JP2014227381A - Loxoprofen sodium-containing oral capsule - Google Patents
Loxoprofen sodium-containing oral capsule Download PDFInfo
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- JP2014227381A JP2014227381A JP2013108736A JP2013108736A JP2014227381A JP 2014227381 A JP2014227381 A JP 2014227381A JP 2013108736 A JP2013108736 A JP 2013108736A JP 2013108736 A JP2013108736 A JP 2013108736A JP 2014227381 A JP2014227381 A JP 2014227381A
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- propylene glycol
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- soft capsule
- loxoprofen sodium
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- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 229960002373 loxoprofen Drugs 0.000 title claims abstract description 30
- 229940100691 oral capsule Drugs 0.000 title 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 99
- 239000002775 capsule Substances 0.000 claims abstract description 29
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 21
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 21
- 239000007901 soft capsule Substances 0.000 claims abstract description 21
- 238000011049 filling Methods 0.000 claims abstract description 16
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 13
- 239000000194 fatty acid Substances 0.000 claims abstract description 13
- 229930195729 fatty acid Natural products 0.000 claims abstract description 13
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims abstract description 12
- -1 propylene glycol fatty acid ester Chemical class 0.000 claims abstract description 12
- 239000001069 triethyl citrate Substances 0.000 claims abstract description 11
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 235000013769 triethyl citrate Nutrition 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 8
- 108010010803 Gelatin Proteins 0.000 claims description 3
- 229920000159 gelatin Polymers 0.000 claims description 3
- 239000008273 gelatin Substances 0.000 claims description 3
- 235000019322 gelatine Nutrition 0.000 claims description 3
- 235000011852 gelatine desserts Nutrition 0.000 claims description 3
- 150000004676 glycans Chemical class 0.000 claims description 2
- 229920001282 polysaccharide Polymers 0.000 claims description 2
- 239000005017 polysaccharide Substances 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- 239000000243 solution Substances 0.000 abstract 4
- 239000011259 mixed solution Substances 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 229960003511 macrogol Drugs 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- GHHURQMJLARIDK-UHFFFAOYSA-N 2-hydroxypropyl octanoate Chemical compound CCCCCCCC(=O)OCC(C)O GHHURQMJLARIDK-UHFFFAOYSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000001079 digestive effect Effects 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000007902 hard capsule Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 208000008035 Back Pain Diseases 0.000 description 1
- 235000004035 Cryptotaenia japonica Nutrition 0.000 description 1
- 244000146493 Cryptotaenia japonica Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- 206010034464 Periarthritis Diseases 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 229940125716 antipyretic agent Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000007160 gastrointestinal dysfunction Effects 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 108010013480 succinylated gelatin Proteins 0.000 description 1
- 229940007079 succinylated gelatin Drugs 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
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- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は、ロキソプロフェンナトリウムを溶解した溶液を軟カプセルに充填した経口投与用のカプセル剤に関する。 The present invention relates to a capsule for oral administration in which a soft capsule is filled with a solution in which loxoprofen sodium is dissolved.
ロキソプロフェンナトリウムは、消化管障害作用が比較的弱いにもかかわらず鎮痛・抗炎症作用が強い、フェニルピロピオン酸系の非ステロイド性鎮痛・抗炎症・解熱医薬品成分である。本成分は、生体内で活性体に変換されたのち作用を示すプロドラッグであるため、他の非ステロイド性鎮痛・抗炎症・解熱剤と比較し、消化管障害が少ない等、優れた特性を有している。臨床的には、関節リウマチ、変形性関節症、腰痛症、肩関節周囲炎、歯痛ならびに手術後・外傷後・抜歯後の疼痛・炎症、急性上気道炎の発熱・疼痛に有用性の高い薬剤であることが認められている。 Loxoprofen sodium is a non-steroidal analgesic / anti-inflammatory / antipyretic medicinal component of the phenylpyroponic acid type that has a strong analgesic / anti-inflammatory effect despite its relatively weak gastrointestinal dysfunction. Since this component is a prodrug that exhibits an action after being converted to an active form in vivo, it has superior properties such as less gastrointestinal disorders compared to other nonsteroidal analgesics / anti-inflammatory / antipyretic agents. doing. Clinically, it is a highly useful drug for rheumatoid arthritis, osteoarthritis, low back pain, shoulder periarthritis, toothache and pain / inflammation after surgery / posttraumatic / extraction, acute upper respiratory tract fever / pain It is recognized that
ロキソプロフェンナトリウムは、付着性が高い薬物として知られ、通常の方法ではキャッピングやスティキング等の打錠障害のため打錠できない。このため吸収能の高い賦形剤と共に湿式造粒し、滑沢剤を添加して打錠するなど、特別の工夫が必要である。 Loxoprofen sodium is known as a highly adherent drug and cannot be tableted by conventional methods due to tableting problems such as capping and sticking. For this reason, special measures are required, such as wet granulation with excipients with high absorbability, tableting with a lubricant added.
