JP2018030810A - Method for producing pharmaceutical tablet comprising gefitinib as active ingredient - Google Patents
Method for producing pharmaceutical tablet comprising gefitinib as active ingredient Download PDFInfo
- Publication number
- JP2018030810A JP2018030810A JP2016164220A JP2016164220A JP2018030810A JP 2018030810 A JP2018030810 A JP 2018030810A JP 2016164220 A JP2016164220 A JP 2016164220A JP 2016164220 A JP2016164220 A JP 2016164220A JP 2018030810 A JP2018030810 A JP 2018030810A
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical tablet
- gefitinib
- tablet
- binder
- mass
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 239000005411 L01XE02 - Gefitinib Substances 0.000 title claims abstract description 77
- 229960002584 gefitinib Drugs 0.000 title claims abstract description 73
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Abstract
Description
本発明は、ゲフィチニブを有効成分として含有する医薬錠剤の製造方法に関する。 The present invention relates to a method for producing a pharmaceutical tablet containing gefitinib as an active ingredient.
ゲフィチニブは、化学名をＮ−（３−クロロ−４−フルオロフェニル）−７−メトキシ−６−［３−（モルフォリン−４−イル）プロポキシ］キナゾリン−４−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。
ゲフィチニブは水にほとんど溶解しない物性（１ｇを溶解するために＞１００，０００ｍＬを要する。（２０±５℃））である。一方、ゲフィチニブは弱塩基性化合物であり、水に対する溶解度はｐＨに大きく依存する。すなわち、ｐＨ１では可溶性（１ｇを溶解するために１０〜３０ｍＬの水性溶媒を要する。）であるが、ｐＨ４〜６で溶解度は大きく低下し、ｐＨ６では溶解度が１ｍｇ／ｍＬ程度に低下し、ｐＨ７では実質的に不溶性である。
ゲフィチニブのｐＨ依存的な水溶解性は、経口投与した際の有効成分の溶出性や吸収性に大きく影響する。すなわち、ゲフィチニブを有効成分とする医薬製剤を経口投与すると、酸性環境であるｐＨ１〜４の胃内では良好な水溶解度を有していることから、ゲフィチニブは溶液状態を取り得て、該医薬製剤から十分な溶出がなされ、ゲフィチニブも溶液状態で存在するものと考えられる。しかしながら、経口投与による薬剤が最も吸収される部位として考えられる小腸はｐＨ４〜８である。小腸内環境下では、ゲフィチニブは水溶解度が極端に低下するため溶液状態を取り得ることができず、製剤からの溶出性が低下する懸念がある。また、製剤から放出されたゲフィチニブは固体状態となり消化管吸収ができなくなってしまう懸念がある。その結果、有効成分のバイオアベイラビリティが低下して、薬物動態が大きく変化してしまう問題がある。このため、ゲフィチニブを有効成分とする医薬製剤は、経口投与の消化器経路におけるｐＨ変動域に亘り、製剤からの溶出性の変化がほとんど無いことが重要である。
Gefitinib is a physical property that hardly dissolves in water (> 100,000 mL is required to dissolve 1 g (20 ± 5 ° C.)). On the other hand, gefitinib is a weakly basic compound, and its solubility in water greatly depends on pH. That is, it is soluble at pH 1 (10-30 mL of aqueous solvent is required to dissolve 1 g), but the solubility is greatly reduced at pH 4-6, the solubility is reduced to about 1 mg / mL at pH 6, and at pH 7 It is substantially insoluble.
The pH-dependent water solubility of gefitinib greatly affects the dissolution and absorption of the active ingredient when administered orally. That is, when a pharmaceutical preparation containing gefitinib as an active ingredient is orally administered, it has good water solubility in the stomach of pH 1 to 4 which is an acidic environment. Therefore, gefitinib can take a solution state, and from the pharmaceutical preparation Sufficient elution is achieved and gefitinib is also considered to exist in solution. However, the small intestine, which is considered as the most absorbed site for drugs by oral administration, has a pH of 4-8. In the small intestine environment, gefitinib is extremely low in water solubility, so it cannot take a solution state, and there is a concern that the dissolution property from the preparation may be reduced. Moreover, there is a concern that gefitinib released from the preparation becomes solid and cannot be absorbed in the digestive tract. As a result, there is a problem that the bioavailability of the active ingredient is lowered and the pharmacokinetics are greatly changed. For this reason, it is important that a pharmaceutical preparation containing gefitinib as an active ingredient has almost no change in dissolution from the preparation over the pH fluctuation range in the digestive route for oral administration.
ゲフィチニブの医薬錠剤製造方法が特許文献１の実施例に開示されている。結合剤の水溶液を添加する湿式顆粒化、圧縮およびフィルムコーティング工程によりゲフィチニブの医薬錠剤が製造できることが記載されている。 A method for producing a pharmaceutical tablet of gefitinib is disclosed in the example of Patent Document 1. It is described that a pharmaceutical tablet of gefitinib can be produced by wet granulation, compression and film coating processes to which an aqueous solution of binder is added.
本発明の目的は、ゲフィチニブを有効成分とする医薬組成物であって、中性域でも溶出性に変化がない医薬錠剤の製造方法であり、含量均一性を保つことができる医薬錠剤の製造方法を提供することを課題とする。 The object of the present invention is a pharmaceutical composition comprising gefitinib as an active ingredient and having no change in dissolution even in the neutral range, and a method for producing a pharmaceutical tablet capable of maintaining content uniformity It is an issue to provide.
本発明者は、有効成分としてゲフィチニブを用い、ゲフィチニブと固体状の結合剤を混合する第１工程、水性媒体を添加して造粒体を調製する第２工程、造粒体を圧縮して医薬錠剤を得る第３工程を包含する製造方法とすることで、中性域でも溶出に変化がない医薬錠剤を製造でき、さらに含量均一性を保つことができる医薬錠剤の製造方法を提供できることを見出し、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。 The present inventor uses gefitinib as an active ingredient, the first step of mixing gefitinib and a solid binder, the second step of adding an aqueous medium to prepare a granule, and compressing the granule to produce a pharmaceutical It has been found that a production method including a third step for obtaining a tablet can produce a pharmaceutical tablet that does not change in dissolution even in the neutral range, and can provide a method for producing a pharmaceutical tablet that can maintain content uniformity. The present invention has been completed. That is, the gist of the present invention is the following [1] to [6].
