JP2007186450A - Paroxetine hydrochloride-containing preparation and method for producing the same - Google Patents
Paroxetine hydrochloride-containing preparation and method for producing the same Download PDFInfo
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Abstract
Description
本発明は、変色を抑えるとともに含量均一性に優れた塩酸パロキセチン含有製剤及びその製造方法に関する。 The present invention relates to a paroxetine hydrochloride-containing preparation that suppresses discoloration and is excellent in content uniformity and a method for producing the same.
塩酸パロキセチンはうつ病・うつ状態、パニック障害に効能、効果を有する薬物として世界中の多くの国で販売されている。
塩酸パロキセチンを含有する製剤は、しばしばピンク色に発色することが認められ、これを防止する方法として特許第３０３７７５７号公報に水の存在しない処方・製法を用いて錠剤化することが開示されている。
これは、塩酸パロキセチンの乾燥直接打錠または塩酸パロキセチンの乾燥造粒後、錠剤に圧縮するものである。
しかしながら、乾燥直接打錠法は、一般的に、薬理活性成分とその他の賦形剤などとの偏析を起こしやすく、錠剤中の薬理活性成分の含量がばらつきやすい欠点を有する。
塩酸パロキセチンは水に溶けにくい性質を有し、適切な溶解性を確保するには粒子径を小さくするなど工夫が必要であり、賦形剤は、打錠工程で適度な流動性を確保するため粒子径の大きいものを選択する必要が生じる。
従って塩酸パロキセチン粒子と賦形剤粒子との粒子径の違いやみかけ比重の違いが要因となり打錠工程で塩酸パロキセチン粒子と賦形剤との偏析が生じやすくなる。
一方、塩酸パロキセチンを乾燥造粒後、錠剤に圧縮する方法は、上記含量均一性を考慮した製法であると思われるが、一般的には、乾燥造粒後は粉砕機を用いた解砕工程、篩を用いた整粒工程が必要となり、工程が煩雑になる。また、打錠工程で錠剤硬度が低くなるなどの欠点を有する。
Paroxetine hydrochloride is marketed in many countries around the world as an effective drug for depression / depressed state and panic disorder.
Preparations containing paroxetine hydrochloride are often observed to develop a pink color, and as a method for preventing this, Japanese Patent No. 3037757 discloses that tablets are prepared using a prescription / production method that does not contain water. .
In this method, dry direct compression of paroxetine hydrochloride or dry granulation of paroxetine hydrochloride is compressed into tablets.
However, the dry direct compression method generally has a drawback that segregation between the pharmacologically active ingredient and other excipients tends to occur, and the content of the pharmacologically active ingredient in the tablet tends to vary.
Paroxetine hydrochloride has the property of being hardly soluble in water, and in order to ensure appropriate solubility, it is necessary to devise measures such as reducing the particle diameter, and the excipient is used to ensure proper fluidity in the tableting process. It is necessary to select one having a large particle size.
Therefore, segregation between paroxetine hydrochloride particles and excipient tends to occur in the tableting process due to differences in particle diameter and apparent specific gravity between paroxetine hydrochloride particles and excipient particles.
On the other hand, the method of compressing paroxetine hydrochloride after dry granulation and then compressing into tablets seems to be a method that takes into account the above content uniformity, but in general, after dry granulation, a crushing step using a pulverizer In addition, a sizing process using a sieve is required, and the process becomes complicated. In addition, there are drawbacks such as tablet hardness being lowered in the tableting process.
本発明は、変色を抑え、煩雑な工程を用いることなく含量均一性に優れた塩酸パロキセチン含有製剤及びその製造方法の提供を目的とする。 An object of the present invention is to provide a paroxetine hydrochloride-containing preparation excellent in content uniformity without suppressing discoloration and using a complicated process, and a method for producing the same.
