JP2017200959A - Composition for oral quickly-disintegrating tablets - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an oral quickly-disintegrating tablet that can be produced by a simple process with a simple production device, quickly disintegrates in an oral cavity, and has moderate moldability enough for practical use, a method for producing the same, and a granule that serves as constitutional materials for the oral quickly-disintegrating tablet.SOLUTION: A composition for oral quickly-disintegrating tablets contains at least one excipient selected from the group consisting of saccharides and sugar alcohols, and tannic acid. The composition is obtained by mixing and drying the raw materials using tannic acid in a dissolved state.SELECTED DRAWING: None

Description

  The present invention relates to a granulated product for a rapidly disintegrating tablet in the oral cavity that rapidly and well disintegrates in the presence of saliva or a small amount of water in the oral cavity, an intraoral rapidly disintegrating tablet containing the granulated product, and an oral cavity The present invention relates to a method for producing an internally disintegrating tablet.

  As dosage forms of oral solid preparations, tablets, capsules, granules, powders and the like are generally known. However, few of these dosage forms are easy to handle and easy to take. For example, tablets and capsules have a problem that it becomes difficult to swallow as the shape thereof becomes larger, and granules and powders have a problem that they are peeled off when taken and a problem that they enter between teeth. Further, all of these dosage forms require water at the time of taking, and there is a problem that it is difficult to take while sleeping in an emergency or a serious patient.

  Chewable tablets that can be taken without water are known as chewable tablets that can be taken without water, but what is currently offered is poorly disintegrative and is elderly, pediatric and infant patients, patients who have difficulty swallowing There is a problem that it is difficult for a bedridden patient or the like to take.

  Accordingly, there is a demand for the development of an orally rapidly disintegrating tablet that can be easily taken without water and can be taken easily at any time and anywhere.

As a technique for producing such an orally rapidly disintegrating tablet, a method of precisely filling a drug suspension into a PTP mold and drying at low temperature by ventilation (Patent Document 1), a mixture of a drug, a saccharide, and a binder is used. There is known a method (Patent Document 2) in which a small amount of water or a water / alcohol mixture is moistened, and this wet mixture (powder) is molded at an extremely low pressure and dried.
However, these methods have a problem that a special manufacturing facility is required and the manufacturing process is complicated accordingly.

  Therefore, it is desired to develop a preparation that can be produced by a simple process using a simple production facility, has excellent disintegration properties in the oral cavity, and has moldability that is not problematic in practice.

Japanese Patent No. 2807346 Japanese Patent No. 29197771

  Therefore, the present invention is an intraoral rapidly disintegrating tablet that can be manufactured in a simple process using a simple manufacturing apparatus and has a rapid disintegration property in the oral cavity and an appropriate moldability that can withstand practical use, It is an object of the present invention to provide a production method and a granulated product that is a constituent material of the intraoral rapidly disintegrating tablet.

  As a result of intensive studies to solve the above-described problems, the present inventors have found that the present invention includes an excipient containing at least one selected from the group consisting of saccharides and sugar alcohols, and an intraoral rapidly disintegrating tablet containing tannic acid. In preparing the composition, each raw material is mixed using dissolved tannic acid and dried to prepare a tablet composition, and the obtained tablet composition is combined with a binder as necessary. , And / or compression molding together with disintegrants, etc., with a disintegration and moldability equivalent to or higher than conventional intraoral quick disintegrating tablets in a simple process without using a special manufacturing device It was found that an intraoral rapidly disintegrating tablet can be produced.