［１］ ゲフィチニブを有効成分とする医薬錠剤の製造方法であって、
（１）ゲフィチニブと固体状の結合剤を混合する第１工程、
（２）水性媒体を添加して造粒体を調製する第２工程、
（３）造粒体を圧縮して医薬錠剤を得る第３工程、を包含する、医薬錠剤の製造方法。
［２］ 結合剤がカルボキシビニルポリマー、ポリビニルピロリドン、酢酸ビニル−ビニルピロリドン共重合体、アミノアルキルメタクリレート共重合体、アンモニオアルキルメタクリレート共重合体、ポリビニルアルコール−アクリル酸−メタクリル酸メチル共重合物、ポリアクリル酸部分中和物及びポリビニルアルコールからなる群から選択される１種以上である、［１］に記載の医薬錠剤の製造方法。
［３］ 第２工程の水性媒体は、界面活性剤を含有する、［１］又は［２］に記載の医薬錠剤の製造方法。
［４］ 医薬錠剤全体における結合剤の含有率が２．５質量％以上３０質量％以下である、［１］〜［３］の何れか一項に記載の医薬錠剤の製造方法。
［５］ 医薬錠剤全体におけるゲフィチニブの含有率が５０質量％以上である、［１］〜［４］の何れか一項に記載の医薬錠剤の製造方法。
［６］ 第１工程は、崩壊剤も合わせて混合する工程であって、結合剤及び崩壊剤の含有量質量比率が、１〜５：１である、［１］〜［５］の何れか一項に記載の医薬錠剤の製造方法。
本発明の医薬錠剤の製造方法は、ゲフィチニブと固体状の結合剤を混合する第１工程を含むことを特徴とする。
[1] A method for producing a pharmaceutical tablet comprising gefitinib as an active ingredient,
(1) a first step of mixing gefitinib and a solid binder,
(2) a second step of preparing a granulated body by adding an aqueous medium,
(3) A method for producing a pharmaceutical tablet, comprising a third step of compressing the granulated body to obtain a pharmaceutical tablet.
[2] The binder is carboxyvinyl polymer, polyvinyl pyrrolidone, vinyl acetate-vinyl pyrrolidone copolymer, aminoalkyl methacrylate copolymer, ammonio alkyl methacrylate copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, The method for producing a pharmaceutical tablet according to [1], which is at least one selected from the group consisting of a partially neutralized polyacrylic acid and polyvinyl alcohol.
[3] The method for producing a pharmaceutical tablet according to [1] or [2], wherein the aqueous medium in the second step contains a surfactant.
[4] The method for producing a pharmaceutical tablet according to any one of [1] to [3], wherein the content of the binder in the entire pharmaceutical tablet is 2.5% by mass or more and 30% by mass or less.
[5] The method for producing a pharmaceutical tablet according to any one of [1] to [4], wherein the content of gefitinib in the whole pharmaceutical tablet is 50% by mass or more.
[6] The first step is a step in which the disintegrant is also mixed and the content mass ratio of the binder and disintegrant is 1 to 5: 1, and any one of [1] to [5] A method for producing a pharmaceutical tablet according to one item.
The manufacturing method of the pharmaceutical tablet of this invention is characterized by including the 1st process of mixing a gefitinib and a solid binder.
本発明のゲフィチニブを有効成分とする医薬錠剤の製造方法は、ゲフィチニブを有効成分とする医薬組成物であって、中性域でも溶出性に変化がない医薬錠剤の製造方法であり、含量均一性を保つことができる医薬錠剤の製造方法を提供することができる。 The method for producing a pharmaceutical tablet comprising gefitinib of the present invention as an active ingredient is a pharmaceutical composition comprising gefitinib as an active ingredient, which is a method for producing a pharmaceutical tablet having no change in elution even in the neutral range, and content uniformity Can be provided.
本発明は、有効成分としてゲフィチニブを用い、ゲフィチニブと固体状の結合剤を混合する第１工程、水性媒体を添加して造粒体を調製する第２工程、造粒体を圧縮して医薬錠剤を得る第３工程を包含する医薬錠剤の製造方法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 uses gefitinib as an active ingredient, a first step of mixing gefitinib and a solid binder, a second step of adding an aqueous medium to prepare a granule, and compressing the granule to produce a pharmaceutical tablet It is the manufacturing method of the pharmaceutical tablet including the 3rd process of obtaining. The details will be described below.
本発明は、有効成分としてゲフィチニブ又はその医薬的に許容な塩である薬剤を用いる。ゲフィチニブは、化学名をＮ−（３−クロロ−４−フルオロフェニル）−７−メトキシ−６−［３−（モルフォリン−４−イル）プロポキシ］キナゾリン−４−アミンである。当該化合物は、特表平１１−５０４０３３号公報にて開示されており、それに記載の方法により合成することができる。
ゲフィチニブは、弱塩基性化合物であることから、適当な酸との酸付加塩の態様であっても良い。例えば、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、メタンスルホン酸又は４−トルエンスルホン酸とのモノ−又はジ−酸付加塩を用いても良い。
ゲフィチニブは医薬品の有効成分として用いることができる品質レベルの化合物を用いることが望ましい。本発明において、有効成分であるゲフィチニブは酸付加塩ではなく遊離塩基体のゲフィチニブを用いることが好ましい。
The present invention uses a drug that is gefitinib or a pharmaceutically acceptable salt thereof as an active ingredient. Gefitinib has the chemical name N- (3-chloro-4-fluorophenyl) -7-methoxy-6- [3- (morpholin-4-yl) propoxy] quinazolin-4-amine. This compound is disclosed in JP-T-11-504033 and can be synthesized by the method described therein.
Since gefitinib is a weakly basic compound, it may be in the form of an acid addition salt with an appropriate acid. For example, using mono- or di-acid addition salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, maleic acid, tartaric acid, fumaric acid, methanesulfonic acid or 4-toluenesulfonic acid May be.
Gefitinib is desirably a compound of a quality level that can be used as an active ingredient of a pharmaceutical product. In the present invention, gefitinib which is an active ingredient is preferably a free base gefitinib rather than an acid addition salt.
