JPWO2016088816A1 - Zinc acetate hydrate tablets and process for producing the same - Google Patents
Zinc acetate hydrate tablets and process for producing the same Download PDFInfo
- Publication number
- JPWO2016088816A1 JPWO2016088816A1 JP2016562663A JP2016562663A JPWO2016088816A1 JP WO2016088816 A1 JPWO2016088816 A1 JP WO2016088816A1 JP 2016562663 A JP2016562663 A JP 2016562663A JP 2016562663 A JP2016562663 A JP 2016562663A JP WO2016088816 A1 JPWO2016088816 A1 JP WO2016088816A1
- Authority
- JP
- Japan
- Prior art keywords
- zinc acetate
- acetate hydrate
- tablet
- zinc
- present
- 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
Links
- DJWUNCQRNNEAKC-UHFFFAOYSA-L zinc acetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O DJWUNCQRNNEAKC-UHFFFAOYSA-L 0.000 title claims abstract description 104
- 238000000034 method Methods 0.000 title claims description 45
- 238000004519 manufacturing process Methods 0.000 claims abstract description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000011701 zinc Substances 0.000 claims abstract description 31
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 20
- 239000012085 test solution Substances 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims description 24
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 16
- 239000007884 disintegrant Substances 0.000 claims description 14
- 238000010828 elution Methods 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 12
- 239000007888 film coating Substances 0.000 claims description 11
- 238000009501 film coating Methods 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 6
- 238000011978 dissolution method Methods 0.000 claims description 3
- 238000007922 dissolution test Methods 0.000 claims 1
- 230000008034 disappearance Effects 0.000 abstract description 9
- 239000013078 crystal Substances 0.000 abstract description 8
- 238000004090 dissolution Methods 0.000 abstract description 3
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 88
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 18
- 238000005469 granulation Methods 0.000 description 16
- 230000003179 granulation Effects 0.000 description 16
- 239000002775 capsule Substances 0.000 description 14
- 239000000843 powder Substances 0.000 description 12
- 239000000314 lubricant Substances 0.000 description 10
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 9
- 239000011230 binding agent Substances 0.000 description 9
- 235000019359 magnesium stearate Nutrition 0.000 description 9
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 8
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- 229920002261 Corn starch Polymers 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 7
- 229950008138 carmellose Drugs 0.000 description 7
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- 239000003795 chemical substances by application Substances 0.000 description 7
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000008187 granular material Substances 0.000 description 6
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- 239000000454 talc Substances 0.000 description 6
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- 239000001863 hydroxypropyl cellulose Substances 0.000 description 5
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- 238000003756 stirring Methods 0.000 description 5
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- 208000002972 Hepatolenticular Degeneration Diseases 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 229920000881 Modified starch Polymers 0.000 description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 208000018839 Wilson disease Diseases 0.000 description 4
- 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 description 4
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- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 4
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- 229920001592 potato starch Polymers 0.000 description 3
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- 239000004246 zinc acetate Substances 0.000 description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
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- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
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- 229920000084 Gum arabic Polymers 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 2
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 2
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- 235000001465 calcium Nutrition 0.000 description 2
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- 229910052791 calcium Inorganic materials 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
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- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/30—Zinc; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
造粒物の製造工程における品温を40℃未満にコントロールすることで、製造工程における酢酸亜鉛水和物中の結晶水の消失が抑制された、占有する容積が少ない酢酸亜鉛水和物のコンパクト化された造粒物及びその製造方法を提供する。このような造粒物は、酢酸亜鉛水和物(C4H6O4Zn・2H2O)を5〜200mg含有し、大きさが直径5〜12mm、厚さ1〜6mmであって、日局溶出試験法パドル法50回転(試験液:水900mL)によって測定される15分後の亜鉛の溶出量が85%以上である、酢酸亜鉛水和物錠である。By controlling the product temperature in the production process of the granulated product to less than 40 ° C., the disappearance of crystal water in the zinc acetate hydrate in the production process is suppressed, and the compact volume of zinc acetate hydrate that occupies less volume A granulated product and a method for producing the same are provided. Such a granulated product contains 5 to 200 mg of zinc acetate hydrate (C4H6O4Zn · 2H2O), has a diameter of 5 to 12 mm, and a thickness of 1 to 6 mm. It is a zinc acetate hydrate tablet in which the dissolution amount of zinc after 15 minutes measured by rotation (test solution: 900 mL of water) is 85% or more.
Description
本発明は、酢酸亜鉛水和物を有効成分とする酢酸亜鉛水和物錠及びその製造方法に関する。 The present invention relates to a zinc acetate hydrate tablet containing zinc acetate hydrate as an active ingredient and a method for producing the same.
ウィルソン病は、食事によって摂取された銅が肝臓から胆汁及び腸管中に正常に排泄されず、肝臓、脳、腎臓等に銅が多量に蓄積することによって、肝臓や神経等に重い障害を引き起こす病気である。
ウィルソン病の治療薬としては、米国では1997年に、欧州では2004年に、日本では2008年に、酢酸亜鉛水和物(C4H6O4Zn・2H2O)を有効成分とするカプセル剤が認可され、現在使用されている。Wilson's disease is a disease that causes severe damage to the liver, nerves, etc., because copper ingested by diet is not normally excreted from the liver into the bile and intestinal tract, and a large amount of copper accumulates in the liver, brain, kidney, etc. It is.
As a therapeutic agent for Wilson's disease, capsules containing zinc acetate hydrate (C 4 H 6 O 4 Zn.2H 2 O) as an active ingredient in 1997 in the United States, 2004 in Europe, and 2008 in Japan The agent has been approved and is currently in use.
しかしながら、現在使用されている酢酸亜鉛水和物のカプセル剤は、カプセルに詰め込まれる成分の総量が非常に多く、また、物理混合物であるため、製造工程において成分をカプセルに充填する際に成分の流動性が悪く、充填不均一などの問題をおこし、製剤を連続生産する上での大きな障害となっている。
また、該カプセル剤は、剤径が大きいため(例えば、1号カプセルは、外径が7mmで長さが19〜20mm)、服用時に飲み込みにくい(嚥下しにくい)という問題がある。よって、酢酸亜鉛水和物を有効成分とする剤として、剤径(直径)がより小さいものが必要とされている。However, the zinc acetate hydrate capsules currently used have a very large total amount of ingredients packed in the capsule and are a physical mixture. Therefore, when the ingredients are filled into the capsule in the manufacturing process, The fluidity is poor, causing problems such as uneven filling, which is a major obstacle to continuous production of the preparation.
In addition, since the capsule has a large drug diameter (for example, the No. 1 capsule has an outer diameter of 7 mm and a length of 19 to 20 mm), there is a problem that it is difficult to swallow (does not swallow) when taking. Therefore, an agent having zinc acetate hydrate as an active ingredient is required to have a smaller agent diameter (diameter).