本発明者らは、従来技術に内在する課題を解決するため鋭意検討したところ、湿式造粒法の際、使用する溶媒をエタノール、またはエタノールと水の混合溶媒を用いることで製造中の変色防止、製剤後の変色防止及び製剤中の塩酸パロキセチン含量均一性が良好な製剤を得ることができることを見出した。
なお、エタノールと水との混合溶媒の場合には、変色を抑える観点から水の量が少ない方がよく理想的には、水の混合割合を５０％以下にするのがよい。
本発明における湿式造粒法とは、溶媒としてエタノール、またはエタノールと水の混合液を用い、塩酸パロキセチンとその他医薬用添加剤を混合した粉体に対して、一括添加やスプレー等の操作で粒状物にするものであり、練合造粒法、押出造粒法、攪拌造粒法、流動層造粒法と称される方法が挙げられる。
塩酸パロキセチンと混合される医薬用添加剤は特に限定されることはなく、目的に応じて配合することができ、例えば、賦形剤、崩壊剤、結合剤、着色剤、甘味剤、界面活性剤などが挙げられる。
賦形剤としては乳糖、Ｄ−マンニトール、トウモロコシデンプンなどのデンプン類、結晶セルロースなどのセルロース類、リン酸水素カルシウムなどが挙げられる。
崩壊剤としてはカルメロース、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、カルボキシメチルスターチナトリウム、低置換度ヒドロキシプロピルセルロース、クロスポビドンなどが挙げられる。
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、メチルセルロース、などが挙げられる。
これら結合剤は塩酸パロキセチンと混合し造粒機内に入れることもできるし、エタノール、またはエタノールと水の混合液中に溶解させ加えることもできる。
湿式造粒法で得られた造粒末は、滑沢剤と混合し散剤や細粒剤の形態にできるし、硬カプセルに充填することでカプセル剤とすることもできる。
また、打錠機を用いて錠剤の形態とすることもできる。
錠剤はそのまま素錠の形態でもよいし、適当なフィルム層を錠剤表面にコーティングすることでフィルムコーティング錠とすることもできる。
望ましい形態はフィルムコーティング錠剤である。フィルムコーティングは通常、錠剤のコーティングに使用されるコーティングパンを用い、具体的にはハイコーター（商品名）、ドリアコーター（商品名）などによりコーティング錠を製造することができる。
コーティング層に用いる成分は特に限定されることはないが、フィルム形成可能な水溶性高分子化合物を含む組成物からなることが好ましい。
水溶性高分子化合物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、メチルセルロース、などが挙げられる。
その他、必要に応じてポリソルベート８０（商品名）、マクロゴール類などのフィルム可塑剤、タルク、酸化チタン、各種着色剤などを配合することも可能である。
湿式造粒法で得られた造粒末は、塩酸パロキセチンと各医薬品添加剤とが、ほぼ均一な状態で存在することから、最終製剤に仕上げた際には、塩酸パロキセチン含有量にばらつきが少ない製剤が得られる。
塩酸パロキセチンは無水物あるいは１／２水和物の形態が知られているが、本発明の塩酸パロキセチンはこれらいずれの形態にも用いることができる。
本発明の方法で製造した塩酸パロキセチン含有製剤、とりわけ錠剤は、４０℃及び７５％相対湿度下に開放状態で保存したとき従来の技術である乾燥直接打錠法で製した錠剤と比較して、錠剤の変色具合に差はなく、同等な保存安定性を保持している。
The present inventors diligently studied to solve the problems inherent in the prior art, and in the case of wet granulation, the use of ethanol or a mixed solvent of ethanol and water prevents the discoloration during production. The present inventors have found that a preparation with good discoloration prevention after preparation and good uniformity of paroxetine hydrochloride content in the preparation can be obtained.
In the case of a mixed solvent of ethanol and water, the amount of water is preferably small from the viewpoint of suppressing discoloration, and ideally the mixing ratio of water is 50% or less.
The wet granulation method in the present invention uses ethanol or a mixed solution of ethanol and water as a solvent, and the powder is a mixture of paroxetine hydrochloride and other pharmaceutical additives. Examples thereof include kneading granulation method, extrusion granulation method, stirring granulation method and fluidized bed granulation method.
The pharmaceutical additive to be mixed with paroxetine hydrochloride is not particularly limited and can be blended according to the purpose. For example, excipient, disintegrant, binder, colorant, sweetener, surfactant Etc.
Examples of excipients include lactose, D-mannitol, starches such as corn starch, celluloses such as crystalline cellulose, and calcium hydrogen phosphate.
Examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, carboxymethyl starch sodium, low-substituted hydroxypropylcellulose, and crospovidone.
Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, and the like.
These binders can be mixed with paroxetine hydrochloride and put in a granulator, or dissolved in ethanol or a mixture of ethanol and water.
