阅读说明：本技术 含有微小纤维状纤维素和有效成分的崩解片剂用组合物 (Composition for disintegrating tablet containing microfibrillar cellulose and active ingredient ) 是由 松冈美绪 桥川尚弘 浜崎桃子 泷川嘉久 于 2018-05-16 设计创作，主要内容包括：[课题]利用微小纤维状纤维素的优异特性,提供以高浓度含有药效成分、营养成分或补品/食品成分等各种有效成分的、具有医药/中药和各种食品等各种各样的目的/用途的各种崩解片剂；以及该崩解片剂用的组合物等。[手段]含有仅由微小纤维状纤维素构成的崩解剂成分和有效成分的崩解片剂用组合物；以及含有崩解片剂用组合物的食品用或医药用崩解片剂。(To provide various disintegrating tablets having various purposes/uses such as medicines/Chinese medicines and various foods, which contain various active ingredients such as medicinal ingredients, nutritional ingredients, supplements/food ingredients at a high concentration by utilizing the excellent characteristics of microfibrillar cellulose; and a composition for the disintegrating tablet. [ means ] a composition for disintegrating tablets comprising a disintegrant component consisting only of microfibrous cellulose and an active ingredient; and a disintegrating tablet for food or medicine containing the composition for disintegrating tablet.)

1. A composition for disintegrating tablets, which comprises a disintegrant component consisting only of microfibrous cellulose and an active ingredient.

2. The composition for disintegrating tablets according to claim 1, which comprises a microfibrous cellulose and an active ingredient.

3. The composition for disintegrating tablets according to claim 1 or 2, wherein the microfibrous cellulose has an average fiber length of 0.01 to 2mm and an average fiber diameter of 0.001 to 1 μm.

4. The composition for disintegrating tablets according to any of claims 1 to 3, which comprises 80 to 90% by weight of an active ingredient.

5. The composition for disintegrating tablets as claimed in any one of claims 1 to 4, which further comprises an excipient.

6. The composition for disintegrating tablets according to claim 5, which contains a sugar alcohol or a sugar as an excipient.

7. A disintegrating tablet for food or medicine, which comprises the composition for disintegrating tablets as claimed in any one of claims 1 to 6.

8. The disintegrating tablet according to claim 7, wherein the hardness is 10 to 200(N), the disintegration time in water is 6 minutes or less, and/or the disintegration time in water (D)/tablet hardness (H) is 30 (sec/N) or less.

9. A method for producing the composition for disintegrating tablets as claimed in any one of claims 1 to 6, said method comprising: in the fluidized bed granulator, hot air is blown from the lower part of powder consisting of components other than microfibrous cellulose to fluidize the powder, and a dispersion liquid which is an aqueous suspension of microfibrous cellulose is sprayed from the upper part of the powder.

Technical Field

The present invention relates to a composition for disintegrating tablets, which contains various active ingredients such as a medicinal ingredient, a nutritional ingredient, or a tonic/food ingredient, and a disintegrant ingredient composed of only microfibrillar cellulose; and various disintegrating tablets and the like containing the composition.

Background

Cellulose produced from plant fibers and having a fiber diameter (short diameter) or thickness of about ~ μm, which is several nm, is generally called "microfibrous cellulose" (or "microfibrous cellulose"). examples of production of such microfibrous cellulose and their structure, characteristics, functions, and the like are described in patent documents 1 and 2.

These fine or microfibrillated celluloses have a significantly increased surface area without impairing the basic properties (physical and chemical stability, etc.) of the cellulose as a raw material, and have a three-dimensional network structure formed by entanglement of the microfibrils while having significantly increased hydrophilicity, which is the original feature of cellulose. As a result, when blended in a paste/paste product, the product exhibits water retention (dehydration prevention) or shape retention by interaction with water/oil droplets, fine particles, or the like. Further, the three-dimensional network structure can be used for modification for improving the strength of colloidal commercial products and the like.

Therefore, these celluloses have been widely used in various applications such as binders for various powder/fibrous materials, paper strength enhancers for sandpaper, thickeners for improving food texture, water retention agents for improving water retention of foods, and filter aids for alcoholic beverages.