本発明は、上記現状に鑑み、造粒物の製造工程における乾燥温度を品温40℃未満にコントロールすることで、製造工程における酢酸亜鉛水和物中の結晶水の消失が抑制された、占有する容積が少ない酢酸亜鉛水和物のコンパクト化された造粒物及びその製造方法を提供することを課題とする。 In view of the present situation, the present invention controls the drying temperature in the production process of the granulated product to a product temperature of less than 40 ° C., thereby suppressing the disappearance of crystal water in the zinc acetate hydrate in the production process. An object of the present invention is to provide a compacted granulated product of zinc acetate hydrate with a small volume and a method for producing the same.
カプセル剤よりも製造効率が良く、嚥下しやすい酢酸亜鉛水和物の剤を得る方法としては、より直径の小さいカプセルに充填するか、錠剤等の他の剤形に変更する方法が考えられる。
一方、酢酸亜鉛水和物は、二水和物として知られており、比較的安定(例えば、硫酸中で加熱しても100℃程度まで安定)であると認識されていた。しかしながら、本発明者らが酢酸亜鉛水和物について研究を重ねたところ、酢酸亜鉛水和物は、比較的低温(例えば、約40℃)で加熱されると、該水和物中の結晶水が消失して無水物に転移し、ウィルソン病の治療薬の有効成分としては承認されていない無水物となってしまう場合があった。
よって、本発明者らは、酢酸亜鉛水和物を有効成分とする錠剤の製造においては、酢酸亜鉛水和物の無水物化を避ける必要があり、湿式造粒では乾燥工程で加熱するため、結晶水の消失が避けられないと考え、乾式造粒によって剤径が小さい酢酸亜鉛水和物錠を製造することを試みた。しかしながら、乾式造粒法では、剤径が小さい酢酸亜鉛水和物錠を得ることができなかった。As a method for obtaining an agent of zinc acetate hydrate that is more efficient than capsules and easy to swallow, a method of filling capsules with smaller diameters or changing to other dosage forms such as tablets can be considered.
On the other hand, zinc acetate hydrate is known as dihydrate and has been recognized to be relatively stable (for example, stable to about 100 ° C. even when heated in sulfuric acid). However, when the present inventors have conducted research on zinc acetate hydrate, when zinc acetate hydrate is heated at a relatively low temperature (for example, about 40 ° C.), Disappeared and metastasized to an anhydride, resulting in an anhydride that was not approved as an active ingredient for Wilson's disease treatment.
Therefore, the present inventors have to avoid the anhydrous formation of zinc acetate hydrate in the manufacture of tablets containing zinc acetate hydrate as an active ingredient. Considering that the disappearance of water is inevitable, an attempt was made to produce zinc acetate hydrate tablets with a small drug size by dry granulation. However, the dry granulation method could not obtain a zinc acetate hydrate tablet with a small dosage size.
本発明者らは、上記課題を解決するためにさらに鋭意研究を重ねた結果、酢酸亜鉛水和物(C4H6O4Zn・2H2O)を5〜200mg含有し、大きさが直径5〜12mm、厚さ1〜6mmであって、日局溶出試験法パドル法50回転(試験液:水900mL)によって測定される15分後の亜鉛の溶出量が85%以上である酢酸亜鉛水和物錠は、意外にも、特定の製造方法(例えば、湿式造粒法、流動層造粒法)によって製造することができることを見出した。
本発明者らは、上記以外にも下記するように種々の思いがけない新知見を得て、さらに鋭意検討を重ねて本発明を完成するに至った。As a result of further diligent research to solve the above problems, the inventors of the present invention contain 5-200 mg of zinc acetate hydrate (C 4 H 6 O 4 Zn.2H 2 O), and the size is a diameter. Zinc acetate water having 5 to 12 mm and thickness of 1 to 6 mm, and having an elution amount of zinc after 15 minutes measured by 50 rotations of the paddle method (test solution: 900 mL water) of 85% or more. Surprisingly, it has been found that Japanese tablets can be produced by a specific production method (for example, wet granulation method, fluidized bed granulation method).
In addition to the above, the present inventors have obtained various unexpected new findings as described below, and have further conducted intensive studies to complete the present invention.
即ち、本発明は、以下の酢酸亜鉛水和物錠等に関する。
[1]酢酸亜鉛水和物(C4H6O4Zn・2H2O)を5〜200mg含有し、大きさが直径5〜12mm、厚さ1〜6mmであって、日局溶出試験法パドル法50回転(試験液:水900mL)によって測定される15分後の亜鉛の溶出量が85%以上であることを特徴とする、酢酸亜鉛水和物錠。
[2]前記大きさが、直径5〜10mm、厚さ2〜5mmである前記[1]に記載の酢酸亜鉛水和物錠。
[3]総質量が、酢酸亜鉛水和物含有量の2倍以下である前記[1]又は[2]に記載の酢酸亜鉛水和物錠。
[4](1)酢酸亜鉛水和物(C4H6O4Zn・2H2O)、賦形剤、崩壊剤及び溶媒の混合物を造粒した後乾燥して造粒物を得る工程、(2)該造粒物を打錠して素錠を得る工程、及び(3)該素錠にフィルムコーティングした後乾燥する工程を含み、前記工程(1)における品温が40℃を越えず、前記工程(3)における品温が50℃以下であることを特徴とする、酢酸亜鉛水和物(C4H6O4Zn・2H2O)を5〜200mg含有し、大きさが直径5〜12mm、厚さ1〜6mmであって、日局溶出試験法パドル法50回転(試験液:水900mL)によって測定される15分後の亜鉛の溶出量が85%以上である酢酸亜鉛水和物錠の製造方法。That is, the present invention relates to the following zinc acetate hydrate tablets and the like.
[1] containing 5 to 200 mg of zinc acetate hydrate (C 4 H 6 O 4 Zn · 2H 2 O), having a diameter of 5 to 12 mm and a thickness of 1 to 6 mm. A zinc acetate hydrate tablet, wherein the zinc elution amount after 15 minutes measured by the paddle method 50 rotations (test solution: water 900 mL) is 85% or more.
[2] The zinc acetate hydrate tablet according to [1], wherein the size is 5 to 10 mm in diameter and 2 to 5 mm in thickness.
[3] The zinc acetate hydrate tablet according to [1] or [2], wherein the total mass is twice or less the zinc acetate hydrate content.
[4] (1) A step of granulating a mixture of zinc acetate hydrate (C 4 H 6 O 4 Zn · 2H 2 O), an excipient, a disintegrant, and a solvent and then drying to obtain a granulated product, (2) comprising a step of tableting the granulated product to obtain an uncoated tablet, and (3) a step of film-coating the uncoated tablet and then drying, wherein the product temperature in the step (1) does not exceed 40 ° C. The zinc oxide hydrate (C 4 H 6 O 4 Zn.2H 2 O) is contained in an amount of 5 to 200 mg, and the size is a diameter. Zinc acetate water having 5 to 12 mm, thickness of 1 to 6 mm, and having an elution amount of zinc of 15% or more after 15 minutes as measured by 50 rotations of the Japanese Pharmacopoeia Paddle Method (test solution: 900 mL of water) Manufacturing method of Japanese tablets.
