JP6945377B2 - Pharmaceutical tablets containing erlotinib as an active ingredient and methods for manufacturing them - Google Patents
Pharmaceutical tablets containing erlotinib as an active ingredient and methods for manufacturing them Download PDFInfo
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- JP6945377B2 JP6945377B2 JP2017146374A JP2017146374A JP6945377B2 JP 6945377 B2 JP6945377 B2 JP 6945377B2 JP 2017146374 A JP2017146374 A JP 2017146374A JP 2017146374 A JP2017146374 A JP 2017146374A JP 6945377 B2 JP6945377 B2 JP 6945377B2
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- amino group
- erlotinib
- modified polymer
- active ingredient
- pharmaceutical
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- 239000005551 L01XE03 - Erlotinib Substances 0.000 title claims description 30
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- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 239000001054 red pigment Substances 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229940023144 sodium glycolate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 description 1
- 239000003021 water soluble solvent Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Description
本発明は、エルロチニブ又はその医薬的に許容な塩を有効成分として含有する医薬錠剤であって、アミノ基修飾高分子添加剤を含有する医薬錠剤及びその製造方法に関する。 The present invention relates to a pharmaceutical tablet containing erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient, and which contains an amino group-modified polymer additive, and a method for producing the same.
エルロチニブは、化学名をN−3−(エチニル−フェニル)−6,7−ビス−(2−メトキシエトキシ)−4−キナゾリンアミンとする、一般式(1)で示される構造を有する化合物である。 Erlotinib is a compound having a structure represented by the general formula (1), having a chemical name of N-3- (ethynyl-phenyl) -6,7-bis- (2-methoxyethoxy) -4-quinazolineamine. ..
エルロチニブは、キナゾリン誘導体であり、上皮増殖因子受容体(Epidermal Growth Factor Receptor:EGFR)を標的とした選択的チロシンキナーゼ阻害剤(Tyrosine Kinase Inhibitor:TKI)である。EGFR細胞内チロシンキナーゼ領域のATP結合部位においてATPと競合的に拮抗することにより、癌細胞の増殖抑制、アポトーシス誘導に基づいて抗腫瘍効果を示すと考えられている。タルセバ(TARCEVA)(登録商標)の商標名で市販されており、本邦においては、切除不能な再発・進行性で、がん化学療法施行後に増悪した非小細胞肺癌、EGFR遺伝子変異陽性の切除不能な再発・進行性で、がん化学療法未治療の非小細胞肺癌、治癒切除不能な膵癌の治療剤として承認されている。 Elrotinib is a quinazoline derivative and is a selective tyrosine kinase inhibitor (TKI) that targets the Epidermal Growth Factor Receptor (EGFR). It is thought that by competitively antagonizing ATP at the ATP binding site of the intracellular tyrosine kinase region of EGFR, it exhibits an antitumor effect based on suppression of cancer cell growth and induction of apoptosis. It is marketed under the trade name of TARCEVA (registered trademark), and in Japan, it is unresectable recurrence / progression, non-small cell lung cancer exacerbated after cancer chemotherapy, and EGFR gene mutation positive unresectable. It has been approved as a therapeutic agent for non-small cell lung cancer that has not been treated with cancer chemotherapy and pancreatic cancer that cannot be cured and resected due to its recurrence and progression.
エルロチニブの医薬錠剤が報告されており、特許文献1には、錠剤内部に微結晶質セルロース、ラクトース含水、ポビドンK30、澱粉グリコール酸ナトリウム、ステアリン酸マグネシウムを含み、錠剤外部である被覆層にヒドロキシプロピルメチルセルロース、ポリエチレングリコール6000、タルク、酸化鉄(黄色)、酸化チタンを含む薄層被覆錠剤が記載されている。 Pharmaceutical tablets of errotinib have been reported, and Patent Document 1 contains microcrystalline cellulose, lactose-containing water, povidone K30, sodium starch glycolate, and magnesium stearate inside the tablet, and hydroxypropyl in the coating layer outside the tablet. Thin-layer coated tablets containing methyl cellulose, polyethylene glycol 6000, starch, iron oxide (yellow), titanium oxide are described.
医薬錠剤において有効成分の溶出性は、有効成分が効果を十分に発揮するために重要なことである。有効成分の初期溶出を抑え、急激な有効成分の溶出を回避することのできるエルロチニブ又はその医薬的に許容な塩を有効成分として含有する医薬錠剤が望ましい。 The elution of the active ingredient in pharmaceutical tablets is important for the active ingredient to fully exert its effect. A pharmaceutical tablet containing erlotinib or a pharmaceutically acceptable salt thereof, which can suppress the initial elution of the active ingredient and avoid the rapid elution of the active ingredient, is desirable.
本発明の目的は、水中での有効成分の初期溶出を抑え、急激な有効成分の溶出を回避することのできるエルロチニブ又はその医薬的に許容な塩を有効成分として含有する医薬錠剤及びその製造方法を提供することである。 An object of the present invention is a pharmaceutical tablet containing erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient, which can suppress the initial elution of the active ingredient in water and avoid the rapid elution of the active ingredient, and a method for producing the same. Is to provide.
上記課題である水中での有効成分の初期溶出の抑制を解決するための手段として、崩壊剤を種々変えることが検討されることが一般的である。崩壊剤にはデンプングリコール酸ナトリウムやクロスカルメロースナトリウムのような膨脹型崩壊剤やクロスポビドンのような導水型崩壊剤があり目的とする溶出性を得るために種々選択される。しかしエルロチニブ又はその医薬的に許容な塩を有効成分として含有する医薬錠剤において、崩壊剤の変更では水中での有効成分の初期溶出を抑えることはできず、すなわち、水中での急激な有効成分の溶出を回避することのできる医薬錠剤を得ることはできなかった。 It is common to consider changing various disintegrants as a means for solving the above-mentioned problem of suppressing the initial elution of the active ingredient in water. Disintegrants include swelling-type disintegrants such as sodium starch glycolate and croscarmellose sodium, and water-conducting disintegrants such as crospovidone, which are variously selected in order to obtain the desired elution property. However, in pharmaceutical tablets containing erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient, the initial elution of the active ingredient in water cannot be suppressed by changing the disintegrant, that is, the rapid active ingredient in water. It was not possible to obtain a pharmaceutical tablet capable of avoiding elution.
