JPWO2020246120A5 - - Google Patents
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- JPWO2020246120A5 JPWO2020246120A5 JP2021524680A JP2021524680A JPWO2020246120A5 JP WO2020246120 A5 JPWO2020246120 A5 JP WO2020246120A5 JP 2021524680 A JP2021524680 A JP 2021524680A JP 2021524680 A JP2021524680 A JP 2021524680A JP WO2020246120 A5 JPWO2020246120 A5 JP WO2020246120A5
- Authority
- JP
- Japan
- Prior art keywords
- orally disintegrating
- disintegrating tablet
- powder
- tablet
- acetaminophen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 88
- 239000006191 orally-disintegrating tablet Substances 0.000 claims description 59
- 229960005489 paracetamol Drugs 0.000 claims description 44
- 239000003826 tablet Substances 0.000 claims description 39
- 239000000843 powder Substances 0.000 claims description 36
- 239000002245 particle Substances 0.000 claims description 33
- 238000002156 mixing Methods 0.000 claims description 26
- 238000004519 manufacturing process Methods 0.000 claims description 17
- 229920002678 cellulose Polymers 0.000 claims description 14
- 239000007884 disintegrant Substances 0.000 claims description 14
- 239000001913 cellulose Substances 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 12
- 239000000796 flavoring agent Substances 0.000 claims description 10
- 210000000214 mouth Anatomy 0.000 claims description 9
- 235000003599 food sweetener Nutrition 0.000 claims description 7
- 239000003765 sweetening agent Substances 0.000 claims description 7
- 235000013355 food flavoring agent Nutrition 0.000 claims description 6
- 239000003205 fragrance Substances 0.000 claims description 5
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 4
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 4
- 235000019634 flavors Nutrition 0.000 claims description 4
- 229940041616 menthol Drugs 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims description 2
- 239000000120 Artificial Saliva Substances 0.000 claims description 2
- 108010011485 Aspartame Proteins 0.000 claims description 2
- 235000005979 Citrus limon Nutrition 0.000 claims description 2
- 244000131522 Citrus pyriformis Species 0.000 claims description 2
- 240000000560 Citrus x paradisi Species 0.000 claims description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- 235000016623 Fragaria vesca Nutrition 0.000 claims description 2
- 240000009088 Fragaria x ananassa Species 0.000 claims description 2
- 235000011363 Fragaria x ananassa Nutrition 0.000 claims description 2
- 244000246386 Mentha pulegium Species 0.000 claims description 2
- 235000016257 Mentha pulegium Nutrition 0.000 claims description 2
- 235000004357 Mentha x piperita Nutrition 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
- 244000228451 Stevia rebaudiana Species 0.000 claims description 2
- 239000004376 Sucralose Substances 0.000 claims description 2
- 235000010358 acesulfame potassium Nutrition 0.000 claims description 2
- 229960004998 acesulfame potassium Drugs 0.000 claims description 2
- 239000000619 acesulfame-K Substances 0.000 claims description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000000605 aspartame Substances 0.000 claims description 2
- 235000010357 aspartame Nutrition 0.000 claims description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 2
- 229960003438 aspartame Drugs 0.000 claims description 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 229940065115 grapefruit extract Drugs 0.000 claims description 2
- 235000001050 hortel pimenta Nutrition 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 claims description 2
- 235000019204 saccharin Nutrition 0.000 claims description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims description 2
- 229940081974 saccharin Drugs 0.000 claims description 2
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 claims description 2
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 2
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 2
- 239000008109 sodium starch glycolate Substances 0.000 claims description 2
- 235000019408 sucralose Nutrition 0.000 claims description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 16
- 235000019658 bitter taste Nutrition 0.000 description 16