本発明の医薬錠剤の製造方法は、ゲフィチニブと固体状の結合剤を混合する第１工程を含むことを特徴とする。前記特許文献１では結合剤を溶解させた後、薬剤と混合している。本発明で用いる結合剤は、水性媒体例えば水に溶解すると、粘度が高くなることが考えられる。そのため、秤量した結合剤を水性媒体に溶解すると容器の壁面に付着するなどして、秤量した結合剤全量をゲフィチニブと混合することができないことが懸念される。結合剤はゲフィチニブの溶出性に影響を与え、特に中性域でのゲフィチニブの溶解性に影響を与えることから、秤量した分量全量をゲフィチニブと混合することが望ましい。そのため、秤量した結合剤を全量固体状のままゲフィチニブと混合することができ含量均一性を保つことができるこの第１工程は重要である。 The manufacturing method of the pharmaceutical tablet of this invention is characterized by including the 1st process of mixing a gefitinib and a solid binder. In Patent Document 1, the binder is dissolved and then mixed with the drug. The binder used in the present invention is considered to increase in viscosity when dissolved in an aqueous medium such as water. Therefore, there is a concern that when the weighed binder is dissolved in the aqueous medium, it adheres to the wall surface of the container, and the total amount of the weighed binder cannot be mixed with gefitinib. Since the binder affects the elution of gefitinib, and particularly affects the solubility of gefitinib in the neutral range, it is desirable to mix the total amount weighed with gefitinib. Therefore, this first step, in which the weighed binder can be mixed with gefitinib in the solid state as a whole and the content uniformity can be maintained, is important.
本明細書における中性域とは、ゲフィチニブが最も吸収される部位として考えられる小腸領域環境のｐＨ域のことであり、ｐＨ４〜８の範囲のことである。 The neutral range in this specification is a pH range of the small intestine region environment considered as a site where gefitinib is most absorbed, and is a range of pH 4-8.
本明細書における含量均一性とは、医薬錠剤１錠あたりの有効成分であるゲフィチニブ及び結合剤の各含有量にばらつきがないことである。本発明の製造方法では、ゲフィチニブと結合剤を水性媒体の添加なしに混合することにより、秤量した結合剤全量を薬剤と混合することができる。 The content uniformity in this specification means that there is no variation in the contents of gefitinib, which is an active ingredient per pharmaceutical tablet, and the binder. In the production method of the present invention, gefitinib and the binder can be mixed without adding an aqueous medium, whereby the total amount of the weighed binder can be mixed with the drug.
本発明における結合剤とは、当該医薬錠剤の主要成分であるゲフィチニブ又はその医薬的に許容な塩及びその他の医薬製剤用添加剤を結合して錠剤型として成型してそれを維持させるための機能を有する添加剤である。本発明に用いられる結合剤としては合成高分子系の結合剤が該当し、これらに分類される結合剤が好適に用いられる。合成高分子系の結合剤は、医薬錠剤の成形性を向上させるだけでなく、ゲフィチニブの中性域における水溶性を向上させるための溶解促進剤としても機能することから、極めて重要な添加剤である。
当該結合剤としては、固体状の結合剤であることが好ましく、例えば、カルボキシビニルポリマー、ポリビニルピロリドン（ポビドン）、酢酸ビニル−ビニルピロリドン共重合体、アミノアルキルメタクリレート共重合体、アンモニオアルキルメタクリレート共重合体、ポリビニルアルコール−アクリル酸−メタクリル酸メチル共重合物、ポリアクリル酸部分中和物、ポリビニルアルコール等を挙がることができる。好ましくは、ポリビニルピロリドン、酢酸ビニル−ビニルピロリドン共重合体、ポリビニルアルコール−アクリル酸−メタクリル酸メチル共重合物、ポリビニルアルコールである。これらは単独で用いても良く、２種類以上の混合物として用いても良い。
The binder in the present invention is a function for binding gefitinib, which is the main component of the pharmaceutical tablet, or a pharmaceutically acceptable salt thereof, and other additives for pharmaceutical preparations to form a tablet and maintain it. Is an additive. The binder used in the present invention corresponds to a synthetic polymer binder, and binders classified into these are preferably used. Synthetic polymer binders not only improve the moldability of pharmaceutical tablets, but also function as solubility promoters to improve the water solubility in the neutral region of gefitinib. is there.
The binder is preferably a solid binder, for example, carboxyvinyl polymer, polyvinylpyrrolidone (povidone), vinyl acetate-vinylpyrrolidone copolymer, aminoalkyl methacrylate copolymer, ammonioalkyl methacrylate copolymer. A polymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyacrylic acid partial neutralized product, polyvinyl alcohol and the like can be mentioned. Preferred are polyvinyl pyrrolidone, vinyl acetate-vinyl pyrrolidone copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and polyvinyl alcohol. These may be used alone or as a mixture of two or more.
前記結合剤は、医薬製剤全体における結合剤の含有率が２．５質量％以上３０質量％以下で用いることが望ましい。当該結合剤は、有効成分であるゲフィチニブのｐＨ５〜８における水溶解度を向上させ、当該医薬錠剤の中性域での溶出性を向上させることができることから、積極的に添加することが望ましく、５質量％以上で３０質量％以下の処方であることが好ましい。より好ましくは、５質量％以上で２５質量％以下の処方である。 The binder is preferably used at a binder content of 2.5% by mass to 30% by mass in the entire pharmaceutical preparation. The binder is desirably added positively because it can improve the water solubility of the active ingredient gefitinib at pH 5 to 8 and improve the dissolution in the neutral region of the pharmaceutical tablet. It is preferable that the prescription is not less than 30% by mass and not more than 30% by mass. More preferably, it is 5 mass% or more and 25 mass% or less.