This invention is completed based on the said knowledge, and provides the manufacturing method of the following intraoral quick disintegrating tablet composition, an intraoral quick disintegrating tablet, and an intraoral quick disintegrating tablet.
Item 1. A composition for an orally rapidly disintegrating tablet comprising at least one excipient selected from the group consisting of sugars and sugar alcohols, and tannic acid, wherein each raw material is mixed using dissolved tannic acid And a composition for rapidly disintegrating tablets in the oral cavity, obtained by drying.
Item 2. Item 2. The composition for rapidly disintegrating tablets in the oral cavity according to Item 1, obtained by spraying the dissolved tannic acid onto the other raw materials of the composition for rapidly disintegrating tablets in the oral cavity and drying the mixture.
Item 3. Item 2. The granulation operation is carried out while spraying dissolved tannic acid on the composition material for rapidly disintegrating tablets in the oral cavity containing at least one excipient selected from the group consisting of sugars and sugar alcohols. The composition for intraoral rapidly disintegrating tablets as described in 2. above.
Item 4. Item 4. The intraoral rapidly disintegrating tablet composition according to any one of Items 1 to 3, wherein the saccharide is lactose hydrate and the sugar alcohol is mannitol.
Item 5. Item 5. An intraoral rapidly disintegrating tablet comprising the composition for intraorally rapidly disintegrating tablet according to any one of Items 1 to 4.
Item 6. Furthermore, the intraoral quick disintegrating tablet of claim | item 5 containing a binder and / or a disintegrating agent.
Item 7. Item 7. The intraoral rapidly disintegrating tablet according to Item 6, wherein the binder is at least one selected from the group consisting of magnesium aluminate metasilicate, synthetic aluminum silicate, light anhydrous silicic acid, calcium silicate, and crystalline cellulose.
Item 8. Item 8. The intraorally rapidly disintegrating tablet according to Item 6 or 7, wherein the disintegrant is at least one selected from the group consisting of crospovidone, carmellose calcium, carmellose, croscarmellose sodium, and low-substituted hydroxypropylcellulose.
Item 9. Item 9. The intraoral rapidly disintegrating tablet according to any one of Items 5 to 8, wherein the disintegration time measured by a disintegration test specified in the Japanese Pharmacopoeia is within 30 seconds.
Item 10. Item 10. The intraoral rapidly disintegrating tablet according to any one of Items 5 to 9 having a hardness of 40 N or more.
Item 11. A method for producing a composition for an orally rapidly disintegrating tablet comprising at least one excipient selected from the group consisting of saccharides and sugar alcohols, and tannic acid, wherein each tannic acid is used in a dissolved state. The manufacturing method of the composition for intraoral quick disintegrating tablets including the 1st process of mixing a raw material and the 2nd process of drying the obtained mixture.
Item 12. Item 12. The method for producing an intraoral rapidly disintegrating tablet composition according to Item 11, wherein in the first step, dissolved tannic acid is mixed by spraying the other raw materials of the intraoral rapidly disintegrating tablet composition. .
Item 13. Item 13. The method according to Item 12, wherein in the first step, the granulated operation is performed while spraying the dissolved tannic acid to the other raw materials of the composition for rapidly disintegrating tablets in the oral cavity.
Item 14. Item 14. The method according to Item 12 or 13, wherein the saccharide is lactose hydrate and the sugar alcohol is mannitol.
Item 15. A first step of mixing at least one excipient selected from the group consisting of saccharides and sugar alcohols, and a raw material containing tannic acid using tannic acid in a dissolved state, and drying the resulting mixture; A second step of obtaining a composition for rapidly disintegrating tablets in the oral cavity, compressing the composition for rapidly disintegrating tablets in the oral cavity, or a composition for rapidly disintegrating tablets in the oral cavity, and additives, and And / or a third step of compression-molding a mixture of pharmaceutically active ingredients.
Item 16. Item 16. The method for producing an orally rapidly disintegrating tablet according to Item 15, wherein in the first step, the dissolved tannic acid is mixed by spraying the other raw materials of the composition for rapidly disintegrating tablet in the oral cavity.
Item 17. Item 17. The method according to Item 16, wherein in the first step, granulation is performed while spraying dissolved tannic acid on the other raw materials of the composition for rapidly disintegrating tablets in the oral cavity.
Item 18. Item 18. The method according to any one of Items 15 to 17, wherein the additive is a binder and / or a disintegrant.

  The intraoral rapidly disintegrating tablet of the present invention is a formulation that exhibits excellent disintegration properties in the oral cavity and has an appropriate moldability, and therefore has excellent dosing properties.