The granulated powder obtained by the wet granulation method can be mixed with a lubricant to form a powder or fine granule, or it can be made into a capsule by filling into a hard capsule.
Moreover, it can also be made into the form of a tablet using a tableting machine.
The tablet may be in the form of an uncoated tablet as it is, or may be formed into a film-coated tablet by coating an appropriate film layer on the surface of the tablet.
A desirable form is a film-coated tablet. Film coating usually uses a coating pan used for tablet coating, and specifically, coated tablets can be produced with a high coater (trade name), a doria coater (trade name), or the like.
Although the component used for a coating layer is not specifically limited, It is preferable to consist of a composition containing the water-soluble high molecular compound which can form a film.
Examples of the water-soluble polymer compound include hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, and the like.
In addition, it is also possible to mix | blend polysorbate 80 (brand name), film plasticizers, such as a macrogol, talc, titanium oxide, various coloring agents, etc. as needed.
The granulated powder obtained by the wet granulation method has paroxetine hydrochloride and each pharmaceutical additive in an almost uniform state, so there is little variation in paroxetine hydrochloride content when finished into the final formulation. A formulation is obtained.
Paroxetine hydrochloride is known in anhydrous or hemihydrate forms, but the paroxetine hydrochloride of the present invention can be used in any of these forms.
The paroxetine hydrochloride-containing preparation produced by the method of the present invention, particularly the tablet, compared with the tablet produced by the dry direct compression method which is a conventional technique when stored in an open state at 40 ° C. and 75% relative humidity, There is no difference in the discoloration of tablets, and the same storage stability is maintained.
錠剤の変色の少ない塩酸パロキセチン錠を製造する方法としては乾燥直接打錠法あるいは乾燥造粒後、錠剤に圧縮する方法が公知であったが、湿式造粒法でも造粒溶媒としてエタノール、またはエタノール・水混合溶媒を用いることで公知の方法と同等の変色の少ない錠剤が得られる。
また、本発明の方法で製剤化した錠剤は塩酸パロキセチンの含量バラツキが少なく、品質的に優れた製剤を容易に製造することが可能である。
As a method for producing paroxetine hydrochloride tablets with little discoloration of tablets, a dry direct tableting method or a method of compressing into tablets after dry granulation was known, but ethanol or ethanol as a granulation solvent also in wet granulation method -A tablet with little discoloration equivalent to a known method can be obtained by using a water mixed solvent.
In addition, since the tablet formulated by the method of the present invention has little variation in the content of paroxetine hydrochloride, it is possible to easily produce a formulation excellent in quality.
以下に実施例、比較例を示し本発明を具体的に説明する。 The present invention will be specifically described below with reference to examples and comparative examples.
（素錠の製造）
塩酸パロキセチン無水物４４．４ｇ、リン酸水素カルシウム（商品名リカミットＵ１００）６１５．２ｇ、カルボキシメチルスターチナトリウム３０．０ｇを秤量し、ビニル袋内で混合後流動層造粒機（マルチプレックスＭＰ−０１、株式会社パウレック製）に入れる。
エタノール１４０ｇにヒドロキシプロピルセルロース（ＨＰＣ−Ｌ）７．０ｇを溶解させ、これを噴霧しながら流動層造粒を行う。
造粒品を乾燥したのち２２Ｍ篩で篩過整粒する。
篩過整粒品６２６．９ｇ及びステアリン酸マグネシウム３．０６ｇを秤量しビニル袋内で混合したのち、ロータリー打錠機にて１錠３５０ｍｇの素錠を得た。
（フィルムコーティング錠の製造）
精製水１００ｇにヒドロキシプロピルメチルセルロース２９１０（商品名ＴＣ−５ＲＷ）５ｇ、マクロゴール６０００を０．７ｇ溶解させたのち、さらにタルク０．５ｇ、酸化チタン０．８ｇを添加し、フィルムコーティング溶液を調製した。
素錠１０００錠相当（３５０ｇ）をハイコーターラボ（フロイント産業製）に投入し、フィルムコーティング液を噴霧しフィルムコーティング錠を得た。
(Manufacture of uncoated tablets)
44.4 g of paroxetine hydrochloride anhydrous, 615.2 g of calcium hydrogen phosphate (trade name Ricamit U100) and 30.0 g of sodium carboxymethyl starch were weighed and mixed in a vinyl bag, and then fluidized bed granulator (Multiplex MP-01). , Made by POWREC Co., Ltd.).
