JP2020183359A - Celecoxib-containing pharmaceutical composition - Google Patents
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- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 229960000590 celecoxib Drugs 0.000 title claims abstract description 23
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 17
- 150000005846 sugar alcohols Chemical class 0.000 claims abstract description 12
- 239000004094 surface-active agent Substances 0.000 claims abstract description 11
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- 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 claims description 14
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 9
- 238000004040 coloring Methods 0.000 claims description 9
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 9
- 235000010355 mannitol Nutrition 0.000 claims description 8
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 7
- 239000003826 tablet Substances 0.000 description 16
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- 229940079593 drug Drugs 0.000 description 6
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- 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 2
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- MCRNHLQVPJEMSQ-UHFFFAOYSA-N C(C=CC(=O)O)(=O)O.C(CCCCCCCCCCCCCCCCC)[Na] Chemical compound C(C=CC(=O)O)(=O)O.C(CCCCCCCCCCCCCCCCC)[Na] MCRNHLQVPJEMSQ-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
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- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 1
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
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- 229930006000 Sucrose Natural products 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 239000012190 activator Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229940024546 aluminum hydroxide gel Drugs 0.000 description 1
- SMYKVLBUSSNXMV-UHFFFAOYSA-K aluminum;trihydroxide;hydrate Chemical compound O.[OH-].[OH-].[OH-].[Al+3] SMYKVLBUSSNXMV-UHFFFAOYSA-K 0.000 description 1
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
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- 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
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
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- 229920001577 copolymer Polymers 0.000 description 1
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- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- JAUGGEIKQIHSMF-UHFFFAOYSA-N dialuminum;dimagnesium;dioxido(oxo)silane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O JAUGGEIKQIHSMF-UHFFFAOYSA-N 0.000 description 1
- GDVKFRBCXAPAQJ-UHFFFAOYSA-A dialuminum;hexamagnesium;carbonate;hexadecahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-]C([O-])=O GDVKFRBCXAPAQJ-UHFFFAOYSA-A 0.000 description 1
- XLIDPNGFCHXNGX-UHFFFAOYSA-N dialuminum;oxygen(2-);silicon(4+) Chemical compound [O-2].[O-2].[O-2].[O-2].[O-2].[Al+3].[Al+3].[Si+4] XLIDPNGFCHXNGX-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
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- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
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- 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
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- 238000011835 investigation Methods 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical class CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
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- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- 229940082004 sodium laurate Drugs 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
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Abstract
Description
本発明は、難溶性薬物であるセレコキシブの溶解性を改善しつつ、着色化を抑えた医薬組成物に関する。 The present invention relates to a pharmaceutical composition that suppresses colorization while improving the solubility of celecoxib, which is a poorly soluble drug.
セレコキシブ（４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−ピラゾール−１−イル］ベンゼンスルホンアミド）は下記構造式（１）で示される化合物であり、難溶性の薬物である。
セレコキシブを含む製剤は、炎症部位のシクロオキシゲナーゼ−２を選択的に阻害し、プロスタグランジンの合成を抑えることにより、消炎・鎮痛作用を示し、炎症及び炎症関連疾患に対する治療薬として知られている。
Preparations containing celecoxib exhibit anti-inflammatory and analgesic effects by selectively inhibiting cyclooxygenase-2 at the site of inflammation and suppressing the synthesis of prostaglandins, and are known as therapeutic agents for inflammation and inflammation-related diseases.
前記有効成分を含む製剤として、日本では「セレコックス錠１００ｍｇ」及び「セレコックス錠２００ｍｇ」が発売されている。
本発明者による調査では、上記市販錠剤に界面活性剤としてラウリル酸ナトリウムが含まれているが、保存中に着色する課題を有していた。
As preparations containing the active ingredient, "Celecox Tablets 100 mg" and "Celecox Tablets 200 mg" are on the market in Japan.
According to the investigation by the present inventor, the above-mentioned commercially available tablet contains sodium laurate as a surfactant, but has a problem of coloring during storage.