本発明によれば、造粒物の製造工程における乾燥を品温40℃未満の温度で行うことで、製造工程における酢酸亜鉛水和物中の結晶水の消失が抑制された酢酸亜鉛水和物錠を得ることができる。
また、本発明の酢酸亜鉛水和物錠は、大きさが小さいため、従来の酢酸亜鉛水和物のカプセル剤と比べて服用時に飲み込みやすい。
なお、本発明の酢酸亜鉛水和物錠の打錠用粉体は、そのまま顆粒剤としたり、或いはカプセルに充填することができる。ADVANTAGE OF THE INVENTION According to this invention, the zinc acetate hydrate by which the loss | disappearance of the crystal water in the zinc acetate hydrate in a manufacturing process was suppressed by performing the drying in the manufacturing process of a granulated material at the temperature below 40 degreeC. You can get a lock.
In addition, since the zinc acetate hydrate tablet of the present invention is small in size, it is easier to swallow at the time of taking than the conventional zinc acetate hydrate capsule.
In addition, the powder for tableting of the zinc acetate hydrate tablet of the present invention can be used as a granule as it is or filled into a capsule.
以下、本発明を詳細に説明する。
<酢酸亜鉛水和物錠>
本発明の酢酸亜鉛水和物錠は、酢酸亜鉛水和物(C4H6O4Zn・2H2O)を5〜200mg含有し、大きさが直径5〜12mm、厚さ1〜6mmであって、日局溶出試験法パドル法50回転(試験液:水900mL)によって測定される15分後の亜鉛の溶出量が85%以上であることを特徴とする。尚、酢酸亜鉛水和物錠は、通常、酢酸亜鉛水和物の素錠であってよいし、該素錠のフィルムコーティング錠であってもよい。Hereinafter, the present invention will be described in detail.
<Zinc acetate hydrate tablets>
Zinc acetate hydrate tablets of the present invention, zinc acetate hydrate (C 4 H 6 O 4 Zn · 2H 2 O) containing 5 to 200 mg, size diameter 5-12 mm, a thickness of 1~6mm Then, the elution amount of zinc after 15 minutes as measured by 50 revolutions of the paddle method of JP (equivalent to 900 mL of water) is 85% or more. In addition, the zinc acetate hydrate tablet may be an uncoated tablet of zinc acetate hydrate, or a film-coated tablet of the uncoated tablet.
本発明の酢酸亜鉛水和物錠において、酢酸亜鉛水和物の含有量は、通常は約5〜200mgであり、好ましくは約50〜180mgであり、より好ましくは約80〜170mgである。このような範囲であれば、酢酸亜鉛水和物錠の製造工程における造粒後の乾燥を品温40℃未満の温度で行うことができ、製造工程における酢酸亜鉛水和物中の結晶水の消失を抑制できるため、好ましい。 In the zinc acetate hydrate tablet of the present invention, the content of zinc acetate hydrate is usually about 5-200 mg, preferably about 50-180 mg, more preferably about 80-170 mg. If it is such a range, the drying after granulation in the manufacturing process of a zinc acetate hydrate tablet can be performed at a temperature of less than 40 ° C., and the crystal water in the zinc acetate hydrate in the manufacturing process Since disappearance can be suppressed, it is preferable.
本発明の酢酸亜鉛水和物錠の直径は、通常は約5〜12mmであり、好ましくは約5〜10mmであり、より好ましくは約6〜9mmである。
また、本発明の酢酸亜鉛水和物錠の厚さは、通常は約1〜6mmであり、好ましくは約2〜5mmであり、より好ましくは約3〜4mmである。
本発明において、酢酸亜鉛水和物錠の直径及び厚さの測定方法は、特に限定されず、従来公知の錠剤の大きさの測定方法に従ってよい。The diameter of the zinc acetate hydrate tablet of the present invention is usually about 5 to 12 mm, preferably about 5 to 10 mm, more preferably about 6 to 9 mm.
Moreover, the thickness of the zinc acetate hydrate tablet of the present invention is usually about 1 to 6 mm, preferably about 2 to 5 mm, more preferably about 3 to 4 mm.
In this invention, the measuring method of the diameter and thickness of a zinc acetate hydrate tablet is not specifically limited, You may follow the measuring method of the conventionally well-known tablet size.
本発明の酢酸亜鉛水和物錠は、日局溶出試験法パドル法50回転(試験液:水900mL)によって測定される15分後の亜鉛の溶出量が、85%以上である。本発明の酢酸亜鉛水和物錠は、造粒物の製造工程における乾燥を品温40℃未満の温度で行うことができ、製造工程における酢酸亜鉛水和物中の結晶水の消失を抑制できるため、前記亜鉛の溶出量がこのような範囲となる。 The zinc acetate hydrate tablet of the present invention has an elution amount of zinc of 15% or more after 15 minutes as measured by the JP dissolution method paddle method 50 rotations (test solution: water 900 mL). The zinc acetate hydrate tablet of the present invention can be dried in the granulated product production process at a temperature of less than 40 ° C., and can suppress the disappearance of crystal water in the zinc acetate hydrate in the production process. Therefore, the zinc elution amount falls within such a range.
本発明の酢酸亜鉛水和物錠の総質量は、通常は、酢酸亜鉛水和物含有量の約2倍以下であり、好ましくは約1.6倍以下である。 The total mass of the zinc acetate hydrate tablet of the present invention is usually about 2 times or less, preferably about 1.6 times or less the zinc acetate hydrate content.
本発明の酢酸亜鉛水和物錠は、医薬品に一般的に使用される添加剤、医薬有効成分を適量含むことができる。これらは、1種を単独で又は2種以上を使用することができる。
該添加剤としては、例えば、賦形剤、崩壊剤、滑沢剤、結合剤、コーティング剤、光沢化剤、着色剤、矯味剤、甘味剤、香料等が挙げられ、好ましくは、賦形剤、崩壊剤、結合剤、滑沢剤等である。The zinc acetate hydrate tablet of the present invention can contain appropriate amounts of additives and pharmaceutically active ingredients generally used in pharmaceuticals. These can be used alone or in combination of two or more.
Examples of the additive include an excipient, a disintegrant, a lubricant, a binder, a coating agent, a brightener, a coloring agent, a corrigent, a sweetener, and a fragrance, and preferably an excipient. Disintegrants, binders, lubricants and the like.
賦形剤としては、特に限定されないが、例えば、マンニトール、ソルビトール、キシリトール、エリスリトール、マルチトール、イソマルト等の糖アルコール類;乳糖水和物、果糖、ショ糖、ブドウ糖、トレハロース等の糖類;トウモロコシデンプン、バレイショデンプン、コムギデンプン、コメデンプン等のデンプン類;グリシン、アラニン等のアミノ酸類;軽質無水ケイ酸、合成ケイ酸アルミニウム、メタケイ酸アルミン酸マグネシウム、ケイ酸カルシウム等のケイ酸類;結晶セルロース、粉末セルロース等のセルロース類;タルク;酸化チタン等が挙げられる。賦形剤としては、好ましくは、結晶セルロース、トウモロコシデンプン、乳糖水和物等である。これら賦形剤は、1種又は2種以上を使用することができる。 Examples of excipients include, but are not limited to, sugar alcohols such as mannitol, sorbitol, xylitol, erythritol, maltitol, isomalt; sugars such as lactose hydrate, fructose, sucrose, glucose, trehalose; corn starch , Starches such as 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; crystalline cellulose, powder Celluloses such as cellulose; talc; titanium oxide and the like. The excipient is preferably crystalline cellulose, corn starch, lactose hydrate or the like. These excipients can be used alone or in combination of two or more.