本発明者は、上記課題を解決するために鋭意研究を行なった結果、有効成分としてエルロチニブ又はその医薬的に許容な塩を有効成分とする医薬錠剤であって、アミノ基修飾高分子添加剤を含む医薬錠剤とすることで水中での有効成分の初期溶出の抑制を可能とすることを見出し、本発明を完成させた。すなわち、本発明は以下の[1]〜[6]を要旨とする。 As a result of diligent research to solve the above problems, the present inventor has obtained a pharmaceutical tablet containing erlotinib as an active ingredient or a pharmaceutically acceptable salt thereof as an active ingredient, and an amino group-modified polymer additive. The present invention has been completed by finding that it is possible to suppress the initial elution of the active ingredient in water by using a pharmaceutical tablet containing the active ingredient. That is, the gist of the present invention is the following [1] to [6].
[1]エルロチニブ又はその医薬的に許容な塩を有効成分とする医薬錠剤であって、アミノ基修飾高分子添加剤を含む医薬錠剤。
[2]アミノ基修飾高分子添加剤が、アミノアルキルメタクリレートコポリマーE、ポリビニルアセタールジエチルアミノアセテート、アンモニオアルキルメタクリレートコポリマーからなる群より選択される1種類以上である[1]に記載の医薬錠剤。
[3]アミノ基修飾高分子添加剤が医薬錠剤内部に分散している[1]又は[2]に記載の医薬錠剤。
[4]アミノ基修飾高分子添加剤が0.1質量%以上7質量%以下含まれている、[1]〜[3]の何れか一項に記載の医薬錠剤。
[5]エルロチニブ又はその医薬的に許容な塩がエルロチニブ塩酸塩である[1]〜[4]の何れか一項に記載の医薬錠剤。
[1] A pharmaceutical tablet containing erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient and containing an amino group-modified polymer additive.
[2] The pharmaceutical tablet according to [1], wherein the amino group-modified polymer additive is one or more selected from the group consisting of the aminoalkyl methacrylate copolymer E, the polyvinyl acetal diethylaminoacetate, and the ammonioalkyl methacrylate copolymer.
[3] The pharmaceutical tablet according to [1] or [2], wherein the amino group-modified polymer additive is dispersed inside the pharmaceutical tablet.
[4] The pharmaceutical tablet according to any one of [1] to [3], which contains 0.1% by mass or more and 7% by mass or less of an amino group-modified polymer additive.
[5] The pharmaceutical tablet according to any one of [1] to [4], wherein erlotinib or a pharmaceutically acceptable salt thereof is erlotinib hydrochloride.
[6][1]〜[5]の何れかに記載の医薬錠剤の製造方法であって、(A)エルロチニブ又はその医薬的に許容な塩、アミノ基修飾高分子添加剤及びその他の添加剤を混合する工程、(B)工程(A)で得られた混合物を圧縮成型し錠剤にする工程を含む[1]〜[5]の何れか一項に記載の医薬錠剤の製造方法。 [6] The method for producing a pharmaceutical tablet according to any one of [1] to [5], wherein (A) erlotinib or a pharmaceutically acceptable salt thereof, an amino group-modified polymer additive and other additives. The method for producing a pharmaceutical tablet according to any one of [1] to [5], which comprises a step of mixing the above and (B) a step of compression-molding the mixture obtained in the step (A) into tablets.
本発明のエルロチニブ又はその医薬的に許容な塩を有効成分とする医薬錠剤は、水中での有効成分の初期溶出の抑制できる医薬錠剤を提供することができる。より具体的には、水中での有効成分の初期溶出を抑え、急激な有効成分の溶出を回避することのできるエルロチニブ又はその医薬的に許容な塩を有効成分とする医薬錠剤を提供することができる。 The pharmaceutical tablet containing erlotinib of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can provide a pharmaceutical tablet capable of suppressing the initial elution of the active ingredient in water. More specifically, it is possible to provide a pharmaceutical tablet containing erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient, which can suppress the initial elution of the active ingredient in water and avoid the rapid elution of the active ingredient. can.
本発明は、エルロチニブ又はその医薬的に許容な塩を有効成分とする医薬錠剤であって、アミノ基修飾添加剤を含む医薬錠剤であることを特徴とする。以下にその詳細について説明する。 The present invention is characterized in that it is a pharmaceutical tablet containing erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient and containing an amino group-modifying additive. The details will be described below.
本発明は、有効成分としてエルロチニブ又はその医薬的に許容な塩を用いる。エルロチニブの化学名はN−3−(エチニル−フェニル)−6,7−ビス−(2−メトキシエトキシ)−4−キナゾリンアミンである。当該化合物は、特開2016−104717に記載の方法により合成することができる。エルロチニブは医薬品として容認できる品質であることが好ましい。 The present invention uses erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient. The chemical name for erlotinib is N-3- (ethynyl-phenyl) -6,7-bis- (2-methoxyethoxy) -4-quinazolineamine. The compound can be synthesized by the method described in JP-A-2016-104717. Erlotinib is preferably of medicinal quality.
本発明の有効成分には、エルロチニブの医薬的に許容な塩も含まれる。エルロチニブは、弱塩基性化合物であることから、適当な酸との付加塩の様態であっても良い。例えば、特に限定されないが、塩酸、臭化水素酸、硫酸、リン酸、トリフルオロ酢酸、クエン酸、マレイン酸、酒石酸、フマル酸、メタンスルホン酸または4−トルエンスルホン酸等が挙げられる。本発明においてエルロチニブ塩酸塩を用いることが好ましく、医薬品として容認できる品質であることが好ましい。該化合物は、特許第4689916号においてA型結晶及びB型結晶が、特許第4456079号においてE型結晶開示されている。特許第4456079号においてA型結晶、B型結晶、E型結晶の溶解度が開示されており、A型結晶は水中での溶解度がA型結晶、B型結晶、E型結晶の中で一番高いことが示されている。本発明の医薬錠剤は、水中での有効成分が徐放される医薬錠剤であり、溶解度が高いA型結晶を含んでいるエルロチニブ塩酸塩を使用することで発明の効果が発揮できることが考えられる。そのため、本発明において、使用するエルロチニブ塩酸塩はA型結晶のエルロチニブ塩酸塩を含んでいることが好ましい。 The active ingredient of the present invention also includes a pharmaceutically acceptable salt of erlotinib. Since erlotinib is a weakly basic compound, it may be in the form of an addition salt with an appropriate acid. For example, without particular limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, maleic acid, tartrate acid, fumaric acid, methanesulfonic acid, 4-toluenesulfonic acid and the like can be mentioned. In the present invention, it is preferable to use erlotinib hydrochloride, and it is preferable that the quality is acceptable as a pharmaceutical product. As for the compound, A-type crystals and B-type crystals are disclosed in Japanese Patent No. 4689916, and E-type crystals are disclosed in Japanese Patent No. 4456079. Patent No. 4456079 discloses the solubility of A-type crystals, B-type crystals, and E-type crystals, and A-type crystals have the highest solubility in water among A-type crystals, B-type crystals, and E-type crystals. Is shown. The pharmaceutical tablet of the present invention is a pharmaceutical tablet in which the active ingredient is slowly released in water, and it is considered that the effect of the invention can be exhibited by using erlotinib hydrochloride containing A-type crystals having high solubility. Therefore, in the present invention, the erlotinib hydrochloride used preferably contains A-type crystalline erlotinib hydrochloride.