As an example of the use of such microfibrous cellulose, patent document 3, for example, describes a gel composition containing a water-dispersible complex containing microfibrous cellulose and a hydrophilic polymer dissolved in warm water at a specific ratio, a gelling agent, and water at a specific ratio. The composition has the characteristics of inhibiting protein denaturation or water insoluble component sedimentation during heating or warming treatment, and has good taste and mouthfeel.

Patent document 4 describes a gelling agent containing a highly dispersible cellulose complex containing microfibrous cellulose, a water-soluble polymer and a hydrophilic substance at specific ratios, and a specific type of polysaccharide at specific ratios. It is characterized by being excellent in disintegration/dispersibility in water as compared with the prior art highly dispersible cellulose composites and being usable under industrially practical dispersion conditions.

As described above, in the invention described in any of patent documents 3 and 4, the microfibrous cellulose is finally used as one component of the gel composition or gelling agent. In addition, a hydrophilic polymer is an essential component in the water-dispersible composite described in patent document 3, and a water-soluble polymer is an essential component in the highly dispersible cellulose composite described in patent document 4.

Patent document 5 describes a flowable powder composition obtained by adding and dispersing a drug, cosmetic, or food having high hygroscopicity to a microfibrous cellulose, as an invention for the purpose of providing a powder that is easy to handle even with a hygroscopic substance. Specifically, a flowable powder composition containing a yeast extract powder or a pueraria decoction powder at a concentration of 50% to 70% is described, and a tablet obtained by tableting the composition is also described to have excellent moldability. However, nothing is mentioned about the disintegration of these tablets.

Further, patent document 6 describes that the specific surface area of bacterial cellulose, microfibrillar cellulose, or the like is about 5m for the purpose of providing a binder capable of obtaining sufficient tablet hardness even with a small molding pressure²A binder comprising cellulose in an amount of at least one gram, a composition containing the binder, and a method for producing a solid preparation using the composition. In the examples, it is described that the tablet hardness of the solid preparation is improved. But do notThe solid preparation contains substantially no active ingredient such as a medicinal ingredient. In addition, nothing is mentioned about the disintegration of the tablets produced.

Patent document 7 describes a composition for disintegrating tablets containing microfibrous cellulose, which is characterized by containing a disintegrant component in addition to microfibrous cellulose, and has the following effects due to the synergistic effect of these components: on the one hand, the tablet hardness of various disintegrating tablets containing the composition is increased, and on the other hand, the disintegration time in water is further shortened.

Disclosure of Invention

Problems to be solved by the invention

In the prior art, there has been no example of producing a composition for disintegrating tablets utilizing the above-mentioned excellent characteristics of microfibrous cellulose and various disintegrating tablets containing the composition.

In particular, there has been no disintegrating tablet for pharmaceutical/pharmaceutical use, various foods such as an auxiliary food, a nutritional functional food and a health food, which contains various active ingredients such as a medicinal ingredient, a nutritional ingredient and a tonic/food ingredient at a high concentration of about 80% to 90%.

The present invention has been made to solve the above problems, and an object of the present invention is to provide various disintegrating tablets and the like having various purposes and applications such as medicines, Chinese medicines, and various foods, which contain various active ingredients such as active ingredients, nutritional ingredients, supplements, food ingredients, and the like at high concentrations.

Means for solving the problems

The present inventors have conducted intensive studies to solve the above problems, and as a result, have found that: the present invention has been completed by preparing a tablet having excellent moldability and disintegratability only by using only microfibrillar cellulose as a disintegrant.

More specifically, the present invention provides the following.

[ solution 1] A composition for disintegrating tablets, which comprises a disintegrant component consisting only of microfibrous cellulose and an active ingredient.

[ claim 2] the composition for disintegrating tablets according to claim 1, which comprises a microfibrous cellulose and an active ingredient.

[ claim 3] the composition for disintegrating tablets according to claim 1 or 2, wherein the microfibrous cellulose has an average fiber length of 0.01 to 2mm and an average fiber diameter of 0.001 to 1 μm.

[ claim 4] the composition for disintegrating tablets according to any one of claims 1 to 3, which contains 80 to 90% by weight of the active ingredient.