7.0 g of hydroxypropyl cellulose (HPC-L) is dissolved in 140 g of ethanol, and fluidized bed granulation is performed while spraying this.
The granulated product is dried and then sieved with a 22M sieve.
626.9 g of the sieved granulated product and 3.06 g of magnesium stearate were weighed and mixed in a vinyl bag, and then a single tablet of 350 mg was obtained with a rotary tableting machine.
(Manufacture of film-coated tablets)
After dissolving 5 g of hydroxypropylmethylcellulose 2910 (trade name TC-5RW) and 0.7 g of Macrogol 6000 in 100 g of purified water, 0.5 g of talc and 0.8 g of titanium oxide were further added to prepare a film coating solution. .
An uncoated tablet equivalent of 1000 tablets (350 g) was put into a high coater lab (manufactured by Freund Corporation), and a film coating solution was sprayed to obtain a film coated tablet.
（素錠の製造）
塩酸パロキセチン無水物４４．４ｇ、リン酸水素カルシウム（商品名リカミットＵ１００）５５５．２ｇ、カルボキシメチルスターチナトリウム３０．０ｇを秤量しビニル袋内で混合後流動層造粒機（マルチプレックスＭＰ−０１、株式会社パウレック製）に入れる。
エタノール７０ｇ、水７０ｇの混合溶媒にヒドロキシプロピルセルロース（ＨＰＣ−Ｌ）７．０ｇを溶解させ、これを噴霧しながら流動層造粒を行う。
造粒品を乾燥したのち２２Ｍ篩で篩過整粒する。
篩過整粒品５７２．９ｇ及びステアリン酸マグネシウム３．０６ｇを秤量しビニル袋内で混合したのち、ロータリー打錠機にて１錠３２０ｍｇの素錠を得た。
（フィルムコーティング錠の製造）
精製水１００ｇにヒドロキシプロピルメチルセルロース２９１０（商品名ＴＣ−５ＲＷ）５ｇ、マクロゴール６０００を０．７ｇ溶解させたのち、さらにタルク０．５ｇ、酸化チタン０．８ｇを添加し、フィルムコーティング溶液を調製した。
素錠１０００錠相当（３２０ｇ）をハイコーターラボに投入し、フィルムコーティング液を噴霧しフィルムコーティング錠を得た。
(Manufacture of uncoated tablets)
44.4 g of paroxetine hydrochloride anhydrous, 555.2 g of calcium hydrogen phosphate (trade name Ricamit U100) and 30.0 g of sodium carboxymethyl starch were weighed and mixed in a vinyl bag and then fluidized bed granulator (Multiplex MP-01, (Made by Paulec Co., Ltd.)
In a mixed solvent of 70 g of ethanol and 70 g of water, 7.0 g of hydroxypropyl cellulose (HPC-L) is dissolved, and fluidized bed granulation is performed while spraying this.
The granulated product is dried and then sieved with a 22M sieve.
A sieved granulated product (572.9 g) and magnesium stearate (3.06 g) were weighed and mixed in a vinyl bag, and then a single tablet (320 mg) was obtained using a rotary tableting machine.
(Manufacture of film-coated tablets)
After dissolving 5 g of hydroxypropylmethylcellulose 2910 (trade name TC-5RW) and 0.7 g of Macrogol 6000 in 100 g of purified water, 0.5 g of talc and 0.8 g of titanium oxide were further added to prepare a film coating solution. .
Uncoated tablets equivalent to 1000 tablets (320 g) were put into a high coater lab, and the film coating solution was sprayed to obtain film coated tablets.
（素錠の製造）
塩酸パロキセチン無水物４４．４ｇ、無水リン酸水素カルシウム５５５．２ｇ、カルボキシメチルスターチナトリウム３０．０ｇ、ヒドロキシプロピルセルロース７．０ｇを攪拌造粒機（バーチカルグラニュレーターＶＧ−０１、株式会社パウレック製）に入れ、攪拌混合する。
エタノール１００ｇを攪拌造粒機内に添加し高速攪拌しながら造粒した。
造粒物は流動層乾燥機で乾燥後、２２Ｍ篩過した。
篩過整粒品５７２．９ｇ及びステアリン酸マグネシウム３．０６ｇを秤量しビニル袋内で混合したのち、ロータリー打錠機にて１錠３２０ｍｇの素錠を得た。
(Manufacture of uncoated tablets)
44.4 g of paroxetine hydrochloride anhydrous, 555.2 g of anhydrous calcium hydrogen phosphate, 30.0 g of sodium carboxymethyl starch, and 7.0 g of hydroxypropyl cellulose were added to a stirring granulator (vertical granulator VG-01, manufactured by POWREC Co., Ltd.). Add and stir to mix.
