JP2017039687A - Nalfurafine hydrochloride-containing capsule formulation - Google Patents
Nalfurafine hydrochloride-containing capsule formulation Download PDFInfo
- Publication number
- JP2017039687A JP2017039687A JP2015204880A JP2015204880A JP2017039687A JP 2017039687 A JP2017039687 A JP 2017039687A JP 2015204880 A JP2015204880 A JP 2015204880A JP 2015204880 A JP2015204880 A JP 2015204880A JP 2017039687 A JP2017039687 A JP 2017039687A
- Authority
- JP
- Japan
- Prior art keywords
- capsule
- stabilizer
- hydrochloride
- solution
- meglumine
- 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
Links
- 229960000441 nalfurafine Drugs 0.000 title claims abstract description 34
- 239000007963 capsule composition Substances 0.000 title claims abstract description 15
- XGZZHZMWIXFATA-UEZBDDGYSA-N nalfurafine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@H]3N(C)C(=O)\C=C\C1=COC=C1)CN2CC1CC1 XGZZHZMWIXFATA-UEZBDDGYSA-N 0.000 title claims abstract description 8
- 239000002775 capsule Substances 0.000 claims abstract description 70
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000003381 stabilizer Substances 0.000 claims abstract description 37
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims abstract description 36
- 229960003194 meglumine Drugs 0.000 claims abstract description 36
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 17
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 17
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- 238000000034 method Methods 0.000 claims description 18
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- XKKTVIWAHIWFAN-UHFFFAOYSA-M sodium;2-[2-[2-(dodecylamino)ethylamino]ethylamino]acetate Chemical compound [Na+].CCCCCCCCCCCCNCCNCCNCC([O-])=O XKKTVIWAHIWFAN-UHFFFAOYSA-M 0.000 description 1
- 239000006076 specific stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 235000019263 trisodium citrate Nutrition 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、ナルフラフィン塩酸塩を含有するカプセル製剤に関し、より詳しくは、ナルフラフィン塩酸塩と、基剤と、安定化剤とを含有するカプセル内容液を皮膜で被覆したカプセル製剤であって、上記安定化剤が、リドカイン、チオクト酸（α−リポ酸）、メグルミン、グルタチオン、ラウリルジアミノエチルグリシンナトリウム液及びＬ−メチオニンからなる群から選ばれる少なくとも一種、特にメグルミンであるカプセル製剤に関する。 The present invention relates to a capsule preparation containing nalfurafine hydrochloride, and more specifically, a capsule preparation in which a capsule content liquid containing nalfurafine hydrochloride, a base, and a stabilizer is coated with a film, The present invention relates to a capsule preparation in which the agent is at least one selected from the group consisting of lidocaine, thioctic acid (α-lipoic acid), meglumine, glutathione, sodium lauryldiaminoethylglycine and L-methionine, particularly meglumine.
従来、痒みの治療には抗ヒスタミン剤、抗アレルギー剤等の内服剤や、副腎皮質ステロイド、非ステロイド系抗消炎剤等の外用剤が用いられてきた。しかしながら、上記内服剤の場合には、眠気やだるさ、口の渇き、排尿障害等の副作用が生じやすく、外用剤の場合には、皮膚の委縮、毛細血管拡張等の副作用が生じやすいという問題があり、新たな止痒剤の開発が求められていた。 Conventionally, internal preparations such as antihistamines and antiallergic agents, and external preparations such as corticosteroids and nonsteroidal anti-inflammatory agents have been used for the treatment of pruritus. However, in the case of the above-mentioned internal preparation, side effects such as drowsiness, dullness, dry mouth and dysuria are likely to occur, and in the case of an external preparation, there are problems that side effects such as skin contraction and capillary vasodilation are likely to occur. There was a need to develop a new antipruritic agent.
近年、痒みにはオピオイド受容体が関与しており、内因性オピオイドが痒みを惹起することが明らかとなってきた（特許文献１、２参照）。かかるオピオイド受容体には、主にμ受容体、κ受容体、δ受容体の３つのサブタイプが存在している。ナルフラフィン塩酸塩は、μ受容体を制御しているκ受容体に選択的に作用し、内因性オピオイドの刺激により生じるμ受容体を介した痒みを抑制することが可能である。現在ナルフラフィン塩酸塩は、レミッチ（登録商標）カプセルとして鳥居薬品社から販売されており、透析療法中に生じるそう痒症の改善剤として用いられている。ナルフラフィン塩酸塩は熱、光、酸素等に対して化学的に不安定である。そこで、ナルフラフィン塩酸塩を含有するカプセル製剤においては、０．０５％〜１％チオ硫酸ナトリウム（特許文献１参照）や、酸化防止剤、シネルギスト、糖類、又は界面活性剤（特許文献３参照）を用いてナルフラフィン塩酸塩を安定化させる方法が提案されている。 In recent years, it has become clear that opioid receptors are involved in itching and that endogenous opioids cause itching (see Patent Documents 1 and 2). There are mainly three subtypes of such opioid receptors: μ receptor, κ receptor, and δ receptor. Nalfurafine hydrochloride selectively acts on the kappa receptor that regulates the μ receptor, and can suppress the itch caused through the stimulation of endogenous opioids. At present, narfrafin hydrochloride is sold by Torii Pharmaceutical Co., Ltd. as Remitch (registered trademark) capsules, and is used as an remedy for pruritus that occurs during dialysis therapy. Nalfurafine hydrochloride is chemically unstable to heat, light, oxygen and the like. Therefore, in a capsule preparation containing nalfrafin hydrochloride, 0.05% to 1% sodium thiosulfate (see Patent Document 1), antioxidant, synergist, saccharide, or surfactant (see Patent Document 3). A method for stabilizing nalflaphine hydrochloride using it has been proposed.
