JP2007182400A - Meloxicam-containing tablet composition having excellent stability with time - Google Patents
Meloxicam-containing tablet composition having excellent stability with time Download PDFInfo
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- JP2007182400A JP2007182400A JP2006001842A JP2006001842A JP2007182400A JP 2007182400 A JP2007182400 A JP 2007182400A JP 2006001842 A JP2006001842 A JP 2006001842A JP 2006001842 A JP2006001842 A JP 2006001842A JP 2007182400 A JP2007182400 A JP 2007182400A
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- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 229960001929 meloxicam Drugs 0.000 title claims abstract description 21
- 239000007916 tablet composition Substances 0.000 title claims abstract description 17
- 229920002678 cellulose Polymers 0.000 claims abstract description 17
- 239000001913 cellulose Substances 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229920000881 Modified starch Polymers 0.000 claims abstract description 10
- 235000019426 modified starch Nutrition 0.000 claims abstract description 10
- 239000004480 active ingredient Substances 0.000 claims abstract 2
- 239000007884 disintegrant Substances 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 10
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 7
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 3
- 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 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 3
- 229950008138 carmellose Drugs 0.000 claims description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 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
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
- 230000000052 comparative effect Effects 0.000 description 14
- 238000003860 storage Methods 0.000 description 12
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 11
- 239000008101 lactose Substances 0.000 description 11
- 239000008213 purified water Substances 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 238000009472 formulation Methods 0.000 description 8
- 235000019359 magnesium stearate Nutrition 0.000 description 8
- 239000001509 sodium citrate Substances 0.000 description 8
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 8
- 238000005469 granulation Methods 0.000 description 6
- 230000003179 granulation Effects 0.000 description 6
- 230000000704 physical effect Effects 0.000 description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 5
- 229960000913 crospovidone Drugs 0.000 description 5
- 239000011812 mixed powder Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 5
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 238000009477 fluid bed granulation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000007909 melt granulation Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 230000002522 swelling effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
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Abstract
Description
本発明は速やかな崩壊性を維持し、経時的な硬度の低下を防止したメロキシカム含有錠剤組成物に関する。 The present invention relates to a meloxicam-containing tablet composition that maintains rapid disintegration and prevents a decrease in hardness over time.
一般に素錠は保存環境（湿度や光）に影響を受けやすく、時に硬度低下や外観変化、崩壊時間の遅延などが生じやすい。
特に速やかな崩壊が要求される錠剤では、打錠圧力を比較的低く抑えたり、吸湿性・膨潤性の高い崩壊剤の配合が必須条件となり、保存中に吸湿することで錠剤硬度が低下することが見受けられる。
保存環境の影響を受けにくくするため、アルミニウムピローなど防湿、遮光性の高い資材を用いて包装を施すことが多いが、これは最終包装形態における保存安定性を保証できるが、開封後の安定性を担保できない。
近年、外来患者のコンプライアンスの向上を目指して一包化調剤を実施する病院が増加したこと、また、自動錠剤包装機の普及により開封後の製剤の取り扱いが増加したこと、さらには長期投与処方が飛躍的に増加しているなどの理由で、無包装状態での安定性情報の必要性が指摘されている。
市販のメロキシカム製剤は素錠であるが、無包装状態での保存により錠剤硬度の著しい低下が生じることを本発明者は確認した。
錠剤硬度の著しい低下は錠剤の取り扱い時に欠けが生じる等の問題があることから、添付文書にも取り扱い上の注意として吸湿に注意することとの記載がなされている。
このことから、無包装状態においても３０Ｎ以上の錠剤硬度を保つ、より一包化調剤に適したメロキシカム錠剤の開発が望まれていた。
In general, uncoated tablets are easily affected by the storage environment (humidity and light), sometimes causing a decrease in hardness, a change in appearance, and a delay in disintegration time.
Especially for tablets that require rapid disintegration, it is essential to keep the tableting pressure relatively low or to incorporate a disintegrant with high hygroscopicity and swelling properties, and the tablet hardness will decrease by absorbing moisture during storage. Can be seen.
In order to make it less susceptible to the storage environment, packaging is often performed using materials with high moisture and light shielding properties such as aluminum pillows, but this can guarantee storage stability in the final packaging form, but stability after opening Cannot be secured.