100 g of ethanol was added to the stirring granulator and granulated while stirring at high speed.
The granulated product was dried with a fluid bed dryer and then passed through 22M sieve.
A sieved granulated product (572.9 g) and magnesium stearate (3.06 g) were weighed and mixed in a vinyl bag, and then a single tablet (320 mg) was obtained using a rotary tableting machine.
（素錠の製造）
塩酸パロキセチン１／２水和物４５．５ｇ、無水リン酸水素カルシウム５５４．１ｇ、カルボキシメチルスターチナトリウム３０．０ｇを秤量しビニル袋内で混合後流動層造粒機（マルチプレックスＭＰ−０１、株式会社パウレック製）に入れる。
エタノール１４０ｇにヒドロキシプロピルセルロース（ＨＰＣ−Ｌ）７．０ｇを溶解させ、これを噴霧しながら流動層造粒を行う。
造粒品を乾燥したのち２２Ｍ篩で篩過整粒する。
篩過整粒品５７２．９ｇ及びステアリン酸マグネシウム３．０６ｇを秤量しビニル袋内で混合したのち、ロータリー打錠機にて１錠３５０ｍｇの素錠を得た。
（フィルムコーティング錠の製造）
精製水１００ｇにヒドロキシプロピルメチルセルロース２９１０（商品名ＴＣ−５ＲＷ）５ｇ、マクロゴール６０００を０．７ｇ溶解させたのち、さらにタルク０．５ｇ、酸化チタン０．８ｇを添加し、フィルムコーティング溶液を調製した。
素錠１０００錠相当（３５０ｇ）をハイコーターラボ（フロイント産業製）に投入し、フィルムコーティング液を噴霧しフィルムコーティング錠を得た。
(Manufacture of uncoated tablets)
Paroxetine hydrochloride hemihydrate 45.5 g, anhydrous calcium hydrogen phosphate 554.1 g, carboxymethyl starch sodium 30.0 g were weighed and mixed in a vinyl bag, and then fluidized bed granulator (Multiplex MP-01, stock Into the company Paulek).
7.0 g of hydroxypropyl cellulose (HPC-L) is dissolved in 140 g of ethanol, and fluidized bed granulation is performed while spraying this.
The granulated product is dried and then sieved with a 22M sieve.
A sieved granulated product (572.9 g) and magnesium stearate (3.06 g) were weighed and mixed in a vinyl bag, and then a single tablet of 350 mg was obtained with a rotary tableting machine.
(Manufacture of film-coated tablets)
After dissolving 5 g of hydroxypropylmethylcellulose 2910 (trade name TC-5RW) and 0.7 g of Macrogol 6000 in 100 g of purified water, 0.5 g of talc and 0.8 g of titanium oxide were further added to prepare a film coating solution. .
An uncoated tablet equivalent of 1000 tablets (350 g) was put into a high coater lab (manufactured by Freund Corporation), and a film coating solution was sprayed to obtain a film coated tablet.
（比較例１）
（素錠の製造）
塩酸パロキセチン無水物４４．４ｇ、リン酸水素カルシウム（商品名リカミットＵ１００）５６２．２ｇ、カルボキシメチルスターチナトリウム３０．０ｇ、を秤量しビニル袋内で混合する。
さらにステアリン酸マグネシウム３．４ｇを秤量し、上記混合物と混合した後、ロータリー打錠機にて１錠３２０ｍｇの素錠を製造した。
（フィルムコーティング錠の製造）
精製水１００ｇにヒドロキシプロピルメチルセルロース２９１０（商品名ＴＣ−５ＲＷ）５ｇ、マクロゴール６０００を０．７ｇ溶解させたのち、さらにタルク０．５ｇ、酸化チタン０．８ｇを添加し、フィルムコーティング溶液を調製した。
素錠１０００錠相当（３２０ｇ）をハイコーターラボ（フロイント産業製）に投入し、フィルムコーティング液を噴霧しフィルムコーティング錠を得た。
(Comparative Example 1)
(Manufacture of uncoated tablets)
44.4 g of paroxetine hydrochloride anhydrous, 562.2 g of calcium hydrogen phosphate (trade name Ricamit U100), and 30.0 g of sodium carboxymethyl starch are weighed and mixed in a vinyl bag.