一方、リドカイン（塩酸塩）は世界で最も広く使用される局所麻酔薬であり、抗不整脈薬としても知られており、チオクト酸はα−リポ酸とも呼ばれ、補酵素として働くビタミン様物質として知られており、メグルミンはソルビトールから誘導されたアミノ糖であり、調合薬の賦形剤、又は造影剤として用いられており、還元型グルタチオン（ＧＳＨ）は３つのアミノ酸からなるトリペプチドで、抗酸化物質として知られており、ラウリルジアミノエチルグリシンナトリウム液は両性界面活性剤であり、ヨード系以外のうがい薬として知られており、Ｌ−メチオニンは側鎖にイオウを含んだ疎水性の必須アミノ酸として知られている。 On the other hand, lidocaine (hydrochloride) is the most widely used local anesthetic in the world and is also known as an antiarrhythmic agent. Thioctic acid is also called α-lipoic acid and is a vitamin-like substance that acts as a coenzyme. It is known that meglumine is an amino sugar derived from sorbitol and is used as an excipient or contrast agent in pharmaceutical preparations, and reduced glutathione (GSH) is a tripeptide consisting of three amino acids Known as an oxidant, sodium lauryldiaminoethylglycine solution is an amphoteric surfactant, known as a mouthwash other than iodine, and L-methionine is a hydrophobic essential amino acid containing sulfur in the side chain Known as.
本発明の課題は、ナルフラフィン塩酸塩を長期間安定な状態で含有するカプセル製剤や、かかるカプセル製剤の製造方法等を提供することにある。 An object of the present invention is to provide a capsule preparation containing nalflaphine hydrochloride in a stable state for a long period of time, a method for producing such a capsule preparation, and the like.
本発明者らは、上記課題を解決すべく種々研究を重ねた結果、特定の安定化剤を用いることで、ナルフラフィン塩酸塩を長期間安定な状態で含有するカプセル製剤を製造することが可能であることを見いだし、本発明を完成した。 As a result of repeating various studies to solve the above-mentioned problems, the present inventors can produce a capsule preparation containing nalfrafin hydrochloride in a stable state for a long period of time by using a specific stabilizer. I found something and completed the present invention.
すなわち、本発明は以下のとおりである。
（１）ナルフラフィン塩酸塩と、基剤と、安定化剤とを含有するカプセル内容液を皮膜で被覆したカプセル製剤であって、
前記安定化剤が、メグルミンであるカプセル製剤。
（２）基剤が、ポリエチレングリコール、プロピレングリコール、エタノール、グリセリンモノカプリル酸エステル、プロピレングリコールモノオレイン酸エステル、プロピレングリコールモノカプリル酸エステルからなる群から選ばれる少なくとも一種であることを特徴とする上記（１）のカプセル製剤。
（３）カプセル内容液が、さらにトコフェロール及び／又はチオ硫酸ナトリウムを含有することを特徴とする上記（１）又は（２）のカプセル製剤。
（４）カプセル内容液が、安定化剤としてさらにラウリルジアミノエチルグリシンナトリウム液を含有することを特徴とする上記（１）〜（３）のいずれか記載のカプセル製剤
（５）以下に示す（ａ）〜（ｃ）の工程を備えたカプセル製剤の製造方法。
（ａ）ナルフラフィン塩酸塩を緩衝液又は水に溶解してナルフラフィン塩酸塩原液を調製する工程；
（ｂ）前記ナルフラフィン塩酸塩原液と、基剤と、安定化剤としてのメグルミンとを混合してカプセル内容液を調製する工程；
（ｃ）前記カプセル内容液を皮膜で被覆する工程；
（６）基剤の存在下、ナルフラフィン塩酸塩と、安定化剤としてのメグルミンとを接触させることを特徴とするカプセル製剤中のナルフラフィン塩酸塩の安定化方法。
That is, the present invention is as follows.
(1) A capsule formulation in which a capsule content liquid containing nalfurafine hydrochloride, a base, and a stabilizer is coated with a film,
A capsule preparation wherein the stabilizer is meglumine.
(2) The above base is at least one selected from the group consisting of polyethylene glycol, propylene glycol, ethanol, glycerin monocaprylate, propylene glycol monooleate, propylene glycol monocaprylate (1) Capsule formulation.
(3) The capsule preparation according to (1) or (2) above, wherein the capsule content liquid further contains tocopherol and / or sodium thiosulfate.
(4) Capsule content solution further contains sodium lauryldiaminoethylglycine solution as a stabilizer, and the capsule formulation (5) described in any one of (1) to (3) below (a) )-(C) The manufacturing method of the capsule formulation provided with the process.
(A) a step of preparing a nalfurafine hydrochloride stock solution by dissolving nalfurafine hydrochloride in a buffer or water;
(B) A step of preparing a capsule content liquid by mixing the nalflaphine hydrochloride stock solution, a base, and meglumine as a stabilizer;
(C) coating the capsule content liquid with a film;
(6) A method for stabilizing nalfurafine hydrochloride in a capsule preparation, comprising bringing nalfurafine hydrochloride into contact with meglumine as a stabilizer in the presence of a base.