Hereinafter, the present invention will be described in detail.
(I) Composition for intraorally rapidly disintegrating tablets The composition for intraorally rapidly disintegrating tablets of the present invention comprises at least one excipient selected from the group consisting of saccharides and sugar alcohols, and tannic acid. It is a composition for intraoral rapidly disintegrating tablets containing, and is a composition obtained by mixing each raw material using a dissolved tannic acid and drying.
In the present invention, “for intraorally rapidly disintegrating tablets” means having use as a constituent material or a production material of intraoral rapidly disintegrating tablets.

  Examples of the saccharide of the excipient include lactose hydrate, anhydrous lactose, sucrose, purified sucrose, fructose, glucose, glucose hydrate, trehalose and the like, and sugar alcohols include mannitol, sorbitol, xylitol, erythritol, Examples include maltitol and isomalt. Lactose hydrate of saccharides and mannitol of sugar alcohols are preferable in that the granulated product can be rapidly disintegrated in the oral cavity.

  The amount of at least one selected from the group consisting of saccharides and sugar alcohols is preferably about 10% by weight or more, more preferably about 20% by weight or more based on the total amount of the composition for rapidly disintegrating tablets in the oral cavity. Preferably, about 30% by weight or more is even more preferred.

  Tannic acid can be extracted from various plant materials. For example, water or ethanol can be extracted from persimmon fruit, chestnut astringent skin, pentaploid, gallic, cod powder, leguminous tamarind seed skin, or mimosa bark. Preferably, tannic acid extracted from pentaploid or gallic acid listed in the 16th revised Japanese Pharmacopoeia can be used. Tannic acid may be an unpurified product or a purified product, but a purified product is more preferable.

The amount of tannic acid used is preferably about 0.001% by weight or more, more preferably about 0.01% by weight, even more preferably about about 1% by weight, based on the total amount of the composition for rapidly disintegrating buccal tablets after drying. The amount may be 0.1% by weight or more. If it is this range, the tablet manufactured using this intraoral quick disintegrating tablet composition will have sufficient disintegration. The amount of tannic acid used is preferably about 30% by weight or less, more preferably about 20% by weight or less, still more preferably about 10% by weight based on the total amount of the composition for rapidly disintegrating buccal tablets after drying. What is necessary is just to set it as the quantity used as weight% or less. If it is this range, the tablet manufactured using this granulated material will have sufficient moldability.
Examples of the tannic acid solution include a solution in which tannic acid is dissolved in a liquid containing at least one selected from the group consisting of alcohols such as water, ethanol, and isopropyl alcohol. The concentration of tannic acid in this solution can be determined as appropriate depending on the type of material other than tannic acid, the type of preparation operation (for example, granulation operation) of the composition for rapidly disintegrating tablets in the oral cavity, and the like. 0.001 to 30% by weight.

  The tannic acid solution may be mixed or blended with other raw materials as it is without any special operation, or may be mixed or blended by spraying on other raw materials. In any case, the tannic acid concentration in the resulting composition may be made uniform.

  In addition, raw materials other than tannic acid can be mixed with tannic acid or separately from tannic acid and mixed with other raw materials by a method such as spraying. Furthermore, all the raw materials containing tannic acid can be made into a solution state and sprayed onto a plate or the like for molding.

  The composition for rapidly disintegrating tablets in the oral cavity can contain excipients in addition to saccharides and sugar alcohols. Examples of such excipients include starches such as corn starch, potato starch, wheat starch, and rice starch. Amino acids such as glycine and alanine; silicic acids such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate and calcium silicate; celluloses such as crystalline cellulose and powdered cellulose; talc; titanium oxide; povidone; One or more of hydroxypropyl cellulose; pullulan; polyvinyl alcohol / polyethylene glycol graft copolymer; copolyvidone and the like.

Moreover, the composition for intraoral quick disintegrating tablets can contain an appropriate amount of additives generally used in pharmaceutical products such as lubricants, colorants, flavoring agents, sweeteners, flavors, and preservatives.
Examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate and the like.
Examples of the colorant include food dyes, food lake dyes, iron sesquioxide, and yellow iron sesquioxide.
Examples of the corrigent include citric acid hydrate, tartaric acid, malic acid, ascorbic acid and the like.
Examples of the sweetening agent include aspartame, acesulfame potassium, saccharin, sodium saccharin, dipotassium glycyrrhizinate, stevia, thaumatin, sucralose and the like.
Examples of the fragrances include fennel oil, orange oil, chamomile oil, spearmint oil, cinnamon oil, clove oil, mint oil, bergamot oil, eucalyptus oil, lavender oil, lemon oil, rose oil, roman chamomile oil, menthol and the like.
Examples of preservatives include benzoic acid, sodium benzoate, benzyl benzoate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, sodium propyl paraoxybenzoate, paraoxybenzoic acid Examples thereof include methyl and methyl sodium paraoxybenzoate.
An additive may be used individually by 1 type and may use 2 or more types.