本発明の医薬錠剤は、アミノ基修飾高分子添加剤を含むことを特徴とする。本発明は、アミノ基修飾高分子添加剤であれば特に限定されずに適用することができる。アミノ基修飾高分子添加剤は、医薬品として容認できる品質であることが好ましい。 The pharmaceutical tablet of the present invention is characterized by containing an amino group-modified polymer additive. The present invention can be applied without particular limitation as long as it is an amino group-modified polymer additive. The amino group-modified polymer additive is preferably of a quality that is acceptable as a pharmaceutical product.
本明細書におけるアミノ基修飾高分子添加剤としては、アミノアルキルメタクリレートコポリマーE、ポリビニルアセタールジエチルアミノアセテート、アンモニオアルキルメタクリレートコポリマー等が挙げられ、アミノアルキルメタクリレートコポリマーE、ポリビニルアセタールジエチルアミノアセテートを用いることが好ましく、アミノアルキルメタクリレートコポリマーEを用いることがより好ましい。
アミノ基修飾高分子添加剤であるアミノアルキルメタクリレートコポリマーEは市販品を用いても良い。例えば商品名オイドラギット(登録商標)E100、オイドラギット(登録商標)EPO(株式会社樋口商会)等のアミノアルキルメタクリレートコポリマー等を挙げることができ、オイドラギット(登録商標)EPOを用いることが好ましい。また、ポリビニルアセタールジエチルアミノアセテートは市販品を用いても良い。例えば商品名AEA(三菱ケミカルフーズ)を挙げることができる。
Examples of the amino group-modified polymer additive in the present specification include aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, ammonioalkyl methacrylate copolymer and the like, and aminoalkyl methacrylate copolymer E and polyvinyl acetal diethylaminoacetate are preferably used. , Aminoalkyl Methacrylate Copolymer E is more preferred.
As the aminoalkyl methacrylate copolymer E, which is an amino group-modified polymer additive, a commercially available product may be used. For example, aminoalkyl methacrylate copolymers such as trade name Eudragit (registered trademark) E100 and Eudragit (registered trademark) EPO (Higuchi Shokai Co., Ltd.) can be mentioned, and it is preferable to use Eudragit (registered trademark) EPO. Further, as the polyvinyl acetal diethylaminoacetate, a commercially available product may be used. For example, the trade name AEA (Mitsubishi Chemical Foods) can be mentioned.
本発明は医薬錠剤の様態である。医薬錠剤の形状は、経口的な服用に適する通常の形状及び大きさであれば特に限定されない。 The present invention is in the form of a pharmaceutical tablet. The shape of the pharmaceutical tablet is not particularly limited as long as it has a normal shape and size suitable for oral administration.
本発明の医薬錠剤は、エルロチニブ又はその医薬的に許容な塩及びアミノ基修飾高分子添加剤の他に本発明の効果を妨げない範囲で医薬錠剤を調製するために通常用いられる他の添加剤を含んでいても良い。例えば、崩壊剤、結合剤、滑沢剤、可溶化剤、賦形剤、隠蔽剤や着色剤等の、医薬錠剤を調製するための通常の医薬錠剤用添加剤を用いても良い。
これらの添加剤は、医薬品製剤用途で許容される純度であれば特に制限されることなく用いることができる。これらの添加剤は1種のみを用いても良く、これらの混合物として用いても良い。当該医薬錠剤を調製する際に、任意に使用される。
The pharmaceutical tablets of the present invention include erlotinib or a pharmaceutically acceptable salt thereof and an amino group-modified polymer additive, as well as other additives usually used for preparing a pharmaceutical tablet within a range that does not interfere with the effects of the present invention. May include. For example, ordinary pharmaceutical tablet additives for preparing pharmaceutical tablets, such as disintegrants, binders, lubricants, solubilizers, excipients, concealing agents and colorants, may be used.
These additives can be used without particular limitation as long as the purity is acceptable for pharmaceutical pharmaceutical use. Only one of these additives may be used, or a mixture thereof may be used. It is optionally used when preparing the pharmaceutical tablet.
本発明において崩壊剤としては、カルボキシメチルスターチナトリウム(デンプングリコール酸ナトリウム)、クロスポビドン、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、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、低置換度カルボキシメチルスターチナトリウム等が挙げられる。 In the present invention, as the disintegrant, sodium carboxymethyl starch (sodium starch glycolate), crospovidone, carmellose, sodium carmellose, carmellose calcium, croscarmellose, croscarmellose sodium, low-substituted hydroxypropyl cellulose, low-substitution Degree carboxymethyl starch sodium and the like can be mentioned.
本発明において結合剤としては、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、結晶セルロース、トウモロコシデンプン、部分アルファー化デンプンポリビニルアルコール、ポリビニルピロリドン等が挙げられる。 Examples of the binder in the present invention include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, crystalline cellulose, corn starch, partially pregelatinized starch polyvinyl alcohol, polyvinylpyrrolidone and the like.
本発明において滑沢剤としては、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸亜鉛、ステアリン酸アルミニウム、モノステアリン酸グリセリン、フマル酸ステアリルナトリウム、ステアリン酸カルシウム、タルク、カルナウバロウ等が挙げられる。 Examples of the lubricant in the present invention include stearic acid, magnesium stearate, zinc stearate, aluminum stearate, glycerin monostearate, sodium stearyl fumarate, calcium stearate, talc, carnauba wax and the like.
本発明において可溶化剤としては界面活性剤が用いられ、例えば、ラウリル硫酸ナトリウム、大豆レシチン、精製大豆レシチン、ソルビタン脂肪酸エステル、ラウロマクロゴール等が挙げられる。 In the present invention, a surfactant is used as the solubilizer, and examples thereof include sodium lauryl sulfate, soybean lecithin, purified soybean lecithin, sorbitan fatty acid ester, and lauromacrogol.