In recent years, there has been an increase in the number of hospitals that carry out single-packed preparations for the purpose of improving compliance for outpatients, the increased handling of preparations after opening due to the widespread use of automatic tablet packaging machines, and long-term prescriptions. The necessity of stability information in the unwrapped state has been pointed out for reasons such as a dramatic increase.
The commercially available meloxicam preparation is an uncoated tablet, but the present inventor has confirmed that a significant decrease in tablet hardness occurs due to storage in an unwrapped state.
Since a significant decrease in tablet hardness has a problem such as chipping during tablet handling, the package insert also states that attention should be paid to moisture absorption as a handling precaution.
Therefore, it has been desired to develop a meloxicam tablet suitable for a single-packed preparation that maintains a tablet hardness of 30 N or more even in an unwrapped state.
本発明は、メロキシカム含有錠剤組成物において、速やかな崩壊性を有し、開封条件下で保存しても錠剤硬度３０Ｎ以上を確保しやすい錠剤組成物を提供することを目的とする。 An object of the present invention is to provide a meloxicam-containing tablet composition that has a rapid disintegration property and can easily secure a tablet hardness of 30 N or more even when stored under an opening condition.
本発明者らは、従来技術に内在する問題を解決すべく鋭意研究した結果、メロキシカム含有錠剤組成物中に崩壊剤としてセルロース誘導体及び／またはデンプン誘導体を配合し、かつ２５℃及び相対湿度７５％条件下で３０日間保存したときの錠剤水分量が７％以下となるような錠剤組成とすることで、錠剤硬度が３０Ｎ以上確保され、経時的に錠剤硬度低下が少ない錠剤が得られることを見出した。
本発明において、崩壊剤として用いるセルロース誘導体及びデンプン誘導体としては、クロスカルメロースナトリウム、カルメロースカルシウム、カルボキシメチルスターチナトリウム、低置換度ヒドロキシプロピルセルロースが挙げられ、これらを１種以上用いることが望ましい。
これら崩壊剤の配合量は目標とする錠剤の崩壊時間により異なるが、通常１質量％から５質量％配合することで、良好な崩壊時間を確保しながら、かつ経時的硬度変化を抑えることを可能とした。
本発明では、セルロース誘導体及びデンプン誘導体の崩壊剤以外に通常経口投与製剤に使用可能な医薬品添加剤を用いることができる。
例えば賦形剤、結合剤、滑沢剤以外にも、界面活性剤や色素成分などを圧縮成型性に影響を及ぼさない程度に配合することが可能である。
２５℃、相対湿度７５%条件下で３０日間保存したとき、錠剤水分量が７％以下となるようにするには、同条件での使用する添加剤の吸湿量を調べ、１錠中の配合率を乗じた値の総和が７％以下となるような配合量とすることで達成され、これらの条件に該当すれば、いずれの添加剤も任意の配合量で添加することができる。
賦形剤としては乳糖、Ｄ-マンニトール、結晶セルロース、リン酸水素カルシウム、クエン酸ナトリウムなどが挙げられる。
結合剤としては水溶性の高分子、たとえばヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、ポリビニルピロリドン、マクロゴール類などが挙げられる。
滑沢剤としてはステアリン酸マグネシウム、タルク、硬化油、ステアリン酸カルシウム、フマル酸ステアリルナトリウムなどが挙げられる。
界面活性剤としてラウリル硫酸ナトリウムなどが挙げられ、色素成分としては三二酸化鉄などが挙げられる。
本発明における錠剤の製法は、公知の方法により製造することができ、例えば直接圧縮法、乾式造粒法、流動層造粒法、転動流動層造粒法、押出し造粒法、溶融造粒法などが挙げられる。
好ましくは流動層造粒法がよい。
例えば流動層造粒法により錠剤を得る場合は、メロキシカム、セルロース誘導体及び／またはデンプン誘導体からなる崩壊剤、賦形剤などを流動層造粒機に入れ、混合したのち結合剤溶液を噴霧しながら造粒する。
造粒物を乾燥した後、滑沢剤を混合し、打錠機を用いて製錠することで得ることができる。
錠剤の製造条件においては、一般的に打錠圧の違いが錠剤硬度値に影響する。
打錠圧を高く設定すれば製錠時の錠剤硬度値は高い値を示し、硬度のみの観点からは、２５℃及び相対湿度７５％条件下で３０日間保存したとき錠剤硬度３０Ｎ以上の錠剤を得ることも可能であるが、崩壊試験における崩壊時間が延長し、それに伴い溶出試験においても薬物の放出遅延を引き起こす問題が生じる。
メロキシカム製剤は消炎鎮痛作用を有しており、服用後の速やかな薬効発現が期待される。
このため、本製剤については崩壊試験で５分以内に崩壊し、溶出試験において速やかに薬物が放出されることが望ましく、錠剤の直径が６ｍｍ〜８ｍｍ程度の場合には、５００ｋｇ〜１０００ｋｇの打錠圧で打錠を行うことが望ましい。
As a result of diligent research to solve the problems inherent in the prior art, the present inventors formulated a cellulose derivative and / or starch derivative as a disintegrant in a meloxicam-containing tablet composition, and at 25 ° C. and a relative humidity of 75%. It has been found that a tablet composition having a tablet moisture content of 7% or less when stored for 30 days under conditions can obtain a tablet with a tablet hardness of 30 N or more and a small decrease in tablet hardness over time. It was.