本発明の医薬錠剤の製造方法は、第１工程で得られた混合物に水性媒体を添加して造粒体を調製する第２工程を含む。本発明の水性媒体としては、水を主たる成分とする液体媒体であり、水、又は水と任意の比率で混和し得る有機溶剤と水との混合媒体である。該有機溶剤としては、医薬品製造に許容される有機溶剤であれば特に限定されるものでないが、メタノール、エタノール、１−プロパノール、２−プロパノール等のアルコール性溶媒を挙がることができる。水性媒体の適用量は、第１工程で得られた混合物同士が付着して顆粒状の造粒体を形成し得る量を適宜調整して用いればよい。好ましくは該混合物１００質量部に対して１０〜５００容量部である。より好ましくは１０〜１００容量部である。 The manufacturing method of the pharmaceutical tablet of this invention includes the 2nd process of adding an aqueous medium to the mixture obtained at the 1st process, and preparing a granulated body. The aqueous medium of the present invention is a liquid medium containing water as a main component, and is a mixed medium of water or an organic solvent that can be mixed with water at an arbitrary ratio. Although it will not specifically limit as this organic solvent if it is an organic solvent accept | permitted for pharmaceutical manufacture, Alcoholic solvents, such as methanol, ethanol, 1-propanol, 2-propanol, can be mentioned. The application amount of the aqueous medium may be adjusted as appropriate so that the mixture obtained in the first step adheres to form a granular granule. Preferably it is 10-500 volume parts with respect to 100 mass parts of this mixture. More preferably, it is 10 to 100 parts by volume.
前記水性媒体は、界面活性剤を含有していても良い。本発明において、界面活性剤はゲフィチニブの水溶解性を補助するための可溶化剤として用いる。当該界面活性剤としては、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、これらを単独又は２種以上の混合物として用いても良い。界面活性剤としては、ラウリル硫酸ナトリウムを用いることが好ましい。界面活性剤は医薬錠剤中において、５質量部以下で用いることが好ましい。 The aqueous medium may contain a surfactant. In the present invention, the surfactant is used as a solubilizer for assisting the water solubility of gefitinib. Examples of the surfactant include sodium lauryl sulfate, soybean lecithin, purified soybean lecithin, sorbitan fatty acid ester, lauromacrogol and the like, and these may be used alone or as a mixture of two or more. As the surfactant, sodium lauryl sulfate is preferably used. The surfactant is preferably used at 5 parts by mass or less in the pharmaceutical tablet.
本発明における造粒体とは、ゲフィチニブと固体状の結合剤を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、いわゆる湿式造粒操作であり、前記混合物に前記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。本発明の第２工程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。 The granulated material in the present invention is a granular material having a certain particle diameter formed by adhering a mixture containing gefitinib and a solid binder, and improves compression molding ability in a later step. It is a granular material to be prepared. The granulation operation for preparing the granulated body is a so-called wet granulation operation. An appropriate amount of the aqueous medium is added to the mixture, and mechanical pressure such as a mixing operation is applied to adhere the mixtures to each other. And granulating it as a granular product. Examples of the granulating operation include a rolling granulation method, a fluidized bed granulation method, a stirring granulation method, and a compression granulation method. As granulation operation which concerns on the 2nd process of this invention, it can select suitably from these operation methods, and the said granulated body can be prepared.
前記造粒体は、第３工程で圧縮して医薬錠剤とする前に乾燥工程を経ても良い。第２工程で水性媒体を添加し造粒するため、造粒体は水分を含んでいる。第３工程の圧縮時に造粒体に過剰な水分があると医薬錠剤を再現よく製造できないことが考えられる。乾燥温度は造粒体成分の品質に影響を及ぼさない範囲であれば特に限定されないが、６０℃前後が好ましい。乾燥時間においても、圧縮に支障のない程度に十分に乾燥されれば特に限定されないが、１時間以上乾燥することが望ましい。乾燥方法には、箱型、通気式、流動層方式、真空式等が挙げられるが、通気式もしくは流動層方式が好ましい。 The granulated body may undergo a drying step before being compressed into a pharmaceutical tablet in the third step. Since the aqueous medium is added and granulated in the second step, the granulated body contains moisture. If excessive water is present in the granulated product during the compression in the third step, it is considered that a pharmaceutical tablet cannot be produced with good reproducibility. The drying temperature is not particularly limited as long as it does not affect the quality of the granule components, but is preferably around 60 ° C. The drying time is not particularly limited as long as it is sufficiently dried so as not to hinder the compression, but it is desirable to dry for 1 hour or more. Examples of the drying method include a box type, a ventilation type, a fluidized bed system, and a vacuum type, but a ventilation type or a fluidized bed system is preferable.
本発明の医薬錠剤の製造方法は、第２工程で得られた造粒体を圧縮して医薬錠剤を得る第３工程を含む。圧縮して医薬錠剤を調製する方法としては、通常の医薬錠剤の調製方法である打錠成型方法が用いられる。医薬錠剤の形状としては、特に限定されるものではなく、経口的な服用に適する通常の形状及び大きさの錠剤であって良い。 The manufacturing method of the pharmaceutical tablet of this invention includes the 3rd process which compresses the granulated body obtained at the 2nd process, and obtains a pharmaceutical tablet. As a method for preparing a pharmaceutical tablet by compression, a tableting method, which is an ordinary method for preparing a pharmaceutical tablet, is used. The shape of the pharmaceutical tablet is not particularly limited, and may be a tablet having a normal shape and size suitable for oral administration.
本発明の製造方法により製造される医薬製剤全体におけるゲフィチニブを遊離塩基体含有量として、その含有率が５０質量％以上であることが望ましい。
当該医薬錠剤全体におけるゲフィチニブの含有率は、５０質量部を超え９０質量部以下であることが好ましい。より好ましくは、ゲフィチニブとして５５質量部以上で８５質量部以下であり、６０質量部以上で８０質量部以下であることが特に好ましい。
また、有効成分であるゲフィチニブ又はその医薬的に許容な塩は、当該医薬錠剤の単位製剤当たり、遊離塩基体であるゲフィチニブとして５０ｍｇ〜５００ｍｇ含有することが好ましい。より好ましくは１００ｍｇ〜３００ｍｇであり、１錠当り２５０ｍｇ含有した医薬錠剤とすることが好ましい。
It is desirable that gefitinib in the whole pharmaceutical preparation produced by the production method of the present invention is the free base content, and the content is 50% by mass or more.
The content of gefitinib in the whole pharmaceutical tablet is preferably more than 50 parts by mass and 90 parts by mass or less. More preferably, it is 55 parts by mass or more and 85 parts by mass or less, and particularly preferably 60 parts by mass or more and 80 parts by mass or less as gefitinib.