- 229940088679 drug related substance Drugs 0.000 description 16
- 235000010980 cellulose Nutrition 0.000 description 10
- 238000001000 micrograph Methods 0.000 description 6
- 238000009826 distribution Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000004513 sizing Methods 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010008 shearing Methods 0.000 description 3
- 235000019640 taste Nutrition 0.000 description 3
- 238000003332 Raman imaging Methods 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 235000019606 astringent taste Nutrition 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000001953 sensory effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 206010013911 Dysgeusia Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000007561 laser diffraction method Methods 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Description
【０００５】
ンを７５質量％以上の高濃度で含みながら、錠剤硬度５０Ｎ以上を有し、且つ実用的な口腔内速崩壊性を有する口腔内崩壊錠を提供することを解決すべき課題とする。さらには、本発明は、服用感の良好な口腔内崩壊錠を提供することを解決すべき課題とする。本発明は、アセトアミノフェンの苦味が抑制された口腔内崩壊錠を提供することを解決すべき課題とする。加えて、本発明は、前記口腔内崩壊錠の製造方法を提供することを解決すべき課題とする。
課題を解決するための手段
［００１５］
上記課題の下、本発明者らは、鋭意検討を行った結果、所定範囲の粒子径を有するアセトアミノフェン原薬と高成形性の結晶セルロースと崩壊剤を混合し、直接打錠して製造することにより、アセトアミノフェンを高濃度で含みながら、錠剤硬度５０Ｎ以上を有し、且つ実用的な口腔内速崩壊性を有する口腔内崩壊錠が得られることを見出した。また、上記のように製造されたアセトアミノフェン含有口腔内崩壊錠の苦味は抑制されており、服用しやすい口腔内崩壊錠が得られることを見出した。本発明は、上記の知見に基づいて完成したものである。
［００１６］
即ち、本発明によれば、以下の発明が提供される。
［１］８０～３５０μｍの範囲のメジアン粒子径を有するアセトアミノフェンと、高成形性の結晶セルロースと、崩壊剤とを含む口腔内崩壊錠であって、上記アセトアミノフェンの１錠中含有率は７５質量％以上及び１錠中含有量は１９０ｍｇ以上であり、錠剤硬度５０Ｎ以上を有する口腔内崩壊錠。
［２］口腔内崩壊錠に、人工唾液水溶液を、送液速度６ｍＬ／分、滴下高さ８０ｍｍ、及び荷重１０ｇの条件にて、滴下して測定される崩壊時間が３０秒以内である、［１］に記載の口腔内崩壊錠。
［３］空隙率が２０％未満である、［１］又は［２］に記載の口腔内崩壊錠。
［４］錠剤の気孔率が２５％未満である、［１］～［３］の何れか一に記載の口腔内崩壊錠。0005
It is an object to be solved to provide an orally disintegrating tablet having a tablet hardness of 50 N or more and a practical rapid disintegrating property in the oral cavity while containing a tablet in a high concentration of 75% by mass or more. Furthermore, the present invention is a problem to be solved to provide an orally disintegrating tablet having a good feeling of administration. The present invention is an object to be solved to provide an orally disintegrating tablet in which the bitterness of acetaminophen is suppressed. In addition, the present invention is an object to be solved to provide a method for producing the orally disintegrating tablet.
Means for Solving Problems [0015]
Under the above-mentioned problems, as a result of diligent studies, the present inventors mixed acetaminophen drug substance having a predetermined range of particle size, highly moldable crystalline cellulose and a disintegrant, and directly tableted the drug. By doing so, it has been found that an orally disintegrating tablet having a tablet hardness of 50 N or more and having a practical rapid disintegrating property in the oral cavity can be obtained while containing acetaminophen in a high concentration. It was also found that the bitterness of the acetaminophen-containing orally disintegrating tablet produced as described above is suppressed, and an orally disintegrating tablet that is easy to take can be obtained. The present invention has been completed based on the above findings.
[0016]
That is, according to the present invention, the following invention is provided.
[1] An orally disintegrating tablet containing acetaminophen having a median particle size in the range of 80 to 350 μm, highly moldable crystalline cellulose, and a disintegrant, and the content of the acetaminophen in one tablet. Is an orally disintegrating tablet having a tablet hardness of 50 N or more, having a tablet hardness of 75 mass% or more and a content of 190 mg or more in one tablet.
[2] The disintegration time measured by dropping an artificial saliva aqueous solution onto an orally disintegrating tablet under the conditions of a liquid feeding rate of 6 mL / min, a dropping height of 80 mm, and a load of 10 g is within 30 seconds. 1] The orally disintegrating tablet according to.
[3] The orally disintegrating tablet according to [1] or [2], which has a porosity of less than 20%.
[4] The orally disintegrating tablet according to any one of [1] to [3], wherein the tablet has a porosity of less than 25%.