本発明によれば、ナルフラフィン塩酸塩を長期間安定な状態で含有するカプセル製剤を提供することが可能となる。 ADVANTAGE OF THE INVENTION According to this invention, it becomes possible to provide the capsule formulation which contains a narfrafin hydrochloride in a stable state for a long period of time.
本発明のカプセル製剤としては、ナルフラフィン塩酸塩と、基剤と、安定化剤とを含有するカプセル内容液を皮膜で被覆したカプセル製剤であって、前記安定化剤がメグルミンであるカプセル製剤であれば特に制限されず、また、本発明のカプセル製剤中のナルフラフィン塩酸塩の安定化方法としては、基剤の存在下、ナルフラフィン塩酸塩と、安定化剤としてのメグルミンとを接触させる方法であれば特に制限されないが、上記安定化剤としてメグルミンに加えてラウリルジアミノエチルグリシンナトリウム液を併用することができる。メグルミンの使用濃度としては、０．０５〜０．５％を好適に例示できる。また、上記カプセル製剤としてはソフトカプセル製剤であることが好ましい。 The capsule preparation of the present invention may be a capsule preparation in which a capsule content liquid containing nalfrafin hydrochloride, a base, and a stabilizer is coated with a film, wherein the stabilizer is meglumine. The method for stabilizing nalfurafine hydrochloride in the capsule preparation of the present invention is not particularly limited as long as it is a method of contacting nalfurafine hydrochloride with meglumine as a stabilizer in the presence of a base. Although not particularly limited, sodium lauryldiaminoethylglycine solution can be used in combination with meglumine as the stabilizer. As a use concentration of meglumine, 0.05 to 0.5% can be preferably exemplified. The capsule preparation is preferably a soft capsule preparation.
本発明におけるナルフラフィン塩酸塩（（２Ｅ）−Ｎ−［（５Ｒ，６Ｒ）−１７−（シクロプロピルメチル）−４，５−エポキシ−３，１４−ジヒドロキシモルフィナン−６−イル］−３−（フラン−３−イル）−Ｎ−メチル−２−プロペンアミド・塩酸塩；(2E)-N-[(5R,6R)-17-(Cyclopropylmethyl)-4, 5-epoxy-3, 14-dihydroxymorphinan-6-yl]-3-(furan-3-yl)-N-methyl-2-propenamide monohydrochloride）は、市販品を購入することにより入手することが可能である。 Nalfurafine hydrochloride ((2E) -N-[(5R, 6R) -17- (cyclopropylmethyl) -4,5-epoxy-3,14-dihydroxymorphinan-6-yl] -3- () in the present invention Furan-3-yl) -N-methyl-2-propenamide hydrochloride; (2E) -N-[(5R, 6R) -17- (Cyclopropylmethyl) -4, 5-epoxy-3, 14-dihydroxymorphinan- 6-yl] -3- (furan-3-yl) -N-methyl-2-propenamide monohydrochloride) can be obtained by purchasing a commercial product.
カプセル内容液中のナルフラフィン塩酸塩の含有量は特に制限されないが、１カプセル相当のカプセル内容液中に０．０１〜１００００μｇ、好ましくは０．１〜１０００μｇとすることができる。 The content of nalflaphine hydrochloride in the capsule content liquid is not particularly limited, but may be 0.01 to 10,000 μg, preferably 0.1 to 1000 μg, in the capsule content liquid corresponding to one capsule.
本発明における基剤としては、ポリエチレングリコール（ＰＥＧ）、プロピレングリコール、エタノール、グリセリンモノカプリル酸エステル、プロピレングリコールモノオレイン酸エステル、プロピレングリコールモノカプリル酸エステル等を挙げることができる。 Examples of the base in the present invention include polyethylene glycol (PEG), propylene glycol, ethanol, glycerin monocaprylate, propylene glycol monooleate, propylene glycol monocaprylate.
本発明における基剤において、二種以上組み合わせてもよく、例えばポリエチレングリコール（ＰＥＧ）とグリセリンモノカプリル酸エステルや、ポリエチレングリコール（ＰＥＧ）とプロピレングリコールモノオレイン酸エステルや、ポリエチレングリコール（ＰＥＧ）とプロピレングリコールモノカプリル酸エステルや、ポリエチレングリコール（ＰＥＧ）とプロピレングリコールや、ポリエチレングリコール（ＰＥＧ）とエタノールや、グリセリンモノカプリル酸エステルとプロピレングリコールモノオレイン酸エステルや、グリセリンモノカプリル酸エステルとプロピレングリコールモノカプリル酸エステルや、グリセリンモノカプリル酸エステルとプロピレングリコールや、グリセリンモノカプリル酸エステルとエタノールや、プロピレングリコールモノオレイン酸エステルとプロピレングリコールモノカプリル酸エステルや、プロピレングリコールモノオレイン酸エステルとプロピレングリコールや、プロピレングリコールモノオレイン酸エステルとエタノールや、プロピレングリコールモノカプリル酸エステルとプロピレングリコールや、プロピレングリコールモノカプリル酸エステルとエタノールの組み合わせを挙げることができる。 In the base in the present invention, two or more kinds may be combined. For example, polyethylene glycol (PEG) and glycerol monocaprylate, polyethylene glycol (PEG) and propylene glycol monooleate, polyethylene glycol (PEG) and propylene Glycol monocaprylate, polyethylene glycol (PEG) and propylene glycol, polyethylene glycol (PEG) and ethanol, glycerin monocaprylate and propylene glycol monooleate, glycerin monocaprylate and propylene glycol monocapryl Acid esters, glycerol monocaprylate and propylene glycol, glycerol monocaprylate and ethanol, Pyrene glycol monooleate and propylene glycol monocaprylate, propylene glycol monooleate and propylene glycol, propylene glycol monooleate and ethanol, propylene glycol monocaprylate and propylene glycol, propylene glycol mono A combination of caprylic acid ester and ethanol can be mentioned.