ロキソプロフェンナトリウムは、その有用性の高さから、スイッチＯＴＣ推奨成分とされ、現在、錠剤の剤形で一般用医薬品として市販されている。一般に錠剤は、胃内の環境によって溶出性に差異が生じることが懸念され、また、速やかな薬効発現の点で必ずしも好ましい剤形ではない、という問題がある。特に鎮痛を目的とした使用の場合、服用後に速やかな薬効発現が望まれるが、錠剤の場合、消化液の量やｐＨの状況によっては、錠剤が崩壊する時間やロキソプロフェンが消化液に溶解する時間が遅延することが懸念される。 Loxoprofen sodium is recommended as a switch OTC component because of its high usefulness, and is currently marketed as an over-the-counter drug in tablet form. In general, there is a concern that a difference in dissolution may occur depending on the environment in the stomach of a tablet, and there is a problem that it is not necessarily a preferable dosage form in terms of rapid onset of drug efficacy. Especially for the purpose of analgesia, rapid onset of drug efficacy is desired after taking, but in the case of tablets, depending on the amount of digestive fluid and pH, the time for the tablet to disintegrate or the time for loxoprofen to dissolve in the digestive fluid There is concern that it will be delayed.
ロキソプロフェンナトリウムを含有する経口製剤、特にカプセル剤に関する先行技術としては、特許文献１〜３がある。特許文献１では、ロキソプロフェンナトリウムを基剤に溶解又は分散させてカプセル中に充填することにより、錠剤等の粉体加工製剤化の困難性を回避した製剤を得ることが示されている。ここで、油脂、多価アルコール及び界面活性剤から選ばれる一種以上の基剤に溶解又は分散させることとしている。溶液とする場合、ロキソプロフェンをプロピレングリコールまたはポリエチレングリコールに溶解することが実施例に記載されているが、プロピレングリコールまたはポリエチレングリコールは、カプセル剤皮を軟化、膨潤、溶解または崩壊させる要因となりうる。さらに、ロキソプロフェンを分散する製剤の場合、製剤性状は澄明と成り得ず、商品性が損なわれた製剤となっている。特許文献２では、カプセル充填液としての性能を評価する方法として、カプセル剤皮の軟化を継時的に観察することが示されている。ここでは、イブプロフェンをポリエチレングリコール、水及びテルペン類に溶解させることを特徴としたカプセル充填液が示されており、ポリエチレングリコールが一定の組成範囲内であれば、継時的なカプセルの軟化や割れが生じないことを示している。特許文献３では、ロキソプロフェンをグリセリンに溶解させた後、ヒプロメロースを主成分とした硬カプセルに封入した硬カプセル製剤が示されている。軟カプセル剤では、充てん液にグリセリンを含む場合、継時的にグリセリンがカプセル剤皮に移行し、軟化が進むため、ロキソプロフェンの軟カプセル剤を製する場合、本技術は採用できない。 Patent Documents 1 to 3 are prior arts related to oral formulations containing loxoprofen sodium, particularly capsules. Patent Document 1 discloses that a preparation that avoids difficulty in preparing a powder or the like such as a tablet is obtained by dissolving or dispersing loxoprofen sodium in a base and filling the capsule into a capsule. Here, it is supposed to be dissolved or dispersed in one or more bases selected from fats and oils, polyhydric alcohols and surfactants. When it is used as a solution, it is described in the Examples that loxoprofen is dissolved in propylene glycol or polyethylene glycol. However, propylene glycol or polyethylene glycol can cause the capsule skin to soften, swell, dissolve, or disintegrate. Furthermore, in the case of a formulation in which loxoprofen is dispersed, the formulation properties cannot be clear, and the formulation is a product with impaired merchantability. Patent Document 2 shows that the softening of the capsule skin is observed over time as a method for evaluating the performance as the capsule filling liquid. Here, a capsule filling liquid characterized by dissolving ibuprofen in polyethylene glycol, water and terpenes is shown. If the polyethylene glycol is within a certain composition range, softening and cracking of capsules over time is shown. Indicates that does not occur. Patent Document 3 discloses a hard capsule preparation in which loxoprofen is dissolved in glycerin and then encapsulated in a hard capsule mainly composed of hypromellose. In soft capsules, when glycerin is contained in the filling liquid, glycerin is transferred to the capsule skin over time, and softening proceeds. Therefore, this technique cannot be used when producing loxoprofen soft capsules.