In the present invention, examples of the cellulose derivative and starch derivative used as the disintegrant include croscarmellose sodium, carmellose calcium, sodium carboxymethyl starch, and low-substituted hydroxypropylcellulose. It is desirable to use one or more of these.
The amount of these disintegrants varies depending on the target disintegration time of the tablet, but it is usually possible to suppress changes in hardness over time while ensuring a good disintegration time by blending 1 to 5% by weight. It was.
In the present invention, in addition to the disintegrants of cellulose derivatives and starch derivatives, pharmaceutical additives that can be usually used for oral administration preparations can be used.
For example, in addition to excipients, binders, and lubricants, surfactants and pigment components can be blended to such an extent that they do not affect the compression moldability.
To keep the tablet moisture content to 7% or less when stored at 25 ° C and 75% relative humidity for 30 days, examine the moisture absorption amount of the additive used under the same conditions and mix in one tablet. It is achieved by setting the blending amount such that the sum of the values multiplied by the ratio is 7% or less, and any additive can be added in any blending amount as long as these conditions are satisfied.
Examples of the excipient include lactose, D-mannitol, crystalline cellulose, calcium hydrogen phosphate, sodium citrate and the like.
Examples of the binder include water-soluble polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, macrogol and the like.
Examples of the lubricant include magnesium stearate, talc, hydrogenated oil, calcium stearate, sodium stearyl fumarate and the like.
Examples of the surfactant include sodium lauryl sulfate, and examples of the pigment component include iron sesquioxide.
The tablet production method in the present invention can be produced by a known method, for example, direct compression method, dry granulation method, fluidized bed granulation method, rolling fluidized bed granulation method, extrusion granulation method, melt granulation. Law.
The fluidized bed granulation method is preferable.
For example, when a tablet is obtained by a fluidized bed granulation method, a disintegrant, an excipient, etc. composed of meloxicam, a cellulose derivative and / or a starch derivative are placed in a fluidized bed granulator, mixed and sprayed with a binder solution. Granulate.
After the granulated product is dried, it can be obtained by mixing a lubricant and making a tablet using a tableting machine.
In tablet manufacturing conditions, the difference in tableting pressure generally affects the tablet hardness value.
If the tableting pressure is set high, the tablet hardness value at the time of tableting shows a high value. From the viewpoint of hardness alone, a tablet having a tablet hardness of 30 N or more when stored for 30 days at 25 ° C. and 75% relative humidity. Although it can be obtained, the disintegration time in the disintegration test is prolonged, and as a result, the problem of causing delayed release of the drug also occurs in the dissolution test.
Meloxicam preparations have anti-inflammatory analgesic action and are expected to promptly develop drug efficacy after taking.
For this reason, it is desirable for this preparation to disintegrate within 5 minutes in the disintegration test, and to release the drug quickly in the dissolution test. It is desirable to perform tableting with pressure.