Moreover, it is preferable to contain 50 mg-500 mg of gefitinib which is an active ingredient, or its pharmaceutically acceptable salt as gefitinib which is a free base per unit formulation of the said pharmaceutical tablet. More preferably, it is 100 mg to 300 mg, and it is preferable to prepare a pharmaceutical tablet containing 250 mg per tablet.
前記第１工程は、崩壊剤も合わせて混合する工程であって、結合剤及び崩壊剤の含有量質量比率が、１〜５：１であることが望ましい。医薬錠剤として、錠剤成形性と即放性を達成するためには、この２種類の添加剤を共存させることが必要であり、結合剤と崩壊剤の処方組成比率を調整することにより、溶出の速度や濃度に関連する崩壊速度を制御することができる。したがって、所望の溶出性を奏功させるために、これらの配合比率を適宜設定することが望ましい。一般的には、崩壊剤の処方量を増やすと即放型錠剤となり、溶出性が速い医薬錠剤が得られる。逆に、崩壊剤よりも結合剤の処方量を多くすると、徐放性の錠剤が得られることになる。しかしながら、本発明にて用いられる合成高分子系の結合剤は、ゲフィチニブの水溶解度向上剤としての機能を有することから、ｐＨ４〜８における溶出性向上に大きく寄与する。このため、本発明の課題解決のためには、当該結合剤を崩壊剤の処方量以上で用いることが好ましい。すなわち、結合剤及び崩壊剤の含有量質量比率が１〜５：１の添加剤処方組成とすることが好ましい。より好ましくは、結合剤と崩壊剤の含量組成比率は１〜３：１の範囲にて用いる処方である。 The first step is a step in which a disintegrant is also mixed and the content mass ratio of the binder and the disintegrant is preferably 1 to 5: 1. In order to achieve tablet formability and immediate release as a pharmaceutical tablet, it is necessary to coexist these two types of additives. By adjusting the composition ratio of the binder and disintegrant, Disintegration rate related to rate and concentration can be controlled. Therefore, in order to achieve the desired dissolution properties, it is desirable to appropriately set these blending ratios. Generally, when the amount of the disintegrant is increased, an immediate-release tablet is obtained, and a pharmaceutical tablet with fast dissolution is obtained. Conversely, if the prescription amount of the binder is larger than that of the disintegrant, a sustained-release tablet can be obtained. However, the synthetic polymer-based binder used in the present invention has a function as a water solubility improver of gefitinib, and thus greatly contributes to the improvement of elution at pH 4-8. For this reason, in order to solve the problems of the present invention, it is preferable to use the binder in an amount more than the prescription amount of the disintegrant. That is, it is preferable to set it as the additive prescription composition whose content mass ratio of a binder and a disintegrant is 1-5: 1. More preferably, the content ratio of the binder to the disintegrant is 1 to 3: 1.
本発明における崩壊剤とは、経口投与された医薬錠剤が胃又は小腸等の消化管内において崩壊させるための機能を有する添加剤である。これらは水分を吸収すると膨潤する物性であるものが用いられる。本発明の医薬錠剤は即放性の錠剤が求められ、例えば、カルボキシメチルスターチナトリウム、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、好適に用いられる。なお、ゲフィチニブの中性領域における水溶解度を考慮するとカルボン酸及び／またはその塩を官能基として有する崩壊剤を用いることが好ましく、カルボキシメチルスターチナトリウム、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ナトリウム、低置換度カルボキシメチルスターチナトリウムを用いることがより好ましい。
本発明の医薬錠剤において、当該崩壊剤の含有量として２質量％以上で３０質量％以下であることが好ましい。２質量％以上で２０質量％以下の処方であることが好ましい。より好ましくは、３質量％以上で１５質量％以下の処方である。
The disintegrant in the present invention is an additive having a function for allowing orally administered pharmaceutical tablets to disintegrate in the digestive tract such as the stomach or the small intestine. Those having physical properties that swell when moisture is absorbed are used. The pharmaceutical tablet of the present invention is required to be an immediate release tablet, for example, sodium carboxymethyl starch, crospovidone, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, low substituted hydroxypropylcellulose, low substituted Carboxymethyl starch sodium and the like are preferably used. In consideration of the water solubility in the neutral region of gefitinib, it is preferable to use a disintegrant having a carboxylic acid and / or a salt thereof as a functional group, such as sodium carboxymethyl starch, carmellose, carmellose sodium, carmellose calcium, croscarmale. It is more preferable to use loose sodium and low-substituted sodium carboxymethyl starch.
In the pharmaceutical tablet of the present invention, the content of the disintegrant is preferably 2% by mass or more and 30% by mass or less. The prescription is preferably 2% by mass or more and 20% by mass or less. More preferably, the formulation is 3% by mass or more and 15% by mass or less.
本発明の製造方法により製造される医薬錠剤は、有効成分としてゲフィチニブ又はその医薬的に許容な塩をゲフィチニブとして５０質量％を超える量で含有し、医薬製剤用添加剤として結合剤、崩壊剤及び可溶化剤としての界面活性剤を含有する以外に、滑沢剤、賦形剤、隠蔽剤や着色剤、コーティング剤等の、医薬製剤を調製するための通常の医薬製剤用添加剤を用いても良い。これらの医薬製剤用添加剤は、前記第１工程もしくは前記第２工程のいずれの工程で添加しても良く、また第３工程の造粒体の圧縮後に錠剤表面に付着させても良い。 The pharmaceutical tablet produced by the production method of the present invention contains gefitinib or a pharmaceutically acceptable salt thereof as an active ingredient in an amount exceeding 50% by mass as gefitinib, and as a pharmaceutical formulation additive, a binder, a disintegrant, and In addition to containing a surfactant as a solubilizing agent, using usual additives for pharmaceutical preparations for preparing pharmaceutical preparations such as lubricants, excipients, hiding agents, coloring agents, coating agents, etc. Also good. These additives for pharmaceutical preparations may be added in either the first step or the second step, and may be adhered to the tablet surface after the granulated product is compressed in the third step.
本明細書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。 In the present specification, examples of the lubricant include stearic acid, magnesium stearate, zinc stearate, aluminum stearate, glyceryl monostearate, sodium stearyl fumarate, calcium stearate, talc, carnauba wax and the like.