本発明において賦形剤としては、乳糖無水物、乳糖水和物、マルトース、マンニトール、スクロース、ソルビトール、キシリトール、イノシトール等、上記の結合剤、崩壊剤、可溶化剤、滑沢剤に該当しない添加剤が含まれる。 In the present invention, the excipients include lactose anhydride, lactose hydrate, maltose, mannitol, sucrose, sorbitol, xylitol, inositol and the like, which do not correspond to the above-mentioned binders, disintegrants, solubilizers and lubricants. Contains the agent.
本発明において隠蔽剤や着色剤としては、酸化チタン、黄酸化鉄、三二酸化鉄、黄色三二酸化鉄、黒酸化鉄、酸化亜鉛、褐色酸化鉄、タルク、食用黄色素類、食用青色素類、食用赤色素類等が挙げられる。 In the present invention, the concealing agent and the colorant include titanium oxide, yellow iron oxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, zinc oxide, brown iron oxide, talc, edible chlorophyll, and edible blue pigment. Examples include edible red pigments.
本明細書に記載されているアミノ基修飾高分子添加剤は、通常コーティング基剤として使用され得る添加剤である。本発明の医薬錠剤は、アミノ基修飾高分子添加剤が「医薬錠剤内部」に分散していることが好ましい。 The amino group-modified polymer additives described herein are additives that can usually be used as coating bases. In the pharmaceutical tablet of the present invention, it is preferable that the amino group-modified polymer additive is dispersed "inside the pharmaceutical tablet".
本明細書における「医薬錠剤内部」とは、素錠部分のことである。アミノ基修飾高分子添加剤は素錠の部分に分散した状態で含まれていることが好ましい。 As used herein, the term "inside a pharmaceutical tablet" refers to an uncoated tablet portion. The amino group-modified polymer additive is preferably contained in a dispersed state in the portion of the uncoated tablet.
本発明の医薬錠剤はフィルムコーティングされていても良い。フィルムコーティングされる場合、本発明の効果を妨げない範囲で医薬錠剤外部にあたるフィルムコート部分にアミノ基修飾高分子添加剤が含まれていてもよい。 The pharmaceutical tablet of the present invention may be film-coated. In the case of film coating, an amino group-modified polymer additive may be contained in the film-coated portion corresponding to the outside of the pharmaceutical tablet as long as the effect of the present invention is not impaired.
本明細書における「アミノ基修飾高分子添加剤が医薬錠剤内部に分散している」とは、例えば、素錠に含まれるアミノ基修飾高分子添加剤以外の、例えば、有効成分や他の添加剤と混合されている状態のことである。素錠の構成成分として混合されていればよく、有効成分や他の添加剤を含む造粒物にアミノ基修飾高分子添加剤を含むコーティング層としてアミノ基修飾高分子添加剤を含んでいてもよい。 In the present specification, "the amino group-modified polymer additive is dispersed inside the pharmaceutical tablet" means, for example, addition of an active ingredient or other addition other than the amino group-modified polymer additive contained in the uncoated tablet. It is a state in which it is mixed with an agent. It suffices to be mixed as a constituent component of the uncoated tablet, and even if the granulated product containing the active ingredient and other additives contains the amino group-modified polymer additive as a coating layer containing the amino group-modified polymer additive. good.
本発明は、医薬錠剤内部に前述したアミノ基修飾高分子添加剤を含むことが好ましい。錠剤内部に含まれるアミノ基修飾高分子添加剤の含有率が0.1質量%以上7質量%以下であることが好ましく、0.1質量%以上5質量%以下であることがより好ましく、0.1質量%以上2質量%以下であることがさらに好ましい。 In the present invention, it is preferable that the above-mentioned amino group-modified polymer additive is contained inside the pharmaceutical tablet. The content of the amino group-modified polymer additive contained in the tablet is preferably 0.1% by mass or more and 7% by mass or less, more preferably 0.1% by mass or more and 5% by mass or less, and 0. . More preferably, it is 1% by mass or more and 2% by mass or less.
また、フィルムコート部分にはコーティング基剤、隠蔽剤や着色剤、分散剤等の医薬製剤のコーティング剤に用いられる任意の添加剤が含まれていても良い。コーティング剤に用いる隠蔽剤や着色剤、分散剤は、前述と同義である。 Further, the film-coated portion may contain any additive used as a coating agent for pharmaceutical preparations such as a coating base, a concealing agent, a coloring agent, and a dispersant. The concealing agent, coloring agent, and dispersant used for the coating agent have the same meanings as described above.
本発明においてフィルムコーティング基剤としては、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ポリビニルアルコール・ポリエチレングリコール・グラフトコポリマー等が挙げられる。 Examples of the film coating base in the present invention include hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol / polyethylene glycol / graft copolymer and the like.
本発明における医薬錠剤は、エルロチニブ又はその医薬的に許容される塩として30〜90質量部、アミノ基修飾高分子添加剤を0.1〜7質量部、結合剤を1〜50質量部、崩壊剤を1〜20質量部、滑沢剤を0.1〜5質量部、可溶化剤を0.1〜30質量部、賦形剤を5〜50質量部で含有する処方による医薬組成物を混合し、造粒して顆粒体を調製し、その造粒時に水、エタノール、メタノール等の有機溶媒及びこれらの混合溶媒を添加してもしなくてもよく、これを圧縮成型することで医薬錠剤を調製することができる。その後、この医薬錠剤をフィルムコーティングしてもよい。好ましくは、エルロチニブ又はその医薬的に許容される塩として30〜70質量部、アミノ基修飾高分子添加剤を0.1〜5質量部、結合剤を1〜40質量部、崩壊剤を1〜10質量部、滑沢剤を0.1〜5質量部、可溶化剤を1〜15質量部、賦形剤を5〜30質量部を含有する医薬錠剤である。 The pharmaceutical tablet in the present invention has 30 to 90 parts by mass of errotinib or a pharmaceutically acceptable salt thereof, 0.1 to 7 parts by mass of an amino group-modified polymer additive, 1 to 50 parts by mass of a binder, and disintegration. A pharmaceutical composition according to a formulation containing 1 to 20 parts by mass of an agent, 0.1 to 5 parts by mass of a lubricant, 0.1 to 30 parts by mass of a solubilizer, and 5 to 50 parts by mass of an excipient. Granules are prepared by mixing and granulating, and organic solvents such as water, ethanol, and methanol and a mixed solvent thereof may or may not be added at the time of granulation, and the pharmaceutical tablets are formed by compression molding. Can be prepared. The pharmaceutical tablet may then be film coated. Preferably, 30 to 70 parts by mass of errotinib or a pharmaceutically acceptable salt thereof, 0.1 to 5 parts by mass of an amino group-modified polymer additive, 1 to 40 parts by mass of a binder, and 1 to 1 to 40 parts by mass of a disintegrant. It is a pharmaceutical tablet containing 10 parts by mass of a lubricant, 1 to 15 parts by mass of a solubilizer, and 5 to 30 parts by mass of an excipient.