本発明の酢酸亜鉛水和物錠に含有される賦形剤の含有量は、特に限定されないが、本発明の酢酸亜鉛水和物錠の総質量に対して、好ましくは約5〜80質量%であり、より好ましくは約10〜50質量%である。 The content of the excipient contained in the zinc acetate hydrate tablet of the present invention is not particularly limited, but is preferably about 5 to 80% by mass based on the total mass of the zinc acetate hydrate tablet of the present invention. More preferably, it is about 10-50 mass%.
崩壊剤としては、特に限定されないが、例えば、クロスポビドン、カルメロースカルシウム、カルメロース、クロスカルメロース、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロース、トウモロコシデンプン、バレイショデンプン、コムギデンプン、コメデンプン、部分アルファー化デンプン、アルファー化デンプン、カルボキシメチルスターチナトリウム等が挙げられる。崩壊剤は、好ましくは、クロスポビドン、カルメロース、クロスカルメロース、低置換度ヒドロキシプロピルセルロース等である。これら崩壊剤は、1種又は2種以上を使用することができる。 The disintegrant is not particularly limited, for example, crospovidone, carmellose calcium, carmellose, croscarmellose, croscarmellose sodium, low-substituted hydroxypropylcellulose, corn starch, potato starch, wheat starch, rice starch, partial Alpha-ized starch, pregelatinized starch, carboxymethyl starch sodium and the like can be mentioned. The disintegrant is preferably crospovidone, carmellose, croscarmellose, low-substituted hydroxypropylcellulose, or the like. These disintegrants can be used alone or in combination of two or more.
本発明の酢酸亜鉛水和物錠に含有される崩壊剤の含有量は、特に限定されないが、本発明の酢酸亜鉛水和物錠の総質量に対して、好ましくは約1〜50質量%であり、より好ましくは約5〜20質量%である。 The content of the disintegrant contained in the zinc acetate hydrate tablet of the present invention is not particularly limited, but is preferably about 1 to 50% by mass with respect to the total mass of the zinc acetate hydrate tablet of the present invention. More preferably, it is about 5 to 20% by mass.
滑沢剤としては、特に限定されないが、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、ショ糖脂肪酸エステル、フマル酸ステアリルナトリウム等が挙げられる。滑沢剤は、好ましくは、タルク、ステアリン酸マグネシウム等である。これら滑沢剤は、1種又は2種以上を使用することができる。 The lubricant is not particularly limited, and examples thereof include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, and sodium stearyl fumarate. The lubricant is preferably talc, magnesium stearate or the like. These lubricants can be used alone or in combination of two or more.
本発明の酢酸亜鉛水和物錠に含有される滑沢剤の含有量は、特に限定されないが、本発明の酢酸亜鉛水和物錠の総質量に対して、好ましくは約0.1〜20質量%であり、より好ましくは約0.5〜10質量%である。 The content of the lubricant contained in the zinc acetate hydrate tablet of the present invention is not particularly limited, but is preferably about 0.1 to 20 relative to the total mass of the zinc acetate hydrate tablet of the present invention. % By mass, more preferably about 0.5 to 10% by mass.
結合剤としては、特に限定されないが、例えば、ポビドン、ヒドロキシプロピルセルロース、ヒプロメロースフタル酸エステル、ヒドロキシプロピルメチルセルロースアセテートサクシネート、メタケイ酸アルミン酸マグネシウム、合成ケイ酸アルミニウム、軽質無水ケイ酸、ケイ酸カルシウム、カルメロースナトリウム、エチルセルロース、メチルセルロース、ヒプロメロース、アラビアゴム、アルギン酸ナトリウム、デキストリン、トウモロコシデンプン、バレイショデンプン、コムギデンプン、コメデンプン、部分アルファー化デンプン、アルファー化デンプン、結晶セルロース、粉末セルロース、低置換度ヒドロキシプロピルセルロース、ゼラチン、プルラン、カルボキシビニルポリマー等が挙げられる。これら結合剤は、1種又は2種以上を使用することができる。 The binder is not particularly limited. For example, povidone, hydroxypropylcellulose, hypromellose phthalate, hydroxypropylmethylcellulose acetate succinate, magnesium magnesium aluminosilicate, synthetic aluminum silicate, light anhydrous silicic acid, silicic acid Calcium, sodium carmellose, ethylcellulose, methylcellulose, hypromellose, gum arabic, sodium alginate, dextrin, corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, crystalline cellulose, powdered cellulose, low substitution degree Examples thereof include hydroxypropylcellulose, gelatin, pullulan, carboxyvinyl polymer, and the like. These binders can use 1 type (s) or 2 or more types.
コーティング剤としては、特に限定されないが、例えば、水溶性高分子、水不溶性高分子、胃溶性高分子、腸溶性高分子等が挙げられる。
水溶性高分子としては、例えば、アラビアゴム末、ゼラチンプルラン、デキストリン、カルボキシメチルスターチナトリウム、アルギン酸ナトリウム等の天然高分子類;多糖類;カルメロース、カルメロースナトリウム、カルメロースカルシウム、ヒドロキシプロピルセルロース、ヒプロメロース、ヒドロキシエチルセルロース、ヒドロキシメチルセルロース、メチルセルロース、カルボキシメチルセルロース等のセルロース誘導体;ポリビニルピロリドン、ポリビニルアルコール等の水溶性ビニル誘導体が挙げられる。
水不溶性高分子としては、例えば、エチルセルロース、酢酸ビニルポリマー、アミノアルキルメタクリレートコポリマー、アクリル酸エチル・メタクリル酸メチルコポリマー分散液等が挙げられる。Although it does not specifically limit as a coating agent, For example, water-soluble polymer, water-insoluble polymer, gastric polymer, enteric polymer, etc. are mentioned.
Examples of water-soluble polymers include natural polymers such as gum arabic powder, gelatin pullulan, dextrin, sodium carboxymethyl starch, sodium alginate; polysaccharides; carmellose, carmellose sodium, carmellose calcium, hydroxypropylcellulose, hypromellose , Cellulose derivatives such as hydroxyethyl cellulose, hydroxymethyl cellulose, methyl cellulose, carboxymethyl cellulose; and water-soluble vinyl derivatives such as polyvinyl pyrrolidone and polyvinyl alcohol.
Examples of the water-insoluble polymer include ethyl cellulose, vinyl acetate polymer, aminoalkyl methacrylate copolymer, ethyl acrylate / methyl methacrylate copolymer dispersion, and the like.
