Kanto Chemical) was added to the resulting mixture, and the mixture was granulated for 3 minutes using a pestle to obtain a granulated product. The resulting granulated product was wet-milled using a sieve (JP No. 16, 1000 μm mesh) to obtain wet-milled granules. The resulting wet-milled granules were compressed into tablets with a diameter of 8 mm and a tablet mass of 150 mg using a single-punch tablet press (AUTOGRAPH, Shimadzu Corporation) and dried at 60°C to obtain tablets for impregnation.

[0073] (Test Example 5) The permeability, retention capacity, hardness, and disintegration time of Example 5 were evaluated. The theoretical porosity was also calculated. The results are shown in Table 1. As a result, compared with Examples 1 to 4, Example 5, which further contained low-substituted hydroxypropyl cellulose (LH-31), showed improved permeability while maintaining good retention capacity (A), and showed better results.Furthermore, the disintegration time was shortened and good results were also shown in terms of hardness.

[0074] Example 6 6 g of polyvinyl alcohol (partially saponified) (Gosenol EG-05, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) was dissolved in 30 g of purified water to obtain a 16.7% polyvinyl alcohol solution. 0.3 g of purified water and 0.6 g of absolute ethanol (manufactured by Kanto Chemical Co., Ltd.) were mixed with 0.36 g of the 16.7% polyvinyl alcohol solution to obtain a binding solution. 5.64 g of δ-D-mannitol (Parteck Delta M, manufactured by Merck) and 0.3 g of low-substituted hydroxypropyl cellulose (LH-31, manufactured by Shin-Etsu Chemical Co., Ltd.) were added to a mortar and mixed for 3 minutes using a pestle. The entire amount of the binding solution was added to the resulting mixture, and the mixture was granulated using a pestle for 3 minutes to obtain a granulated product. The resulting granulated product was wet-milled using a sieve (JP No. 16, mesh size 1000 μm) to obtain a wet-milled granule. The obtained wet granules were compressed into tablets using a single punch tablet press (AUTOGRAPH, manufactured by Shimadzu Corporation) to give tablets with a diameter of 8 mm and a weight of 150 mg, and then dried at a temperature of 60°C to obtain tablets for impregnation.

[0075] Example 7 A binder solution was obtained by dissolving 0.6 g of povidone (Plasdone K29-32, manufactured by ISP) in 1.2 g of a mixed solution of purified water and absolute ethanol (50% mixed solution). Tablets to be impregnated were produced using the binder solution according to the composition shown in Table 1 under the same conditions as in Example 6.

[0076] (Test Examples 6 and 7) The permeability, retention capacity, hardness, and disintegration time of Examples 6 and 7 were evaluated. The theoretical porosity was also calculated. The results are shown in Table 1. As a result, in Examples 6 and 7, which further contained a binder, better results were obtained, with shorter disintegration times while maintaining good permeability and retention capacity (A), compared to Example 5. Also, good results were obtained in terms of hardness.

[0077] Example 8 Tablets for impregnation were produced under the same conditions as in Example 6 according to the composition table in Table 1, except that the low-substituted hydroxypropyl cellulose (LH-31) in Example 6 was replaced with low-substituted hydroxypropyl cellulose (LH-11).

[0078] Example 9 Tablets for impregnation were produced under the same conditions as in Example 6 according to the composition table in Table 1, except that the low-substituted hydroxypropyl cellulose (LH-31) in Example 6 was replaced with low-substituted hydroxypropyl cellulose (LH-21).

[0079] Example 10 Tablets for impregnation were produced under the same conditions as in Example 6 according to the composition table in Table 1, except that the low-substituted hydroxypropyl cellulose in Example 6 was replaced with croscarmellose sodium (manufactured by FMC International Inc., Ac-Di-Sol).

[0080] Example 11 Tablets to be impregnated were produced under the same conditions as in Example 6 according to the composition table in Table 1, except that the low-substituted hydroxypropyl cellulose in Example 6 was replaced with carmellose (NS-300, manufactured by Gotoku Pharmaceutical Co., Ltd.).

[0081] Example 12 Tablets for impregnation were produced under the same conditions as in Example 6 according to the composition table in Table 1, except that the low-substituted hydroxypropyl cellulose in Example 6 was replaced with crospovidone (Polyplasdone XL-10, manufactured by ISP).