【０００６】
［５］甘味剤及び／又は香料をさらに含む、［１］～［４］の何れか一に記載の口腔内崩壊錠。
［６］上記結晶セルロースを１錠中８．５質量％より多く含む、［１］～［５］の何れか一に記載の口腔内崩壊錠。
［７］上記結晶セルロースが、０．１０～０．１５ｇ／ｃｍ３の範囲のかさ密度を有する、［１］～［６］の何れか一に口腔内崩壊錠。
［８］上記崩壊剤が、部分アルファ化デンプン、クロスポビドン、クロスカルメロースナトリウム、及びデンプングリコール酸ナトリウムからなる群から選択される何れかである、［１］～［７］の何れか一に記載の口腔内崩壊錠。
［９］上記甘味剤が、アスパルテーム、サッカリン、ステビア、アセスルファムカリウム及びスクラロースからなる群から選択される何れかである、［５］～［８］の何れか一に記載の口腔内崩壊錠。
［１０］上記香料が粉体香料であり、グレープフルーツフレーバー、メントールフレーバー、メントールパウダー、ペパーミントパウダー、グレープフルーツエキスパウダー、レモンパウダー、アップルパウダー、ストロベリーパウダー及び巨峰パウダーからなる群から選択される何れかである、［５］～［９］の何れか一に記載の口腔内崩壊錠。
［１１］８０～３５０μｍの範囲のメジアン粒子径を有するアセトアミノフェンと高成形性の結晶セルロースと崩壊剤とを混合して粉体混合物を得る工程、及び
上記粉体混合物を直接打錠して錠剤を得る工程を含む、
［１］～［１０］の何れか一に記載の口腔内崩壊錠の製造方法。
発明の効果
［００１７］
本発明によれば、アセトアミノフェンを高濃度で含みながら、錠剤硬度５０Ｎ以上を有し、且つ実用的な口腔内速崩壊性を有する口腔内崩壊錠を提供することができる。また、本発明によれば、苦味が抑制されたアセトアミノフェン含有口腔内崩壊錠を提供することができる。加えて、本発明によれば0006
[5] The orally disintegrating tablet according to any one of [1] to [4], further comprising a sweetening agent and / or a flavoring agent.
[6] The orally disintegrating tablet according to any one of [1] to [5], which contains the above crystalline cellulose in an amount of more than 8.5% by mass in one tablet.
[7] An orally disintegrating tablet according to any one of [1] to [6], wherein the crystalline cellulose has a bulk density in the range of 0.10 to 0.15 g / cm3.
[8] The disintegrant is any one selected from the group consisting of partially pregelatinized starch, crospovidone, croscarmellose sodium, and sodium starch glycolate, according to any one of [1] to [7]. The orally disintegrating tablet described.
[9] The orally disintegrating tablet according to any one of [5] to [8], wherein the sweetening agent is selected from the group consisting of aspartame, saccharin, stevia, acesulfame potassium and sucralose.
[10] The above-mentioned fragrance is a powder fragrance, and is any one selected from the group consisting of grapefruit flavor, menthol flavor, menthol powder, peppermint powder, grapefruit extract powder, lemon powder, apple powder, strawberry powder and giant peak powder. , The orally disintegrating tablet according to any one of [5] to [9].
[11] A step of mixing acetaminophen having a median particle size in the range of 80 to 350 μm, highly moldable crystalline cellulose, and a disintegrant to obtain a powder mixture, and directly tableting the powder mixture. Including the step of obtaining tablets,
The method for producing an orally disintegrating tablet according to any one of [1] to [10].
Effect of the invention [0017]
According to the present invention, it is possible to provide an orally disintegrating tablet having a tablet hardness of 50 N or more and having a practical rapid disintegrating property in the oral cavity while containing acetaminophen in a high concentration. Further, according to the present invention, it is possible to provide an orally disintegrating tablet containing acetaminophen with suppressed bitterness. In addition, according to the present invention
【０００７】
、直接打錠法を採用し、簡単で製造コストが低い口腔内崩壊錠の製造方法を提供することができる。
図面の簡単な説明
［００１８］
［図１］図１は、実施例１１の電子顕微鏡像を示す。上の電子顕微鏡像の倍率は１００倍、下は３００倍である。
［図２］図２は、比較例３の電子顕微鏡像を示す。上の電子顕微鏡像の倍率は１００倍、下は３００倍である。
［図３］図３は、比較例７の電子顕微鏡像を示す。上の電子顕微鏡像の倍率は１００倍、下は３００倍である。
［図４］図４は、実施例１１のアセトアミノフェン錠剤のラマンイメージング像である。
［図５］図５は、比較例３のアセトアミノフェン錠剤のラマンイメージング像である。
発明を実施するための形態
［００１９］
以下、本発明を実施するための形態を、詳細に説明する。なお、本明細書において「～」を用いて表される数値範囲は「～」の前後に記載される数値を下限値及び上限値として含む範囲を意味する。
［００２０］
（口腔内崩壊錠）
本発明は、８０～３５０μｍの範囲のメジアン粒子径を有するアセトアミノフェンと、高成形性の結晶セルロースと、崩壊剤とを含む口腔内崩壊錠であって、前記アセトアミノフェンの１錠中含有率は７５質量％以上及び１錠中含有量は１９０ｍｇ以上であり、錠剤硬度５０Ｎ以上を有する口腔内崩壊錠に関する。
［００２１］
本発明の口腔内崩壊錠における生理活性薬物はアセトアミノフェンである。アセトアミノフェンは、解熱鎮痛薬であり、発熱、寒気、頭痛などに対症療法として用いられる。本発明において、口腔内崩壊錠は、口腔内で水を服用することなしに、唾液により実用上十分な崩壊性又は溶解性（本明細書中、実用的な口腔内速崩壊性ともいう）を有する錠剤を意味する。一般に、口0007
, It is possible to provide a method for producing an orally disintegrating tablet which is simple and has a low production cost by adopting a direct tableting method.