セレコキシブは難溶性薬物であることから特許文献１には、セレコキシブル粒子のＤ９０が２００μｍ未満になるように微粒子化し、賦形剤と密に混合することで溶解性を改善した技術を開示し、特許文献２には実施例として、セレコキシブと低成形適正マンニトールとをＣｏ−ミルにおいて粉砕した薬物粉末混合物にラウリル硫酸ナトリウム水溶液と、マルトース水溶液を吹き付けて湿式顆粒を得る経口速融製剤を開示する。
しかし、特許文献１，２には、保存中の着色化の抑制については何ら言及されていない。
Since selecoxib is a poorly soluble drug, Patent Document 1 discloses a technique in which the D 90 of selecoxible particles is made into fine particles so as to be less than 200 μm and mixed closely with an excipient to improve the solubility. As an example, Patent Document 2 discloses an oral fast-melting preparation obtained by spraying an aqueous solution of sodium lauryl sulfate and an aqueous solution of maltose on a drug powder mixture obtained by pulverizing selecoxib and low-formability mannitol in a Co-mill to obtain wet particles. ..
However, Patent Documents 1 and 2 do not mention any suppression of colorization during storage.
本発明者は、セレコキシブの溶解性を改善する目的で、界面活性剤の含有量を増加させることを試みたところ、着色しやすくなることが明らかになり、その着色化の程度は賦形剤の種類によることが見出された。
従って、本発明は溶解性を改善しつつ、着色化を抑えたセレコキシブ含有医薬組成物の提供を目的とする。
When the present inventor tried to increase the content of the surfactant for the purpose of improving the solubility of celecoxib, it became clear that the coloration became easy, and the degree of the coloration was the excipient. It was found that it depends on the type.
Therefore, an object of the present invention is to provide a celecoxib-containing pharmaceutical composition in which colorization is suppressed while improving solubility.
本発明に係る医薬組成物は、有効成分セレコキシブと、界面活性剤及び糖アルコールを含有することで溶解性を改善しつつ、着色化を抑えた点に特徴がある。 The pharmaceutical composition according to the present invention is characterized in that it contains the active ingredient celecoxib, a surfactant and a sugar alcohol to improve solubility and suppress coloring.
市販されているセレコキシブ錠剤には、乳糖水和物が賦形剤として使用されていたので、保存中の着色化の程度が大きいのに対して、本発明は糖アルコールを用いたことで、界面活性剤との組み合せにても着色化を抑制できた。 Since lactose hydrate was used as an excipient in commercially available celecoxib tablets, the degree of coloring during storage is large, whereas in the present invention, sugar alcohol is used, so that the surface is interfaced. Coloring could be suppressed even when combined with an activator.
よって本発明は、乳糖水和物を含有していないのが好ましい。
また、本発明に係る医薬組成物を錠剤にした場合に、６０℃，相対湿度７５％下、２週間の保存にて、色差ΔＥ＝１．５以下に着色化が抑えられる。
Therefore, the present invention preferably does not contain lactose hydrate.
Further, when the pharmaceutical composition according to the present invention is made into tablets, coloring is suppressed to a color difference ΔE = 1.5 or less when stored at 60 ° C. and a relative humidity of 75% for 2 weeks.
本発明により、従来の製剤よりも保存中の着色を抑制することができる。 According to the present invention, coloring during storage can be suppressed as compared with conventional preparations.
以下、本発明を説明する。 Hereinafter, the present invention will be described.
本実施形態における有効成分は、セレコキシブであり、４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−ピラゾール−１−イル］ベンゼンスルホンアミド）の化学名を有する構造式（１）の化合物である。 The active ingredient in this embodiment is celecoxib and has a structural formula (4- [5- (4-methylphenyl) -3- (trifluoromethyl) -pyrazole-1-yl] benzenesulfonamide) having a chemical name. It is a compound of 1).
前記セレコキシブ含有医薬組成物におけるセレコキシブの含有量としては、特に制限はなく、目的に応じて適宜選択することができるが、５０〜６０質量％が好ましい。 The content of celecoxib in the celecoxib-containing pharmaceutical composition is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 50 to 60% by mass.
糖アルコールとしては、たとえば、Ｄ−マンニトール、Ｄ−ソルビトール、キシリトール、エリスリトール、マルチトール等が挙げられる。
中でも、Ｄ−マンニトールを用いることが好ましい。
Examples of sugar alcohols include D-mannitol, D-sorbitol, xylitol, erythritol, maltitol and the like.
Above all, it is preferable to use D-mannitol.
糖アルコールの含有量としては、特に制限はなく、目的に応じて適宜選択することができ、１０〜４０質量％，好ましくは２０〜３０質量％の範囲である。 The content of the sugar alcohol is not particularly limited and may be appropriately selected depending on the intended purpose, and is in the range of 10 to 40% by mass, preferably 20 to 30% by mass.