[0082] Example 13 Tablets for impregnation were produced under the same conditions as in Example 6 according to the composition table in Table 1, except that the low-substituted hydroxypropyl cellulose in Example 6 was replaced with crystalline cellulose (manufactured by Asahi Kasei Chemicals, Japanese Pharmacopoeia CEOLUS PH-101).

[0083] (Test Examples 8 to 13) The permeability, retention capacity, hardness, and disintegration time of Examples 8 to 13 were evaluated. The theoretical porosity was also calculated. The results are shown in Table 1. As a result, Examples 8 to 13, which contained a water-insoluble polymer different from the low-substituted hydroxypropyl cellulose (LH-31) of Example 6, also showed good permeability and retention capacity (A). In addition, good results were also shown in terms of disintegration time and hardness.

[0084] Example 14 A binder solution was obtained by dissolving 0.6 g of hypromellose 2910 (manufactured by Shin-Etsu Chemical Co., Ltd., TC-5E, Japanese Pharmacopoeia hypromellose) in 1.2 g of a mixed solution of sterilized purified water and absolute ethanol (50% mixed solution). Tablets for impregnation were produced using the above binder solution according to the composition shown in Table 1 under the same conditions as in Example 6.

[0085] Example 15 A binder solution was obtained by dissolving 0.6 g of pullulan (Hayashibara, Japanese Pharmacopoeia Pullulan) in 1.2 g of a mixed solution of sterilized purified water and absolute ethanol (50% mixed solution). Tablets for impregnation were produced using the binder solution according to the composition shown in Table 1 under the same conditions as in Example 6.

[0086] Example 16 A binder solution was obtained by dissolving 0.6 g of xanthan gum (Grindsted Xanthan J, manufactured by Danisco) in 1.2 g of a mixed solution of sterilized purified water and absolute ethanol (50% mixed solution). Tablets to be impregnated were produced using the above binder solution according to the composition shown in Table 1 under the same conditions as in Example 6.

[0087] (Test Examples 14-16) The permeability, retention capacity, hardness, and disintegration time were evaluated for Examples 14 to 16. The theoretical porosity was also calculated. The results are shown in Table 1. As a result, Examples 14 to 16, which contained binders different from the polyvinyl alcohol of Example 6, also showed good permeability and retention capacity (A). In addition, good results were also shown in terms of disintegration time and hardness.

[0088] Example 17 Tablets to be impregnated were produced under the same conditions as in Example 6 according to the composition table in Table 1, except that the amount of δ-D-mannitol added in Example 6 was changed to 5.34 g and the amount of low-substituted hydroxypropyl cellulose added to 0.6 g.

[0089] Example 20 Tablets to be impregnated were produced under the same conditions as in Example 6 according to the composition table in Table 1, except that the amount of δ-D-mannitol used in Example 6 was changed to 5.94 g and low-substituted hydroxypropyl cellulose was omitted.

[0090] (Test Examples 17 and 20) The permeability, retention capacity, hardness, and disintegration time of Examples 17 and 20 were evaluated. The theoretical porosity was also calculated. The results are shown in Table 1. As a result, taking into consideration the results of Example 6 as well, when a binder was included, the content of the water-insoluble polymer was 5% or 10% of the total mass of the tablet for impregnation, and good permeability and retention capacity (A) were exhibited, and good results were also shown in terms of disintegration time and hardness. Furthermore, Example 20, which did not contain a water-insoluble polymer, showed good results in terms of permeability, disintegration time, and hardness, but a slight amount of seepage was observed (retention ability (B)).

[0091] Example 18 A mixture of 0.72 g of 16.7% polyvinyl alcohol solution and 0.6 g of absolute ethanol was used as a binder solution. Furthermore, the amount of δ-D-mannitol used in Example 6 was changed to 5.58 g, and tablets for impregnation were produced according to the composition table in Table 1 under the same conditions as in Example 6.