Further, 3.4 g of magnesium stearate was weighed and mixed with the above mixture, and then a single tablet of 320 mg was produced with a rotary tableting machine.
(Manufacture of film-coated tablets)
After dissolving 5 g of hydroxypropylmethylcellulose 2910 (trade name TC-5RW) and 0.7 g of Macrogol 6000 in 100 g of purified water, 0.5 g of talc and 0.8 g of titanium oxide were further added to prepare a film coating solution. .
An uncoated tablet equivalent to 1000 tablets (320 g) was put into a high coater lab (manufactured by Freund Corporation), and a film coating solution was sprayed to obtain a film coated tablet.
（試験例１）
実施例１〜４及び比較例１で製造した錠剤を無包装状態で４０℃及び７５％相対湿度のインキュベータに保存し、週毎の経時的な錠剤表面の色調変化を色差計（機種名ＣＭ−３５００ｄ：ミノルタ製）にて測定した。
結果を図１の表に示し、表中保存期間（Ｗ）は週単位の保存期間を示す。
実施例１〜４及び比較例１で製造した錠剤はいずれもΔＥ値が小さく、色調変化は開始時と比較して大きな変化は認められず白色を保っていた。
実施例２は、エタノール：水＝１：１の混合溶媒を用いたものであるが変色が少なく、実施例３は、コーティングのない素錠であるが造粒時の変色もなく、３週間の色差変化も少なく白色のままであった。
このことから、実施例１〜４の各錠剤は、比較例１に示した従来技術である乾燥直接打錠法と同等な錠剤変色防止効果を有していることが確認された。
(Test Example 1)
The tablets produced in Examples 1 to 4 and Comparative Example 1 were stored in an incubator at 40 ° C. and 75% relative humidity in an unwrapped state, and the color tone change of the tablet surface over time was measured with a color difference meter (model name CM− 3500d: manufactured by Minolta).
A result is shown in the table | surface of FIG. 1, and the storage period (W) in a table | surface shows the storage period of a week unit.
Each of the tablets produced in Examples 1 to 4 and Comparative Example 1 had a small ΔE value, and the color tone change was not recognized as compared with that at the start and kept white.
Example 2 uses a mixed solvent of ethanol: water = 1: 1, but there is little discoloration, and Example 3 is an uncoated tablet without discoloration during granulation for 3 weeks. There was little change in color difference and it remained white.
From this, it was confirmed that each tablet of Examples 1-4 has the tablet discoloration prevention effect equivalent to the dry direct tableting method which is a prior art shown in Comparative Example 1.
（試験例２）
（錠剤含量均一性試験）
錠剤をサンプリングし、水４ｍＬを加えて超音波処理し、錠剤を完全に崩壊した後、メタノールを加えて正確に２０ｍＬとする。
この液を孔径０．４５μｍのメンブランフィルターでろ過する。
初めのろ液５ｍＬを除き、次のろ液５ｍＬを正確に量り、内標準溶液５ｍＬを正確に加え、メタノールを加えて５０ｍＬとし、試料溶液とする。
別に塩酸パロキセチン水和物標準品約０．０５６ｇ（パロキセチンとして約０．０５ｇ）を精密に量り、メタノールを加えて溶かし、正確に５０ｍＬとする。この液５ｍＬを正確に量り、内標準溶液５ｍＬを正確に加え、メタノールを加えて５０ｍＬとし、標準溶液とする。
試料溶液及び標準溶液１０μＬにつき、下記の条件で液体クロマトグラフ法により試験を行い、内標準物質のピーク面積（ＱＳ）に対するパロキセチンのピーク面積（ＱＴ）を求める。
（試験条件）
検出器：紫外吸光光度計（測定波長：２９５ｎｍ）
カラム：内径４．６ｍｍ、長さ２５ｃｍのステンレス管に５μｍの液体クロマトグラフ用トリメチルシリル化シリカゲルを充てんする。
カラム温度：４０℃付近の一定温度
移動相：ｐＨ５．５の酢酸・酢酸アンモニウム緩衝液／アセトニトリル／トリエチルアミン混液（６０：４０：１）
流量：パロキセチンの保持時間が約５分になるように調整する。
このようにして求めたＱＴ／ＱＳの値から図２に示した計算式に基づいてパロキチセン（Ｃ１９Ｈ２０ＦＮＯ３）の量を測定した結果、標準偏差は０．６と非常に小さく、錠剤としての含量バラツキが少ないことが明らかになった。
(Test Example 2)
(Tablet content uniformity test)
The tablets are sampled, 4 mL of water is added and sonicated to completely disintegrate the tablets, and methanol is added to make exactly 20 mL.