本発明における医薬錠剤は、アミノ基修飾高分子添加剤を0.1〜2質量部、結合剤を25〜35質量部、崩壊剤を5〜10質量部含有する医薬錠剤であることが好ましい。 The pharmaceutical tablet in the present invention is preferably a pharmaceutical tablet containing 0.1 to 2 parts by mass of an amino group-modified polymer additive, 25 to 35 parts by mass of a binder, and 5 to 10 parts by mass of a disintegrant.
本発明は、エルロチニブ又はその医薬的に許容な塩を有効成分とする医薬錠剤の製造方法を含む。 The present invention includes a method for producing a pharmaceutical tablet containing erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient.
本発明の医薬錠剤の製造方法は、(A)エルロチニブ又はその医薬的に許容な塩、アミノ基修飾高分子添加剤及びその他の添加剤を混合する工程を含む。 The method for producing a pharmaceutical tablet of the present invention includes (A) mixing erlotinib or a pharmaceutically acceptable salt thereof, an amino group-modified polymer additive and other additives.
本発明の医薬錠剤の製造方法は、アミノ基修飾高分子添加剤が医薬錠剤内部に分散していることが好ましい。(A)エルロチニブ又はその医薬的に許容な塩、アミノ基修飾高分子添加剤及びその他の添加剤を混合する工程を経ることで、アミノ基修飾高分子添加剤が医薬錠剤内部に分散することが可能となる。そのため、本工程は本発明において重要である。 In the method for producing a pharmaceutical tablet of the present invention, it is preferable that the amino group-modified polymer additive is dispersed inside the pharmaceutical tablet. (A) By going through the step of mixing errotinib or a pharmaceutically acceptable salt thereof, an amino group-modified polymer additive and other additives, the amino group-modified polymer additive can be dispersed inside the pharmaceutical tablet. It will be possible. Therefore, this step is important in the present invention.
本発明の医薬錠剤の製造方法において、アミノ基修飾高分子添加剤は粉末のままエルロチニブ又はその医薬的に許容な塩及びその他の添加剤と混合してもよく、アミノ基修飾高分子添加剤を水、エタノール、メタノール等の有機溶媒及びこれらの混合溶媒等の水性媒体に溶解しエルロチニブ又はその医薬的に許容な塩及びその他の添加剤と混合してもよい。また、エルロチニブ又はその医薬的に許容な塩及びその他の添加剤の混合後にアミノ基修飾高分子添加剤を上記水性媒体に溶解し、スプレー等することで混合物としてもよい。 In the method for producing a pharmaceutical tablet of the present invention, the amino group-modified polymer additive may be mixed as a powder with errotinib or a pharmaceutically acceptable salt thereof and other additives, and the amino group-modified polymer additive may be mixed. It may be dissolved in an organic solvent such as water, ethanol or methanol and an aqueous medium such as a mixed solvent thereof and mixed with errotinib or a pharmaceutically acceptable salt thereof and other additives. Further, after mixing erlotinib or a pharmaceutically acceptable salt thereof and other additives, the amino group-modified polymer additive may be dissolved in the above aqueous medium and sprayed or the like to form a mixture.
本発明の医薬錠剤の製造方法は、(B)工程(A)で得られた混合物を圧縮成型し錠剤にする工程を含む。本発明は医薬錠剤である。医薬錠剤を得るための本圧縮成型工程は重要である。 The method for producing a pharmaceutical tablet of the present invention includes (B) a step of compression-molding the mixture obtained in step (A) into tablets. The present invention is a pharmaceutical tablet. This compression molding process for obtaining pharmaceutical tablets is important.
本発明の医薬錠剤の製造方法において、医薬錠剤を圧縮成型する前に、造粒化操作を行い、造粒体を調製することが好ましい。造粒体とは、有効成分と種々の添加剤含有する混合物同士が付着して成形された一定の粒子径を有する顆粒状物であり、後の工程において圧縮成型能を向上させるために調製する粒状物である。該造粒体を調製する造粒化操作は、乾式造粒でも湿式造粒でもよい。乾式造粒とは、造粒時に水を添加しない造粒方法であり、湿式造粒とは前記混合物に水、エタノール、メタノール等の有機溶媒及びこれらの混合溶媒等の水性媒体を適当量添加して、混合操作等の機械的圧力を付加して該混合物同士を付着させ、顆粒状物として造粒する操作である。造粒化操作としては、転動造粒法、流動層造粒法、攪拌造粒法、圧縮造粒法等が挙げられる。本発明に係る造粒化操作としては、これらの操作方法から、適宜選択して当該造粒体を調製することができる。
この造粒物を、打錠成型等により錠剤形に成型することにより、医薬錠剤内部である素錠を調製することができる。
In the method for producing a pharmaceutical tablet of the present invention, it is preferable to perform a granulation operation to prepare a granulated product before compression molding the pharmaceutical tablet. The granulated product is a granule having a constant particle size formed by adhering a mixture containing an active ingredient and various additives to each other, and is prepared in order to improve the compression molding ability in a later step. It is a granular material. The granulation operation for preparing the granulated material may be dry granulation or wet granulation. Dry granulation is a granulation method in which water is not added at the time of granulation, and wet granulation is an appropriate amount of an organic solvent such as water, ethanol, methanol or the like and an aqueous medium such as a mixed solvent thereof added to the mixture. Then, a mechanical pressure such as a mixing operation is applied to attach the mixtures to each other, and the mixture is granulated as a granular material. Examples of the granulation operation include a rolling granulation method, a fluidized bed granulation method, a stirring granulation method, and a compression granulation method. As the granulation operation according to the present invention, the granulated product can be prepared by appropriately selecting from these operation methods.
