JP5490691B2 - Fast disintegrating preparation containing calcium carbonate - Google Patents

Description

  The present invention belongs to the pharmaceutical field and relates to a rapidly disintegrating preparation containing calcium carbonate.

  Calcium carbonate preparations are used not only as antacids but also as therapeutic agents for hyperphosphatemia. Calcium carbonate forms food-derived phosphate ions and calcium phosphate in the digestive tract, and suppresses absorption of phosphorus from the intestinal tract, thereby reducing blood phosphorus concentration. Currently, the calcium carbonate preparation marketed as a therapeutic agent for hyperphosphatemia is a normal tablet, and water is required for taking it. However, dialysis patients whose water intake is restricted are required to have a rapidly disintegrating preparation that can be taken with a small amount of water.

  Fast disintegrating formulations are designed to disintegrate easily in saliva, and thus generally have low hardness and high friability. However, preparations with low hardness and high friability are prone to cracking and chipping, and need to be handled with care. Fast disintegration and moldability are contradictory, and it is not easy to coexist them, and coexistence becomes more difficult as the content of the active ingredient increases. Therefore, it is desired to provide a tablet in which both coexist.

  As a method for producing a rapidly disintegrating preparation, Patent Document 1 discloses a technique of directly compressing active ingredients brotizolam, lactose, crystalline cellulose, and starch. The content is as low as about 0.1%. If this technique is applied to a calcium carbonate preparation with a high content, the drug size becomes large or the dose becomes large, which is not preferable from the viewpoint of patient QOL. Patent Document 2 discloses an orally disintegrating tablet produced by directly compressing an aromatic stomachic agent, an antacid, and a sugar alcohol, but the content of the aromatic stomachic agent that is an active ingredient is still a formulation. It is about 20% of the total.

  On the other hand, regarding the technology for formulating calcium carbonate as an active ingredient, Patent Document 3 discloses that a calcium compound is granulated using a water-soluble diluent and a water-soluble binder, and Patent Document 4 discloses a galactomannan aqueous solution. A technique of using and granulating is disclosed. In general, calcium carbonate preparations need to be sized after granulation with a fluidized bed granulator or the like, and there is a problem that the process is complicated and a special machine such as a granulator is necessary.

JP 2005-162613 A JP 2005-187349 A Japanese translation of PCT publication No. 2002-529496 JP 2006-124321 A

  An object of this invention is to provide the technique which manufactures a calcium carbonate containing rapidly disintegrating formulation, without requiring complicated processes, such as granulation, and special manufacturing equipment. Furthermore, it aims at provision of the fast disintegrating formulation which made quick disintegration and moldability coexist.

  The inventors of the present invention required a complicated process such as granulation for the preparation of calcium carbonate. It has been found that when the 50% particle size of calcium carbonate is 20 μm to 100 μm, the poor fluidity of the powder for tableting is improved and direct tableting becomes possible. Furthermore, when a component that enhances moldability is added to the above calcium carbonate and directly compressed, quick disintegration (rapid disintegration) when placed in the oral cavity and excellent tablet physical properties (sufficient hardness and friability) The present invention was completed by finding that a calcium carbonate-containing rapidly disintegrating preparation having the above-mentioned properties can be obtained.

That is, the configuration of the present invention is as follows.
(1) Tablets having a hardness of 40N to 200N and a tablet friability of 1% or less formed by directly compressing a molding material containing at least the following components (A) and (B) with a compression molding machine A calcium carbonate-containing rapidly disintegrating preparation that has a disintegration time in the oral cavity of 60 seconds or less.
(A) A component that enhances the moldability of the entire preparation when mixed with calcium carbonate (B) calcium carbonate with a 50% particle size of 20 μm to 100 μm when the powder particle size is measured by laser diffraction method

(2) The content of the component (A) is 70% by mass to 95% by mass of the total formulation, and the content of the component (B) is 2% by mass to 25% by mass of the total formulation. A calcium carbonate-containing rapidly disintegrating preparation.