本発明において、メグルミンに加えて、リドカイン、チオクト酸、還元型グルタチオン、ラウリルジアミノエチルグリシンナトリウム液及びＬ−メチオニンからなる群から選ばれる少なくとも一種の他の安定化剤を併用することができる外、チオ硫酸ナトリウム、没食子酸ｎ−プロピル、亜硫酸水素ナトリウム、Ｌ−アスコルビン酸、ブチルヒドロキシアニソール（ＢＨＡ）、ジブチルヒドロキシトルエン（ＢＨＴ）、トコフェロール、Ｌ−アスコルビン酸ステアレート等をカプセル内容液に添加することができるが、特にトコフェロールやチオ硫酸ナトリウムを好適に例示することができる。メグルミンに加えて、トコフェロール及び／又はチオ硫酸ナトリウムを併用する場合、トコフェロールの使用濃度としては０．０５〜０．２％、好ましくは０．０７５〜０．１５％を、チオ硫酸ナトリウムの使用濃度としては０．０１〜０．０４％、好ましくは０．０３〜０．０４％を好適に例示できる。 In the present invention, in addition to meglumine, at least one other stabilizer selected from the group consisting of lidocaine, thioctic acid, reduced glutathione, sodium lauryldiaminoethylglycine and L-methionine can be used in combination. Adding sodium thiosulfate, n-propyl gallate, sodium bisulfite, L-ascorbic acid, butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT), tocopherol, L-ascorbic acid stearate, etc. to the capsule content liquid In particular, tocopherol and sodium thiosulfate can be preferably exemplified. When tocopherol and / or sodium thiosulfate is used in combination with meglumine, the use concentration of tocopherol is 0.05 to 0.2%, preferably 0.075 to 0.15%. Can be suitably exemplified by 0.01 to 0.04%, preferably 0.03 to 0.04%.
本発明におけるカプセル内容液には、ナルフラフィン塩酸塩と、基剤と、安定化剤とが含まれているが、ナルフラフィン塩酸塩と、基剤と、安定化剤以外に油脂、界面活性剤、緩衝液、水、ゲル化剤、ｐＨ調整剤、多孔性微粒子粉末、甘味料等の呈味剤、香料、溶解助剤、粘度調整剤等の他の物質を含有していてもよい。緩衝液としては酢酸緩衝液を好適に挙げることができる。 The capsule content liquid in the present invention contains nalfurafine hydrochloride, a base, and a stabilizer. In addition to nalfurafine hydrochloride, a base, and a stabilizer, oils and fats, surfactants, buffers It may contain other substances such as liquid, water, gelling agent, pH adjusting agent, porous fine particle powder, flavoring agent such as sweetener, flavoring agent, dissolution aid, viscosity adjusting agent. A preferable example of the buffer is an acetate buffer.
本発明におけるカプセル内容液のｐＨとしては、好ましくは５．０〜８．６、より好ましくは７．０〜８．２、さらに好ましくは７．１〜７．６を挙げることができる。ｐＨの調整は、用いる基剤又は安定化剤の種類若しくは量によって調整する方法や、緩衝液を用いて調整する方法を挙げることができる。カプセル内容液、若しくは各段階における調製途中の溶液のｐＨを中性〜弱酸性に調整しつつ溶液を調製することにより、ナルフラフィン塩酸塩の安定性をより向上させることが可能となる。 The pH of the capsule content liquid in the present invention is preferably 5.0 to 8.6, more preferably 7.0 to 8.2, and still more preferably 7.1 to 7.6. Examples of the pH adjustment include a method of adjusting depending on the type or amount of the base or stabilizer used, and a method of adjusting using a buffer solution. By preparing the solution while adjusting the pH of the capsule content solution or the solution being prepared at each stage to neutral to weakly acidic, it becomes possible to further improve the stability of nalfurafine hydrochloride.
本発明において、皮膜としては特に制限されず、疎水性皮膜でも親水性皮膜でもよいが、親水性皮膜であることが好ましい。 In the present invention, the film is not particularly limited, and may be a hydrophobic film or a hydrophilic film, but is preferably a hydrophilic film.
親水性皮膜の材料としては、ゼラチン、コハク化ゼラチン等の修飾ゼラチン、カラギーナン、寒天、アルギン酸ナトリウム、プルラン、グルコマンナン、アラビアゴム、ファーセレラン、ユーケマ藻類、ジェランガム、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、ポリビニルピロリドン、ポリビニルアルコール、デンプン類等の親水性高分子の一種又は二種以上の組合せを挙げることができ、ゼラチン、又は修飾ゼラチンを好適に挙げることができる。 Materials for the hydrophilic film include gelatin, modified gelatin such as succinated gelatin, carrageenan, agar, sodium alginate, pullulan, glucomannan, gum arabic, fur cerelan, Eugema algae, gellan gum, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone In addition, one or a combination of two or more hydrophilic polymers such as polyvinyl alcohol and starch can be used, and gelatin or modified gelatin can be preferably used.
