JP2012214444A - Loxoprofen-containing external preparation - Google Patents
Loxoprofen-containing external preparation Download PDFInfo
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- JP2012214444A JP2012214444A JP2012059521A JP2012059521A JP2012214444A JP 2012214444 A JP2012214444 A JP 2012214444A JP 2012059521 A JP2012059521 A JP 2012059521A JP 2012059521 A JP2012059521 A JP 2012059521A JP 2012214444 A JP2012214444 A JP 2012214444A
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- castor oil
- hydrogenated castor
- polyoxyethylene hydrogenated
- loxoprofen
- purified water
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- 229960002373 loxoprofen Drugs 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 title abstract description 68
- -1 polyoxyethylene Polymers 0.000 claims abstract description 54
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 50
- 239000004359 castor oil Substances 0.000 claims abstract description 48
- 235000019438 castor oil Nutrition 0.000 claims abstract description 48
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims abstract description 48
- 230000002378 acidificating effect Effects 0.000 claims abstract description 14
- 239000000126 substance Substances 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims description 6
- 230000001804 emulsifying effect Effects 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 230000003381 solubilizing effect Effects 0.000 claims description 4
- 230000000699 topical effect Effects 0.000 claims description 2
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical compound O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 claims 4
- 238000001556 precipitation Methods 0.000 abstract description 29
- 239000004094 surface-active agent Substances 0.000 abstract description 8
- 230000008021 deposition Effects 0.000 abstract 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 57
- 239000008213 purified water Substances 0.000 description 56
- 239000012085 test solution Substances 0.000 description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- 150000008064 anhydrides Chemical class 0.000 description 23
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 231100000245 skin permeability Toxicity 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
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- FDCJDKXCCYFOCV-UHFFFAOYSA-N 1-hexadecoxyhexadecane Chemical compound CCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCC FDCJDKXCCYFOCV-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
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- 229920001451 polypropylene glycol Polymers 0.000 description 3
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- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 2
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- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical compound CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 description 2
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 2
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 2
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 2
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 2
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
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- 206010061218 Inflammation Diseases 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 235000019437 butane-1,3-diol Nutrition 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940031578 diisopropyl adipate Drugs 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000005063 solubilization Methods 0.000 description 2
- 230000007928 solubilization Effects 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- 229940042585 tocopherol acetate Drugs 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010061459 Gastrointestinal ulcer Diseases 0.000 description 1
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- 239000002211 L-ascorbic acid Substances 0.000 description 1
- 235000000069 L-ascorbic acid Nutrition 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 206010034464 Periarthritis Diseases 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 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
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- DTPCFIHYWYONMD-UHFFFAOYSA-N decaethylene glycol Polymers OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO DTPCFIHYWYONMD-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229960003720 enoxolone Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
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- 241000411851 herbal medicine Species 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 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、ロキソプロフェン及び／又はその医学的に許容できる塩を含有する外用剤の分野に関する。さらに詳しくは、本分野で、酸性条件で生じる析出あるいは沈殿の生成を防止する技術に関する。 The present invention relates to the field of external preparations containing loxoprofen and / or a medically acceptable salt thereof. More specifically, the present invention relates to a technique for preventing precipitation or precipitation generation that occurs under acidic conditions.
ロキソプロフェン(正式名：２−［p−(２−オキソシクロペンチルメチル)フェニル］プロピオン酸)のナトリウム塩、すなわちロキソプロフェンナトリウムはフェニルプロピオン酸系の非ステロイド性消炎鎮痛剤の一つである。関節リウマチ、変形性関節症、腰痛症、肩関節周囲炎、頸肩腕症候群、歯痛、外傷後並びに抜歯後の鎮痛・消炎、急性上気道炎の解熱・鎮痛に対して効果を示し、汎用されている(非特許文献１)。ロキソプロフェンナトリウムは、生体内で作用の強い活性代謝物に変換されたのち作用を発揮するいわゆるプロドラッグであり、この薬物は消化管傷害が比較的少ないという特性を有するものの、消化管潰瘍の既往歴のある患者または長期投与する時には慎重に投与することが必要である。このため、係る副作用を軽減することを目的として、炎症部位での局所薬物濃度を高め全身性の副作用を回避する目的で経皮投与型の外用剤が考えられる(特許文献１)。 Loxoprofen (formal name: 2- [p- (2-oxocyclopentylmethyl) phenyl] propionic acid) sodium salt, that is, loxoprofen sodium is one of the non-steroidal anti-inflammatory analgesics based on phenylpropionic acid. Rheumatoid arthritis, osteoarthritis, low back pain, periarthritis, neck-shoulder arm syndrome, toothache, post-traumatic and post-extraction analgesia / anti-inflammation, acute upper respiratory tract antipyretic / analgesic (Non-patent Document 1). Loxoprofen sodium is a so-called prodrug that acts after being converted to a strong active metabolite in vivo, and this drug has the characteristic of relatively little gastrointestinal damage, but has a history of gastrointestinal ulcers It is necessary to administer with caution in patients with or for long-term administration. Therefore, for the purpose of reducing such side effects, an external preparation of a transdermal administration type can be considered for the purpose of increasing the local drug concentration at the site of inflammation and avoiding systemic side effects (Patent Document 1).