(3) The calcium carbonate-containing rapidly disintegrating preparation according to (1) or (2), wherein the component (B) is a highly moldable component and / or starch.

(4) The calcium carbonate-containing product according to (3), wherein the high moldability component is one or more excipients selected from the group consisting of crystalline cellulose, carmellose, ethylcellulose, and low-substituted hydroxypropylcellulose. Fast disintegrating formulation.

(5) The calcium carbonate-containing rapidly disintegrating preparation according to (3), wherein the starch is one or more excipients selected from the group consisting of potato starch, rice starch, wheat starch, and corn starch.

(6) The component (B) is one or more excipients selected from the group consisting of crystalline cellulose, carmellose, ethyl cellulose, low-substituted hydroxypropyl cellulose, potato starch, rice starch, wheat starch, and corn starch. A calcium carbonate-containing rapidly disintegrating preparation according to (1) or (2).

(7) The calcium carbonate-containing rapidly disintegrating preparation according to (1) or (2), further comprising a rapidly disintegrating component.

(8) The calcium carbonate-containing rapidly disintegrating preparation according to (7), wherein the rapidly disintegrating component is crospovidone.

(9) The calcium carbonate-containing rapidly disintegrating preparation according to (7), wherein the content of the rapidly disintegrating component is 20% by mass or less of the entire preparation.

(10) The calcium carbonate-containing rapidly disintegrating preparation according to (1) or (2), wherein the calcium carbonate has a 50% particle size of 22 μm to 50 μm.

(11) The calcium carbonate-containing rapidly disintegrating preparation according to (1) or (2), which does not contain a sugar alcohol.

(12) At least (A) calcium carbonate having a 50% particle size of 20 μm to 100 μm when powder particle size is measured by a laser diffraction method, and (B) an ingredient that improves the moldability of the entire preparation when mixed with calcium carbonate , Mixed directly and compressed with a compression molding machine. Tablet hardness is 40N to 200N, friability is 1% or less, and disintegration time in the oral cavity is within 60 seconds. Preparation method of the preparation.

  According to the present invention, the target molding material is directly compressed without requiring complicated steps such as granulation and special production equipment, and without using a sugar alcohol that is generally used. As such, it is possible to provide a calcium carbonate-containing rapidly disintegrating preparation having both fast disintegrating properties and excellent tablet physical properties (sufficient hardness and friability). Moreover, although calcium carbonate is a hard granular material and is anxious about abrasion of a manufacturing facility, since it is not necessary to use a special manufacturing facility in this invention, the abrasion of these facilities can be avoided. Furthermore, since the calcium carbonate-containing rapidly disintegrating preparation has sufficient hardness and friability, it is not damaged in the production process and distribution process and can be applied to an automatic packaging machine.

  Hereinafter, the calcium carbonate-containing rapidly disintegrating preparation of the present invention (hereinafter referred to as “the present preparation”) and the production method thereof will be described in detail. This preparation is mainly used as a therapeutic agent or an antacid for hyperphosphatemia, but is not limited to these uses.

  This preparation is a rapidly disintegrating preparation. A rapidly disintegrating preparation refers to a preparation exhibiting excellent disintegrating properties with a small amount of water or oral saliva. The time from when the preparation is moistened with saliva in the oral cavity and then lightly loaded (to the extent of licking) with the tongue and upper jaw until disintegration is preferably within 60 seconds, more preferably within 30 seconds. is there.

  The hardness of the tablet measured with a load cell hardness tester is 40N to 200N, preferably 50N to 170N, more preferably 60N to 140N. In addition, the friability of this preparation measured by the 15th revised Japanese Pharmacopoeia Tablet friability test method is 1% or less.

  In the preparation of this preparation, a direct tableting method is used. Here, the direct tableting method indicates that the intended tableting powder is directly compression molded by a compression molding machine as it is without passing through a further granulation step. That is, the present preparation can be produced by a compression molding machine, preferably by a rotary compression molding machine, without requiring special production equipment such as a granulating apparatus.