皮膜を製造する際には、皮膜材料にグリセリン等の可塑剤、二酸化チタン等の遮光剤、リン酸ナトリウム等のｐＨ調整剤、クエン酸三ナトリウム、メタリン酸ナトリウム等のキレート剤、乳酸カルシウム、塩化カリウム等のゲル化促進剤、ポリグリセリン脂肪酸エステル、レシチン等の界面活性剤、呈味剤、香料、防腐剤、着色剤、溶解助剤等を添加してもよい。 When manufacturing the film, the film material is made of plasticizer such as glycerin, light-shielding agent such as titanium dioxide, pH adjuster such as sodium phosphate, chelating agent such as trisodium citrate and sodium metaphosphate, calcium lactate, chloride A gelling accelerator such as potassium, a surfactant such as polyglycerin fatty acid ester and lecithin, a flavoring agent, a fragrance, a preservative, a coloring agent, a dissolution aid and the like may be added.
本発明のカプセル製剤の製造方法は、次の（ａ）〜（ｃ）の工程を備えていれば特に制限されず、ナルフラフィン塩酸塩を緩衝液又は水、好ましくは緩衝液、より好ましくは酢酸緩衝液に溶解したうえで基剤や安定化剤と混合することにより、ナルフラフィン塩酸塩の安定性をより向上させることが可能となる。
（ａ）ナルフラフィン塩酸塩を緩衝液又は水に溶解してナルフラフィン塩酸塩原液を調製する工程；
（ｂ）前記ナルフラフィン塩酸塩原液と、基剤と、安定化剤としてのメグルミン、あるいはメグルミン及びラウリルジアミノエチルグリシンナトリウム液とを混合してカプセル内容液を調製する工程；
（ｃ）前記カプセル内容液を皮膜で被覆する工程；
The method for producing the capsule preparation of the present invention is not particularly limited as long as it comprises the following steps (a) to (c), and nalfrafin hydrochloride is buffered or water, preferably buffered, more preferably acetate buffered. It becomes possible to further improve the stability of nalfurafine hydrochloride by mixing with a base or a stabilizer after being dissolved in the liquid.
(A) a step of preparing a nalfurafine hydrochloride stock solution by dissolving nalfurafine hydrochloride in a buffer or water;
(B) A step of preparing a capsule content solution by mixing the nalflaphine hydrochloride stock solution, a base, and meglumine as a stabilizer, or meglumine and sodium lauryldiaminoethylglycine solution;
(C) coating the capsule content liquid with a film;
本発明のカプセル製剤の製造方法の別の態様としては、次の（ｄ）〜（ｆ）の工程を備えた方法を挙げることができる。
（ｄ）ナルフラフィン塩酸塩をポリエチレングリコール（ＰＥＧ）、プロピレングリコール、エタノール、グリセリンモノカプリル酸エステル、プロピレングリコールモノオレイン酸エステル、プロピレングリコールモノカプリル酸エステルからなる群から選ばれる少なくとも一種の基剤に溶解してナルフラフィン塩酸塩原液を調製する工程；
（ｅ）上記ナルフラフィン塩酸塩原液と、安定化剤としてのメグルミン、あるいはメグルミン及びラウリルジアミノエチルグリシンナトリウム液とを混合してカプセル内容液を調製する工程；
（ｆ）前記カプセル内容液を皮膜で被覆する工程；
As another aspect of the manufacturing method of the capsule formulation of this invention, the method provided with the process of following (d)-(f) can be mentioned.
(D) Nalfurafine hydrochloride is dissolved in at least one base selected from the group consisting of polyethylene glycol (PEG), propylene glycol, ethanol, glycerin monocaprylate, propylene glycol monooleate, and propylene glycol monocaprylate. And preparing a nalflaphine hydrochloride stock solution;
(E) A step of preparing a capsule content solution by mixing the above-described nalfurafine hydrochloride stock solution and meglumine as a stabilizer, or meglumine and sodium lauryldiaminoethylglycine solution;
(F) coating the capsule content solution with a film;
本発明のカプセル製剤の製造方法において緩衝液を用いる場合には、かかる緩衝液のｐＨとしては、４．５〜５．５、好ましくは４．８〜５．２を挙げることができる。 When a buffer solution is used in the method for producing the capsule preparation of the present invention, the pH of the buffer solution may be 4.5 to 5.5, preferably 4.8 to 5.2.
本発明のカプセル製剤や、本発明のカプセル製剤の製造方法において、カプセル内容液を皮膜で被覆する方法としては、平板法、ロータリーダイ法、シームレス法等の公知の方法を用いることができる。 In the capsule preparation of the present invention and the method for producing the capsule preparation of the present invention, known methods such as a flat plate method, a rotary die method, and a seamless method can be used as a method for coating the capsule content liquid with a film.