By molding this granulated product into a tablet shape by tableting or the like, an uncoated tablet inside a pharmaceutical tablet can be prepared.
本発明の医薬錠剤の製造方法において、圧縮成型後、素錠をフィルムコーティングする工程を経てもよい。フィルムコーティングを行う場合、前記医薬錠剤外部であるフィルムコート部分は、水又は水と任意の割合で混合し得る有機溶剤を含む水溶性溶剤に前記コーティング剤に用いられる任意の添加剤を溶解し、錠剤内部である素錠が入ったコーティングパンの中へ注入またはスプレーし、錠剤表面に熱風を送り錠剤表面から溶媒を除去乾燥させる方法により、フィルムコーティングを行うことができる。乾燥工程は、室温〜80℃程度で行うことが好ましい。減圧下で行うことで水性溶剤を揮発させて乾燥しても良い。 In the method for producing a pharmaceutical tablet of the present invention, a step of film-coating an uncoated tablet may be performed after compression molding. When film coating is performed, the film-coated portion outside the pharmaceutical tablet is prepared by dissolving any additive used in the coating agent in water or a water-soluble solvent containing an organic solvent that can be mixed with water at an arbitrary ratio. Film coating can be performed by injecting or spraying into a coating pan containing an uncoated tablet inside the tablet, blowing hot air onto the tablet surface to remove the solvent from the tablet surface, and drying the tablet. The drying step is preferably performed at room temperature to about 80 ° C. The aqueous solvent may be volatilized and dried by carrying out under reduced pressure.
本発明の医薬錠剤は、水中での有効成分の初期溶出を抑制した医薬錠剤である。本明細書において、溶出性を評価する溶出試験は、日本薬局方溶出試験第2法(パドル法)による溶出試験である。 The pharmaceutical tablet of the present invention is a pharmaceutical tablet in which the initial elution of the active ingredient in water is suppressed. In the present specification, the dissolution test for evaluating the dissolution property is the dissolution test by the second method (paddle method) of the Japanese Pharmacopoeia dissolution test.
日本薬局方溶出試験第2法(パドル法)による溶出試験法により、本発明の医薬錠剤から有効成分であるエルロチニブ又はその医薬的に許容される塩を試験溶液中へ溶出させ、紫外可視吸光度計もしくは液体クロマトグラフィーを用いて試験液へのエルロチニブの溶出率を評価することで、本発明の医薬錠剤が水中での有効成分の初期溶出を抑え、急激な有効成分の溶出を回避することのできる特性を有する医薬錠剤であることを確認することができる。 The active ingredient errotinib or a pharmaceutically acceptable salt thereof is eluted from the pharmaceutical tablet of the present invention into the test solution by the dissolution test method according to the second method (paddle method) of the Japanese Pharmacopoeia dissolution test, and an ultraviolet visible absorptiometer is used. Alternatively, by evaluating the elution rate of erlotinib into the test solution using liquid chromatography, the pharmaceutical tablet of the present invention can suppress the initial elution of the active ingredient in water and avoid the rapid elution of the active ingredient. It can be confirmed that it is a pharmaceutical tablet having characteristics.
本発明の医薬錠剤は、水中での有効成分の初期溶出を抑制した医薬錠剤である。より具体的には、日本薬局方溶出試験第2法(パドル法)による溶出試験において、試験溶液が900mLの水である時、試験開始から15分で70%以下の溶出率であり、より好ましくは5分で35%以下、且つ15分で60%以下の溶出率である。 The pharmaceutical tablet of the present invention is a pharmaceutical tablet in which the initial elution of the active ingredient in water is suppressed. More specifically, in the dissolution test by the second method (paddle method) of the Japanese Pharmacopoeia dissolution test, when the test solution is 900 mL of water, the dissolution rate is 70% or less within 15 minutes from the start of the test, which is more preferable. Has an elution rate of 35% or less in 5 minutes and 60% or less in 15 minutes.
また、本発明の医薬錠剤は、溶出性試験を1%SLS(ラウリル硫酸ナトリウム)を含む0.1M塩酸水溶液試験溶液で試験した時、試験開始から15分で60%以上の溶出率であり、より好ましくは70%以上90%以下の溶出率である。 Further, the pharmaceutical tablet of the present invention has an dissolution rate of 60% or more within 15 minutes from the start of the test when the dissolution test is performed with a 0.1 M hydrochloric acid aqueous solution test solution containing 1% SLS (sodium lauryl sulfate). More preferably, the elution rate is 70% or more and 90% or less.
本発明の医薬錠剤を用いた医薬品の用途は、エルロチニブにより治療効果を奏する疾病であれば特に限定されるものではない。例えば、悪性腫瘍の治療に適用することができる。より具体的には、非小細胞肺癌、膵癌、グリオーマ、結腸直腸癌、乳癌、卵巣癌、肝細胞癌、腎癌、頭頸部癌、骨髄異形成症候群、食道癌、を挙げることができる。これらの疾患に限定されるものではないが、適用する好ましい疾患として挙げることができる。 The use of the pharmaceutical product using the pharmaceutical tablet of the present invention is not particularly limited as long as it is a disease for which erlotinib has a therapeutic effect. For example, it can be applied to the treatment of malignant tumors. More specifically, non-small cell lung cancer, pancreatic cancer, glioma, colorectal cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, renal cancer, head and neck cancer, myelodysplastic syndrome, and esophageal cancer can be mentioned. Although not limited to these diseases, it can be mentioned as a preferable disease to be applied.
本発明の医薬製剤を用いた医薬品の投与量は、患者の性別、年齢、生理的状態、病態等により当然変更されうるが、例えば成人1日当たり、エルロチニブとして10mg〜1gの範囲の薬剤を投与する。この投与量に限定されるものではないが、適用する好ましい投与量として挙げることができる。 The dose of the drug using the pharmaceutical preparation of the present invention can be naturally changed depending on the gender, age, physiological condition, pathological condition, etc. of the patient, but for example, a drug in the range of 10 mg to 1 g as erlotinib is administered per day for an adult. .. Although not limited to this dose, it can be mentioned as a preferred dose to be applied.
以下、本発明を実施例により更に説明する。ただし、本発明がこれらの実施例に限定されるものではない。 Hereinafter, the present invention will be further described with reference to Examples. However, the present invention is not limited to these examples.