  The composition for orally rapidly disintegrating tablets can contain an appropriate amount of an active ingredient of a medicine. The pharmaceutical active ingredient is not particularly limited as long as it is a kind and an amount that do not impair the disintegration property and moldability of the intraoral rapidly disintegrating tablet containing the granulated product.

The composition for intraorally rapidly disintegrating tablets of the present invention containing the above-described components may be in the form of a granulated product such as a granule, or may be in the form of an ungranulated powder. In the case of obtaining a granulated product, the granulation operation may be performed while spraying the tannic acid solution or the solution containing tannic acid and other raw materials on the other raw materials. Moreover, it can also granulate on a board | plate by spraying the solution containing all raw materials, such as a tannic acid, on a board | substrate.
Examples of the granulation method include spray drying granulation method, fluidized bed drying granulation method, etc., and fluidized bed drying granulation method is particularly preferable in terms of excellent convenience. Those well known to those skilled in the art can be used.
When the excipient contains a component that also functions as a binder, fluidized bed granulation is preferred. In addition, when the excipient does not contain a component that also functions as a binder, a stirring granulation method is preferable. Thereby, the tablet excellent in quick disintegration property and moldability is obtained. Examples of excipients that also function as binders include starches, povidone, hydroxypropylcellulose, pullulan, polyvinyl alcohol / polyethylene glycol graft copolymers, and copolyvidone.

(II) Orally rapidly disintegrating tablets
Tableting In order to produce the intraorally rapidly disintegrating tablet of the present invention (hereinafter sometimes referred to as “tablet of the present invention”) using the composition for intraorally rapidly disintegrating tablet described above, The composition for rapidly disintegrating tablets in the oral cavity according to the present invention may be mixed with other components such as a binder and a disintegrant, if necessary, and compression molded.
For the compression molding, a method and an apparatus generally used for tablet formation such as a rotary tableting machine and a single tableting machine can be used. The compression pressure in this compression molding is preferably about 1 kN or more, more preferably about 2 kN or more, and even more preferably about 4 kN or more. Moreover, 60 kN or less is preferable, about 30 kN or less is more preferable, and about 15 kN or less is still more preferable. If it is this range, the burden of the mortar at the time of tableting is small, and also it is easy to maintain the tableting pressure at the time of tableting.

  Prior to the above compression molding, it may be subjected to operations necessary for the production of tablets such as sizing using a screen mill, jet mill, hammer mill, pin mill or the like; sieving using a vibrating sieve.

The tablet can be composed substantially only of the composition for rapidly disintegrating buccal tablets of the present invention described above, but can also contain other components such as a binder and a disintegrant.
Even when other components are contained, the content of the composition for rapidly disintegrating buccal tablets in the tablet of the present invention is preferably about 10% by weight or more, more preferably about 30% by weight or more based on the total amount of the tablet. About 60% by weight or more is even more preferred. That is, when the tablet of the present invention contains components other than the composition for rapidly disintegrating tablets in the oral cavity, the content other than the composition for rapidly disintegrating tablets in the oral cavity is about 90% by weight or less based on the total amount of the tablet. About 70% by weight or less is more preferred, and about 40% by weight or less is even more preferred. If it is the said range, practically sufficient moldability and disintegration can be obtained.

  In addition, since the tablet of the present invention is produced by compression molding, the shape of the granulated product is usually different from the shape of the granulated product in the tablet of the present invention.