（供試材料と略号）
カプセル内容液における主薬としてナルフラフィン塩酸塩を、主薬の安定化剤として還元型グルタチオン（Ｇｌ）、メグルミン（Ｍｇ）、ラウリルジアミノエチルグリシンナトリウム液（Ａｎ；日油株式会社製「ニッサンアノン［登録商標］ＬＧ−Ｒ）、チオクト酸（ＳＡ）、リドカイン（Ｌｄ）、及びＬ−メチオニン（Ｍｔ）を、抗酸化剤としてチオ硫酸ナトリウム（Ｓｔ）及びトコフェロール（ＶＥ）を、基剤としてポリエチレングリコール４００（ＰＥＧ４００）を用いた。また、カプセル皮膜として、コハク化ゼラチン、濃グリセリン、及び二酸化チタンを用いた。図中において、主分解物はＮ-Ｏｘｉｄｅを表し、ＮＮ；未添加、X.XX％；カプセル内容液中に含まれる添加剤濃度（w/w）、＋；コハク化ゼラチン皮膜浸漬あり、−；コハク化ゼラチン皮膜浸漬なし、をそれぞれ示す。
(Test materials and abbreviations)
Nalfurafine hydrochloride as the active ingredient in the capsule content liquid, and reduced glutathione (Gl), meglumine (Mg), sodium lauryldiaminoethylglycine (An; manufactured by NOF Corporation "Nissan Anon [registered trademark]" LG-R), thioctic acid (SA), lidocaine (Ld), and L-methionine (Mt), sodium thiosulfate (St) and tocopherol (VE) as antioxidants, polyethylene glycol 400 (PEG400) as a base In addition, succinylated gelatin, concentrated glycerin, and titanium dioxide were used as the capsule film, in which the main degradation product represents N-Oxide, NN: not added, X.XX%; Concentration of additives contained in the liquid (w / w), +: Succinic gelatin film is immersed,-; It is shown click gelatin film without immersion, respectively.
（カプセル内容液の調製）
脂溶性固体添加物であるチオクト酸及びリドカイン、並びに脂溶性液体添加物であるトコフェロールは秤量後にＰＥＧ４００と混和・溶解し、水溶性固体添加物であるチオ硫酸ナトリウム、メグルミン、還元型グルタチオン、Ｌ−メチオニンは秤量後に水と混和・溶解し、水溶性液体添加物であるラウリルジアミノエチルグリシンナトリウム液は秤量後にプロピレングリコールと混和・溶解した。これら添加物の溶解物をＰＥＧ４００に混和・溶解させ、これら混和・溶解液それぞれに、ナルフラフィン塩酸塩水溶液を混合し、（＋）検体は各混合物２ｇにコハク化ゼラチン皮膜片１ｇを浸漬した状態でガラスバイアルに密閉し、また（−）検体は各混合物をそのままガラスバイアルに密閉して各カプセル内容液とした。各カプセル内容液はそれぞれの保存期間につきバイアルを１本ずつ用意した。
(Preparation of capsule content liquid)
The fat-soluble solid additives thioctic acid and lidocaine and the fat-soluble liquid additive tocopherol are mixed and dissolved with PEG400 after weighing, and the water-soluble solid additives sodium thiosulfate, meglumine, reduced glutathione, L- Methionine was mixed and dissolved in water after weighing, and lauryl diaminoethylglycine sodium solution, which is a water-soluble liquid additive, was mixed and dissolved in propylene glycol after weighing. The additive lysate is mixed and dissolved in PEG400, and each of the mixture and solution is mixed with an aqueous solution of nalflaphine hydrochloride. (+) The specimen is obtained by immersing 1 g of a succinylated gelatin film piece in 2 g of each mixture. The mixture was sealed in a glass vial, and the (-) specimen was sealed in a glass vial as it was to prepare each capsule content solution. For each capsule content solution, one vial was prepared for each storage period.
（カプセル内容液の保存及び安定化分析）
保存期間０週間（保存開始時）のサンプルとして４℃の冷蔵庫でバイアル１本ずつ保存し、残りのカプセル内容液の入ったバイアルは、５０℃の恒温槽に入れて保存した。保存期間は１週間乃至８週間とし、５０℃での保存期間が終了したら、バイアルを恒温槽から取り出した。（＋）検体は浸漬した皮膜を取り出してから、（−）検体はそのまま４℃で分析日まで保管した。また、主薬であるナルフラフィン塩酸塩の残存率を求めるため、採取したカプセル内容液のうち約２００ｍｇを水で約５倍に希釈し、高速液体クロマトグラフィー（ＨＰＬＣ）分析を行った。ＨＰＬＣ分析はHorikiriらの文献（Horikiri H. et al., Chem. Pharm. Bull. 52(6):664-669(2004)）に従い、以下に示す条件により行った。また、ナルフラフィン主薬の保持時間を１としたときの相対保持時間１．１３のピークを主分解物（Ｎ-Ｏｘｉｄｅ）として解析した。
(Storage and stabilization analysis of capsule contents)
One vial was stored in a 4 ° C. refrigerator as a sample with a storage period of 0 weeks (at the start of storage), and the remaining vial containing the capsule content solution was stored in a 50 ° C. thermostat. The storage period was 1 to 8 weeks, and when the storage period at 50 ° C. was completed, the vial was taken out of the thermostatic bath. The (+) specimen was taken out of the immersed film, and the (-) specimen was stored as it was at 4 ° C. until the day of analysis. Further, in order to determine the residual rate of nalflaphine hydrochloride as the main drug, about 200 mg of the collected capsule content liquid was diluted about 5 times with water and subjected to high performance liquid chromatography (HPLC) analysis. HPLC analysis was performed according to the following conditions according to Horikiri et al. (Horikiri H. et al., Chem. Pharm. Bull. 52 (6): 664-669 (2004)). Moreover, the peak of the relative retention time 1.13 when the retention time of the nalfurafine active agent was set to 1 was analyzed as a main decomposition product (N-Oxide).