[ claim 5] the composition for disintegrating tablets according to any one of claims 1 to 4, which further comprises an excipient.

[ claim 6] the composition for disintegrating tablets according to claim 5, which contains a sugar alcohol or a sugar as an excipient.

[ solution 7] A disintegrating tablet for food or medicine, which comprises the composition for a disintegrating tablet described in any one of solutions 1 to 6.

[ claim 8] the disintegrating tablet according to claim 7, which has a hardness of 10 to 200(N), a disintegration time in water of 6 minutes or less, and/or a disintegration time in water (D)/tablet hardness (H) of 30 (sec/N) or less.

[ solution 9] A method for producing the composition for disintegrating tablets described in any of the solutions 1 to 6, the method comprising: in the fluidized bed granulator, hot air is blown from the lower part of powder consisting of components other than microfibrous cellulose to fluidize the powder, and an aqueous suspension (dispersion) of microfibrous cellulose is sprayed from the upper part thereof.

Effects of the invention

In the composition of the present invention, since it is not necessary to contain a disintegrant component in addition to the microfibrous cellulose contained in a small amount, a composition containing a high content of an active ingredient of, for example, about 80 to 90% by weight can be obtained. Further, by preparing a formulation using the composition, a disintegrating tablet exhibiting excellent tablet hardness and disintegrating property or dispersibility and having excellent moldability at the time of tablet preparation can be prepared.

Detailed Description

The present invention relates to a composition for disintegrating tablets containing a disintegrant component composed of only microfibrous cellulose and an active ingredient, and a disintegrating tablet containing the composition. That is, the composition for a disintegrating tablet of the present invention and the disintegrating tablet are both characterized by not containing any substance known to those skilled in the art as a disintegrant component except for microfibrous cellulose.

Here, the "active ingredient" refers to a substance that can exert any activity or action such as nutritional, physiological, pharmaceutical, etc. as an application/purpose of the disintegrating tablet in a subject such as a human taking the disintegrating tablet containing the same, and the composition, raw material, source, and route of acquisition thereof are not limited. The effective components include natural products, natural extracts, chemical synthetic substances, single chemical substances, mixtures and compositions.

As an example of the composition for disintegrating tablets of the present invention, there may be mentioned: a composition for disintegrating tablets comprising only microfibrous cellulose and an active ingredient as described in examples of the present specification.

As the microfibrous cellulose, any cellulose known in the art as "microfibrous cellulose" or "microfibrous cellulose" can be used.

As described above, the "microfibrillar cellulose" generally refers to cellulose prepared from plant fibers and having a fiber diameter (short diameter) or a fiber thickness of about ~ 1 μm, and is significantly increased in surface area without impairing basic characteristics (physical and chemical stability and the like) of cellulose as a raw material, and forms a three-dimensional network structure composed of intertwining of microfibrils while significantly increasing hydrophilicity, which is an original characteristic of cellulose.

Suitable examples of the microfibrous cellulose contained in the composition for disintegrating tablets of the present invention include: a microfibrillar cellulose having an average fiber length of about 0.01 to 2mm and an average fiber diameter of about 0.001 to 1 μm, preferably an average fiber diameter of about 0.01 to 0.1 μm, as a fiber aggregate (patent document 2). For example, such microfibrous cellulose (in a state of 10 to 35% water content as a solid component) is sold by Daicel FineChem under the trade name "CELISH" (average fiber diameter of about 0.01 to 0.1 μm) in various grades.

Alternatively, such a dried product of microfibrous cellulose can be obtained by pulverizing cellulose fibers such as crystalline cellulose and/or powdered cellulose, which are known to those skilled in the art, by any conventionally known technique, for example, by a ball mill, and drying the pulverized cellulose fibers in a dried state (patent document 1). Alternatively, in the substitution step, a solvent is substituted for the microfibrillar cellulose in an aqueous suspension state, which is composed of microfibrillated microfibrillar cellulose obtained by microfibrillating an aqueous dispersion of cellulose fibers with a high-pressure homogenizer, and then the solvent is removed in the drying step, and further the microfibrillar cellulose is pulverized in the pulverization step, thereby obtaining a dried product of the microfibrillar cellulose (patent document 2). Alternatively, a wet body of microfibrous cellulose can be produced by the method described in patent document 8.