Binder The tablet of the present invention may contain a binder. The binder has an action of binding the granulated materials to each other during compression.
Examples of the binder include magnesium aluminate metasilicate, synthetic aluminum silicate, light anhydrous silicic acid, calcium silicate, crystalline cellulose, powdered cellulose, low-substituted hydroxypropylcellulose, and the like. Among these, magnesium aluminate metasilicate, synthetic aluminum silicate, light anhydrous silicic acid, calcium silicate, and crystalline cellulose are preferable.
The content of the binder is preferably about 0.01% by weight or more, more preferably about 0.1% by weight or more, and still more preferably about 1% by weight or more based on the total amount of the tablet. Moreover, about 30 weight% or less is preferable with respect to the whole quantity of a tablet, About 20 weight% or less is more preferable, About 10 weight% or less is further more preferable. If it is the said range, practically sufficient moldability and disintegration can be obtained.
A binder may be used individually by 1 type and may use 2 or more types.

Disintegrant The tablet of the present invention may contain a disintegrant. The disintegrant is a component that swells with water or a component that collapses with water.
Disintegrants include crospovidone, carmellose calcium, carmellose, alginic acid, croscarmellose sodium, low-substituted hydroxypropylcellulose, corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, carboxy Examples include methyl starch sodium. Of these, crospovidone, carmellose calcium, carmellose, croscarmellose sodium, and low-substituted hydroxypropylcellulose are preferred.
The content of the disintegrant is preferably about 0.01% by weight or more, more preferably about 0.1% by weight or more, and still more preferably about 1% by weight or more based on the total amount of the tablet. Moreover, about 30 weight% or less is preferable with respect to the whole quantity of a tablet, About 20 weight% or less is more preferable, About 10 weight% or less is further more preferable. If it is the said range, practically sufficient moldability and disintegration can be obtained.
A disintegrating agent may be used individually by 1 type, and may use 2 or more types.

Other Components The tablet of the present invention can contain an appropriate amount of additives generally used in pharmaceuticals such as excipients, lubricants, coloring agents, flavoring agents, sweeteners, fragrances, and preservatives. Moreover, a pharmaceutical active ingredient can also be included.
Each of the additive and the active pharmaceutical ingredient may be used alone or in combination of two or more.

  The tablet thus obtained has an appropriate moldability with no practical problem, and further has an excellent disintegration property in the oral cavity.

The tablet of the present invention has a disintegration time (particularly, a disintegration time measured using a disintegration tester (manufactured by Toyama Sangyo)) of 30 seconds or less according to the disintegration test method prescribed in the 16th revised Japanese Pharmacopoeia Manual. Is preferably 20 seconds or shorter, and more preferably 10 seconds or shorter.
The tablet of the present invention preferably has a hardness (particularly, a hardness measured using a tablet hardness meter (manufactured by Toyama Sangyo)) of 50 N or more, more preferably 60 N or more, and even more preferably 70 N or more. More preferred.

EXAMPLES Hereinafter, although an Example and a comparative example are given and this invention is demonstrated in more detail, this invention is not limited to these.
(1) Physical property test <Disintegration test>
The test follows the disintegration test method stipulated in the 16th revised Japanese Pharmacopoeia Manual, except that the disintegration tester (manufactured by Toyama Sangyo Co., Ltd.) is used, the number of tests is 6 tablets, and the average value of disintegration time is evaluated. did.
<Hardness test>
The test was carried out using a tablet hardness tester (manufactured by Toyama Sangyo Co., Ltd.), the number of tests was 10 tablets, and the average value of the hardness was evaluated.

(2) Manufacture of tablets
Example 1
Based on the composition shown in Table 1 below, mannitol was charged into a fluidized bed granulator / dryer and then granulated by gradually spraying a liquid in which tannic acid was dissolved in an appropriate amount of water while flowing. Next, the granulated product was subsequently dried with a fluidized bed granulator, and then the dried product was sized. Furthermore, after adding other additives to this sized product and mixing, a tablet with a tableting pressure of about 8 kN and a tablet diameter of 8.5 mm and a mass of 240 mg using a tableting machine. Obtained.

Comparative Example 1
Based on the composition shown in Table 1 below, mannitol was charged into a fluidized bed granulator / dryer, and then granulated by gradually spraying an appropriate amount of water while flowing. Further, the granulated product was subsequently dried with a fluidized bed granulator, and then the dried product was sized. Furthermore, after adding other additives to this sized product and mixing, a tablet with a tableting pressure of about 8 kN and a tablet diameter of 8.5 mm and a mass of 240 mg using a tableting machine. Obtained.