  As the calcium carbonate used in the present preparation, a commercially available product can be used, and the pulverized raw material of limestone that has been crushed and classified can be used. The 50% particle size of the calcium carbonate is 20 μm to 100 μm, preferably 20 μm to 50 μm, and more preferably 22 μm to 35 μm. If the 50% particle size is less than 20 μm, the fluidity of the tableting powder will be poor. On the other hand, if the 50% particle size exceeds 100 μm, the hardness of the finished tablet is lowered, not only the physical properties of the tablet are deteriorated, but also the feeling of taking is deteriorated. Here, the 50% particle size refers to the particle size at the time point when the cumulative frequency of occurrence is 50% when the particle size is measured by the laser diffraction method after being dispersed in water.

  The calcium carbonate content in this preparation is preferably 95% by mass or less. When the calcium carbonate content exceeds 95% by mass, the hardness of the finished tablet is lowered and the moldability is deteriorated. Considering the size of the tablet, the content of calcium carbonate in this preparation is preferably 70% to 95% by weight of the total preparation, and more preferably 75% to 90% by weight of the total preparation. That is, since the calcium carbonate preparation has a large dose, if the calcium carbonate content is less than 70% by mass, the size of the tablet will increase, or multiple tablets will be taken in a single dose. It is not preferable.

  (B) component in this formulation means the component added in order to improve the moldability of this formulation. Specifically, highly moldable components and / or starches. Here, the high moldability component is a load cell when 1% by weight lubricant (magnesium stearate) is mixed with the single component and tableted at 10kN / 杵 using a φ10mm sugar coating R (8.5R) punch. The excipient | filler whose hardness of the tablet measured with the type | formula hardness meter is 100 N or more is shown. Examples of the high moldability component include crystalline cellulose, carmellose, ethyl cellulose, and low-substituted hydroxypropyl cellulose. A preferred highly moldable component is crystalline cellulose. Examples of starches include potato starch, rice starch, wheat starch, and corn starch. Preferred starches are potato starch or corn starch. Originally, starches are not highly moldable components, but when mixed with calcium carbonate, the moldability of the entire preparation can be increased. As the component (B) in the present preparation, one or more excipients can be selected from the above description given as examples of highly moldable components or starches.

  The content of the component (B) in this preparation is preferably 2% by mass to 25% by mass of the total preparation, and more preferably 2% by mass to 20% by mass of the total preparation. The content of the component (B) is mainly determined by the relationship with the content of the component (A), but if the content of the component (B) exceeds 25% by mass, the disintegration is deteriorated, which is not preferable. . Further, if it is less than 2% by mass, there is a problem of moldability, which is not preferable.

  In this preparation, a rapidly disintegrating component may or may not be further added. A rapidly disintegrating component is an excipient that promotes the penetration of water into a tablet, promotes disintegration by containing water, or an excipient that promotes disintegration by swelling when water is included, or a combination of both properties. Indicates a dosage form and is classified as a disintegrant in the pharmaceutical formulation industry. Examples of the rapidly disintegrating component include low-substituted hydroxypropyl cellulose, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, potato starch, corn starch, crospovidone, and partially pregelatinized starch. Of these, low-substituted hydroxypropylcellulose, carmellose, potato starch, and corn starch are also mentioned as the component (B) in the tablet. A preferred fast disintegrating component is crospovidone. The content of the rapidly disintegrating component is preferably 20% by mass or less of the total preparation, and more preferably 15% by mass or less of the total preparation.

  This preparation can be made into a rapidly disintegrating preparation without adding sugar alcohol. In general quick-disintegrating preparations, sugar alcohol is often added in order to obtain disintegration. However, according to this preparation, excellent disintegration can be obtained without adding sugar alcohol.