以上に鑑み、本発明の課題は、ロキソプロフェンナトリウムを溶解させた状態で投与可能な軟カプセル剤であって、該軟カプセル剤が、崩壊性、溶出性に優れることから、速やかな効き目が期待され、また、カプセル剤皮が継時的に割れや軟化を生じず、主薬の安定性も良好である医薬品製剤を提供することである。 In view of the above, an object of the present invention is a soft capsule that can be administered in a state in which loxoprofen sodium is dissolved, and since the soft capsule is excellent in disintegration and dissolution properties, a rapid effect is expected. Another object of the present invention is to provide a pharmaceutical preparation in which the capsule skin does not crack or soften over time and the stability of the active ingredient is good.
本発明により前記課題は、ロキソプロフェンナトリウム（Ａ）、プロピレングリコール（Ｂ）及びプロピレングリコール脂肪酸エステルからなる室温で澄明な溶液であり、任意にクエン酸トリエチル（Ｃ）をも含むことができ、このとき、溶液の組成比（重量基準、以下同じ）が
Ａ ≦ ２×Ｂ ＋ Ｃ／４
を満たし、且つ、（Ｂ）が溶液の１０％以下となる組成物を充填して成る軟カプセル剤により達成することが可能となった。
According to the present invention, the above-mentioned problem is a clear solution at room temperature comprising loxoprofen sodium (A), propylene glycol (B) and propylene glycol fatty acid ester, and can optionally contain triethyl citrate (C), The composition ratio of the solution (weight basis, the same applies hereinafter) is A ≦ 2 × B + C / 4
And a soft capsule formed by filling a composition in which (B) is 10% or less of the solution.
また、プロピレングリコールの代わりにポリエチレングリコールを用いて、ロキソプロフェンナトリウム（Ａ）、ポリエチレングリコール（Ｄ）及びプロピレングリコール脂肪酸エステルからなる室温で澄明な溶液であり、任意にクエン酸トリエチル（Ｃ）をも含むことができ、このとき、溶液の組成比が
Ａ ≦ Ｄ／２ ＋ Ｃ／４
を満たし、且つ、（Ｄ）が溶液の８５％以下となる組成物を充填して成る軟カプセル剤でも同様の効果が得られることが判明した。
Moreover, it is a clear solution at room temperature consisting of loxoprofen sodium (A), polyethylene glycol (D) and propylene glycol fatty acid ester using polyethylene glycol instead of propylene glycol, and optionally also containing triethyl citrate (C) At this time, the composition ratio of the solution is A ≦ D / 2 + C / 4
It was also found that the same effect can be obtained with a soft capsule filled with a composition satisfying the above and (D) is 85% or less of the solution.