[0092] (Test Example 18) The permeability, retention capacity, hardness, and disintegration time of Example 18 were evaluated. The theoretical porosity was also calculated. The results are shown in Table 1. As a result, considering both Examples 5 and 6, when the water-insoluble polymer was included, good permeability and retention ability (A) were exhibited regardless of whether the binder content was 0%, 1%, or 2% of the total mass of the tablet for impregnation, and good values ​​were also exhibited for disintegration time and hardness.

[0093] Example 19 A mixture of 0.3 g of 16.7% polyvinyl alcohol solution, 0.25 g of purified water, and 0.5 g of absolute ethanol was used as a binder solution. Furthermore, the amount of δ-D-mannitol used in Example 6 was changed to 4.7 g, and the amount of low-substituted hydroxypropyl cellulose used was changed to 0.25 g. Tablets for impregnation were produced under the same conditions as in Example 6, according to the composition table in Table 1.

[0094] Example 21 A mixture of 0.3 g of 16.7% polyvinyl alcohol solution and 0.75 g of purified water was used as a binder solution. Furthermore, the amount of δ-D-mannitol added in Example 6 was changed to 4.7 g and the amount of low-substituted hydroxypropyl cellulose added to 0.25 g, and tablets for impregnation were produced under the same conditions as in Example 6 according to the composition table in Table 1.

[0095] (Comparative Example 1) 4.7 g of δ-D-mannitol (Merck, Parteck Delta M), 0.25 g of low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., LH-31), and 0.05 g of polyvinyl alcohol (partially saponified) were placed in a mortar and mixed for 3 minutes using a pestle. 1.0 g of absolute ethanol was added to the resulting mixture, and the mixture was granulated for 3 minutes using a pestle to obtain a granulated product. The resulting granulated product was wet-milled using a sieve (JP No. 16, 1000 μm mesh) to obtain wet-milled granules. Forming and drying were performed under the same conditions as in Example 6 to produce tablets.

[0096] (Test Examples 19 and 21, Comparative Test Example 1) The permeability, retention capacity, and hardness were evaluated for Examples 19 and 21 and Comparative Example 1. The theoretical porosity was also calculated. The results are shown in Table 1. As a result, Example 19, which used a mixed solvent of sterilized purified water and absolute ethanol, showed good permeability, retention capacity (A), and hardness. Furthermore, Example 21, in which the solvent was sterilized purified water alone, also showed good results in terms of permeability and hardness, but a small amount of seepage was observed (retention ability (B)). On the other hand, in Comparative Example 1, in which the solvent was only absolute ethanol, the hardness, which is a property that tablets should have, was significantly low, and the tablets were brittle and unsuitable as tablets for impregnation.

[0097] Example 22 Tablets were produced under the same conditions as in Example 6 according to the composition table in Table 1, except that the δ-D-mannitol in Example 6 was replaced with sorbitol (Rocket Japan, Neosorb P650).

[0098] Example 23 Tablets were produced under the same conditions as in Example 6 according to the composition table in Table 1, except that the δ-form D-mannitol in Example 6 was replaced with lactose hydrate (Pharmatose 200M, manufactured by DMV).

[0099] Example 24 Tablets were produced under the same conditions as in Example 6 according to the composition table in Table 1, except that the delta D-mannitol (Parteck Delta M, manufactured by Merck) in Example 6 was replaced with beta D-mannitol (Partech M100, manufactured by Merck).

[0100] (Test Examples 22-24) The permeability, retention capacity, hardness, and disintegration time were evaluated for Examples 22 to 24. The theoretical porosity was also calculated. The results are shown in Table 1. As a result, in Examples 22 to 24, in which sorbitol, lactose hydrate, or β-D-mannitol was used instead of δ-D-mannitol, good values ​​were observed in permeability, hardness, and disintegration time. Regarding retention ability, a slight amount of seepage was observed in Examples 22, 23, and 24 (retention ability (B)).