Brief description of drawings [0018]
FIG. 1 shows an electron microscope image of Example 11. The magnification of the upper electron microscope image is 100 times, and the lower one is 300 times.
[FIG. 2] FIG. 2 shows an electron microscope image of Comparative Example 3. The magnification of the upper electron microscope image is 100 times, and the lower one is 300 times.
[FIG. 3] FIG. 3 shows an electron microscope image of Comparative Example 7. The magnification of the upper electron microscope image is 100 times, and the lower one is 300 times.
FIG. 4 is a Raman imaging image of the acetaminophen tablet of Example 11.
FIG. 5 is a Raman imaging image of the acetaminophen tablet of Comparative Example 3.
A mode for carrying out the invention [0019]
Hereinafter, embodiments for carrying out the present invention will be described in detail. In this specification, the numerical range represented by using "-" means a range including the numerical values before and after "-" as the lower limit value and the upper limit value.
[0020]
(Orally disintegrating tablet)
The present invention is an orally disintegrating tablet containing acetaminophen having a median particle size in the range of 80 to 350 μm, highly moldable crystalline cellulose, and a disintegrant, and is contained in one tablet of the acetaminophen. The present invention relates to an orally disintegrating tablet having a rate of 75% by mass or more, a content in one tablet of 190 mg or more, and a tablet hardness of 50 N or more.
[0021]
The bioactive drug in the orally disintegrating tablet of the present invention is acetaminophen. Acetaminophen is an antipyretic analgesic and is used as a symptomatic treatment for fever, chills, headache and the like. In the present invention, the orally disintegrating tablet has practically sufficient disintegration or solubility (also referred to as practical intraoral rapid disintegration in the present specification) by saliva without taking water in the oral cavity. Means a tablet to have. Generally, the mouth
【０００８】
腔内崩壊錠は、ＯＤ錠ともいう。本発明の口腔内崩壊錠の製造方法については後述する。
［００２２］
本発明の口腔内崩壊錠に用いられるアセトアミノフェン原薬（以下、本アセトアミノフェン原薬）のメジアン粒子径（Ｄ５０）は８０～３５０μｍの範囲であり、好ましくは１００～３００μｍの範囲であり、より好ましくは１００～２５０μｍの範囲であり、さらにより好ましくは１００～２００μｍの範囲である。本アセトアミノフェン原薬が有する粒度分布は、Ｄ１０が５～１００μｍの範囲、好ましくは１０～１００μｍの範囲、より好ましくは２０～１００μｍの範囲であり、かつ、Ｄ９０が、２００～５００μｍの範囲、好ましくは２５０～４００μｍの範囲、より好ましくは２５０～３５０μｍの範囲である。製造ロット間により多少の差はあってもよい。また、本アセトアミノフェン原薬の体積平均粒子径（ＭＶ）は、８０～３００μｍの範囲であることができ、１００～２５０μｍの範囲でもよい。なお、本発明における粒度分布はレーザー回折法による乾式粒子径測定（Ｌａｓｅｒ Ｍｉｃｒｏｎ Ｓｉｚｅｒ ＬＭＳ－２０００ｅ（株式会社セイシン企業））を用いた体積分布評価により求められ、Ｄ１０、Ｄ５０、Ｄ９０とは、粒度分布の小径側から各々体積の累積１０％、５０％、９０％の粒子径をいう。特に、Ｄ５０をメジアン粒子径という。
［００２３］
本発明の一実施態様では、本アセトアミノフェン原薬は、晶析後に粉砕処理を受けていないものを用いることができる。本アセトアミノフェン原薬は、晶析後に特別な処理を受けていないものを用いてもよいし、晶析後に篩過処理されたものを用いてもよい。本発明の好ましい実施態様では、本アセトアミノフェン原薬は、晶析後に篩過処理されたものである。篩過処理により、本発明の口腔内崩壊錠の製造に適した粒子径の粒子をより多く含んだ粉体を得るためである。粗大なアセトアミノフェン結晶（例えば、６００μｍ以上）が多く含まれる原薬を使用した場合、アセトアミノフェン高含有の錠剤を打錠成型することは困難であると考えられる。また、アセトアミノフェン微小物（例えば、３０μｍ以下）が多く含まれる原薬を使用して打錠された錠剤は、崩壊性が悪いため口腔内崩壊錠として成り立たないと考えられる。0008
Intracavitary disintegrating tablets are also called OD tablets. The method for producing the orally disintegrating tablet of the present invention will be described later.