界面活性剤としては、ラウリル硫酸ナトリウム、ポリソルベート８０等が挙げられる。
中でも、ラウリル硫酸ナトリウムが好ましい。
Examples of the surfactant include sodium lauryl sulfate, polysorbate 80 and the like.
Of these, sodium lauryl sulfate is preferable.
本実施形態における、前記セレコキシブ含有医薬組成物における界面活性剤の含有量としては、３〜１２質量％が好ましい。 The content of the surfactant in the celecoxib-containing pharmaceutical composition in the present embodiment is preferably 3 to 12% by mass.
その他の成分としては、本発明の効果を損なわない限り、特に制限はなく、製剤分野において通常使用される添加剤を目的に応じて適宜選択することができる。
たとえば、崩壊剤、結合剤、滑沢剤、流動化剤などが挙げられる。
崩壊剤としては、たとえば、セルロース系崩壊剤（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、カルメロース、低置換度ヒドロキシプロピルセルロース等）、クロスポピドン、デンプン系崩壊剤、（トウモロコシデンプン、デンプングリコール酸ナトリウム、部分アルファー化デンプン、ヒドロキシプロピルスターチ等）等を使用することができる。
結合剤としては、たとえば、ポリビニルピロリドン、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、ポリビニルアルコール、ステアリルアルコール、アンモニオメタクリレート・コポリマー、アミノアルキルメタクリレートコポリマーＥなどを使用することができる。
滑沢剤としては、たとえば、ステアリン酸マグネシウム、ステアリン酸カルシウム等のステアリン酸金属塩、グリセリン脂肪酸エステル、ショ糖脂肪酸エステル等の脂肪酸エステル類、フマル酸ステアリルナトリウム等を使用することができる。
流動化剤としては、たとえば、含水二酸化ケイ素、軽質無水ケイ酸、合成ケイ酸アルミニウム、合成ヒドロタルサイト、乾燥水酸化アルミニウムゲル、ケイ酸カルシウム、メタケイ酸アルミン酸マグネシウム等を使用することができる。
The other components are not particularly limited as long as the effects of the present invention are not impaired, and additives usually used in the pharmaceutical field can be appropriately selected depending on the intended purpose.
For example, disintegrants, binders, lubricants, fluidizers and the like.
Examples of the disintegrant include cellulosic disintegrants (croscarmellose sodium, carmellose calcium, carmellose, low-substituted hydroxypropyl cellulose, etc.), crospopidone, starch-based disintegrants, (corn starch, sodium starch glycolate, partial) Alfarated starch, hydroxypropyl starch, etc.) can be used.
As the binder, for example, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, stearyl alcohol, ammonio methacrylate copolymer, aminoalkyl methacrylate copolymer E and the like can be used.
As the lubricant, for example, metal stearate salts such as magnesium stearate and calcium stearate, fatty acid esters such as glycerin fatty acid ester and sucrose fatty acid ester, and stearyl sodium fumarate can be used.
As the fluidizing agent, for example, hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, synthetic hydrotalcite, dry aluminum hydroxide gel, calcium silicate, magnesium aluminometasilicate and the like can be used.
本発明のセレコキシブ含有医薬組成物としては、特に制限はなく、普通錠、口腔内崩壊錠、チュアブル錠などの錠剤が挙げられる。これらの中でも、普通錠が好ましい。
前記錠剤の形状、構造、大きさとしては、特に制限はなく、目的に応じて適宜選択することができる。
The celecoxib-containing pharmaceutical composition of the present invention is not particularly limited, and examples thereof include tablets such as ordinary tablets, orally disintegrating tablets, and chewable tablets. Among these, ordinary tablets are preferable.
The shape, structure, and size of the tablet are not particularly limited and may be appropriately selected depending on the intended purpose.
本発明に係る医薬組成物の製造方法としては、セレコキシブと、糖アルコールと、界面活性剤とを含む固形製剤を製造できる方法であれば特に制限はなく、剤形に応じた公知の製法により製造できる。
たとえば、剤形が錠剤の場合、経口医薬組成物の構成成分を必要に応じて混合、造粒、整粒などの工程を経て、常法により圧縮成形することによって製造することができる。
The method for producing the pharmaceutical composition according to the present invention is not particularly limited as long as it can produce a solid preparation containing celecoxib, a sugar alcohol, and a surfactant, and is produced by a known production method according to the dosage form. it can.