Crystalline cellulose and powdered cellulose are white powdery water-insoluble substances obtained by partially depolymerizing and purifying α -cellulose obtained from fibrous plants with an acid. Since it is odorless and chemically inert, it is unchanged even when mixed with a drug, and therefore it is useful for pharmaceutical additives (additives), particularly, for applications such as excipient aids, binders, and disintegrants in the preparation of tablets. In addition, the compound can be used as an emulsion stabilizer or the like in foods such as cosmetics and dairy products, in addition to pharmaceuticals.

Typical examples of such crystalline cellulose include: commercially available products such as AVICEL (FMC corporation), CEOLUS (Asahi Kasei Chemicals Co., Ltd.), VIVAPUR (Rettenmaier), and the like. Further, as typical examples of the powdered cellulose, there can be mentioned: KC FLOCK (Japan paper-making chemical), ARBOCEL (Rettenmaier), and SOLKA FLOC (Wood village industry).

The composition for a disintegrating tablet of the present invention may further contain any sugar alcohol or sugar known to those skilled in the art as an excipient in order to impart excellent tablet hardness and disintegrating property to the disintegrating tablet.

Representative examples of sugar alcohols and sugars include: mannitol, erythritol, xylitol, trehalose, lactose, maltose, maltitol, glucose, sucrose, fructose, mannose, isomalt, palatinose, sorbitol and the like. Further, as suitable examples, there may be mentioned: mannitol, erythritol, xylitol, trehalose, and lactose. The sugar or sugar alcohol may be 1 type, or 2 or more types of compounds appropriately selected from these may be used.

In the composition for disintegrating tablets of the present invention, in addition to the above-mentioned components, any component known to those skilled in the art may be added and mixed as appropriate (except for a disintegrant component other than microfibrillar cellulose, which is known to those skilled in the art) in order to adjust various characteristics such as disintegrating ability, adhesive strength, and feeling of taking of the tablet, within a range not impairing the effect of the present invention by the above-mentioned components. Examples of such components include: shaping aids, glidants, sweeteners, flavorings, fragrances, colorants and the like, which are known to the person skilled in the art.

Examples of the auxiliary agents include: the crystalline cellulose and/or powdered cellulose, and an inorganic excipient. Examples of the inorganic excipient include: light anhydrous silicic acid, hydrous silicon dioxide, anhydrous calcium phosphate, anhydrous calcium hydrogen phosphate, aluminum metasilicate, calcium silicate, magnesium oxide, and the like.

As the disintegrant component not used in the present invention, as examples of substances known to those skilled in the art, for example, there can be exemplified: carboxymethyl cellulose, crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose calcium, corn starch, potato starch, waxy corn starch, partially gelatinized starch, and processed starch such as sodium starch glycolate and hydroxypropyl starch. Crospovidone is a generic name of a crosslinked polymer of 1-vinyl-2-pyrrolidone, and croscarmellose sodium is a generic name of a crosslinked product of sodium carboxymethylcellulose.

The blending amount of each component in the composition for a disintegrating tablet of the present invention can be appropriately determined by those skilled in the art according to the kind of each component, the kind and use of the disintegrating tablet containing the composition for a disintegrating tablet, and the like. In general, the content of the active ingredient is relatively high, for example, 80 to 90% by weight, the content of the microfibrous cellulose (in terms of dry matter) is 0.1 to 20% by weight, the content of the excipient such as sugar or sugar alcohol is 0 to 19.9% by weight, and the content of the excipient auxiliary is 0 to 19.9% by weight, based on the total weight of the composition.

The composition for disintegrating tablets of the present invention can be prepared by any method and means known to those skilled in the art.

For example, the composition for disintegrating tablets of the present invention can be prepared by simultaneously mixing the various ingredients contained in the composition.

Alternatively, the compound can be prepared by various granulation processes. The granulation method is not particularly limited, and the granules can be prepared by a dry granulation method, a wet granulation process method, or the like.

The dry granulation method includes a step of granulating each component powder contained in the composition for disintegrating tablets directly or by mixing with an appropriate binder or the like, making the mixture into small pieces by pressing, and appropriately pulverizing the small pieces. Specific examples of the dry granulation method include: a pulverization granulation method or a roll compression method, etc.