  The preparation may contain excipients that can be generally used as pharmaceutical additives. For example, when there is discomfort due to the rapid disintegration of the preparation in the oral cavity, a binder may be added to adjust the disintegration time. Moreover, in order to improve discomfort in the oral cavity, a corrigent, sweetener, fragrance and the like may be blended. Moreover, you may mix | blend a lubricant agent for the tableting trouble improvement at the time of tableting. Examples of the binder include hydroxypyrrole cellulose, hydroxypropyl methylcellulose, povidone, pullulan, gelatin, polyvinyl alcohol, and methylcellulose. Examples of the flavoring agent and sweetener include aspartame, saccharin, saccharin sodium hydrate, and stevia. However, as the fragrance, for example, orange fragrance, lemon fragrance, pineapple fragrance, strawberry fragrance, matcha fragrance, chocolate fragrance, vanilla fragrance, etc., as the lubricant, for example, magnesium stearate, talc, stearic acid, calcium stearate Etc. These excipients may be used alone or in admixture of two or more.

  EXAMPLES Hereinafter, although an Example, a comparative example, and an experiment example are given and this invention is demonstrated in detail, these do not restrict | limit this invention at all. The 50% particle size of calcium carbonate (manufactured by Bihoku Flour Industry Co., Ltd .: precipitated calcium carbonate (C)) used in Examples and Comparative Examples was 28.9 μm. The 50% particle size was determined by measuring the particle size of the powder using a laser diffraction method.

(Example 1)
1000g calcium carbonate (Bihoku Powder Chemical Co., Ltd .: precipitated calcium carbonate (C)) and crystalline cellulose 194g (Asahi Kasei Chemicals Co., Ltd .: Theolas KG-802) V-type mixer : V-5), 6 g of magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd .: magnesium stearate) was added and mixed with a V-type mixer to obtain powder granules for tableting. Tableting powder granules using a rotary compression molding machine (manufactured by Kikusui Seisakusho Co., Ltd .: VIRGO) and φ10mm Meteorite R (13R) with a compression pressure of about 13kN / 杵, 600mg per tablet Tablets were obtained.

(Example 2)
Corn starch (Nihon Shokuhin Kako Co., Ltd. product: corn starch) was used instead of crystalline cellulose, and it was manufactured in the same manner as in Example 1 at a compression pressure of about 15 kN / kg.

(Example 3)
Potato starch (manufactured by Matsutani Chemical Industry Co., Ltd .: potato starch) was used instead of crystalline cellulose, and the same as in Example 1 was performed at a compression pressure of about 20 kN / kg.

(Example 4)
Instead of crystalline cellulose, 48.5 g of ethyl cellulose (The Dow Chemical Campany: etosel) and 145.5 g of crospovidone (BASF: Kollidon CL) were used and produced in the same manner as in Example 1 at a compression pressure of about 15 kN / 杵.

(Comparative Example 1)
Lactose hydrate (manufactured by DMV: lactose 200M) was used instead of crystalline cellulose, and the mixture was produced in the same manner as in Example 1 at a compression pressure of about 8 kN / kg.

(Comparative Example 2)
D-mannitol (manufactured by Towa Kasei Kogyo Co., Ltd .: Mannit P) was used in place of the crystalline cellulose, and it was produced in the same manner as in Example 1 at a compression pressure of about 10 kN / kg.

(Comparative Example 3)
Instead of crystalline cellulose, erythritol (manufactured by Nikken Kasei Co., Ltd .: erythritol (fine powder)) was used and produced in the same manner as in Example 1 at a compression pressure of about 12 kN / kg.

(Comparative Example 4)
A crospovidone was used instead of the crystalline cellulose, and it was produced in the same manner as in Example 1 at a compression pressure of about 20 kN / kg.