Examples 2-4
Based on the composition shown in Table 2 below, the pharmaceutically active ingredient and mannitol are charged into a fluidized bed granulator / dryer, and then a solution of tannic acid dissolved in an appropriate amount of water is gradually sprayed and granulated while flowing. did. Further, the granulated product was subsequently dried with a fluidized bed granulator, and then the dried product was sized. Furthermore, after adding other additives to this sized product and mixing, using a tableting machine, a tablet having a tablet diameter of 8.5 mm and a mass of 240 mg with a tableting pressure of about 8 kN. Got.

(3) Results The results of the composition, disintegration test, and hardness test of the tablets of Example 1 and Comparative Example 1 are shown in Table 1 below.

  As is apparent from Table 1, the tablet of Example 1 showed excellent disintegration and moldability with a disintegration time of 15 seconds and a hardness of 62N. On the other hand, the tablet of Comparative Example 1 containing no tannic acid had a disintegration time of 12 seconds and had no particular problem in disintegration, but had a hardness of 24 N and was lower than the tablet of Example 1, and was molded. The nature was bad.

The composition of the tablets of Examples 2 to 4, the results of the disintegration test and the hardness test are shown in Table 2 below.

  As is apparent from Table 2, the tablets of Examples 2 to 4 have a disintegration time of 12 seconds, 15 seconds, and 16 seconds, respectively, and hardnesses of 65 N, 65 N, and 59 N, respectively. Indicated.

  The intraoral rapidly disintegrating tablet of the present invention can be manufactured without using a complicated manufacturing process or a special manufacturing apparatus, and has excellent disintegration and moldability regardless of the kind of active pharmaceutical ingredient to be contained. It is a combination. Therefore, it is suitable for industrial large-scale production, and at the same time, can be widely used as an orally rapidly disintegrating tablet in which various active pharmaceutical ingredients can be blended.

Claims (13)

  A composition for rapidly disintegrating tablets in the oral cavity comprising a dried product of a mixture of at least one excipient selected from the group consisting of saccharides and sugar alcohols and dissolved tannic acid.   The composition for an intraoral rapidly disintegrating tablet according to claim 1, wherein the mixture is a spray mixture.   The composition for intraoral quick disintegrating tablets according to claim 2, wherein the composition is in the form of a granulated product or a non-granulated powder.   The composition for an orally rapidly disintegrating tablet according to any one of claims 1 to 3, wherein the saccharide is lactose hydrate and the sugar alcohol is mannitol.   The intraoral quick disintegrating tablet containing the composition for intraoral quick disintegrating tablet in any one of Claims 1-4.   Furthermore, the intraoral quick disintegrating tablet of Claim 5 containing a binder and / or a disintegrating agent.   The intraoral rapidly disintegrating tablet according to claim 6, wherein the binder is at least one selected from the group consisting of magnesium aluminate metasilicate, synthetic aluminum silicate, light anhydrous silicic acid, calcium silicate, and crystalline cellulose. .   The orally rapidly disintegrating tablet according to claim 6 or 7, wherein the disintegrant is at least one selected from the group consisting of crospovidone, carmellose calcium, carmellose, croscarmellose sodium, and low-substituted hydroxypropylcellulose. .   The intraoral rapidly disintegrating tablet according to any one of claims 5 to 8, wherein the disintegration time measured by a disintegration test prescribed in the Japanese Pharmacopoeia is within 30 seconds.   Hardness is 40N or more, The intraoral quick disintegrating tablet in any one of Claims 5-9.   Improving the moldability of an orally rapidly disintegrating tablet containing at least one excipient selected from the group consisting of saccharides and sugar alcohols, wherein tannic acid in a dissolved state is mixed and dried Method.   The method according to claim 11, wherein the tablet has a hardness of 40 N or more.   The method according to claim 11 or 12, wherein the disintegration time of the tablet is 30 seconds or less as measured by a disintegration test prescribed in the Japanese Pharmacopoeia.