２５℃及び相対湿度７５％条件下に３０日間保存した際、錠剤水分量を７％以下となるように錠剤組成物を選定し、かつ崩壊剤としてセルロース誘導体及び／またはデンプン誘導体を用いることにより、経時的に錠剤硬度変化の少ないメロキシカム含有錠剤組成物を得ることが可能であることが判明した。
これにより、硬度低下による錠剤の欠け等を防ぎ一包化調剤や開封後の製剤の取り扱いが容易になる。
By selecting a tablet composition so that the tablet moisture content is 7% or less when stored at 25 ° C. and a relative humidity of 75% for 30 days, and using a cellulose derivative and / or a starch derivative as a disintegrant, It has been found that it is possible to obtain a meloxicam-containing tablet composition with little change in tablet hardness over time.
Thereby, chipping of the tablet due to a decrease in hardness is prevented, and handling of the packaged preparation and the preparation after opening becomes easy.
以下に実施例、比較例を示し詳細に説明する。 Examples and comparative examples will be described below in detail.
図１に本発明に該当する実施例１と、後述する比較例１の錠剤処方を示し、錠剤硬度変化と錠剤水分変化を確認することを目的とするため、メロキシカムの代わりに乳糖を用いた。
崩壊剤としては、図１の崩壊剤の欄に示すように（１）クロスカルメロースＮａ、（２）カルボキシメチルスターチＮａ、（３）カルメロースＣａ、（４）低置換度ヒドロキシプロピルセルロースを選定し、この群の一種と、乳糖、結晶セルロースを図１の表に示した値に基づいて秤量し流動層造粒機（ＦＬ−ｍｉｎｉ、フロイント産業株式会社製）に入れた。
次にポリビニルピロリドン（Ｋ３０）、クエン酸ナトリウムを秤量し、精製水に溶解後、これを噴霧して流動層造粒品を得た。
造粒品及びステアリン酸マグネシウムを規定量秤量・混合し、混合末を打錠して１錠１２０ｍｇ（直径７ｍｍ）の錠剤を得た（打錠圧８００ｋｇ）。
FIG. 1 shows a tablet formulation of Example 1 corresponding to the present invention and Comparative Example 1 described later, and lactose was used instead of meloxicam for the purpose of confirming tablet hardness change and tablet moisture change.
As the disintegrant, (1) croscarmellose Na, (2) carboxymethyl starch Na, (3) carmellose Ca, and (4) low-substituted hydroxypropylcellulose are selected as shown in the disintegrant column of FIG. One kind of this group, lactose, and crystalline cellulose were weighed based on the values shown in the table of FIG. 1 and placed in a fluidized bed granulator (FL-mini, manufactured by Freund Corporation).
Next, polyvinylpyrrolidone (K30) and sodium citrate were weighed, dissolved in purified water, and sprayed to obtain a fluidized bed granulated product.
The granulated product and magnesium stearate were weighed and mixed in a specified amount, and the mixed powder was tableted to obtain one tablet of 120 mg (
（比較例１）
図１の表に示すように、乳糖、結晶セルロース、崩壊剤としてクロスポビドン（商品名ｐｏｌｙｐｌａｓｄｏｎｅ ＸＬ）を秤量し流動層造粒機（Ｆｌ−ｍｉｎｉ、フロイント産業株式会社製）に入れた。
ポリビニルピロリドン（Ｋ３０）、クエン酸ナトリウムを精製水に溶解後、これを噴霧して流動層造粒品を得た。
造粒品及びステアリン酸マグネシウムを規定量秤量・混合し、この混合末を打錠して１錠１２０ｍｇ（直径７ｍｍ）の錠剤を得た（打錠圧８００ｋｇ）。
(Comparative Example 1)
As shown in the table of FIG. 1, lactose, crystalline cellulose, and crospovidone (trade name: polyplasmone XL) as a disintegrant were weighed and placed in a fluidized bed granulator (Fl-mini, manufactured by Freund Sangyo Co., Ltd.).
Polyvinylpyrrolidone (K30) and sodium citrate were dissolved in purified water and sprayed to obtain a fluidized bed granulated product.