さらに、プロピレングリコールとポリエチレングリコールを共に用い、ロキソプロフェンナトリウム（Ａ）、プロピレングリコール（Ｂ）、ポリエチレングリコール（Ｄ）及びプロピレングリコール脂肪酸エステルからなる室温で澄明な溶液であり、任意にクエン酸トリエチル（Ｃ）をも含むことができ、このとき、溶液の組成比が
Ａ ≦ ２×Ｂ ＋ Ｄ／２ ＋ Ｃ／４
を満たし、且つ、（Ｂ）が溶液の１０％以下となる組成物を充填して成る軟カプセル剤でも同様の効果が得られることが判明した。
Furthermore, it is a clear solution at room temperature composed of sodium loxoprofen (A), propylene glycol (B), polyethylene glycol (D) and propylene glycol fatty acid ester using propylene glycol and polyethylene glycol, and optionally triethyl citrate (C In this case, the composition ratio of the solution is A ≦ 2 × B + D / 2 + C / 4
It was found that the same effect can be obtained even in a soft capsule filled with a composition satisfying the above and (B) is 10% or less of the solution.
なお、これら軟カプセル剤は、ロータリーダイ法または滴下法で製造することができ、カプセル剤皮の主構成成分がゼラチン、コハク化ゼラチン及び／又はプルランのような植物由来多糖類から選択される。 These soft capsules can be produced by a rotary die method or a dropping method, and the main component of the capsule skin is selected from plant-derived polysaccharides such as gelatin, succinylated gelatin and / or pullulan.
ロキソプロフェンナトリウムは、その水和物を使用することもできる。ロキソプロフェンナトリウムは、プロピレングリコールに良く溶ける。しかしながら、プロピレングリコールは、カプセル剤皮を溶解又は膨潤するため、配合できる量には制限がある。本発明においては、種々の検討から、カプセル充填用溶液に対して１０％まで添加することが可能であった。 Loxoprofen sodium can also be used as its hydrate. Loxoprofen sodium is well soluble in propylene glycol. However, since propylene glycol dissolves or swells the capsule skin, the amount that can be blended is limited. In the present invention, it was possible to add up to 10% with respect to the capsule filling solution from various studies.
本発明において鋭意検討した結果、プロピレングリコール及び／又はポリエチレングリコールと共に、プロピレングリコール脂肪酸エステルを配合することによって、ロキソプロフェンナトリウムが安定して溶解した状態となる軟カプセル剤の充填液に適した組成物を得ることが可能となった。 As a result of intensive studies in the present invention, a composition suitable for a soft capsule filling liquid in which loxoprofen sodium is stably dissolved by blending propylene glycol fatty acid ester together with propylene glycol and / or polyethylene glycol. It became possible to get.
プロピレングリコール脂肪酸エステルは、脂肪酸低級アルキルエステルによるプロピレングリコールの直接エステル化により、または触媒の存在下天然油脂とプロピレングリコールとのエステル交換によって合成されるＨＬＢ３．４程度の親油性界面活性剤である。市販品として、ＳＥＦＳＯＬ−２１８、ＳＥＦＳＯＬ−２２８、ＰＤＤ（日本サーファクタント工業）、ディフォーマーＰＳ（日本活性剤）、ホモテックスＰＳ−２００Ｖ（花王）、ミグリオールＳ４０（ミツバ貿易）などがある。 Propylene glycol fatty acid ester is a lipophilic surfactant of about HLB 3.4 that is synthesized by direct esterification of propylene glycol with a fatty acid lower alkyl ester or by transesterification of natural fat and oil with propylene glycol in the presence of a catalyst. Commercially available products include SEFSOL-218, SEFSOL-228, PDD (Nippon Surfactant Industries), Deformer PS (Nippon Activator), Homotex PS-200V (Kao), Miglyol S40 (Mitsuba Trading) and the like.