胃溶性高分子としては、例えば、ポリビニルアセタール・ジエチルアミノアセテート等のアミノアセタール類化合物等が挙げられる。
腸溶性高分子としては、例えば、セルロースアセテートプロピオネート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒプロメロースフタル酸エステル、ヒドロキシメチルエチルセルロースフタレート、カルボキシメチルエチルセルロース、セルロースアセテートフタレート等の腸溶性セルロースエステル類等が挙げられる。
コーティング剤としては、上記以外にも、酸化チタン、ポリエチレングリコール、タルク等を使用することもできる。
これらコーティング剤は、1種又は2種以上を使用することができる。Examples of the gastric soluble polymer include aminoacetal compounds such as polyvinyl acetal and diethylaminoacetate.
Examples of the enteric polymer include enteric cellulose esters such as cellulose acetate propionate, hydroxypropylmethylcellulose acetate succinate, hypromellose phthalate, hydroxymethylethylcellulose phthalate, carboxymethylethylcellulose, and cellulose acetate phthalate. Can be mentioned.
In addition to the above, titanium oxide, polyethylene glycol, talc, etc. can also be used as the coating agent.
These coating agents can use 1 type (s) or 2 or more types.
光沢化剤としては、特に限定されないが、例えば、カルナウバロウ、硬化油、酢酸ビニル樹脂、サラシミツロウ、酸化チタン、ステアリン酸、ステアリン酸カルシウム、ステアリン酸ポリオキシル40、ステアリン酸マグネシウム、精製セラック、精製パラフィン・カルナウバロウ混合ワックス、セタノール、タルク、白色セラック、パラフィン、ポビドン(ポリビニルピロリドン)、ポリエチレングリコール1500、ポリエチレングリコール4000、ポリエチレングリコール6000、ミツロウ、モノステアリン酸グリセリン、ロジン等が挙げられる。 The brightening agent is not particularly limited. For example, carnauba wax, hydrogenated oil, vinyl acetate resin, white beeswax, titanium oxide, stearic acid, calcium stearate, polyoxyl 40 stearate, magnesium stearate, purified shellac, purified paraffin and carnauba wax. Examples thereof include mixed wax, cetanol, talc, white shellac, paraffin, povidone (polyvinylpyrrolidone), polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, beeswax, glyceryl monostearate, and rosin.
着色剤としては、例えば、食用色素、食用レーキ色素、三二酸化鉄、黄色三二酸化鉄等が挙げられる。
矯味剤としては、例えば、クエン酸、酒石酸、リンゴ酸、アスコルビン酸等が挙げられる。
甘味剤としては、例えば、アスパルテーム、アセスルファムカリウム、サッカリン、サッカリンナトリウム、グリチルリチン酸二カリウム、ステビア、ソーマチン、スクラロース等が挙げられる。
香料としては、例えば、ウイキョウ油、オレンジ油、カミツレ油、スペアミント油、ケイヒ油、チョウジ油、ハッカ油、ベルガモット油、ユーカリ油、ラベンダー油、レモン油、ローズ油、ローマカミツレ油、メントール等が挙げられる。Examples of the colorant include food dyes, food lake dyes, iron sesquioxide, yellow iron sesquioxide, and the like.
Examples of the corrigent include citric acid, tartaric acid, malic acid, ascorbic acid and the like.
Examples of the sweetening agent include aspartame, acesulfame potassium, saccharin, saccharin sodium, dipotassium glycyrrhizinate, stevia, thaumatin, and sucralose.
Examples of the fragrance 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. It is done.
本発明の酢酸亜鉛水和物錠は、医薬有効成分を適量含むことができる。医薬有効成分は、本発明の酢酸亜鉛水和物錠の製造工程における酢酸亜鉛水和物中の結晶水の消失抑制性、並びに該錠の崩壊性及び成型性を損なわない種類及び量であれば良く、特に限定されない。 The zinc acetate hydrate tablet of the present invention can contain an appropriate amount of a pharmaceutically active ingredient. The active pharmaceutical ingredient is a kind and amount that does not impair the disappearance of crystallization water in the zinc acetate hydrate in the production process of the zinc acetate hydrate tablet of the present invention and the disintegration and moldability of the tablet. Good, not particularly limited.
<酢酸亜鉛水和物錠の製造方法>
本発明の酢酸亜鉛水和物錠の製造方法は、通常は、(1)酢酸亜鉛水和物(C4H6O4Zn・2H2O)、賦形剤、崩壊剤及び溶媒の混合物を造粒した後乾燥して造粒物を得る工程、(2)該造粒物を打錠して素錠を得る工程、及び(3)該素錠にフィルムコーティングした後乾燥する工程を含み、前記工程(1)における品温は、通常40℃を越えない。また、前記工程(3)におけるフィルムコーティング後の乾燥において、品温は、通常50℃以下である。本発明において、これらの工程は、通常、工程(1)〜(3)の順で実施される。また、本発明の酢酸亜鉛水和物錠の製造方法は、前記工程(1)〜(3)以外の工程を含んでもよい。<Method for producing zinc acetate hydrate tablet>
The method for producing a zinc acetate hydrate tablet of the present invention usually comprises (1) a mixture of zinc acetate hydrate (C 4 H 6 O 4 Zn · 2H 2 O), an excipient, a disintegrant and a solvent. A step of granulating and drying to obtain a granulated product, (2) tableting the granulated product to obtain an uncoated tablet, and (3) a step of film-coating the uncoated tablet and then drying. The product temperature in the step (1) usually does not exceed 40 ° C. In the drying after film coating in the step (3), the product temperature is usually 50 ° C. or lower. In the present invention, these steps are usually performed in the order of steps (1) to (3). Moreover, the manufacturing method of the zinc acetate hydrate tablet of this invention may also include processes other than the said process (1)-(3).
<造粒>
本発明において、酢酸亜鉛水和物(C4H6O4Zn・2H2O)、賦形剤、崩壊剤及び溶媒の混合物を造粒する方法としては、特に限定されないが、例えば、流動層造粒法、湿式造粒法等が好ましい。これらの造粒方法は、従来十分に確立されており、本発明も従来公知の方法に従ってよい。<Granulation>
In the present invention, a method for granulating a mixture of zinc acetate hydrate (C 4 H 6 O 4 Zn · 2H 2 O), an excipient, a disintegrant and a solvent is not particularly limited. A granulation method, a wet granulation method and the like are preferable. These granulation methods have been well established in the past, and the present invention may also follow conventionally known methods.
流動層造粒法は、原料粉粒体を、溶媒又は溶媒と結合剤の混合液を噴霧しながら造粒する処理であり、必要に応じて、一般的な錠剤の製造に用いられる方法や装置(流動層造粒機等)を使用することができる。尚、本発明において、流動層造粒処理は、転動流動層造粒処理であってもよい。
本発明において、流動層造粒法は、例えば、酢酸亜鉛水和物、賦形剤及び崩壊剤を、流動層造粒機に入れて混合し、結合剤と溶媒の溶液を噴霧することにより、行うことができる。The fluidized bed granulation method is a process of granulating raw material granules while spraying a solvent or a mixed solution of a solvent and a binder, and, if necessary, a method or an apparatus used for general tablet production. (A fluidized bed granulator or the like) can be used. In the present invention, the fluidized bed granulation process may be a rolling fluidized bed granulation process.