(Experiment 1)
After pulverizing calcium carbonate (produced by Asahi-Kou Sue Co., Ltd .: cold water crushed stone), calcium carbonate of each particle size shown in Table 1 was obtained by sieving. Using calcium carbonate of each particle size, mix 5000 mg of calcium carbonate, 670 mg of crystalline cellulose (Asahi Kasei Chemicals Co., Ltd .: Theolas KG-802), corn starch 300 mg (Nihon Shokuhin Kako Co., Ltd .: corn starch) in a plastic bag. Thereafter, 30 mg of magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd .: magnesium stearate) was added and further mixed in a plastic bag to obtain tableting granules. The tableting powder was tableted using a hydraulic press and a φ10 mm sugar coated R (8.5R) punch at a compression pressure of about 15 kN / 杵 to obtain 600 mg tablets per tablet.

  Table 1 shows the hardness and oral disintegration time of each tablet. The hardness was highest when the 50% particle size was about 29 μm, and it was low, both finer and coarser. The disintegration time in the oral cavity was the fastest when the 50% particle size was about 29 μm to 71 μm, and it became slower whether it was finer or coarser.

(Experiment 2)
Commercially available calcium carbonate (Bihoku Flour Industry Co., Ltd .: Precipitated calcium carbonate (A), Precipitated calcium carbonate (B), Precipitated calcium carbonate (C)) was mixed in the proportions shown in Table 2, and Table 2 Calcium carbonate of each particle size shown was obtained. Using calcium carbonate of each particle size, 1000g of calcium carbonate and 194g of crystalline cellulose (Asahi Kasei Chemicals Co., Ltd .: Theolas KG-802) are mixed with a V-type mixer (Tokuju Kogyo Co., Ltd .: V-5) Thereafter, 6 g of magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd .: magnesium stearate) was added and further mixed with a V-type mixer to obtain a powder for tableting. It was evaluated whether or not the powder for tableting could be tableted using a rotary compression molding machine (manufactured by Kikusui Seisakusho Co., Ltd .: VIRGO) and φ10 mm meteorite R (13R).

  Table 2 shows whether tableting is possible. Calcium carbonate having a 50% particle size of about 15 μm and about 18 μm could not be directly compressed by a rotary compression molding machine due to insufficient fluidity. From this result, it was determined that calcium carbonate of less than 20 μm cannot be tableted with a rotary compression molding machine.

(Experiment 3)
After pulverizing calcium carbonate (manufactured by Asahi Minesue Co., Ltd .: cold water crushed stone), calcium carbonate having the particle sizes shown in Table 3 was obtained by sieving. Using calcium carbonate of each particle size, calcium carbonate 5000mg, crystalline cellulose 670mg (Asahi Kasei Chemicals Co., Ltd .: Theolas KG-802), corn starch 300mg (Nihon Shokuhin Kako Co., Ltd .: corn starch), saccharin sodium hydrate 6mg (Daito Chemical Industry Co., Ltd .: saccharin sodium) and powdered fragrance 6mg (Takasago Fragrance Industry Co., Ltd .: Pineapple Micron) were mixed in a plastic bag, and then magnesium stearate 30mg (Taihei Chemical Industry Co., Ltd .: stearin) Magnesium acid) was added and further mixed in a plastic bag to obtain tablet granules. The tableting powder was tableted using a hydraulic press and a φ10 mm sugar coated R (8.5R) punch at a compression pressure of about 15 kN / 杵 to obtain 600 mg tablets per tablet. Table 3 shows the results of examining the feeling of administration when each tablet was disintegrated in the oral cavity by five panelists.

  The feeling of taking is "-" for "I don't feel rough", "±" for "I feel slightly rough", "+" for "I feel rough", "++" for "I feel foreign", “I feel a sense of foreign material” was evaluated as “++++”. As a result, when the 50% particle size was about 30 to 100 μm, it was determined as “not feel rough” to “feel rough”, and about 150 μm to “feel rough” to “feel a noticeable foreign body”. From this result, it was judged that calcium carbonate having a 50% particle size exceeding 100 μm was not suitable from the viewpoint of taking feeling.