本明細書において賦形剤としては、乳糖、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、結晶セルロース、ヒドロキシプロピルメチルセルロース、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。
なお、本発明の製造方法により製造される医薬錠剤は有効成分であるゲフィチニブ又はその塩を５０質量％を超える量で含有し、結合剤を２．５質量％以上で３０質量％以下の処方、及び崩壊剤を２質量％以上で３０質量％以下の処方が好ましいことから、その反面、賦形剤の含有量は低減することになり、該医薬錠剤全体における該賦形剤の含有率が３０質量％以下であることが好ましい。医薬錠剤中のゲフィチニブ又はその塩の含量均一性を確保するため、乳糖等の糖類及び／又は結晶セルロース等のセルロース誘導体を賦形剤として用いることが好ましいが、その含有率は該医薬錠剤全体において、３０質量％以下であることが好ましい。本発明の製造方法により製造される医薬錠剤は、賦形剤含有率を３０質量％以下にすることで、錠剤の小型化を達成することができることから好ましい。
As excipients in this specification, lactose, maltose, mannitol, sucrose, sorbitol, xylitol, inositol, crystalline cellulose, hydroxypropylmethylcellulose, corn starch, partially pregelatinized starch, etc., the above binders, disintegrants, solubilizing agents Additives that do not fall under the category of agents and lubricants are included.
The pharmaceutical tablet produced by the production method of the present invention contains gefitinib or a salt thereof as an active ingredient in an amount exceeding 50% by mass, and a prescription of a binder of 2.5% by mass to 30% by mass, And a disintegrant of 2% by mass or more and 30% by mass or less is preferable. On the other hand, the content of the excipient is reduced, and the content of the excipient in the whole pharmaceutical tablet is 30%. It is preferable that it is below mass%. In order to ensure the uniformity of the content of gefitinib or a salt thereof in the pharmaceutical tablet, it is preferable to use a sugar derivative such as lactose and / or a cellulose derivative such as crystalline cellulose as an excipient, but the content ratio is 30% by mass or less is preferable. The pharmaceutical tablet produced by the production method of the present invention is preferable because the tablet content can be reduced by setting the excipient content to 30% by mass or less.
本明細書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 specification, the masking agent and colorant include titanium oxide, yellow iron oxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, zinc oxide, brown iron oxide, talc, edible yellow pigments, edible blue pigments. And edible red pigments.
本明細書においてコーティング剤としては、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、カルボキシメチルセルロースの水溶性塩等の水溶性セルロースエーテルや、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共重合体、ポリ（ビニルアルコール−（メタ）アクリレート）共重合体、ポリ（（メタ）アクリル酸ジアルキルアミノアルキル−アルキル（メタ）アクリレート）共重合体、ポリビニルアセタールジエチルアミノアセテート等の水溶性共重合体を挙げることができる。コーティング剤には、マクロゴール３００、マクロゴール６０００等のポリエチレングリコール類を可塑剤として共存させて用いても良い。コーティング剤は、即放性を達成するために、胃内溶解性の材料を選択することが好ましい。 In this specification, examples of the coating agent include water-soluble cellulose ethers such as hydroxypropylmethylcellulose, hydroxypropylcellulose, and water-soluble salts of carboxymethylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymers, and poly (vinyl alcohol- (meth) acrylate). ) Copolymers, poly ((meth) acrylic acid dialkylaminoalkyl-alkyl (meth) acrylate) copolymers, and water-soluble copolymers such as polyvinyl acetal diethylaminoacetate. As the coating agent, polyethylene glycols such as Macrogol 300 and Macrogol 6000 may be used together as a plasticizer. As the coating agent, it is preferable to select a gastric soluble material in order to achieve immediate release.
本発明はゲフィチニブを有効成分とする経口投与用の医薬錠剤の製造方法に関する。その製剤型は、裸錠、フィルムコーティング錠、分散錠、口腔内崩壊錠、チュアブル錠、発泡錠等の形態の何れの態様であっても良い。
フィルムコーティング剤を調製する場合は、前記の圧縮成型した医薬錠剤に、コーティング剤及び、任意の可塑剤、隠蔽剤や着色剤を、水又は水と任意の割合で混合し得る有機溶剤を含む水性溶剤にて溶解又は懸濁させたコーティング剤水性溶液を、スプレー等により錠剤表面付着させ、その後、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、調製することができる。
The present invention relates to a method for producing a pharmaceutical tablet for oral administration containing gefitinib as an active ingredient. The dosage form may be any form such as a naked tablet, a film-coated tablet, a dispersible tablet, an orally disintegrating tablet, a chewable tablet, and an effervescent tablet.
In the case of preparing a film coating agent, water or an aqueous solvent containing an organic solvent that can be mixed with the above-mentioned compression-molded pharmaceutical tablet with a coating agent and any plasticizer, hiding agent, or colorant in any proportion with water. The aqueous solution of the coating agent dissolved or suspended in a solvent can be prepared by a method of adhering to the tablet surface by spraying or the like, and then sending hot air to remove the solvent from the tablet surface and drying.
更に、コーティング剤、隠蔽剤や着色剤、分散剤及び可塑剤を含有する水性溶液を前記医薬錠剤表層に付着させて、フィルムコーティング錠を調製しても良い。
フィルムコーティング剤を調製する場合は、内核となる錠剤に被覆するコーティング剤を含有する水性溶液を用いる。これには、コーティング剤を６０〜１００質量部、隠蔽剤及び／又は着色剤を０〜１０質量部、分散剤を０〜１０質量部、可塑剤を０〜２０質量部で含有する処方の組成物を、水又はエタノールやアセトン等の水と任意に混和する有機溶剤を含有する水性溶剤による溶液である。なお、隠蔽剤や着色剤等は当該水性溶液に溶解して用いても、懸濁状態で用いても良いなお、分散剤とは例えばマクロゴールが挙げられる。また、可塑剤とは例えば、グリセリン、プロピレングリコール、分子量３００〜６０００のポリエチレングリコール、ヒマシ油等のトリグリセリド、ジエチルフタレート等を挙がることができる。
フィルムコーティング剤を調製するためには、前記コーティング剤を含有する水性溶液を、前記内核錠の表面に噴霧等の操作により均一に付着させて、これを乾燥することで当該コーティング層を設けることができる。具体的には、内核錠が入ったコーティングパンの中へ、コーティング剤を含有する水性溶液を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、素錠表面に当該コーティング剤を均一に付着させ、その後、乾燥することでコーティング層を設けることができる。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。
Furthermore, a film-coated tablet may be prepared by attaching an aqueous solution containing a coating agent, a hiding agent, a colorant, a dispersant and a plasticizer to the surface of the pharmaceutical tablet.