In the present invention, the fluidized bed granulation method includes, for example, mixing zinc acetate hydrate, excipient and disintegrant in a fluidized bed granulator and spraying a solution of a binder and a solvent, It can be carried out.
湿式造粒法は、原料粉粒体を溶媒と混合し、次いでこれを造粒する処理であり、必要に応じて、一般的な錠剤の製造に用いられる方法や装置を使用することができる。本発明においては、湿式造粒法の中でも撹拌造粒法が好ましい。
本発明において、撹拌造粒法は、例えば、酢酸亜鉛水和物、賦形剤、崩壊剤、結合剤及び溶媒の混合物を撹拌造粒機に投入して撹拌することにより、行うことができる。The wet granulation method is a process of mixing a raw material granule with a solvent and then granulating it, and a method and an apparatus used for general tablet production can be used as necessary. In the present invention, the stirring granulation method is preferable among the wet granulation methods.
In the present invention, the stirring granulation method can be performed, for example, by putting a mixture of zinc acetate hydrate, excipient, disintegrant, binder and solvent into an agitation granulator and stirring.
また、これら流動層造粒法及び湿式造粒法で用いられる溶媒としては、特に限定されないが、例えば、一般的な錠剤の製造に用いられるエタノール、イソプロパノール等のアルコール類や水等を使用することができる。 In addition, the solvent used in the fluidized bed granulation method and the wet granulation method is not particularly limited. For example, alcohols such as ethanol and isopropanol used for the production of general tablets, water, and the like are used. Can do.
前記造粒に続いて、該造粒により得られた処理物を乾燥することにより、造粒物を得ることができる。
該乾燥方法は、特に限定されず、乾燥温度が品温40℃未満であれば、流動層乾燥機、棚式乾燥装置等を用いた従来公知の錠剤製造における乾燥方法に従ってよい。Subsequent to the granulation, a processed product obtained by the granulation is dried to obtain a granulated product.
The drying method is not particularly limited. If the drying temperature is less than 40 ° C., a conventionally known drying method in tablet production using a fluidized bed dryer, a shelf dryer or the like may be used.
一般に、造粒物の製造工程における造粒後の乾燥温度は、60℃付近である。酢酸亜鉛水和物は、40℃以上の温度で加熱されると、酢酸亜鉛水和物中の結晶水が消失して無水物に転移しまうが、本発明の酢酸亜鉛水和物錠の製造においては、造粒後の乾燥を品温40℃未満で行うことで、造粒物の製造工程における酢酸亜鉛水和物中の結晶水の消失を抑制することができる。 Generally, the drying temperature after granulation in the production process of the granulated product is around 60 ° C. When zinc acetate hydrate is heated at a temperature of 40 ° C. or higher, water of crystallization in zinc acetate hydrate disappears and transitions to an anhydride. In the production of zinc acetate hydrate tablets of the present invention, Can suppress the loss of crystal water in the zinc acetate hydrate in the granulated product production process by performing drying after granulation at a product temperature of less than 40 ° C.
また、前記乾燥後に、コーミル、スクリーンミル、ジェットミル、ハンマーミル、ピンミル等を用いた整粒;振動ふるいを用いた篩過等の錠剤の製造に必要な操作にさらに付してもよい。 Moreover, after the said drying, you may further attach to operation required for manufacture of tablets, such as sizing using a comb mill, a screen mill, a jet mill, a hammer mill, a pin mill, etc .; sieving using a vibration sieve.
前記造粒物は、打錠工程の前に、均一化するために混合して打錠用粉体を得ることが好ましい。該混合方法は、特に限定されず、従来公知の方法を用いることができるが、例えば、該造粒物と滑沢剤を容器回転式混合機に投入して混合することにより、行うことができる。得られた打錠用粉体は、そのまま顆粒剤とすることができるし、或いは常法を用いてカプセルに充填してカプセル剤とすることもできる。本発明の酢酸亜鉛水和物錠の打錠用粉体が充填されたカプセル剤は、従来の酢酸亜鉛水和物のカプセル剤と比べて大きさが小さいものとすることができる。 Prior to the tableting step, the granulated product is preferably mixed in order to obtain a tableting powder. The mixing method is not particularly limited, and a conventionally known method can be used. For example, the granulated product and the lubricant can be put into a container rotary mixer and mixed. . The obtained powder for tableting can be directly used as a granule, or can be filled into a capsule by a conventional method to form a capsule. The capsule filled with the tableting powder of the zinc acetate hydrate tablet of the present invention can be smaller in size than the conventional zinc acetate hydrate capsule.
<打錠>
本発明の酢酸亜鉛水和物錠の製造においては、前記造粒物の製造工程に続いて、該造粒物を圧縮成型することにより打錠して素錠が得られる。圧縮成型の際には、必要に応じて、前記添加剤や医薬有効成分を混合して圧縮成型してよい。
圧縮成型方法は、特に限定されず、例えば、ロータリー式打錠機、単発打錠機等の一般に錠剤の成型に使用される方法や装置を使用することができる。また、この圧縮成型における圧縮圧は、特に限定されない。
尚、前記打錠して得られる素錠の質量は、例えば、最終的に得られる本発明の酢酸亜鉛水和物錠が亜鉛を25mg含有する場合は、約120〜130mgであり、最終的に得られる本発明の酢酸亜鉛水和物錠が亜鉛を50mg含有する場合は、約245〜255mgである。<Tablet>
In the production of the zinc acetate hydrate tablet of the present invention, subsequent to the granulated product production step, the granulated product is compressed and molded to give a plain tablet. At the time of compression molding, if necessary, the additives and pharmaceutical active ingredients may be mixed and compression molded.
The compression molding method is not particularly limited, and for example, a method or an apparatus generally used for tablet formation such as a rotary tableting machine and a single-shot tableting machine can be used. Moreover, the compression pressure in this compression molding is not specifically limited.
The mass of the uncoated tablet obtained by tableting is, for example, about 120 to 130 mg when the finally obtained zinc acetate hydrate tablet of the present invention contains 25 mg of zinc. When the obtained zinc acetate hydrate tablet of the present invention contains 50 mg of zinc, it is about 245 to 255 mg.
<フィルムコーティング>
前記素錠を得る打錠工程に続いて、該素錠にフィルムコーティングした後乾燥することにより、本発明の酢酸亜鉛水和物錠が得られる。
フィルムコーティング方法は、特に限定されず、錠剤の製造において一般に使用される方法に従ってよい。フィルムコーティングは、例えば、コーティング機を用いて、コーティング剤と溶媒との懸濁液を、前記素錠に湿式スプレーコーティングすることによって行うことができる。該溶媒としては、例えば、エタノール、イソプロパノール等のアルコール類;水を使用することができる。<Film coating>
Subsequent to the tableting step of obtaining the uncoated tablet, the uncoated tablet is coated with a film and then dried to obtain the zinc acetate hydrate tablet of the present invention.