The granulated product and magnesium stearate were weighed and mixed in a specified amount, and the mixed powder was tableted to obtain one tablet of 120 mg (
（比較例２）
図２に示す処方の錠剤を流動層造粒法にて製造した。
乳糖、トウモロコシデンプン、結晶セルロースおよびクロスカルメロースＮａを流動層造粒機（ＦＬ−ｍｉｎｉ）にて混合後、精製水に溶解させたポリビニルピロリドン（Ｋ３０）、クエン酸ナトリウムを噴霧し流動層造粒品を得た。
造粒品及びステアリン酸マグネシウムを規定量秤量・混合し、この混合末を打錠して直径７ｍｍ、１２０ｍｇの錠剤（比較例２−１、２−２）を得た（打錠圧８００ｋｇ）。
(Comparative Example 2)
Tablets having the formulation shown in FIG. 2 were produced by a fluidized bed granulation method.
After mixing lactose, corn starch, crystalline cellulose and croscarmellose Na with a fluid bed granulator (FL-mini), sprayed with polyvinylpyrrolidone (K30) dissolved in purified water and sodium citrate, fluid bed granulation I got a product.
The granulated product and magnesium stearate were weighed and mixed in specified amounts, and the mixed powder was tableted to obtain tablets (Comparative Examples 2-1 and 2-2) having a diameter of 7 mm and 120 mg (Tablet pressure 800 kg).
（実験例１）
実施例１及び比較例１、２で製した錠剤を２５℃及び相対湿度７５％条件下無包装状態で３０日間の保存試験を実施し、錠剤硬度、錠剤水分を測定した。
錠剤硬度は錠剤物性測定機ＴＭ３−３（菊水製作所製）にて測定し、錠剤水分は、試料錠剤を乳鉢で粉砕し、赤外線水分計ＥＢ−３４０ＭＯＣ（島津製作所製）にて測定した。
結果を図３の表に示す。
崩壊剤としてセルロース誘導体及びデンプン誘導体を用いた実施例１は、２５℃、相対湿度７５％の条件下に３０日間保存試験をしたとき、錠剤中の水分量は７％以下であり、錠剤硬度が３０Ｎ以上を有していた。
一方、崩壊剤としてクロスポビドン（商品名ｐｏｌｙｐｌａｓｄｏｎｅ ＸＬ）を用いた比較例１は、同条件下で３０日間保存したとき、錠剤水分量は７％以下であったが、錠剤硬度は３０Ｎを下回る結果となった。
また、比較例２−１、２−２では崩壊剤にセルロース誘導体を用いているが、乳糖の一部をそれより吸湿性が高いトウモロコシデンプンに置き換えた結果、錠剤水分量が７％以上となり、錠剤硬度が３０Ｎを下回る結果となった。
(Experimental example 1)
The tablets prepared in Example 1 and Comparative Examples 1 and 2 were subjected to a storage test for 30 days in an unwrapped state at 25 ° C. and a relative humidity of 75%, and tablet hardness and tablet moisture were measured.
Tablet hardness was measured with a tablet physical property measuring machine TM3-3 (manufactured by Kikusui Seisakusho), and tablet moisture was measured with an infrared moisture meter EB-340MOC (manufactured by Shimadzu Corporation) after pulverizing a sample tablet with a mortar.
The results are shown in the table of FIG.
In Example 1 using a cellulose derivative and a starch derivative as a disintegrant, when a 30-day storage test was performed at 25 ° C. and a relative humidity of 75%, the water content in the tablet was 7% or less, and the tablet hardness was Had more than 30N.
On the other hand, in Comparative Example 1 using crospovidone (trade name: polyplasmone XL) as a disintegrant, the tablet moisture content was 7% or less when stored for 30 days under the same conditions, but the tablet hardness was less than 30N. It became.
In Comparative Examples 2-1 and 2-2, a cellulose derivative is used as a disintegrant, but as a result of replacing part of lactose with corn starch having higher hygroscopicity, the tablet moisture content is 7% or more, The tablet hardness was less than 30N.
図４の表に示す処方に基づき、この場合もメロキシカムを含まない乳糖と表の崩壊剤の欄に示した各種崩壊剤を流動層造粒機（ＦＬ−ｍｉｎｉ）にて混合後、精製水に溶解させたクエン酸ナトリウム溶液を噴霧し、さらに精製水に溶解させたヒドロキシプロピルセルロース溶液を噴霧して流動層造粒品を得た。
造粒品及びステアリン酸マグネシウムを規定量秤量・混合し、この混合末を打錠して直径８ｍｍ、１８０ｍｇの錠剤を得た（打錠圧８００ｋｇ）。
Based on the formulation shown in the table of FIG. 4, in this case as well, lactose not containing meloxicam and various disintegrants shown in the column of disintegrant in the table are mixed in a fluidized bed granulator (FL-mini) and then purified water. The dissolved sodium citrate solution was sprayed, and further the hydroxypropylcellulose solution dissolved in purified water was sprayed to obtain a fluidized bed granulated product.