In the case of preparing a film coating agent, an aqueous solution containing a coating agent that coats the core tablet is used. For this, a composition of a formulation containing 60 to 100 parts by mass of a coating agent, 0 to 10 parts by mass of a concealing agent and / or a colorant, 0 to 10 parts by mass of a dispersant, and 0 to 20 parts by mass of a plasticizer. The solution is an aqueous solvent containing an organic solvent that is arbitrarily mixed with water or water such as ethanol or acetone. In addition, a masking agent, a coloring agent, etc. may be used by dissolving in the aqueous solution, or may be used in a suspended state. Examples of the dispersing agent include macrogol. Examples of the plasticizer include glycerin, propylene glycol, polyethylene glycol having a molecular weight of 300 to 6000, triglycerides such as castor oil, diethyl phthalate, and the like.
In order to prepare a film coating agent, an aqueous solution containing the coating agent is uniformly adhered to the surface of the inner core tablet by an operation such as spraying, and the coating layer is provided by drying the solution. it can. Specifically, an aqueous solution containing a coating agent is poured or sprayed into a coating pan containing an inner core tablet, and hot air is sent to the surface of the tablet to remove the solvent from the tablet surface and dry it. The coating agent can be uniformly deposited and then dried to provide a coating layer. 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.
本発明の製造方法により製造される医薬錠剤は、ゲフィチニブとして５０〜９０質量部、結合剤を２．５〜３０質量部、崩壊剤を２〜２０質量部、可溶化剤である界面活性剤を０〜５質量部、賦形剤を５〜３０質量部で含有する処方による医薬組成物を混合し、水性媒体を添加して湿式造粒を行い、更に任意に滑沢剤を０．１〜５質量部添加して、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。 The pharmaceutical tablet produced by the production method of the present invention comprises 50 to 90 parts by mass as gefitinib, 2.5 to 30 parts by mass of a binder, 2 to 20 parts by mass of a disintegrant, and a surfactant that is a solubilizer. 0 to 5 parts by weight, a pharmaceutical composition with a formulation containing 5 to 30 parts by weight of excipients is mixed, an aqueous medium is added to perform wet granulation, and optionally a lubricant is added to 0.1 to 10 parts by weight. A pharmaceutical tablet can be prepared by adding 5 parts by mass and compressing it.
本発明の製造方法により製造される医薬錠剤のより好ましい態様としては、ゲフィチニブとして５５〜８５質量部、結合剤を５〜３０質量部、崩壊剤を２〜２０質量部、可溶化剤である界面活性剤を０．１〜５質量部、滑沢剤を０．１〜５質量部、賦形剤を５〜２０質量部を含有する処方の錠剤である。これのフィルムコーティング錠であることが更に好ましい。 As a more preferable embodiment of the pharmaceutical tablet produced by the production method of the present invention, 55 to 85 parts by mass as gefitinib, 5 to 30 parts by mass of a binder, 2 to 20 parts by mass of a disintegrant, and an interface that is a solubilizer It is the tablet of the prescription containing 0.1-5 mass parts of active agents, 0.1-5 mass parts of lubricants, and 5-20 mass parts of excipients. More preferably, it is a film-coated tablet.
本発明の製造方法により製造される医薬錠剤は、ゲフィチニブを有効成分とする疾患治療剤として用いることができる。特に適用が可能な疾患としては悪性腫瘍であり、抗腫瘍剤として用いられる。本邦ではゲフィチニブはＥＧＦＲ遺伝子変異陽性の手術不能又は再発非小細胞肺癌に対する治療剤として提供されていることから、同じ疾患治療剤に用いることが好ましい。
本発明の製造方法により製造される医薬錠剤の処方は、経口投与によることが好ましく、１日当り５０ｍｇ〜５００ｍｇ服用することが好ましい。より好ましくは１００ｍｇ〜３００ｍｇであり、２５０ｍｇを服用することが好ましい。
The pharmaceutical tablet produced by the production method of the present invention can be used as a disease therapeutic agent containing gefitinib as an active ingredient. A particularly applicable disease is a malignant tumor, which is used as an antitumor agent. In Japan, gefitinib is provided as a therapeutic agent for EGFR gene mutation-positive inoperable or recurrent non-small cell lung cancer, and thus is preferably used as a therapeutic agent for the same disease.
The prescription of the pharmaceutical tablet produced by the production method of the present invention is preferably by oral administration, and preferably taken from 50 mg to 500 mg per day. More preferably, it is 100 mg-300 mg, and it is preferable to take 250 mg.
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。
［実施例１］
ゲフィチニブ１５０ｇ、乳糖水和物（ダイラクトーズ、フロイント産業株式会社製）２ｇ、結晶セルロース（セオラス、旭化成ケミカルズ株式会社製）１２ｇ、ポビドン（Ｋｏｌｌｉｄｏｎ、ＢＡＳＦ製）２１ｇ、クロスカルメロースナトリウム（Ｐｒｉｍｅｌｌｏｓｅ、ＤＦＥ Ｐｈａｒｍａ製）１２ｇを撹拌造粒機（深江パウテック株式会社：ＬＦＳ−ＧＳ−１Ｊ型）で混合した。
この混合物に、ラウリル硫酸ナトリウム（ラウリル硫酸ナトリウム「製造専用」、国産化学株式会社製）１．２ｇを精製水６０ｍＬに溶解した造粒水を加えて、撹拌造粒機にて造粒を行った。これを６０℃にて６０分間以上乾燥した後、２０メッシュの篩で整粒し、整粒顆粒を得た。整粒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、日油株式会社製）１．８ｇを混合し、打錠用顆粒を得た。
この打錠用顆粒を、打錠機を用いて、錠剤径約９ｍｍ、厚み約５．４ｍｍ、質量約３３５ｍｇ、硬度１００Ｎ以上のゲフィチニブの素錠を製造した。
表１に素錠の調製の処方をまとめた。
The present invention will be further described below with reference to examples. However, the present invention is not limited to these examples.