The film coating method is not particularly limited, and may be a method generally used in tablet production. Film coating can be performed, for example, by wet spray coating the uncoated tablet with a suspension of a coating agent and a solvent using a coating machine. As the solvent, for example, alcohols such as ethanol and isopropanol; water can be used.
前記フィルムコーティング後の錠剤の質量は、例えば、最終的に得られる本発明の酢酸亜鉛水和物錠が亜鉛を25mg含有する場合は、約124〜134mgであり、最終的に得られる本発明の酢酸亜鉛水和物錠が亜鉛を50mg含有する場合は、約251〜261mgである。 The weight of the tablet after film coating is, for example, about 124 to 134 mg when the finally obtained zinc acetate hydrate tablet of the present invention contains 25 mg of zinc. When the zinc acetate hydrate tablet contains 50 mg of zinc, it is about 251 to 261 mg.
前記フィルムコーティングした後、得られた錠剤を乾燥することによって、本発明の酢酸亜鉛水和物錠を得ることができる。
該乾燥方法は、特に限定されず、乾燥温度が品温50℃以下であれば、従来公知の錠剤の製造におけるコーティング剤の乾燥方法に従ってよい。
本発明において、該乾燥は、品温50℃以下で行うことができ、酢酸亜鉛水和物中の結晶水の消失を抑制することができる。尚、造粒物を得る前記工程(1)では品温が40℃未満であるが、素錠を得た後の当該フィルムコーティング後の乾燥温度は、品温50℃以下であれば酢酸亜鉛水和物中の結晶水の消失を抑制することができる。
該乾燥して得られた本発明の酢酸亜鉛水和物錠には、常法を用いて、光沢化剤を散布してもよい。After the film coating, the obtained tablet is dried to obtain the zinc acetate hydrate tablet of the present invention.
The drying method is not particularly limited, and the drying method of the coating agent in the production of a conventionally known tablet may be used as long as the drying temperature is 50 ° C. or less.
In the present invention, the drying can be performed at a product temperature of 50 ° C. or lower, and the disappearance of crystal water in the zinc acetate hydrate can be suppressed. In the step (1) for obtaining a granulated product, the product temperature is less than 40 ° C. If the drying temperature after film coating after obtaining the uncoated tablet is 50 ° C or less, the zinc acetate water is used. Disappearance of crystal water in the Japanese product can be suppressed.
The zinc acetate hydrate tablet of the present invention obtained by drying may be sprayed with a brightening agent using a conventional method.
上記のようにして得られた本発明の酢酸亜鉛水和物錠は、通常、常法により、容器又は袋に収容することができる。容器又は袋は、錠剤の容器又は袋として使用可能なものであれば特に限定されず、従来公知のものを使用することができる。 The zinc acetate hydrate tablet of the present invention obtained as described above can be usually stored in a container or bag by a conventional method. The container or bag is not particularly limited as long as it can be used as a tablet container or bag, and conventionally known ones can be used.
以下、実施例によって本発明をさらに詳細に説明するが、本発明はこれらの実施例に限定されず、本発明の技術的範囲を逸脱しない範囲において様々な変更や修正が可能である。
尚、以下の実施例1〜3において、15分後の亜鉛の溶出量は、日局溶出試験法パドル法50回転(試験液:水900mL)によって測定した15分後の亜鉛の溶出量である。EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples, A various change and correction are possible in the range which does not deviate from the technical scope of this invention.
In Examples 1 to 3 below, the elution amount of zinc after 15 minutes is the elution amount of zinc after 15 minutes measured by the JP dissolution method paddle method 50 rotations (test solution: water 900 mL). .
<酢酸亜鉛水和物錠の製造>
(実施例1)
酢酸亜鉛水和物83.9g、トウモロコシデンプン(賦形剤)30.1g及び部分アルファ化デンプン(結合剤)10gを撹拌造粒機(深江工業社製、ハイスピードミキサー)にて混合し、精製水を添加して造粒した。これを静置乾燥機(アドバンテック社製、通風乾燥機)を用いて、乾燥減量(水分量)が13.8%に到達するまで品温35℃で乾燥し、得られた乾燥物を22号の篩(710μm)にて整粒した。この整粒物に対して、混合比(質量比)が整粒物/ステアリン酸マグネシウム=124/1となるようにステアリン酸マグネシウム(滑沢剤)を混合して打錠用粉体を製造した。この粉体を直径6mm、1錠質量125mgにて打錠し、酢酸亜鉛水和物錠を得た。得られた酢酸亜鉛水和物錠は、厚み:3.4mm、崩壊時間:7〜15分、15分後の亜鉛の溶出量:88%であった。<Manufacture of zinc acetate hydrate tablets>
Example 1
83.9 g of zinc acetate hydrate, 30.1 g of corn starch (excipient) and 10 g of partially pregelatinized starch (binder) were mixed in a stirring granulator (manufactured by Fukae Kogyo Co., Ltd., high speed mixer) for purification. Granulated by adding water. This was dried at a product temperature of 35 ° C. until the loss on drying (water content) reached 13.8% using a stationary dryer (Advantech, a ventilation dryer). Sized using a sieve (710 μm). To this sized product, magnesium stearate (lubricant) was mixed so that the mixing ratio (mass ratio) was sized product / magnesium stearate = 124/1 to produce a powder for tableting. . This powder was tableted with a diameter of 6 mm and a tablet mass of 125 mg to give zinc acetate hydrate tablets. The obtained zinc acetate hydrate tablet had a thickness of 3.4 mm, a disintegration time of 7 to 15 minutes, and an elution amount of zinc after 15 minutes of 88%.
(実施例2)
酢酸亜鉛水和物83.9g、トウモロコシデンプン(賦形剤)20.1g及びカルメロース(崩壊剤)12gを流動層造粒機(パウレック社製、マルチプレックス)にて混合し、ヒドロキシプロピルセルロース(結合剤)3gを精製水に溶解しこの液を噴霧し造粒した。これを給気温度60℃で品温32℃に到達するまで乾燥後、整粒機(パウレック社製、コーミル)で整粒した。この整粒物に対して、混合比(質量比)が整粒物/ステアリン酸マグネシウム=119/1となるように、ステアリン酸マグネシウム(滑沢剤)を混合して打錠用粉体を製造した。この粉体を直径6mm、1錠質量120mgにて打錠し、酢酸亜鉛水和物錠を得た。得られた酢酸亜鉛水和物錠は、厚み:3.4mm、崩壊時間:4〜7分、15分後の亜鉛の溶出量:98%であった。(Example 2)
83.9 g of zinc acetate hydrate, 20.1 g of corn starch (excipient) and 12 g of carmellose (disintegrant) were mixed in a fluid bed granulator (manufactured by POWREC, multiplex), and hydroxypropylcellulose (bonded) Agent) 3 g was dissolved in purified water, and this liquid was sprayed and granulated. This was dried at an air supply temperature of 60 ° C. until the product temperature reached 32 ° C., and then sized using a granulator (Pauleck Co., Ltd., Comil). For this sized product, magnesium stearate (lubricant) is mixed so that the mixing ratio (mass ratio) is sized product / magnesium stearate = 119/1 to produce a powder for tableting. did. This powder was tableted with a diameter of 6 mm and a tablet mass of 120 mg to give zinc acetate hydrate tablets. The obtained zinc acetate hydrate tablet had a thickness of 3.4 mm, a disintegration time of 4 to 7 minutes, and a zinc elution amount of 98% after 15 minutes.