The wet granulation method is a method of forming a composite by dispersing and drying the respective components in the presence of water, and specific examples of the wet granulation method include: spray methods such as spray drying, roll granulation, stirred granulation, and fluidized bed granulation, freeze drying, and kneaded granulation, and the like can be prepared by any of these methods known to those skilled in the art.

In the case of production by a wet granulation process, the composition for a disintegrating tablet of the present invention may be produced by a one-stage granulation process in which all the components contained in the composition for a disintegrating tablet are used simultaneously, or may be added and mixed in a wet granulation process in a plurality of stages.

In the plurality of wet granulation steps of the above-mentioned production method, one or two of the components contained in the composition for a disintegrating tablet are used, and the type and amount thereof can be appropriately determined by those skilled in the art.

In each granulation step, various conditions such as the spraying (spray) speed, the gas supply temperature, the exhaust temperature, and the gas supply amount may be appropriately determined by those skilled in the art depending on the kind and amount of each component.

In any of the granulation steps, examples of the medium for the spray liquid include: water, ethanol, methanol, acetone, etc. can be added into the medicine or food. Alternatively, examples of the spray liquid include: an aqueous suspension containing less than 10% of the components of the composition for disintegrating tablets, and the like.

For example, as shown in the examples of the present specification, the composition for disintegrating tablets of the present invention can be prepared by blowing hot air from the lower part of a powder composed of a component other than microfibrous cellulose (for example, an active ingredient) in a fluidized bed granulator, and spraying an aqueous suspension (dispersion) of microfibrous cellulose from the upper part of the powder while fluidizing the powder.

In addition, the above-mentioned various optional components that can be appropriately contained in the composition for a disintegrating tablet of the present invention can be appropriately added in each granulation step. Alternatively, a wet granulation step may be separately provided, and these optional components may be added and mixed at this stage.

The composition for disintegrating tablets of the present invention prepared by such a wet granulation process preferably has the following physical properties.

(1) Average particle size: 50-500 μm, (2) moisture: 0.1 to 15 wt%.

These physical property values were measured by the following conditions and methods.

Average particle size: use ofφ5g of the composition for disintegrating tablets was measured with a 75mm electromagnetic shaker (M-3T type, manufactured by Tokaiki chemical Co., Ltd.).

Moisture content: 5g of the composition for disintegrating tablets was measured using a halogen moisture meter (MX-50 type, A & D, Ltd.).

The present invention also relates to disintegrating tablets having various uses, which contain such a composition for disintegrating tablets. Examples of such disintegrating tablets include: including drinks, auxiliary foods, nutritious functional foods, health foods and the like, and pharmaceutical disintegrating tablets. The intake form/form of the disintegrating tablet is not particularly limited.

Specifically, the disintegrating tablet of the present invention includes not only a tablet which rapidly disintegrates in the oral cavity even in the absence of water, which is called an "orally disintegrating tablet", but also any oral tablet known to those skilled in the art which disintegrates more slowly in the gastrointestinal tract or the like after oral ingestion. In addition to such a direct oral intake method, the disintegrating tablet of the present invention may be an indirect oral intake method in which the disintegrating tablet is mixed with a solvent such as hot water or water to prepare a liquid such as a dispersion or a sol, and then the mixture is taken.

Therefore, the active ingredient contained in the composition for a disintegrating tablet of the present invention can be appropriately selected depending on the purpose, use, and the like of the disintegrating tablet.

For example, as the active ingredients contained in the composition for disintegrating tablets for food, there can be mentioned: various nutritional components such as proteins, sugars, lipids, and minerals; various vitamins and their derivatives; and health food materials derived from various extracts of microorganisms, plants or animals.

In addition, as active ingredients contained in the composition for a pharmaceutical disintegrating tablet, there can be mentioned: any of a variety of pharmaceutically effective ingredients known to those skilled in the art. Examples thereof include: central nervous system drug, peripheral nervous system drug, sensory organ drug, circulatory organ drug, respiratory organ drug, digestive organ drug, hormone preparation, genitourinary organ drug, other various organ system drugs, vitamin preparation, tonic drug, blood/body fluid drug, other metabolic drugs, cell activation drug, tumor drug, radioactive drug, allergy drug, other tissue cell function drug, crude drug, Chinese medicinal preparation, other drug based on crude drug and Chinese medicinal prescription, antibiotic preparation, chemotherapy preparation, biological preparation, drug for parasitic animal, other drug for pathogenic organism, dispensing drug, diagnostic drug, public health drug, etc.