[Example 1]
Gefitinib 150 g, lactose hydrate (Dilactos, manufactured by Freund Sangyo Co., Ltd.) 2 g, crystalline cellulose (Theolas, manufactured by Asahi Kasei Chemicals Co., Ltd.) 12 g, povidone (Kollidon, manufactured by BASF) 21 g, croscarmellose sodium (Primellose, manufactured by DFE Pharma) ) 12 g was mixed with a stirring granulator (Fukae Pautech Co., Ltd .: LFS-GS-1J type).
To this mixture, granulated water obtained by dissolving 1.2 g of sodium lauryl sulfate (sodium lauryl sulfate “manufactured exclusively”, manufactured by Kokusan Chemical Co., Ltd.) in 60 mL of purified water was added, and granulated with a stirring granulator. . This was dried at 60 ° C. for 60 minutes or more and then sized with a 20 mesh sieve to obtain sized granules. 1.8 g of magnesium stearate (Japanese Pharmacopoeia magnesium stearate, manufactured by NOF Corporation) was mixed with the granulated granules to obtain granules for tableting.
A gefitinib uncoated tablet having a tablet diameter of about 9 mm, a thickness of about 5.4 mm, a mass of about 335 mg, and a hardness of 100 N or more was produced from the granules for tableting using a tableting machine.
Table 1 summarizes the formulation for the preparation of uncoated tablets.
［表１］
［比較例１］
イレッサ（登録商標）錠２５０を６錠準備し、それぞれの錠剤からコーティングフィルムを剥がし、素錠のイレッサ（登録商標）錠２５０を６錠作成した。
[Table 1]
[Comparative Example 1]
Six Iressa (registered trademark) tablets 250 were prepared, and the coating film was peeled off from each tablet to prepare six Iressa (registered trademark) tablets 250 as plain tablets.
［試験例１］溶出性試験
実施例１で得られたゲフィチニブ素錠および比較例１で得たイレッサ（登録商標）錠２５０素錠をそれぞれ６錠ずつ用意し、日本薬局方に記載される方法で調製したｐＨ５．０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：５０ｒｐｍ
分析機器 ：紫外可視分光度計（ＵＶ−１７００、島津製作所製）
測定波長 ：２４７ｎｍ
定量分析用の標準溶液試料として、ｐＨ５溶液を使用してゲフィチニブ溶液を任意の濃度で調製し、波長２４７ｎｍでの吸光度を測定、これを各ｐＨ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ゲフィチニブ濃度を計算し溶出率を算出した。得られた結果を表２に示す。
[Test Example 1] Dissolution Test 6 gefitinib uncoated tablets obtained in Example 1 and Iressa (registered trademark) 250 uncoated tablets obtained in Comparative Example 1 were each prepared 6 tablets, and the method described in the Japanese Pharmacopoeia The elution rate was evaluated by the Japanese Pharmacopoeia dissolution test method 2 (paddle method) using the pH 5.0 test solution prepared in (1). Details of the dissolution test conditions were set as follows.
Dissolution tester: NTR-6200A, manufactured by Toyama Sangyo Co., Ltd. Test volume: 900 mL
Test solution temperature: 37 ± 0.5 ° C
Paddle rotation speed: 50 rpm
Analytical instrument: UV-visible spectrophotometer (UV-1700, manufactured by Shimadzu Corporation)
Measurement wavelength: 247 nm
As a standard solution sample for quantitative analysis, a gefitinib solution was prepared at an arbitrary concentration using a pH 5 solution, and the absorbance at a wavelength of 247 nm was measured. This was used as a standard value for each pH solution. In the dissolution test, the concentration of gefitinib in the solution at each time point was calculated by measuring the absorbance of the solution at each time point, and the dissolution rate was calculated. The obtained results are shown in Table 2.
［表２］
結合剤を造粒水に溶解させて造粒を実施している比較例１に対し、結合剤を粉末の状態で混合し次いで界面活性剤を含んだ水溶液を添加して造粒を実施した実施例１では、中性域であるｐＨ５溶液下において同等の平均溶出率を示した。しかし、比較例１では個々の溶出率にバラつきが見られたのに対し実施例１ではそのバラつきが抑えられ、個々の錠剤における溶出率の均一性が保たれていた。特に錠剤の崩壊性が溶出率に大きく影響を与えるとされる１５分以下の測定点においても、実施例１は溶出率の均一性が確認された。これは、溶出率に影響を与える結合剤を粉末の状態で混合することにより、結合剤と有効成分であるゲフィチニブが均一に混合され、錠剤を製した場合でも錠剤中の各処方成分の含量均一性が保たれたことに起因していると考えられる。
Implementation in which granulation was performed by mixing the binder in a powder state and then adding an aqueous solution containing a surfactant to Comparative Example 1 in which the binder was dissolved in granulated water and granulated. In Example 1, an equivalent average dissolution rate was exhibited in a neutral pH 5 solution. However, in Comparative Example 1, variation in individual dissolution rate was observed, whereas in Example 1, the variation was suppressed, and the uniformity of dissolution rate in individual tablets was maintained. In particular, the uniformity of dissolution rate was confirmed in Example 1 even at measurement points of 15 minutes or less, where disintegration of the tablet greatly affects the dissolution rate. This is because the binder and the active ingredient gefitinib are uniformly mixed by mixing the binder, which affects the dissolution rate, in the powder state, and even when the tablet is manufactured, the content of each prescription ingredient in the tablet is uniform. This is thought to be due to the fact that the sex was maintained.
Claims (6)
（１）ゲフィチニブと固体状の結合剤を混合する第１工程、
（２）水性媒体を添加して造粒体を調製する第２工程、
（３）造粒体を圧縮して医薬錠剤を得る第３工程、を包含する、医薬錠剤の製造方法。 A method for producing a pharmaceutical tablet comprising gefitinib as an active ingredient,
(1) a first step of mixing gefitinib and a solid binder,
(2) a second step of preparing a granulated body by adding an aqueous medium,
(3) A method for producing a pharmaceutical tablet, comprising a third step of compressing the granulated body to obtain a pharmaceutical tablet.
A 1st process is a process which mixes a disintegrating agent together, Comprising: Content mass ratio of a binder and a disintegrating agent is 1-5: 1, It is any one of Claims 1-5. A method for producing a pharmaceutical tablet.
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