This solution is filtered through a membrane filter having a pore size of 0.45 μm.
Remove 5 mL of the first filtrate, accurately weigh 5 mL of the next filtrate, add exactly 5 mL of internal standard solution, add methanol to make 50 mL, and use this as the sample solution.
Separately, about 0.056 g of paroxetine hydrochloride hydrate standard product (about 0.05 g as paroxetine) is accurately weighed and dissolved in methanol to make exactly 50 mL.
The sample solution and 10 μL of the standard solution are tested by the liquid chromatographic method under the following conditions to determine the peak area (Q T ) of paroxetine relative to the peak area (Q S ) of the internal standard substance.
(Test conditions)
Detector: UV absorptiometer (measurement wavelength: 295 nm)
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 25 cm is packed with 5 μm of trimethylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 40 ° C. Mobile phase: pH 5.5 acetic acid / ammonium acetate buffer / acetonitrile / triethylamine mixture (60: 40: 1)
Flow rate: Adjust so that the retention time of paroxetine is about 5 minutes.
As a result of measuring the amount of paroxitcene (C 19 H 20 FNO 3 ) based on the calculation formula shown in FIG. 2 from the Q T / Q S values thus obtained, the standard deviation is as very small as 0.6. It became clear that there was little content variation as a tablet.
Claims (5)
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| JP2006005565A JP2007186450A (en) | 2006-01-13 | 2006-01-13 | Paroxetine hydrochloride-containing preparation and method for producing the same |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009167110A (en) * | 2008-01-11 | 2009-07-30 | Nichi-Iko Pharmaceutical Co Ltd | Sarpogrelate hydrochloride-containing oral preparation excellent in stability in unpacked state |
| WO2010038689A1 (en) * | 2008-09-30 | 2010-04-08 | アステラス製薬株式会社 | Pharmaceutical composition for oral administration |
| JP2011012018A (en) * | 2009-07-02 | 2011-01-20 | Towa Yakuhin Kk | Pharmaceutical composition for oral administration of paroxetine hydrochloride hydrate, having inhibited retardation of disintegration |
| JP2011236188A (en) * | 2010-05-06 | 2011-11-24 | Takada Seiyaku Kk | Film coated oral formulation containing paroxetine |
-
2006
- 2006-01-13 JP JP2006005565A patent/JP2007186450A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009167110A (en) * | 2008-01-11 | 2009-07-30 | Nichi-Iko Pharmaceutical Co Ltd | Sarpogrelate hydrochloride-containing oral preparation excellent in stability in unpacked state |
| WO2010038689A1 (en) * | 2008-09-30 | 2010-04-08 | アステラス製薬株式会社 | Pharmaceutical composition for oral administration |
| JP4582263B2 (en) * | 2008-09-30 | 2010-11-17 | アステラス製薬株式会社 | Pharmaceutical composition for oral administration |
| CN102170885A (en) * | 2008-09-30 | 2011-08-31 | 安斯泰来制药株式会社 | Pharmaceutical composition for oral administration |
| JPWO2010038689A1 (en) * | 2008-09-30 | 2012-03-01 | アステラス製薬株式会社 | Pharmaceutical composition for oral administration |
| JP2011012018A (en) * | 2009-07-02 | 2011-01-20 | Towa Yakuhin Kk | Pharmaceutical composition for oral administration of paroxetine hydrochloride hydrate, having inhibited retardation of disintegration |
| JP2011236188A (en) * | 2010-05-06 | 2011-11-24 | Takada Seiyaku Kk | Film coated oral formulation containing paroxetine |
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