Since the composition for a disintegrating tablet of the present invention already contains the above-mentioned active ingredient, the composition can be directly prepared into a preparation to easily prepare a disintegrating tablet. Alternatively, the disintegrating tablet of the present invention may further contain, in addition to the composition for disintegrating tablets, any component other than a disintegrant, for example: the food additive of item 10 of the food sanitation act such as a sour seasoning, a sweetener, an excipient, a surfactant, a lubricant, a sweetener, a corrigent, a flavor, a coloring agent, and a stabilizer, or a conventional additive, other optional ingredients that are allowed to be food ingredients (food additives) and are contained in the general food (beverage and food) additive catalog, and optional ingredients described in "drug additives dictionary" (japanese pharmacopoeia, japan).

The blending ratio of the composition for disintegrating tablets and other optional ingredients is not particularly limited as long as the desired effect of the present invention can be exerted, and can be appropriately determined by those skilled in the art. Such a disintegrating tablet can be prepared into a preparation by any method known to those skilled in the art such as tableting. The size, shape, form and the like of the tablet are not particularly limited, and can be appropriately selected according to the above-mentioned use, intake mode, form and the like.

Such a disintegrating tablet contains the composition for disintegrating tablets of the present invention, and therefore has excellent tablet hardness and disintegrating property. That is, as shown in the examples of the present specification, for example, in the case of production at a compression pressure of about 2 to 30kN, the tablet hardness is 10 to 200(N), more preferably 15 to 200(N), and still more preferably 20 to 200(N) in the case of a disintegrating tablet as taken orally as it is, and the disintegration time in water is 40 seconds or less, preferably 30 seconds or less in the case of an oral disintegrating agent, and is 6 minutes or less, preferably 5 minutes or less, and more preferably 4 minutes or less in the case of a disintegrating agent other than the oral disintegrating agent (for example, disintegration in the stomach). Furthermore, the following disintegrating tablets are obtained: the "disintegration time in water (D)/tablet hardness in water (H) (sec/N)" is 0.005 to 2 (sec/N), preferably 0.005 to 0.75 (sec/N) in the case of an intraoral disintegrant, and 0.005 to 15 (sec/N), preferably 0.005 to 6 (sec/N) in the case of a disintegrant other than an intraoral disintegrant.

In the case of a disintegrating tablet of the so-called indirect oral ingestion system in which a disintegrating agent is mixed with a solvent to prepare a liquid such as a dispersion, a sol or the like, and then the mixture is drunk, the disintegrating tablet is characterized in that the disintegration time in water is, for example, 5 minutes or less, preferably 1 minute or less, and the "disintegration time in water (D)/tablet hardness (H) (sec/N)" is 0.005 to 30 (sec/N), preferably 0.005 to 5 (sec/N), and more preferably 0.005 to 3 (sec/N).

The contents of all prior art documents cited in the present specification are incorporated herein by reference.

The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples.

[ evaluation of hardness and disintegratability ]

The results of the tablet hardness, the disintegration time in water, and "disintegration time in water (D)/tablet hardness (H) (sec/N)" for each of the tablets obtained in examples and comparative examples are shown in tables 1 to 4.

These physical property values were measured under the following conditions and methods.

Hardness: the hardness (N) was measured using a digital cabin hardness tester (manufactured by Tayobo Co., Ltd.).

Disintegration time in water: the disintegration time in water was measured by a disintegration tester (NT-400, Fushan industries, Ltd.) according to the method described in the Japanese pharmacopoeia (wherein, no auxiliary plate is used).

The hardness and disintegration time were measured 3 times and 2 times, respectively, and the average value of these measurements was taken as the measurement result. In the comparative examples below, when the tablet hardness after tableting was less than 10(N), the table is described as "not measured due to hardness (N) < 10".