[0022]
The median particle size (D50) of the acetaminophen drug substance (hereinafter referred to as the present acetaminophen drug substance) used in the orally disintegrating tablet of the present invention is in the range of 80 to 350 μm, preferably in the range of 100 to 300 μm. , More preferably in the range of 100 to 250 μm, and even more preferably in the range of 100 to 200 μm. The particle size distribution of the acetaminophen drug substance is such that D10 is in the range of 5 to 100 μm, preferably 10 to 100 μm, more preferably 20 to 100 μm, and D90 is in the range of 200 to 500 μm. It is preferably in the range of 250 to 400 μm, more preferably in the range of 250 to 350 μm. There may be some differences depending on the production lot. The volume average particle size (MV) of the present acetaminophen drug substance can be in the range of 80 to 300 μm, and may be in the range of 100 to 250 μm. The particle size distribution in the present invention is obtained by volume distribution evaluation using a dry particle size measurement (Laser Micron Sizer LMS-2000e (Seishin Corporation)) by a laser diffraction method, and D10, D50, and D90 are particle size distributions. The cumulative particle size of 10%, 50%, and 90% of the volume from the small diameter side of the particle size. In particular, D50 is called the median particle size.
[0023]
In one embodiment of the present invention, the acetaminophen drug substance can be used which has not been pulverized after crystallization. As the acetaminophen drug substance, a drug that has not undergone special treatment after crystallization may be used, or a drug that has been sieved after crystallization may be used. In a preferred embodiment of the invention, the acetaminophen drug substance is sieved after crystallization. This is to obtain a powder containing more particles having a particle size suitable for producing the orally disintegrating tablet of the present invention by sieving. When a drug substance containing a large amount of coarse acetaminophen crystals (for example, 600 μm or more) is used, it is considered difficult to tablet and mold a tablet containing a high amount of acetaminophen. Further, it is considered that a tablet tableted using a drug substance containing a large amount of acetaminophen minute substances (for example, 30 μm or less) cannot be used as an orally disintegrating tablet because of its poor disintegration property.
【００１５】
察されたが、比較例の錠剤では崩壊剤は錠剤表面にはほとんど確認されなかった。本発明は特定の理論に拘束されるものではないが、口腔内崩壊錠の原料に８０～３５０μｍの範囲のメジアン粒子径を有するアセトアミノフェン原薬を用いることにより、崩壊剤の錠剤内での局在化が生じ、従来知られていない口腔内崩壊錠の崩壊機序を発現している可能性が示唆された。
［００４２］
本発明は別の局面では、苦味が抑制されたアセトアミノフェン含有口腔内崩壊錠を提供する。アセトアミノフェンは、特有の苦味を有する。苦味とは、口腔内や咽頭部で感じる苦味や渋みを含む不快な違和感を総称するものである。本明細書において「苦味の抑制」は、苦味物質が口腔内に存在する場合に感じる苦味が抑制、低減、隠ぺい又はマスキングされることを意味し、苦味とともに渋みを含む不快な違和感が抑制、低減、隠ぺい又はマスキングされることを含んでもよい。「抑制」は、例えば、甘味剤、香料、矯味剤や本発明の特定範囲のアセトアミノフェンを使用しない場合に比較して、使用した場合に口腔内で感じる「苦味」が、いくらか減少することを意味し、苦味を全く感じない場合や、ある程度感じるがヒトにとって許容可能である場合を含んでもよい。本発明の口腔内崩壊錠について、苦味の評価は、パネラーによる官能評価試験及び／又は機器測定（味認識装置、味覚センサー）により実施することができる。後記する実施例において本発明の口腔内崩壊錠の味に関して官能評価試験を行ったところ、「１点：非常に悪い、２点：悪い、３点：どちらでもない、４点：良い、５点：非常によい」の評価で平均３．５点（６人）が得られた。口腔内崩壊錠の原料に８０～３５０μｍの範囲のメジアン粒子径を有するアセトアミノフェン原薬を用いることにより、より細粒の原薬を用いた場合よりも、アセトアミノフェン特有の苦味が感じられにくいと考えられる。
［００４３］
本発明の口腔内崩壊錠の大きさは、径６ｍｍ～１８ｍｍの範囲、アスペクト比１～３の範囲、及び厚さ２ｍｍ～１０ｍｍの範囲とすることができるが、この範囲に限定されない。本発明の口腔内崩壊錠の形状は通常錠でも異型錠でもよく、例えば円形、楕円形、カプレット形状とすることができるが、0015.