For example, when the dosage form is a tablet, the components of the oral pharmaceutical composition can be produced by compression molding by a conventional method through steps such as mixing, granulation, and sizing as necessary.
上記造粒に際して用いることのできる造粒法については、湿式造粒法が好ましい。
造粒装置については特に制限はなく、たとえば、流動層造粒乾燥機、転動型造粒乾燥機、ワースター型造粒乾燥機、攪拌造粒機、押出造粒機などの公知の造粒装置を適宜選択して用いることができる。
As for the granulation method that can be used for the above granulation, the wet granulation method is preferable.
The granulator is not particularly limited, and for example, a known granulator such as a fluidized bed granulator, a rolling type granulator, a worster type granulator, a stirring granulator, or an extrusion granulator. Can be appropriately selected and used.
打錠に用いられる打錠機については、特に限定されず、たとえばロータリー式打錠機や単発打錠機などの公知の打錠機を適宜選択して用いることができる。 The locking machine used for locking is not particularly limited, and for example, a known locking machine such as a rotary type locking machine or a single-shot locking machine can be appropriately selected and used.
以下、実施例に基づいて本発明を具体的に説明するが、本発明はこれらの試験例に限定されるものではない。 Hereinafter, the present invention will be specifically described based on Examples, but the present invention is not limited to these Test Examples.
まずは予備試験として、乳糖水和物及び糖アルコールを過酷条件（６０℃、７５％相対湿度）下で２週間保存した際の色差変化を下記表１に記す。
色差変化ΔＥは、試験前後における色測色差の測定値を示す（コニカミノルタジャパン株式会社製）。
First, as a preliminary test, the color difference changes when lactose hydrate and sugar alcohol are stored under harsh conditions (60 ° C., 75% relative humidity) for 2 weeks are shown in Table 1 below.
The color difference change ΔE indicates the measured value of the color measurement color difference before and after the test (manufactured by Konica Minolta Japan Co., Ltd.).
次に、下記表２の処方に従い、セレコキシブの粉末と、Ｄ−マンニトール、低置換度ヒドロキシプロピルセルロースを流動層造粒乾燥機（「ＭＰ−０１」（装置名）、フロイント産業社製）に投入し、ヒドロキシプロピルセルロース及びラウリル硫酸ナトリウムを精製水に溶解した造粒液をスプレーして造粒し、乾燥して造粒物を得た。
得られた造粒物にステアリン酸マグネシウムを加えて混合し、混合末を得た。
得られた混合末をロータリー打錠機（「ＶＩＲＧＯ」（装置名）、菊水製作所社製）で重量１８０ｍｇの錠剤に圧縮成形して、実施例１〜４の素錠を得た。
また、Ｄ−マンニトールの替わりに乳糖水和物を用いて、上記と同様の工程を経て、表３に示す比較例１〜３の素錠を得た。
Next, according to the formulation shown in Table 2 below, the selecoxib powder, D-mannitol, and low-substituted hydroxypropyl cellulose were put into a fluidized bed granulation dryer (“MP-01” (device name), manufactured by Freund Sangyo Co., Ltd.). Then, a granulating solution prepared by dissolving hydroxypropyl cellulose and sodium lauryl sulfate in purified water was sprayed to granulate, and dried to obtain a granulated product.
Magnesium stearate was added to the obtained granules and mixed to obtain a mixed powder.
The obtained mixed powder was compression-molded into tablets weighing 180 mg with a rotary tableting machine (“VIRGO” (device name), manufactured by Kikusui Seisakusho Co., Ltd.) to obtain uncoated tablets of Examples 1 to 4.
Further, using lactose hydrate instead of D-mannitol, the uncoated tablets of Comparative Examples 1 to 3 shown in Table 3 were obtained through the same steps as described above.
実施例１〜４、比較例１〜３について、ポリ塩化ビニルを用いてＰＴＰ包装された錠剤を過酷条件（６０℃、７５％相対湿度）下に２週間保存し、試験前後の色差を測定した。
試験結果について、表４に示す。
For Examples 1 to 4 and Comparative Examples 1 to 3, tablets PTP-wrapped using polyvinyl chloride were stored under harsh conditions (60 ° C., 75% relative humidity) for 2 weeks, and the color difference before and after the test was measured. ..
The test results are shown in Table 4.