(Experimental example 4)
For the tablets of Examples 1 to 3 and Comparative Examples 1 to 3, the hardness was measured with a load cell hardness meter, and the friability was measured according to the 15th revised Japanese Pharmacopoeia tablet friability test method. In addition, the disintegration time in the oral cavity was measured from the time each tablet was moistened with saliva in the oral cavity and then lightly loaded (to the extent of licking) with the tongue and upper jaw until it disintegrated. The component names, measured hardness, friability, and oral disintegration time of these tablets are shown in Table 4. * In the table indicates that the tablet was shattered and could not be measured.

  Example 1 using crystalline cellulose, which is a highly moldable component, had a hardness of 40 N to 200 N, a friability of 1% or less, and excellent characteristics with an oral disintegration time of 30 seconds or less. Examples 2-3 using the starches corn starch or potato starch also showed excellent properties. Further, Comparative Examples 1 to 3 using excipients usually used (lactose hydrate, D-mannitol, erythritol) are not sufficient in hardness and friability, and have problems with tablet physical properties. It was. In addition, Comparative Examples 2 and 3 did not show characteristics as an intraoral rapidly disintegrating tablet.

(Experimental example 5)
Similar to Experimental Example 4, the tablets of Example 4 and Comparative Example 4 were measured for hardness, friability, and oral disintegration time. In addition, Table 5 shows the component names of these tablets and the measured hardness, friability, and oral disintegration time. * In the table indicates that the tablet was shattered and could not be measured.

  In Comparative Example 4 using crospovidone which is a rapidly disintegrating component and not using a high moldability component, the disintegration property in the oral cavity was excellent, but the hardness and friability were not sufficient, and the problem of tablet physical properties was Had. However, Example 4 using both a high moldability component and a rapidly disintegrating component has a hardness of 40N to 200N, a friability of 1% or less, and an excellent characteristic that the oral disintegration time is within 30 seconds. showed that.

Claims (9)

The molding material containing at least the following component (A) and component (B) is directly compressed with a compression molding machine , and the content of the component (A) is 70% to 95% by mass of the total preparation. A fast disintegrating preparation having a tablet hardness of 40 N to 200 N , a tablet friability of 1% or less, and a disintegration time in the oral cavity of 60 seconds or less.
(A) Calcium carbonate (B) crystalline cellulose, carmellose, ethylcellulose, low-substituted hydroxypropylcellulose with a 50% particle size of 20 to 100 μm obtained by measuring the particle size by laser diffraction method , obtained from limestone And one or more excipients selected from the group consisting of starches Content in the pre-SL component (B) is 2 wt% to 25 wt% of the total formulation, rapidly disintegrating formulation according to claim 1. The rapidly disintegrating preparation according to claim 1 or 2, wherein the starches are one or more excipients selected from the group consisting of potato starch, rice starch, wheat starch, and corn starch. The rapidly disintegrating preparation according to any one of claims 1 to 3 , further comprising a rapidly disintegrating component. The rapidly disintegrating component is crospovidone, rapidly disintegrating formulation of claim 4. The content of the rapidly disintegrating component is not more than 20% by weight of the total formulation, rapidly disintegrating formulation according to claim 4 or 5. The rapidly disintegrating preparation according to any one of claims 1 to 6 , wherein the 50% particle size of the calcium carbonate is 22 µm to 50 µm. 8. The rapidly disintegrating preparation according to any one of claims 1 to 7, which does not contain a sugar alcohol. At least (A) and (B) are mixed and compressed directly with a compression molding machine, the content of the component (A) is 70% to 95% by weight of the total preparation, and the tablet hardness is 40N to 200N And a method for producing a rapidly disintegrating preparation, wherein the friability is 1% or less and the disintegration time in the oral cavity is 60 seconds or less.
(A) Calcium carbonate (B) crystalline cellulose, carmellose, ethylcellulose, low-substituted hydroxypropylcellulose with a 50% particle size of 20 to 100 μm obtained by measuring the particle size by laser diffraction method , obtained from limestone And one or more excipients selected from the group consisting of starches