However, in the tablets of the comparative example, the disintegrant was hardly confirmed on the tablet surface. Although the present invention is not bound by a specific theory, by using an acetaminophen drug substance having a median particle size in the range of 80 to 350 μm as a raw material for an orally disintegrating tablet, a disintegrant can be used in a tablet. It was suggested that localization occurred and the mechanism of disintegration of orally disintegrating tablets, which was not known in the past, may be expressed.
[0042]
In another aspect, the present invention provides an acetaminophen-containing orally disintegrating tablet with suppressed bitterness. Acetaminophen has a peculiar bitter taste. Bitter taste is a general term for unpleasant discomfort including bitterness and astringency felt in the oral cavity and pharynx. As used herein, "suppression of bitterness" means that the bitterness felt when a bitterness substance is present in the oral cavity is suppressed, reduced, concealed or masked, and unpleasant discomfort including astringency as well as bitterness is suppressed or reduced. , May include hiding or masking. "Suppression" means that, for example, the "bitter taste" felt in the oral cavity when used is somewhat reduced as compared with the case where a sweetener, a flavoring agent, a flavoring agent or a specific range of acetaminophen of the present invention is not used. It may include the case where the bitterness is not felt at all, or the case where the bitterness is felt to some extent but is acceptable to humans. The bitterness of the orally disintegrating tablet of the present invention can be evaluated by a sensory evaluation test by a panelist and / or an instrument measurement (taste recognition device, taste sensor). When a sensory evaluation test was performed on the taste of the orally disintegrating tablet of the present invention in the examples described later, "1 point: very bad, 2 points: bad, 3 points: neither, 4 points: good, 5 points". An average of 3.5 points (6 people) was obtained in the evaluation of ": very good". By using an acetaminophen drug substance having a median particle size in the range of 80 to 350 μm as a raw material for an orally disintegrating tablet, a bitter taste peculiar to acetaminophen can be felt as compared with the case of using a finer grain drug substance. It is considered difficult.
[0043]
The size of the orally disintegrating lock of the present invention can be in the range of 6 mm to 18 mm in diameter, in the range of aspect ratios 1 to 3, and in the range of 2 mm to 10 mm in thickness, but is not limited to this range. The shape of the orally disintegrating tablet of the present invention may be a normal tablet or a variant tablet, and may be, for example, a circular shape, an elliptical shape, or a caplet shape.
【００１６】
これらに限定されない。
［００４４］
（口腔内崩壊錠の製造方法）
本発明の別の局面は、８０～３５０μｍの範囲のメジアン粒子径を有するアセトアミノフェンと高成形性の結晶セルロースと崩壊剤とを混合して粉体混合物を得る工程、及び前記粉体混合物を直接打錠して錠剤を得る工程を含む、上記口腔内崩壊錠の製造方法に関する。
［００４５］
本発明の製造方法の「８０～３５０μｍの範囲のメジアン粒子径を有するアセトアミノフェンと高成形性の結晶セルロースと崩壊剤とを混合して粉体混合物を得る工程」（以下、混合工程という）は、口腔内崩壊錠を打錠する前に、口腔内崩壊錠の生理活性薬物のアセトアミノフェンと、その他の成分を混合する工程である。その他の成分とは、高成形性の結晶セルロースと崩壊剤のほか、甘味剤、矯味剤及び／又はその他の添加剤である。
［００４６］
本発明の口腔内崩壊錠の製造方法に用いる８０～３５０μｍの範囲のメジアン粒子径を有するアセトアミノフェン、高成形性の結晶セルロース、崩壊剤、甘味剤、香料、矯味剤及びその他の添加剤は、上記（口腔内崩壊錠）に記載のものと同様のものを用いることができる。
［００４７］
本明細書において「混合」は、２種類以上の粉体を混ぜることを意味する。当該分野で用いられる用語に「粉砕」があるが、これは粒子を砕いて小さい粒子を得ることを意味する。一方、本明細書の「混合」は、粉体の粒子径を細かくする作用がない操作である。また、当該技術分野で用いられる「解砕整粒」は、凝集した粒子を引きはがすことを意味する。解砕整粒と粉砕では、粉体に「せん断力」が強くかかるが、混合は「せん断力」が弱い操作である。例えば、微粉領域のアセトアミノフェン粒子が多く凝集している粉体の場合、各粒子を引きはがすための強い「せん断力」が必要となり、この操作が解砕整粒である。さらに強い「せん断力」で粒子を壊す操作は粉砕である。
［００４８］
例えば、特許文献４に記載の錠剤の製造は、未粉砕のアセトアミノフェン原薬を原料として使用するが、解砕整粒機を用いてアセトアミノフェンの粒0016.