分析カラム；YMC-Pack ODS-AM 5μm
カラム温度；４０℃
流速；１．０ｍＬ／ｍｉｎ
注入量；５０μＬ
検出波長；２８０ｎｍ
移動相Ａ液 ５０ｍＭリン酸二水素ナトリウム溶液／アセトニトリル＝９５／５（Ｖ/
Ｖ）
移動相Ｂ液 ５０ｍＭリン酸二水素ナトリウム溶液／アセトニトリル＝６０／４０（Ｖ/Ｖ）
Analytical column: YMC-Pack ODS-AM 5μm
Column temperature: 40 ° C
Flow rate: 1.0 mL / min
Injection volume: 50 μL
Detection wavelength: 280 nm
Mobile phase A solution 50 mM sodium dihydrogen phosphate solution / acetonitrile = 95/5 (V /
V)
Mobile phase B solution 50 mM sodium dihydrogen phosphate solution / acetonitrile = 60/40 (V / V)
また、グラジエント条件は以下の［表１］に示す条件により行った。 The gradient conditions were the same as those shown in [Table 1] below.
（還元型グルタチオン；Ｇｌによる安定化）
各カプセル内容液の処方を［表２］に、４週間後までの安定化試験の結果を図１に示す。
(Reduced glutathione; stabilization by Gl)
The formulation of each capsule content solution is shown in [Table 2], and the results of the stabilization test up to 4 weeks later are shown in FIG.
（メグルミン；Ｍｇによる安定化）
各カプセル内容液の処方を［表３］に、８週間後までの安定化試験の結果を図２に示す。
(Meglumine; stabilization by Mg)
The formulation of each capsule content solution is shown in [Table 3], and the results of the stabilization test up to 8 weeks later are shown in FIG.
（チオクト酸；ＳＡによる安定化）
各カプセル内容液の処方を［表４］に、８週間後までの安定化試験の結果を図３に示す。
(Thioctic acid; stabilization by SA)
The formulation of each capsule content solution is shown in [Table 4], and the results of the stabilization test up to 8 weeks later are shown in FIG.
（リドカイン；Ｌｄによる安定化）
各カプセル内容液の処方を［表５］に、８週間後までの安定化試験の結果を図４に示す。
(Lidocaine; stabilization by Ld)
The formulation of each capsule content solution is shown in [Table 5], and the results of the stabilization test up to 8 weeks later are shown in FIG.
（ラウリルジアミノエチルグリシンナトリウム液；Ａｎによる安定化）
各カプセル内容液の処方を［表６］に、８週間後までの安定化試験の結果を図５に示す。
(Lauryldiaminoethylglycine sodium solution; stabilization by An)
The formulation of each capsule content liquid is shown in [Table 6], and the results of the stabilization test up to 8 weeks later are shown in FIG.
（メチオニン；Ｍｔによる安定化）
各カプセル内容液の処方を［表７］に、１週間後での安定化試験の結果を図６に示す。図６中、ＥＭｔはＶＥ＋Ｍｔを、ＥＭｔＭはＶＥ＋Ｍｔ＋Ｍｇを、ＥＭｔＡはＶＥ＋Ｍｔ＋Ａｎを、ＥＭＭＡはＶＥ＋Ｍｔ＋Ｍｇ＋Ａｎを、それぞれ示す。
(Methionine; Stabilization with Mt)
The formulation of each capsule content solution is shown in [Table 7], and the results of the stabilization test after one week are shown in FIG. In FIG. 6, EMt represents VE + Mt, EMtM represents VE + Mt + Mg, EMtA represents VE + Mt + An, and EMMA represents VE + Mt + Mg + An.
（カプセル製剤の調製）
以下の［表８］に記載の皮膜処方とカプセル内容液処方にしたがって、安定化剤を異にする５種類のカプセル製剤を調製した。具体的には、グルタチオン、メグルミン、ナルフラフィン塩酸塩はそれぞれ水に溶解させ、ポリエチレングリコール４００に投入した。トコフェロール、チオクト酸、リドカインはそれぞれ小分けにしたポリエチレングリコール４００で溶解させ、元のポリエチレングリコール４００に投入した。ニッサンアノンＬＧ−Ｒはプロピレングリコールに溶解させ、ポリエチレングリコール４００に投入した。撹拌により、均一混合し、各カプセル内容液を得た。調製したカプセル内容液はロータリーダイ法によりコハク化ゼラチン、グリセリン、二酸化チタンからなる皮膜に充填し、Ｏｖａｌ３型の軟カプセル製剤を得た。
(Preparation of capsule formulation)
According to the film formulation and capsule content liquid formulation described in [Table 8] below, 5 types of capsule formulations with different stabilizers were prepared. Specifically, glutathione, meglumine, and nalflavine hydrochloride were each dissolved in water and added to polyethylene glycol 400. Tocopherol, thioctic acid, and lidocaine were each dissolved in polyethylene glycol 400 divided into small portions and charged into the original polyethylene glycol 400. Nissan Anon LG-R was dissolved in propylene glycol and charged into polyethylene glycol 400. By stirring, uniform mixing was performed to obtain each capsule content solution. The prepared capsule content solution was filled into a film made of succinated gelatin, glycerin and titanium dioxide by a rotary die method to obtain an Oval3 type soft capsule preparation.