(実施例3)
酢酸亜鉛水和物839g、トウモロコシデンプン(賦形剤)101g及び結晶セルロース(賦形剤)116gを攪拌造粒機(深江工業社製、ハイスピードミキサー)にて混合し、ヒドロキシプロピルセルロース(結合剤)14gを精製水に溶解し、この液を添加して造粒した。これを流動層乾燥機(パウレック社製、マルチプレックス)を用いて、給気温度60℃で品温32℃に到達するまで乾燥し、得られた乾燥物を整粒機(パウレック社製、コーミル)で整粒した。この整粒物に対して、混合比(質量比)が整粒物/クロスカルメロースナトリウム/ステアリン酸マグネシウム=107/12/1となるように、クロスカルメロースナトリウム(崩壊剤)を添加してよく混合した後、ステアリン酸マグネシウム(滑沢剤)を混合して打錠用粉体を製造した。この粉体を直径6mm、1錠質量120mgにて打錠し、酢酸亜鉛水和物錠を得た。得られた酢酸亜鉛水和物錠は、厚み:3.3mm、崩壊時間:8〜9分、15分後の亜鉛の溶出量:95%であった。この錠剤に、精製水420mLにヒプロメロース 21g及びマクロゴール6000 3gを溶解させ、更に酸化チタン3.6g及びタルク2.4gを分散した溶液にてフィルムコーティング機(フロイント産業社製、ハイコーター)を用いてフィルムコーティングを施し、給気温度60℃で乾燥終了温度(品温)50℃に到達するまで乾燥しフィルムコーティング錠を得た。得られた錠剤は、1錠質量123mg、直径6mm、厚み3.4mm、崩壊時間:9〜11分、15分後の亜鉛の溶出量:93%であった。(Example 3)
839 g of zinc acetate hydrate, 101 g of corn starch (excipient) and 116 g of crystalline cellulose (excipient) were mixed with a stirring granulator (manufactured by Fukae Kogyo Co., Ltd., high speed mixer), and hydroxypropylcellulose (binder) ) 14 g was dissolved in purified water, and this liquid was added to granulate. This was dried using a fluidized bed dryer (manufactured by POWREC Co., Ltd., multiplex) until the product temperature reached 32 ° C at an air supply temperature of 60 ° C, and the resulting dried product was granulated (manufactured by POWREC Co., Ltd., Comil). ). To this sized product, croscarmellose sodium (disintegrant) was added so that the mixture ratio (mass ratio) was sized product / croscarmellose sodium / magnesium stearate = 107/12/1. After mixing well, magnesium stearate (lubricant) was mixed to produce tableting powder. This powder was tableted with a diameter of 6 mm and a tablet mass of 120 mg to give zinc acetate hydrate tablets. The obtained zinc acetate hydrate tablet had a thickness of 3.3 mm, a disintegration time of 8 to 9 minutes, and a zinc elution amount of 95% after 15 minutes. A film coating machine (Freund Sangyo Co., Ltd., High Coater) was used in a solution in which 21 g of hypromellose and 3 g of macrogol 6000 were dissolved in 420 mL of purified water, and 3.6 g of titanium oxide and 2.4 g of talc were further dispersed. Then, the film was coated, and dried at an air supply temperature of 60 ° C. until the drying end temperature (article temperature) reached 50 ° C. to obtain a film-coated tablet. The obtained tablet had a tablet mass of 123 mg, a diameter of 6 mm, a thickness of 3.4 mm, a disintegration time of 9 to 11 minutes, and an elution amount of zinc after 15 minutes: 93%.
実施例1〜3の結果から、本発明の酢酸亜鉛水和物錠は、日局溶出試験法パドル法50回転(試験液:水900mL)によって測定される15分後の亜鉛の溶出量が85%以上であり、酢酸亜鉛水和物を十分に含有し、かつコンパクト化された錠剤であることが確認された。 From the results of Examples 1 to 3, the zinc acetate hydrate tablet of the present invention has a zinc dissolution amount of 15 after 15 minutes as measured by the JP dissolution paddle method 50 rotations (test solution: water 900 mL). % Or more, it was confirmed that the tablets were sufficiently compacted and sufficiently containing zinc acetate hydrate.
本発明の酢酸亜鉛水和物錠は、大きさが小さく服用時に飲み込みやすいため、ウィルソン病の治療薬として好適に使用することができる。 Since the zinc acetate hydrate tablet of the present invention is small in size and easy to swallow when taken, it can be suitably used as a therapeutic agent for Wilson disease.
Claims (4)
大きさが直径5〜12mm、厚さ1〜6mmであって、
日局溶出試験法パドル法50回転(試験液:水900mL)によって測定される15分後の亜鉛の溶出量が85%以上であることを特徴とする、酢酸亜鉛水和物錠。Zinc acetate hydrate (C 4 H 6 O 4 Zn · 2H 2 O) containing 5 to 200 mg,
The size is 5-12 mm in diameter and 1-6 mm in thickness,
A zinc acetate hydrate tablet characterized by having an elution amount of zinc of 15% or more after 15 minutes as measured by the JP Dissolution Test Method Paddle Method 50 rotations (test solution: water 900 mL).
酢酸亜鉛水和物(C4H6O4Zn・2H2O)を5〜200mg含有し、
大きさが直径5〜12mm、厚さ1〜6mmであって、
日局溶出試験法パドル法50回転(試験液:水900mL)によって測定される15分後の亜鉛の溶出量が85%以上である酢酸亜鉛水和物錠の製造方法。(1) A step of granulating a mixture of zinc acetate hydrate (C 4 H 6 O 4 Zn · 2H 2 O), an excipient, a disintegrant and a solvent and then drying to obtain a granulated product, (2) A step of tableting the granulated product to obtain an uncoated tablet, and (3) a step of film-coating the uncoated tablet and then drying, wherein the product temperature in the step (1) does not exceed 40 ° C. The product temperature in (3) is 50 ° C. or less,
Zinc acetate hydrate (C 4 H 6 O 4 Zn · 2H 2 O) containing 5 to 200 mg,
The size is 5-12 mm in diameter and 1-6 mm in thickness,
A method for producing a zinc acetate hydrate tablet, wherein the zinc elution amount after 15 minutes measured by the JP dissolution method paddle method 50 rotations (test solution: water 900 mL) is 85% or more.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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JP2014244689 | 2014-12-03 | ||
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