Not limited to these.
[0044]
(Manufacturing method of orally disintegrating lock)
Another aspect of the present invention is a step of mixing acetaminophen having a median particle size in the range of 80 to 350 μm, highly moldable crystalline cellulose, and a disintegrant to obtain a powder mixture, and the powder mixture. The present invention relates to the above-mentioned method for producing an orally disintegrating tablet, which comprises a step of directly tableting to obtain a tablet.
[0045]
The production method of the present invention "a step of mixing acetaminophen having a median particle size in the range of 80 to 350 μm, highly moldable crystalline cellulose, and a disintegrant to obtain a powder mixture" (hereinafter referred to as a mixing step). Is a step of mixing the bioactive drug acetaminophen of the orally disintegrating tablet with other components before the orally disintegrating tablet is beaten. Other components are highly moldable crystalline celluloses and disintegrants, as well as sweeteners, flavoring agents and / or other additives.
[0046]
The acetaminophen having a median particle size in the range of 80 to 350 μm, highly moldable crystalline cellulose, a disintegrant, a sweetener, a fragrance, a flavoring agent and other additives used in the method for producing an orally disintegrating tablet of the present invention are used. , The same as those described in the above (orally disintegrating tablet) can be used.
[0047]
As used herein, "mixing" means mixing two or more types of powder. The term used in the art is "grinding", which means crushing particles to obtain smaller particles. On the other hand, "mixing" in the present specification is an operation that does not have the effect of reducing the particle size of the powder. Further, "crushing and sizing" used in the technical field means peeling off aggregated particles. In crushing and sizing and crushing, a strong "shearing force" is applied to the powder, but in mixing, the "shearing force" is weak. For example, in the case of a powder in which many acetaminophen particles in the fine powder region are aggregated, a strong "shearing force" is required to peel off each particle, and this operation is crushing and sizing. The operation of breaking particles with a stronger "shear force" is crushing.
[0048]
For example, in the production of tablets described in Patent Document 4, uncrushed acetaminophen drug substance is used as a raw material, but acetaminophen granules are produced using a crushing and sizing machine.
【００１７】
子径が大きな結晶や凝集した塊を選択的に解砕整粒する工程を含むため、錠剤に含まれるアセトアミノフェンの粒子は、未粉砕のアセトアミノフェン原薬よりも細粒化していると考えられる。一方、本発明者らは、本製造方法においては、アセトアミノフェン原薬の粒子径（メジアン粒子径８０～３５０μｍ）は、混合工程を経た後でも変化がないことを、粒子径分布測定及び電子顕微鏡像の観察により確認した。
［００４９］
本製造方法の混合工程は、例えば、Ｖ型混合機やコンテナミキサー等を用いて実施することができる。Ｖ型混合機は、Ｖ形状の混合容器を回転させることで、容器内の粉粒体を全体に移動し、対流運動を与えることで、速やかで均一な混合を行う装置である。Ｖ型混合機を用いることで、通常、粉粒体に無理な力をかけない緩和な混合が可能である。混合条件は、スケールによって適宜変更することができるが、例えば回転速度５～５０ｒｐｍで１～１５分間程度実施することができる。
［００５０］
本製造方法の混合工程は、１回の混合操作で実施してもよいし、あるいは２回以上の混合操作に分けて実施することができる。１回の混合操作で行う場合には、口腔内崩壊錠に含まれる全ての成分がＶ型混合機等に投入され、混合される。２回以上の混合操作に分けて行う場合には、口腔内崩壊錠に含まれる成分を種類の別に２回以上に分けてＶ型混合機等に投入・混合することができる。例えば１回目の混合の際には、滑沢剤（例えば、ステアリン酸マグネシウム）以外の成分をＶ型混合機等に投入し混合し、滑沢剤は、１回目の混合後に添加し、再度、混合することができる。これにより、滑沢剤の展延を防ぐことができる。滑沢剤を加えた後の混合は、１～３分間程度とすることができる。本製造方法の混合工程により、粉体混合物を得ることができる。粉体混合物は、口腔内崩壊錠に含まれる成分の粉状の集合体である。
［００５１］
本発明の製造方法の「前記粉体混合物を直接打錠して錠剤を得る工程」（以下、打錠工程という）は、上記混合工程で得られた粉体混合物を直接打錠し、成型する工程である。本明細書において、直接打錠とは、杵臼を用いて、粉体混合物を直接圧縮して錠剤を得る、乾式法による打錠を意味する。[0017]
It is said that the acetaminophen particles contained in the tablets are finer than the uncrushed acetaminophen drug substance because it includes a step of selectively crushing and sizing crystals and agglomerated lumps having a large child diameter. Conceivable. On the other hand, the present inventors have determined that in the present production method, the particle size (median particle size 80 to 350 μm) of the acetaminophen drug substance does not change even after the mixing step, and the particle size distribution measurement and the electron. It was confirmed by observing the microscopic image.