（メグルミン及び／又はラウリルジアミノエチルグリシンナトリウム液による安定化）
メグルミン及び／又はラウリルジアミノエチルグリシンナトリウム液によるナルフラフィン塩酸塩の安定化試験を行った。各カプセル内容液の処方を［表９］〜［表１２］に示す。［表９］〜［表１２］において（＋）はコハク化ゼラチン皮膜浸漬あり、（＋ｇ）はゼラチン皮膜浸漬ありを示す。［表９］〜［表１１］の各処方については、４週間後までの安定化試験の結果をそれぞれ図７〜図９に示す。また、［表１２］の処方については、８週間後までの安定化試験の結果を図１０に示す。これらカプセル内容液の調製や、カプセル内容液の安定化分析は、保存温度を６０℃に変更した以外は、実施例１と同様に行った。
(Stabilization with meglumine and / or lauryldiaminoethylglycine sodium solution)
A stabilization test of nalfurafine hydrochloride with meglumine and / or lauryldiaminoethylglycine sodium solution was performed. The prescription of each capsule content liquid is shown in [Table 9] to [Table 12]. In [Table 9] to [Table 12], (+) indicates succinated gelatin film immersion, and (+ g) indicates gelatin film immersion. About each prescription of [Table 9]-[Table 11], the result of the stabilization test to 4 weeks after is shown in FIGS. 7-9, respectively. Moreover, about the prescription of [Table 12], the result of the stabilization test to 8 weeks after is shown in FIG. Preparation of the capsule content liquid and stabilization analysis of the capsule content liquid were performed in the same manner as in Example 1 except that the storage temperature was changed to 60 ° C.
以下［表１３］に示されるナルフラフィン塩酸塩軟カプセル製剤処方に基づき、４種類のナルフラフィン塩酸塩軟カプセル製剤をロータリーダイ法によりコハク化ゼラチン、グリセリン、二酸化チタンからなる皮膜に充填し、Ｏｖａｌ３型の軟カプセル製剤を得た。 Based on the formulation of nalfurafine hydrochloride soft capsule formulation shown in [Table 13] below, four kinds of nalfurafine hydrochloride soft capsule formulations were filled into a film composed of succinated gelatin, glycerin and titanium dioxide by the rotary die method, and Oval type 3 A soft capsule formulation was obtained.
（メグルミンの効果に関する考察）
前記の特許文献１（特許第３７４３４４９号公報）に示されているように、ナルフラフィン塩酸塩を含有するカプセル製剤における安定剤としてチオ硫酸ナトリウム０．０５％〜１％が添加されている。そこで、チオ硫酸ナトリウム０．１５％添加品をポジティブコントロールとして採用した。図２（サンプル「Ｍｇ０．０５％（＋）」〜「Ｍｇ０．２％（＋）」）より、メグルミン０．０５％以上添加で、ポジティブコントロールと比較して主薬残存率で同等以上であり、さらに、８ｗにおいては（サンプル「Ｍｇ０．１％（＋）」及び「Ｍｇ０．２％（＋）」）より、メグルミン０．１％以上添加で、ポジティブコントロールよりも主分解物含量が明らかに少なくなっており、ポジティブコントロールよりも高い安定化効果が認められた。また、メグルミンとトコフェロールを併用した処方系（サンプル「ＶＥ０．１％＋Ｍｇ０．０２％（＋）」〜「ＶＥ０．１％＋Ｍｇ０．２％（＋）」）でも安定であることが認められた。そして、図９ではさらに、ラウリルジアミノエチルグリシンナトリウム液を添加しても（サンプル「ＳＥ’Ｍ”Ａ”」〜「ＳＥ’Ａ’」）安定であることが認められた。
(Discussion on the effect of meglumine)
As shown in the said patent document 1 (patent 3743449 gazette), 0.05%-1% of sodium thiosulfate is added as a stabilizer in the capsule formulation containing a narfrafin hydrochloride. Therefore, a product containing 0.15% sodium thiosulfate was adopted as a positive control. From FIG. 2 (samples “Mg 0.05% (+)” to “Mg 0.2% (+)”), meglumine 0.05% or more is added, and the residual ratio of the active ingredient is equal to or higher than that of the positive control. In addition, in 8w, the content of main degradation products is clearly lower than that of the positive control when 0.1% or more of meglumine is added compared to (samples “Mg 0.1% (+)” and “Mg 0.2% (+)”). The stabilization effect was higher than that of the positive control. In addition, it was confirmed that the prescription system (sample “VE 0.1% + Mg 0.02% (+)” to “VE 0.1% + Mg 0.2% (+)”) using meglumine and tocopherol was also stable. Further, in FIG. 9, it was confirmed that the sodium lauryldiaminoethylglycine solution was stable (samples “SE′M” A ”” to “SE′A ′”).
本発明のカプセル製剤は、医薬、医薬部外品等の分野において、ナルフラフィン塩酸塩を長期間安定な状態で保持できるカプセル製剤として利用可能である。 The capsule preparation of the present invention can be used as a capsule preparation capable of holding nalfurafine hydrochloride in a stable state for a long period of time in the fields of medicine, quasi drugs and the like.
Claims (6)
（ａ）ナルフラフィン塩酸塩を緩衝液又は水に溶解してナルフラフィン塩酸塩原液を調製する工程；
（ｂ）前記ナルフラフィン塩酸塩原液と、基剤と、安定化剤としてのメグルミンとを混合してカプセル内容液を調製する工程；
（ｃ）前記カプセル内容液を皮膜で被覆する工程； The manufacturing method of a capsule formulation provided with the process of (a)-(c) shown below.
(A) a step of preparing a nalfurafine hydrochloride stock solution by dissolving nalfurafine hydrochloride in a buffer or water;
(B) A step of preparing a capsule content liquid by mixing the nalflaphine hydrochloride stock solution, a base, and meglumine as a stabilizer;
(C) coating the capsule content liquid with a film;
Applications Claiming Priority (4)
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