一般にΔＥが１．５を超えると、錠剤の着色が目視で確認できるとされている。
表１の試験結果から、乳糖水和物よりも糖アルコールの方が耐着色性に優れている。
錠剤化したセレコキシブ含有錠の試験結果を比較すると、比較例１〜３では賦形剤として乳糖水和物を用いた場合に、溶解性の向上を目的にラウリル硫酸ナトリウムの含有量を増大させると、それに伴い着色の程度が大きくなっている。
これに対して、Ｄ−マンニトールを含有させた実施例１〜４においては、ラウリル硫酸ナトリウムの含有量を増加させても色差に殆ど変化がない。
これは、糖アルコール単独での色差が小さいことだけでは説明できない、特有の作用を有していることが分かる。
よって、本発明に係るセレコキシブ含有医薬組成物は、糖アルコールとラウリル硫酸ナトリウム（界面活性剤）とを組み合せたことにより、界面活性剤の増量による溶解性の向上を図りつつ、着色化（色差変化）を抑えることができる。
Generally, when ΔE exceeds 1.5, the coloring of tablets can be visually confirmed.
From the test results in Table 1, sugar alcohol is superior in color resistance to lactose hydrate.
Comparing the test results of tableted celecoxib-containing tablets, in Comparative Examples 1 to 3, when lactose hydrate was used as an excipient, the content of sodium lauryl sulfate was increased for the purpose of improving solubility. As a result, the degree of coloring is increasing.
On the other hand, in Examples 1 to 4 in which D-mannitol was contained, there was almost no change in the color difference even if the content of sodium lauryl sulfate was increased.
It can be seen that this has a peculiar action that cannot be explained only by the small color difference of the sugar alcohol alone.
Therefore, the celekoxyb-containing pharmaceutical composition according to the present invention is colored (color difference change) while improving the solubility by increasing the amount of the surfactant by combining the sugar alcohol and sodium lauryl sulfate (surfactant). ) Can be suppressed.
セレコキシブは難溶性薬物であることから特許文献１には、セレコキシブ粒子のＤ９０が２００μｍ未満になるように微粒子化し、賦形剤と密に混合することで溶解性を改善した技術を開示し、特許文献２には実施例として、セレコキシブと低成形適正マンニトールとをＣｏ−ミルにおいて粉砕した薬物粉末混合物にラウリル硫酸ナトリウム水溶液と、マルトース水溶液を吹き付けて湿式顆粒を得る経口速融製剤を開示する。
しかし、特許文献１，２には、保存中の着色化の抑制については何ら言及されていない。
Celecoxib in Patent Document 1 because it is poorly soluble drugs, and micronized as D 90 of celecoxib particles is less than 200 [mu] m, discloses a technique having improved solubility by mixing the excipient intimately, Patent Document 2 discloses, as an example, an oral fast-melting preparation obtained by spraying an aqueous solution of sodium lauryl sulfate and an aqueous solution of maltose on a drug powder mixture obtained by pulverizing selecoxib and low-formability mannitol in a Co-mill to obtain wet particles.
However, Patent Documents 1 and 2 do not mention any suppression of colorization during storage.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004512274A (en) * | 2000-08-18 | 2004-04-22 | ファルマシア・コーポレーション | Oral fast-melting preparation of cyclooxygenase-2 inhibitor |
| JP2018525435A (en) * | 2015-07-14 | 2018-09-06 | 株式会社柳英製薬Ｙｏｏ Ｙｏｕｎｇ Ｐｈａｒｍ Ｃｏ．， Ｌｔｄ． | Pharmaceutical composition containing celecoxib and tramadol |
| JP2019089758A (en) * | 2017-11-10 | 2019-06-13 | 大原薬品工業株式会社 | Method for improving dissolution in celecoxib-containing tablets |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004512274A (en) * | 2000-08-18 | 2004-04-22 | ファルマシア・コーポレーション | Oral fast-melting preparation of cyclooxygenase-2 inhibitor |
| JP2018525435A (en) * | 2015-07-14 | 2018-09-06 | 株式会社柳英製薬Ｙｏｏ Ｙｏｕｎｇ Ｐｈａｒｍ Ｃｏ．， Ｌｔｄ． | Pharmaceutical composition containing celecoxib and tramadol |
| JP2019089758A (en) * | 2017-11-10 | 2019-06-13 | 大原薬品工業株式会社 | Method for improving dissolution in celecoxib-containing tablets |
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