[0101] (Comparative Example 2) 3 g of polyvinyl alcohol (partially saponified) (Gosenol EG-05, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) was dissolved in 30 g of purified water to obtain a 9.1% polyvinyl alcohol solution. 0.66 g of the 9.1% polyvinyl alcohol solution was mixed with 0.6 g of absolute ethanol (manufactured by Kanto Chemical Co., Ltd.) to obtain a binding solution. 5.94 g of crystalline cellulose (manufactured by Asahi Kasei Corporation, Ceolus PH-101), a polysaccharide, was placed in a mortar, and the entire amount of the binding solution was added. The mixture was then granulated using a pestle for 3 minutes to obtain a granulated product. The resulting granulated product was then wet-milled using a sieve (JP No. 16, 1000 μm mesh) to obtain wet-milled granules. The resulting wet-milled granules were compressed into tablets with a diameter of 8 mm and a weight of 150 mg using a single-punch tablet press (AUTOGRAPH, manufactured by Shimadzu Corporation) and dried at 60°C to obtain tablets for impregnation.

[0102] (Comparative Test Example 2) The permeability, retention ability, and hardness of Comparative Example 2 were evaluated. The theoretical porosity was also calculated. The results are shown in Table 1. As a result, in Comparative Example 2, which did not contain monosaccharides or disaccharides and used crystalline cellulose, a polysaccharide, much of the dripped ethanol leaked out (retention ability (C)), and the tablet could not be used as a tablet for impregnation.

[0103] <Pharmaceutical manufacturing and testing> Example 25 32.5 g of partially saponified polyvinyl alcohol was added to 650 g of heated sterile purified water (Yoshida Pharmaceutical Co., Ltd.) and dissolved by stirring with an air motor to obtain an aqueous polyvinyl alcohol solution. 25 g of absolute ethanol was added to 105 g of aqueous polyvinyl alcohol solution and stirred to obtain 130 g of binding solution. This process was repeated four times to obtain a total of 520 g of binding solution. 2350 g of δ-D-mannitol and 125 g of low-substituted hydroxypropyl cellulose were added to a mixing granulator (Kawada Manufacturing Co., Ltd., Super Mixer SMV-20) and mixed for 3 minutes at an impeller speed of 800 rpm. While continuing to stir, 130 g of binding solution was added and stirred for 1 minute. This process was repeated four times to obtain a granulated product. The granulated product was then crushed using a crusher (Fukae Powtec Co., Ltd., TC-150 model) at an impeller speed of 800 rpm and a screen size of 4.0 mmφ to obtain wet granules. Granules for tableting were compressed using a wet tableting machine (Sankyo Seisakusho, EMT / ETD-18) at a compression pressure of 50-350 N to a diameter of 8.0 mm and a dry mass of 160 mg, and then dried at 60°C using a tray dryer to produce tablets for impregnation. 100 mg of acetaminophen was dissolved in 800 mg of ethanol to obtain an acetaminophen solution. 42 mg of the obtained acetaminophen solution was added dropwise to the above-mentioned tablets to be impregnated, allowing the solution to penetrate the tablets. Subsequently, the tablets were dried in a constant temperature bath at 50°C to obtain 5 mg of acetaminophen-impregnated tablets.

[0104] Example 26 A cimetidine solution was prepared by dissolving 100 mg of cimetidine in 600 mg of methanol. 35 mg of the cimetidine solution was added dropwise to each tablet prepared in Example 25, allowing the solution to penetrate the tablet. The tablets were then dried in a constant temperature bath at 50°C to obtain 5 mg of cimetidine-impregnated tablets.

[0105] Example 27 Famotidine (100 mg) was dissolved in DMF (600 mg) to obtain a famotidine solution. 35 mg of the famotidine solution was added dropwise to each tablet prepared in Example 25, allowing the solution to penetrate the tablet. The tablet was then dried in a constant temperature bath at 50°C to obtain 5 mg of famotidine-impregnated tablets.

[0106] (Test Examples 25-27) 100 mg of acetaminophen, cimetidine, and famotidine were weighed into a 100 mL flask, dissolved in 50% methanol, and then diluted to a volumetric capacity to prepare the respective standard solutions. Each of the impregnated tablets prepared in Examples 25 to 27 was placed in a volumetric flask, 50% methanol was added, and the mixture was stirred with a stirrer to disintegrate the tablets. The resulting dispersion was centrifuged at 10,000 rpm for 10 minutes, and the supernatant was used as the test solution. The absorbance of the standard solution and the test solution was measured using a UV-visible spectrophotometer, and the content was calculated from the absorbance ratio. The measurement wavelengths for acetaminophen, cimetidine, and famotidine were 246, 218, and 287 nm, respectively. The measurement wavelength for background was 650 nm. Three tablets of each type of impregnated tablet were evaluated and the average values ​​were calculated. The contents of the acetaminophen-impregnated tablets, cimetidine-impregnated tablets, and famotidine-impregnated tablets were 99.3%, 97.6%, and 100.0%, respectively.