The granulated product and magnesium stearate were weighed and mixed in a specified amount, and the mixed powder was tableted to obtain a tablet having a diameter of 8 mm and 180 mg (tablet pressure 800 kg).
（比較例３）
図４の表に示す処方に従い、乳糖とクロスポビドン（商品名ｐｏｌｙｐｌａｓｄｏｎｅ ＸＬ）を流動層造粒機（ＦＬ−ｍｉｎｉ）にて混合後、精製水に溶解させたクエン酸ナトリウム溶液を噴霧し、さらに精製水に溶解させたヒドロキシプロピルセルロース溶液を噴霧して流動層造粒品を得た。
造粒品及びステアリン酸マグネシウムを規定量秤量・混合し、この混合末を打錠して直径８ｍｍ、１８０ｍｇの錠剤を得た（打錠圧８００ｋｇ）。
(Comparative Example 3)
According to the formulation shown in the table of FIG. 4, lactose and crospovidone (trade name polyplastdone XL) are mixed in a fluid bed granulator (FL-mini), and then sprayed with a sodium citrate solution dissolved in purified water, A fluidized bed granulated product was obtained by spraying a hydroxypropylcellulose solution dissolved in purified water.
The granulated product and magnesium stearate were weighed and mixed in a specified amount, and the mixed powder was tableted to obtain a tablet having a diameter of 8 mm and 180 mg (tablet pressure 800 kg).
（実験例２）
実施例２及び比較例３で製した錠剤を２５℃相対湿度７５％条件下で無包装状態にて３０日間保存試験をし、錠剤硬度、錠剤水分を測定した。
錠剤硬度は錠剤物性測定機ＴＭ−３−３（菊水製作所製）にて測定し、錠剤水分は試料錠剤を乳鉢で粉砕し、赤外線水分計ＥＢ−３０４ＭＯＣ（島津製作所製）にて測定した。
結果を図５の表に示す。
崩壊剤にセルロース誘導体及びデンプン誘導体を用いた実施例２は、３０日間（１ヶ月）保存試験後の錠剤水分が７％以下であり、錠剤硬度も３０Ｎ以上を確保することが確認された。
一方、崩壊剤をクロスポビドンとした比較例３は錠剤組成中の乳糖比率を高くした結果、錠剤水分量は７％以下であるが、錠剤硬度は３０Ｎ以下となった。
(Experimental example 2)
The tablets produced in Example 2 and Comparative Example 3 were subjected to a storage test for 30 days in an unwrapped state at 25 ° C. and a relative humidity of 75%, and tablet hardness and tablet moisture were measured.
Tablet hardness was measured with a tablet physical property measuring machine TM-3-3 (manufactured by Kikusui Seisakusho), and tablet moisture was measured with an infrared moisture meter EB-304MOC (manufactured by Shimadzu Corporation) after pulverizing a sample tablet with a mortar.
The results are shown in the table of FIG.
In Example 2 using a cellulose derivative and a starch derivative as the disintegrant, it was confirmed that the tablet moisture after the storage test for 30 days (1 month) was 7% or less and the tablet hardness was also secured to 30N or more.
On the other hand, in Comparative Example 3 in which crospovidone was used as the disintegrant, as a result of increasing the lactose ratio in the tablet composition, the tablet water content was 7% or less, but the tablet hardness was 30 N or less.
図６の表に示した処方に基づいて、メロキシカム、乳糖、結晶セルロース、クロスカルメロースＮａを秤量し、流動層造粒機（ＦＬ−ｍｉｎｉ）内に入れた。
クエン酸ナトリウム、ポリビニルピロリドン（Ｋ３０）を秤量し、精製水に溶解させ、これを噴霧して流動層造粒品を得た。
造粒品とステアリン酸マグネシウムを混合し、ロータリー打錠機にて直径７ｍｍ、１錠１２０ｍｇの錠剤を得た（打錠圧８００ｋｇ）。
Based on the formulation shown in the table of FIG. 6, meloxicam, lactose, crystalline cellulose, and croscarmellose Na were weighed and placed in a fluid bed granulator (FL-mini).