[実施例1]オイドラギット(登録商標)EPO添加錠剤の調製
エルロチニブ塩酸塩(A型結晶)365g、乳糖水和物(フロイント産業社製)230g、結晶セルロース(旭化成ケミカルズ株式会社製)290g、オイドラギット(登録商標)EPO(エボニック社製)5g、デンプングリコール酸ナトリウム(JRSファルマ社製)80g、ラウリル硫酸ナトリウム(国産化学社製)10gを混合した後、圧縮造粒法で造粒を行った。造粒した顆粒にステアリン酸マグネシウム(日本薬局方 ステアリン酸マグネシウム)20gを混和し、打錠用粉末を得た。
この打錠用粉末を打錠機にて錠剤径10.5mm、錠剤曲率12.0mm、厚み約5.10mm、質量約450mg、硬度60N以上のエルロチニブ塩酸塩の錠剤を製造した。
表1に実施例1の錠剤の調製の処方をまとめた。
This tableting powder was used in a tableting machine to produce tablets of erlotinib hydrochloride having a tablet diameter of 10.5 mm, a tablet curvature of 12.0 mm, a thickness of about 5.10 mm, a mass of about 450 mg, and a hardness of 60 N or more.
Table 1 summarizes the formulation of the tablet preparation of Example 1.
[実施例2]オイドラギット(登録商標)EPO添加錠剤の調製
エルロチニブ塩酸塩(A型結晶)365g、乳糖水和物(フロイント産業社製)230g、結晶セルロース(旭化成ケミカルズ株式会社製)288g、オイドラギット(登録商標)EPO(エボニック社製)7g、デンプングリコール酸ナトリウム(JRSファルマ社製)80g、ラウリル硫酸ナトリウム(国産化学社製)10gを混合した後、圧縮造粒法で造粒を行った。造粒した顆粒にステアリン酸マグネシウム(日本薬局方 ステアリン酸マグネシウム)20gを混和し、打錠用粉末を得た。
この打錠用粉末を打錠機にて錠剤径10.5mm、錠剤曲率12.0mm、厚み約5.10mm、質量約450mg、硬度60N以上のエルロチニブ塩酸塩の錠剤を製造した。
表2に実施例2の錠剤の調製の処方をまとめた。
This tableting powder was used in a tableting machine to produce tablets of erlotinib hydrochloride having a tablet diameter of 10.5 mm, a tablet curvature of 12.0 mm, a thickness of about 5.10 mm, a mass of about 450 mg, and a hardness of 60 N or more.
Table 2 summarizes the formulation of the tablet preparation of Example 2.
[実施例3]オイドラギット(登録商標)EPO添加錠剤の調製
エルロチニブ塩酸塩(A型結晶)365g、乳糖水和物(フロイント産業社製)230g、結晶セルロース(旭化成ケミカルズ株式会社製)279g、オイドラギット(登録商標)EPO(エボニック社製)16g、デンプングリコール酸ナトリウム(JRSファルマ社製)80g、ラウリル硫酸ナトリウム(国産化学社製)10gを混合した後、圧縮造粒法で造粒を行った。造粒した顆粒にステアリン酸マグネシウム(日本薬局方 ステアリン酸マグネシウム)20gを混和し、打錠用粉末を得た。
この打錠用粉末を打錠機にて錠剤径10.5mm、錠剤曲率12.0mm、厚み約5.10mm、質量約450mg、硬度60N以上のエルロチニブ塩酸塩の錠剤を製造した。
表3に実施例3の錠剤の調製の処方をまとめた。
This tableting powder was used in a tableting machine to produce tablets of erlotinib hydrochloride having a tablet diameter of 10.5 mm, a tablet curvature of 12.0 mm, a thickness of about 5.10 mm, a mass of about 450 mg, and a hardness of 60 N or more.
Table 3 summarizes the formulation of the tablet preparation of Example 3.
[比較例1]オイドラギット(登録商標)EPO無添加錠剤の調製
エルロチニブ塩酸塩(A型結晶)365g、乳糖水和物(フロイント産業社製)230g、結晶セルロース(旭化成ケミカルズ株式会社製)295g、デンプングリコール酸ナトリウム(JRSファルマ社製)80g、ラウリル硫酸ナトリウム(国産化学社製)10gを混合した後、圧縮造粒法で造粒を行った。造粒した顆粒にステアリン酸マグネシウム(日本薬局方 ステアリン酸マグネシウム)20gを混和し、打錠用粉末を得た。
この打錠用粉末を打錠機にて錠剤径10.5mm、錠剤曲率12.0mm、厚み約5.10mm、質量約450mg、硬度60N以上のエルロチニブ塩酸塩の錠剤を製造した。
表4に比較例1の錠剤の調製の処方をまとめた。
This tableting powder was used in a tableting machine to produce tablets of erlotinib hydrochloride having a tablet diameter of 10.5 mm, a tablet curvature of 12.0 mm, a thickness of about 5.10 mm, a mass of about 450 mg, and a hardness of 60 N or more.
Table 4 summarizes the formulations for preparing tablets of Comparative Example 1.
[比較例2]オイドラギット(登録商標)EPO無添加錠剤の調製
エルロチニブ塩酸塩(A型結晶)365g、乳糖水和物(フロイント産業社製)230g、結晶セルロース(旭化成ケミカルズ株式会社製)295g、クロスカルメロースナトリウム(伏見製薬社製)80g、ラウリル硫酸ナトリウム(国産化学社製)10gを混合した後、圧縮造粒法で造粒を行った。造粒した顆粒にステアリン酸マグネシウム(日本薬局方 ステアリン酸マグネシウム)20gを混和し、打錠用粉末を得た。
この打錠用粉末を打錠機にて錠剤径10.5mm、錠剤曲率12.0mm、厚み約5.10mm、質量約450mg、硬度60N以上のエルロチニブ塩酸塩の錠剤を製造した。
表5に比較例2の錠剤の調製の処方をまとめた。
This tableting powder was used in a tableting machine to produce tablets of erlotinib hydrochloride having a tablet diameter of 10.5 mm, a tablet curvature of 12.0 mm, a thickness of about 5.10 mm, a mass of about 450 mg, and a hardness of 60 N or more.
Table 5 summarizes the formulations for preparing tablets of Comparative Example 2.