[0107] Example 28 An acetaminophen solution was prepared by dissolving 500 mg of acetaminophen in 500 μL of absolute ethanol. 20 μL of the acetaminophen solution was added dropwise to the tablets to be impregnated prepared in Example 25, and the tablets were dried at 1000 W for 1 minute in a microwave oven (Sanyo Electric Co., Ltd., EMO-FZ40) to obtain acetaminophen-impregnated tablets.

[0108] (Test Example 28) Using a Raman spectroscopic microscope (Renishaw, inVia), optical and Raman microscopic images of the cross section of the acetaminophen-impregnated tablet prepared in Example 28 were obtained. The laser wavelength was 785 nm, the exposure time was 1 second, and the number of integrations was 1. The image was taken at 1595-1635 cm -1An image was created using the baseline scattering intensity and the signal intensity ratio (Figure 1). The white areas in the image indicate the locations where acetaminophen is present. The image is a cross section perpendicular to the surface of the tablet for impregnation onto which acetaminophen solution has been dropped; the upper side of the image is the dropped surface, and the lower side is the surface opposite the dropped surface. As a result of acetaminophen migrating from the dropped surface to the opposite surface, the image shows that acetaminophen is present unevenly. [Table 1] TIFF0007749538000005.tif255129

Claims

1. A tablet for impregnating a pharmaceutically active ingredient, comprising δ-D-mannitol and a water-insoluble polymer, The active pharmaceutical ingredient is impregnated into the tablet; The hardness of the tablet is 11N or more. tablet.

2. 2. The tablet according to claim 1, wherein the theoretical porosity is 20 to 50%.

3. 3. The tablet according to claim 1, wherein the water-insoluble polymer comprises at least one selected from the group consisting of croscarmellose sodium, carmellose, crospovidone, crystalline cellulose, and low-substituted hydroxypropyl cellulose.

4. The tablet according to any one of claims 1 to 3, wherein the content of the water-insoluble polymer is 0.1 to 30% by mass based on the mass of the tablet.

5. The tablet according to any one of claims 1 to 4, further comprising a binder.

6. The tablet according to claim 5, wherein the binder comprises at least one selected from the group consisting of an organic solvent-insoluble binder, an organic solvent-slightly soluble binder, and polyvinylpyrrolidone.

7. 7. The tablet of claim 6, wherein the organic solvent is ethanol or isopropyl alcohol.

8. 6. The tablet of claim 5, wherein the binder comprises at least one selected from the group consisting of polyvinyl alcohol, pullulan, xanthan gum, and hypromellose.

9. The tablet according to any one of claims 5 to 8, wherein the content of the binder is 0.1 to 10% by mass based on the mass of the tablet.

10. A mixing step of mixing δ-D-mannitol, a water-insoluble polymer, and a solvent to obtain a mixture; a tableting step of compressing the mixture into tablets; A method for producing a tablet for impregnating a pharmaceutically active ingredient, comprising: The active pharmaceutical ingredient is impregnated into the tablet; the solvent comprises water and at least one organic solvent selected from the group consisting of ethanol, isopropyl alcohol, 1-propanol, methanol, and dimethylformamide; the mass ratio of the water to the organic solvent is 1:0.1 to 1:3; Manufacturing method.

11. The method of claim 10, wherein the tableting step is carried out on the mixture in a wet state.

12. The method of claim 10 or 11, wherein the mixture further comprises a binder.

13. A method for producing a pharmaceutical, comprising an impregnation step of impregnating the tablet according to any one of claims 1 to 9 with a pharmaceutically active ingredient.

14. The method of claim 13, wherein the impregnation step comprises dripping the active pharmaceutical ingredient onto the tablet.

15. A medicine comprising the tablet according to any one of claims 1 to 9 impregnated with a pharmaceutically active ingredient.

16. The tablet according to any one of claims 1 to 9, A pharmaceutical active ingredient; Kit including:

Images