ロキソプロフェンナトリウムは、ポリエチレングリコールに溶ける。プロピレングリコールと同様に、ポリエチレングリコールは、カプセル剤皮を溶解又は膨潤させるため、配合できる量には制限がある。本発明においては、種々の検討から、カプセル充填用溶液に対して８５％まで添加することが可能であった。ポリエチレングリコールとしては、マクロゴール２００，マクロゴール３００，マクロゴール４００，マクロゴール６００などの常温で液状のものから選択される。マクロゴール４００が好ましい。市販品として、マクロゴール４００（三洋化成工業、日油）などがある。 Loxoprofen sodium is soluble in polyethylene glycol. Like propylene glycol, polyethylene glycol dissolves or swells the capsule skin, so the amount that can be blended is limited. In the present invention, from various studies, it was possible to add up to 85% to the capsule filling solution. The polyethylene glycol is selected from those which are liquid at room temperature, such as Macrogol 200, Macrogol 300, Macrogol 400, Macrogol 600 and the like. Macrogol 400 is preferred. Examples of commercially available products include Macrogol 400 (Sanyo Chemical Industries, NOF).
クエン酸トリエチルは、無色の粘稠性のある水にやや溶けやすい液である。可塑剤やコーティング剤として利用される。市販品として、シトロフレックスＮｏ．２（ＣＢＣ）、ハイダーゲンＴＥＣ（コグニスジャパン）などがある。 Triethyl citrate is a solution that is slightly soluble in colorless viscous water. Used as a plasticizer and coating agent. As a commercial product, Citroflex No. 2 (CBC), Heidergen TEC (Cognis Japan) and the like.
ロキソプロフェンナトリウムは、あらかじめプロピレングリコールおよび／またはポリエチレングリコールと、プロピレングリコール脂肪酸エステルと、任意にクエン酸トリエチルを所定比率で混合し、これへ溶解してもよいし、またはプロピレングリコールおよび／またはポリエチレングリコールに溶解し、その後プロピレングリコール脂肪酸エステルと、任意にクエン酸トリエチルを加えるなど、任意の方法で本発明のカプセル充填用組成物に調製することができる。その際、ロキソプロフェンナトリウムの充填用組成物全体に占める割合は、カプセルが大型化するのを避けるため、１3％以上とすべきである。 Loxoprofen sodium may be prepared by mixing propylene glycol and / or polyethylene glycol, propylene glycol fatty acid ester, and optionally triethyl citrate in a predetermined ratio, and dissolving them in propylene glycol and / or polyethylene glycol. The capsule filling composition of the present invention can be prepared by any method such as dissolving, and then adding propylene glycol fatty acid ester and optionally triethyl citrate. At that time, the proportion of loxoprofen sodium in the entire filling composition should be 13% or more in order to avoid an increase in the size of the capsule.
一般的に、プロピレングリコールを軟カプセル充填用組成物に使用する場合、継時的にカプセル剤皮にプロピレングリコールが移行する現象が生じる。この移行によって、カプセルが膨潤、変形及び溶解することもある。このため、有効成分、賦形剤やその他製剤特性に応じて、プロピレングリコールが使用不可であるか、また可能であっても適切な使用範囲内であることが理想となる。カプセル剤皮とカプセル充填用組成物間で成分移行は、保存条件（温度、湿度、雰囲気）、時間、成分組成、等張性、pH、水分等、様々な要因が考えられる。本発明では、ロキソプロフェンナトリウムをプロピレングリコールに溶解し、澄明な溶液状態としてカプセルに充填すること、さらにカプセルの商品性、安定性が得られる最適な組成範囲を鋭意研究の上、確立することが達成された。 Generally, when propylene glycol is used in a soft capsule filling composition, a phenomenon occurs in which propylene glycol migrates to the capsule skin over time. This transition can cause the capsule to swell, deform and dissolve. For this reason, it is ideal that propylene glycol is unusable or within an appropriate range of use even if it is possible, depending on the active ingredient, excipient and other preparation characteristics. Various factors such as storage conditions (temperature, humidity, atmosphere), time, component composition, isotonicity, pH, moisture, etc. can be considered for the component transfer between the capsule skin and the capsule filling composition. In the present invention, loxoprofen sodium is dissolved in propylene glycol and filled into a capsule in a clear solution state, and further, an optimum composition range capable of obtaining the commercial properties and stability of the capsule has been established through intensive research. It was done.