[比較例3]オイドラギット(登録商標)EPO無添加錠剤の調製
エルロチニブ塩酸塩(A型結晶)365g、乳糖水和物(フロイント産業社製)230g、結晶セルロース(旭化成ケミカルズ株式会社製)295g、クロスポビドン(BASF社製)80g、ラウリル硫酸ナトリウム(国産化学社製)10gを混合した後、圧縮造粒法で造粒を行った。造粒した顆粒にステアリン酸マグネシウム(日本薬局方 ステアリン酸マグネシウム)20gを混和し、打錠用粉末を得た。
この打錠用粉末を打錠機にて錠剤径10.5mm、錠剤曲率12.0mm、厚み約5.10mm、質量約450mg、硬度60N以上のエルロチニブ塩酸塩の錠剤を製造した。
表6に比較例3の錠剤の調製の処方をまとめた。
This tableting powder was used in a tableting machine to produce tablets of erlotinib hydrochloride having a tablet diameter of 10.5 mm, a tablet curvature of 12.0 mm, a thickness of about 5.10 mm, a mass of about 450 mg, and a hardness of 60 N or more.
Table 6 summarizes the formulations for preparing tablets of Comparative Example 3.
[試験例1]溶出試験
実施例1〜実施例3及び比較例1〜比較例3で得られた錠剤を、日本薬局方に記載される方法で調製した水の試験溶液を用いて、日本薬局方溶出試験第2法(パドル法)により溶出率を評価した。
溶出試験条件詳細は以下のように設定した。
・溶出試験器 :NTR−6200A、富山産業株式会社製
・試験液量 :900mL
・試験液温 :37±0.5℃
・パドル回転数:100rpm
・分析機器 :紫外可視分光度計(UV−1700、島津製作所製)
・測定波長 :250nm
定量分析用の標準溶液試料として、試験溶液である水を使用してエルロチニブ塩酸塩溶液を任意の濃度で調製し、波長250nmでの吸光度を測定、これを試験溶液における標準値とした。溶出試験においては、各経時点の溶液の吸光度を測定することで、各経時点における溶液中のエルロチニブ塩酸塩濃度を計算し溶出率を算出した。得られた結果を表5に示す。
The details of the dissolution test conditions were set as follows.
・ Dissolution tester: NTR-6200A, manufactured by Toyama Sangyo Co., Ltd. ・ Test solution volume: 900 mL
・ Test solution temperature: 37 ± 0.5 ° C
・ Paddle rotation speed: 100 rpm
・ Analytical equipment: Ultraviolet-visible spectrometer (UV-1700, manufactured by Shimadzu Corporation)
-Measurement wavelength: 250 nm
As a standard solution sample for quantitative analysis, an errotinib hydrochloride solution was prepared at an arbitrary concentration using water as a test solution, and the absorbance at a wavelength of 250 nm was measured, and this was used as a standard value in the test solution. In the dissolution test, the absorbance of the solution at each time point was measured to calculate the concentration of erlotinib hydrochloride in the solution at each time point and the elution rate was calculated. The results obtained are shown in Table 5.
表5の結果より、水試験液において実施例1〜実施例3の錠剤は比較例1の錠剤と比較して溶出試験開始から30分後のエルロチニブ塩酸塩の溶出率が大きく異なることが分かった。実施例1〜実施例3の錠剤は水中での初期溶出を抑え有効成分であるエルロチニブ塩酸塩を溶出させることができる。これに対し、比較例1の錠剤は溶出試験開始直後より有効成分が急激に溶出し、水中での初期溶出の抑制を実現できない。従って、オイドラギット(登録商標)EPOを錠剤内に添加することで、錠剤に顕著な水中での初期溶出の抑制をもたらすことができることが確認された。
また、デンプングリコール酸ナトリウムを用いた比較例1とクロスカルメロースナトリウムを用いた比較例2及びクロスポビドンを用いた比較例3を比較し、溶出の傾向に違い見られなかった。よって、膨脹型崩壊剤の種類を変えても、膨張型崩壊剤を導水型崩壊剤に変えても、オイドラギットEPO無添加の条件下では錠剤への水中での初期溶出の抑制を付与できないことが示唆された。
From the results in Table 5, it was found that in the aqueous test solution, the tablets of Examples 1 to 3 had a significantly different dissolution rate of erlotinib hydrochloride 30 minutes after the start of the dissolution test as compared with the tablets of Comparative Example 1. .. The tablets of Examples 1 to 3 can suppress the initial elution in water and elute the active ingredient erlotinib hydrochloride. On the other hand, in the tablet of Comparative Example 1, the active ingredient elutes rapidly immediately after the start of the elution test, and it is not possible to suppress the initial elution in water. Therefore, it was confirmed that the addition of Eudragit® EPO into tablets can bring about significant suppression of initial elution in water.
Further, Comparative Example 1 using sodium starch glycolate, Comparative Example 2 using croscarmellose sodium, and Comparative Example 3 using crospovidone were compared, and no difference was observed in the tendency of elution. Therefore, even if the type of swelling disintegrant is changed or the swelling disintegrant is changed to a water-conducting disintegrant, it is not possible to suppress the initial elution into tablets under the condition that Eudragit EPO is not added. It was suggested.
Claims (4)
前記アミノ基修飾高分子添加剤が、アミノアルキルメタクリレートコポリマーE、ポリビニルアセタールジエチルアミノアセテート、及びアンモニオアルキルメタクリレートコポリマーからなる群より選択される1種類以上であり、
前記アミノ基修飾高分子添加剤が医薬錠剤内部に分散している、
医薬錠剤。 A pharmaceutical tablet containing erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient, which contains an amino group-modified polymer additive and contains an amino group-modified polymer additive.
The amino group-modified polymer additive is one or more selected from the group consisting of the aminoalkyl methacrylate copolymer E, the polyvinyl acetal diethyl aminoacetate, and the ammonioalkyl methacrylate copolymer.
The amino group-modified polymer additive is dispersed inside the pharmaceutical tablet.
Pharmaceutical tablets.
前記アミノ基修飾高分子添加剤が、アミノアルキルメタクリレートコポリマーE、ポリビニルアセタールジエチルアミノアセテート、及びアンモニオアルキルメタクリレートコポリマーからなる群より選択される1種類以上である、
医薬錠剤の製造方法。
A method for producing a pharmaceutical tablet containing erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient, in which (A) erlotinib or a pharmaceutically acceptable salt thereof, an amino group-modified polymer additive and other additives are mixed. Including the step of compression molding the mixture obtained in the step (B) and the step (A) into tablets.
The amino group-modified polymer additive is one or more selected from the group consisting of the aminoalkyl methacrylate copolymer E, the polyvinyl acetal diethyl aminoacetate, and the ammonioalkyl methacrylate copolymer.
Method for manufacturing pharmaceutical tablets.
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