[0049]
The mixing step of this production method can be carried out using, for example, a V-type mixer, a container mixer, or the like. The V-type mixer is a device that rotates a V-shaped mixing container to move the powder or granular material in the container as a whole and gives a convection motion to perform rapid and uniform mixing. By using a V-type mixer, it is usually possible to perform mild mixing without exerting an excessive force on the powder or granular material. The mixing conditions can be appropriately changed depending on the scale, and can be carried out, for example, at a rotation speed of 5 to 50 rpm for about 1 to 15 minutes.
[0050]
The mixing step of this production method may be carried out by one mixing operation, or may be carried out by dividing into two or more mixing operations. When the mixing operation is performed once, all the components contained in the orally disintegrating tablet are put into a V-type mixer or the like and mixed. When the mixing operation is divided into two or more times, the components contained in the orally disintegrating tablet can be divided into two or more times according to the type and put into and mixed in a V-type mixer or the like. For example, at the time of the first mixing, components other than the lubricant (for example, magnesium stearate) are put into a V-type mixer or the like and mixed, and the lubricant is added after the first mixing and again. Can be mixed. This can prevent the spread of the lubricant. Mixing after adding the lubricant can be about 1 to 3 minutes. A powder mixture can be obtained by the mixing step of this production method. The powder mixture is a powdery aggregate of the components contained in the orally disintegrating tablet.
[0051]
In the "step of directly tableting the powder mixture to obtain a tablet" (hereinafter referred to as a tableting step) of the production method of the present invention, the powder mixture obtained in the above mixing step is directly tableted and molded. It is a process. As used herein, direct tableting means tableting by a dry method in which a powder mixture is directly compressed using a mortar to obtain tablets.
Claims (11)
前記粉体混合物を直接打錠して錠剤を得る工程を含む、
請求項１～１０の何れか一項に記載の口腔内崩壊錠の製造方法。A step of mixing acetaminophen having a median particle size in the range of 80 to 350 μm, highly moldable crystalline cellulose, and a disintegrant to obtain a powder mixture, and directly tableting the powder mixture to obtain tablets. Including the process,
The method for producing an orally disintegrating tablet according to any one of claims 1 to 10.
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| JP4719899B2 (en) | 2000-01-07 | 2011-07-06 | 大正製薬株式会社 | Orally rapidly disintegrating tablets |
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| WO2005123040A1 (en) * | 2004-06-22 | 2005-12-29 | Shionogi & Co., Ltd. | Tablet rapidly disintegrating in mouth |
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| CN104080443B (en) * | 2012-03-29 | 2017-12-12 | 株式会社大赛璐 | The preparation method and said composition and the Orally disintegrating tablet containing said composition of the disintegrating particles composition of the carboxymethyl cellulose containing acid |
| JP6926404B2 (en) | 2015-06-12 | 2021-08-25 | ゼリア新薬工業株式会社 | Orally disintegrating tablet |
| US11033501B2 (en) | 2016-05-10 | 2021-06-15 | Nippon Zoki Pharmaceutical Co., Ltd. | Method for manufacturing acetaminophen preparation |
| PT3446684T (en) | 2016-06-16 | 2021-12-16 | Towa Pharmaceutical Co Ltd | Orally disintegrating tablet |
| JP6832753B2 (en) * | 2017-03-09 | 2021-02-24 | 旭化成株式会社 | Cellulose complex |
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2020
- 2020-03-30 WO PCT/JP2020/014429 patent/WO2020246120A1/en active Application Filing
- 2020-03-30 JP JP2021524680A patent/JP7360460B2/en active Active
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