Sodium citrate and polyvinylpyrrolidone (K30) were weighed, dissolved in purified water, and sprayed to obtain a fluidized bed granulated product.
The granulated product and magnesium stearate were mixed, and a tablet with a diameter of 7 mm and one tablet of 120 mg was obtained by a rotary tableting machine (tablet pressure 800 kg).
図６の表に示す処方に基づいて、メロキシカム、乳糖、結晶セルロース、クロスカルメロースＮａを秤量し、流動層造粒機（ＦＬ−ｍｉｎｉ）内に入れた。
精製水に溶解させたクエン酸ナトリウム溶液を流動層にて噴霧し、さらに精製水に溶解させたヒドロキシプロピルセルロース溶液を噴霧して流動層造粒品を得た。
造粒品とステアリン酸マグネシウム１．５ｇを混合し、ロータリー打錠機にて直径７ｍｍ、１錠１２０ｍｇの錠剤を得た（打錠圧８００ｋｇ）。
Based on the formulation shown in the table of FIG. 6, meloxicam, lactose, crystalline cellulose, and croscarmellose Na were weighed and placed in a fluid bed granulator (FL-mini).
A fluidized bed granulated product was obtained by spraying a sodium citrate solution dissolved in purified water in a fluidized bed and further spraying a hydroxypropylcellulose solution dissolved in purified water.
The granulated product and 1.5 g of magnesium stearate were mixed, and tablets with a diameter of 7 mm and one tablet of 120 mg were obtained using a rotary tableting machine (tablet pressure 800 kg).
（実験例３）
実施例３，４で製造した錠剤及び市販のメロキシカム錠剤について２５℃及び相対湿度７５％条件下で３０日間保存試験をしたときの錠剤硬度を測定した。
錠剤硬度は錠剤物性測定機ＴＭ−３−３（菊水製作所製）にて測定した。
結果を図７の表に示す。
崩壊剤としてクロスカルメロースＮａを用いた実施例３，４の処方及び製法で製造したメロキシカム含有錠は、保存試験３０日の水分量が７％以下で、錠剤硬度は３０Ｎ以上であった。
一方、崩壊剤としてクロスポビドンが使用されている市販メロキシカム錠剤は、３０日間保存試験後の水分量は実施例３、４より低値を示したが著しく硬度が低下した。
(Experimental example 3)
Tablet hardness was measured when the tablets produced in Examples 3 and 4 and the commercially available meloxicam tablet were subjected to a storage test for 30 days at 25 ° C. and 75% relative humidity.
Tablet hardness was measured with a tablet physical property measuring machine TM-3-3 (manufactured by Kikusui Seisakusho).
The results are shown in the table of FIG.
The meloxicam-containing tablet produced by the formulation and production method of Examples 3 and 4 using croscarmellose Na as a disintegrant had a water content of 7% or less and a tablet hardness of 30 N or more for 30 days of storage test.
On the other hand, the commercially available meloxicam tablet in which crospovidone was used as a disintegrant showed a lower water content than Examples 3 and 4 after the 30-day storage test, but the hardness was significantly reduced.
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| CN116251067A (en) * | 2023-04-23 | 2023-06-13 | 淄博市中心医院 | Fluconazole tablet, preparation method and application |
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| WO2005094832A1 (en) * | 2004-04-01 | 2005-10-13 | Boehringer Ingelheim International Gmbh | Compositions comprising meloxicam |
| WO2005117895A2 (en) * | 2004-06-04 | 2005-12-15 | Boehringer Ingelheim International Gmbh | Compositions comprising meloxicam |
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| US20050053669A1 (en) * | 2003-09-05 | 2005-03-10 | Boehringer Ingelheim International Gmbh | Administration form for the oral application of poorly soluble acidic and amphorteric drugs |
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| WO2005094832A1 (en) * | 2004-04-01 | 2005-10-13 | Boehringer Ingelheim International Gmbh | Compositions comprising meloxicam |
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