プロピレングリコールと合わせてポリエチレングリコールを使用すること、ならびにプロピレングリコールの代わりにポリエチレングリコールを使用することも本発明の範囲である。ポリエチレングリコールもプロピレングリコール同様、カプセル剤皮への移行現象があるため、その使用は鋭意研究の上、確立に至った。 The use of polyethylene glycol in combination with propylene glycol and the use of polyethylene glycol in place of propylene glycol are also within the scope of the present invention. Polyethylene glycol, like propylene glycol, has a phenomenon of migration to capsule skin, and its use has been established through intensive research.
以下に実施例としてカプセル充填用組成物の例を挙げる。各成分を混合して液状とし、ロータリーダイ方式でゼラチンカプセルに充填し、軟カプセル剤を製造した。なお、実施例及び比較例において、プロピレングリコール脂肪酸エステルとして日本サーファクタント工業（株）製ＳＥＦＳＯＬ−２１８を使用した。なお各成分の量は重量部である。カプセルの安定性について、○印は外観および内容物について異常がないことを示し、析出とはロキソプロフェンナトリウムの析出を意味する。 Examples of capsule filling compositions are given below as examples. Each component was mixed to form a liquid and filled into a gelatin capsule by a rotary die method to produce a soft capsule. In Examples and Comparative Examples, SEFSOL-218 manufactured by Nippon Surfactant Kogyo Co., Ltd. was used as the propylene glycol fatty acid ester. The amount of each component is parts by weight. Regarding the stability of the capsule, the ◯ mark indicates that there is no abnormality in the appearance and contents, and the precipitation means the precipitation of loxoprofen sodium.
次に、実施例及び比較例に従って製造した軟カプセル剤について、ガラス瓶に密閉した状態で５０℃環境下に保存し、ロキソプロフェンの残存率を測定した。その結果、極めて良好な安定性が得られた。結果を表４に示す。 Next, about the soft capsule manufactured according to the Example and the comparative example, it preserve | saved in a 50 degreeC environment in the state sealed in the glass bottle, and the residual rate of the loxoprofen was measured. As a result, very good stability was obtained. The results are shown in Table 4.
Claims (4)
Ａ ≦ ２×Ｂ ＋ Ｃ／４
を満たし、且つ、（Ｂ）が溶液の１０％以下となる組成物を充填して成る軟カプセル剤。 A clear solution at room temperature consisting of sodium loxoprofen (A), propylene glycol (B) and propylene glycol fatty acid ester, optionally containing triethyl citrate (C), wherein the composition ratio by weight of the solution is A ≦ 2 x B + C / 4
And a soft capsule formed by filling a composition in which (B) is 10% or less of the solution.
Ａ ≦ Ｄ／２ ＋ Ｃ／４
を満たし、且つ、（Ｄ）が溶液の８５％以下となる組成物を充填して成る軟カプセル剤。 A clear solution at room temperature consisting of sodium loxoprofen (A), polyethylene glycol (D) and propylene glycol fatty acid ester, optionally containing triethyl citrate (C), wherein the composition ratio by weight of the solution is A ≦ D / 2 + C / 4
And a soft capsule filled with a composition in which (D) is 85% or less of the solution.
Ａ ≦ ２×Ｂ ＋ Ｄ／２ ＋ Ｃ／４
を満たし、且つ、（Ｂ）が溶液の１０％以下となる組成物を充填して成る軟カプセル剤。 A room temperature clear solution consisting of sodium loxoprofen (A), propylene glycol (B), polyethylene glycol (D) and propylene glycol fatty acid ester, optionally containing triethyl citrate (C), where the weight basis of the solution The composition ratio according to A ≦ 2 × B + D / 2 + C / 4
And a soft capsule formed by filling a composition in which (B) is 10% or less of the solution.
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| JP2001031565A (en) * | 1999-07-19 | 2001-02-06 | Nisshin Flour Milling Co Ltd | Capsule preparation containing loxoprofen sodium |
| JP2003055254A (en) * | 2001-08-17 | 2003-02-26 | Toyo Capsule Kk | Cyclosporin preparation for oral administration |
| JP2011084521A (en) * | 2009-10-16 | 2011-04-28 | Toyo Capsule Kk | Azelastine hydrochloride-containing capsule preparation |
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