ロキソプロフェンナトリウムはｐＫａ４．２０の水に極めて溶けやすい薬物であるが(非特許文献２)、精製水に溶解させるとほとんどがイオン型として存在するため、ｐＨ−分配仮説によると皮膚透過性が良好でないことが予測される。 Loxoprofen sodium is a drug that is extremely soluble in water with pKa 4.20 (Non-patent Document 2), but most of it exists as an ionic form when dissolved in purified water. Therefore, according to the pH-partition hypothesis, skin permeability is not good. It is predicted.
本発明者らは、精製水等に溶解したイオン型のロキソプロフェンを、溶液のｐＨを低下させることによりイオンに解離していない分子型とし、皮膚透過性を向上させることを考えた。しかし、分子型ロキソプロフェンの割合が増える酸性条件では、析出もしくは沈殿を生じるため、製造上問題があり、また、商品性を損なうという問題があった。
皮膚透過性を確認する方法としては、フランツ型拡散セルを用いた摘出皮膚透過性試験等が挙げられる。また、皮膚透過性を予測する方法としては、シリコンゴム膜を用いたin vitro放出試験（田中重男ほか、基礎と臨床、22(7) 、1775-1779（1988））等が挙げられる。
The present inventors considered that the ionic form of loxoprofen dissolved in purified water or the like is made into a molecular form that is not dissociated into ions by lowering the pH of the solution to improve skin permeability. However, under acidic conditions in which the proportion of molecular type loxoprofen is increased, precipitation or precipitation occurs, so that there are problems in production, and there is a problem that merchantability is impaired.
Examples of the method for confirming skin permeability include an excised skin permeability test using a Franz diffusion cell. Examples of methods for predicting skin permeability include an in vitro release test using a silicone rubber membrane (Shigeo Tanaka et al., Basic and Clinical, 22 (7), 1775-1779 (1988)).
本発明は、ロキソプロフェンを配合した外用剤のｐＨを酸及び／又は酸性物質により低下させた際に、析出あるいは沈殿の生成を防止することを課題とする。 This invention makes it a subject to prevent the production | generation of precipitation or precipitation, when the pH of the external preparation which mix | blended loxoprofen is lowered | hung with an acid and / or an acidic substance.
本発明者らは、かかる課題を解決するために鋭意検討した結果、特定の界面活性剤を配合することにより、酸性条件においても析出あるいは沈殿の生成を防止可能なことを見出し、本発明を完成した。 As a result of diligent studies to solve such problems, the present inventors have found that by adding a specific surfactant, precipitation or precipitation can be prevented even under acidic conditions, and the present invention has been completed. did.
すなわち本発明は、
（１）a）ロキソプロフェン及び／又はその医学的に許容できる塩、b）ＨＬＢ値が１２．５〜１６．５のポリオキシエチレン硬化ヒマシ油、c）酸及び／又は酸性物質を配合したことを特徴とする可溶化及び／又は乳化した外用剤、
（２）b）のポリオキシエチレン硬化ヒマシ油が、ポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン硬化ヒマシ油５０及びポリオキシエチレン硬化ヒマシ油６０からなる群から選ばれる少なくとも１種である（１）に記載の外用剤、
（３）分子型ロキソプロフェン、及びＨＬＢ値が１２．５〜１６．５のポリオキシエチレン硬化ヒマシ油を含有し、分子型ロキソプロフェンを可溶化及び／又は乳化したことを特徴とする外用剤、
（４）分子型ロキソプロフェンを、ＨＬＢ値が１２．５〜１６．５のポリオキシエチレン硬化ヒマシ油で可溶化及び／又は乳化する方法、
である。
That is, the present invention
(1) a) loxoprofen and / or a medically acceptable salt thereof, b) a polyoxyethylene hydrogenated castor oil having an HLB value of 12.5 to 16.5, c) an acid and / or an acidic substance. Solubilized and / or emulsified external preparation characterized
(2) The polyoxyethylene hydrogenated castor oil of (2) is at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50 and polyoxyethylene hydrogenated castor oil 60 (1 ) External preparations according to
(3) An external preparation characterized by containing molecular type loxoprofen and polyoxyethylene hydrogenated castor oil having an HLB value of 12.5 to 16.5, and solubilizing and / or emulsifying molecular type loxoprofen,
(4) A method of solubilizing and / or emulsifying molecular loxoprofen with polyoxyethylene hydrogenated castor oil having an HLB value of 12.5 to 16.5,
It is.
本発明により、酸性条件においても析出あるいは沈殿の生成を防止した外用剤の提供が可能となった。 According to the present invention, it is possible to provide an external preparation that prevents precipitation or precipitation even under acidic conditions.
本発明に用いられるロキソプロフェン及び／又はその医学的に許容できる塩としては、特にロキソプロフェンナトリウムが好ましい。本発明の外用剤におけるロキソプロフェンナトリウムの配合濃度は適用する疾病の症状に応じて適宜増減することができるが、ロキソプロフェンナトリウム無水物として、外用剤全体の０．５〜１０．０ｗ／ｖ％であることが好ましく、１．０〜５．０ｗ／ｖ％であることが更に好ましい。ただし、その剤形によって適宜変えることができる。 As loxoprofen and / or a medically acceptable salt thereof used in the present invention, loxoprofen sodium is particularly preferable. The compounding concentration of loxoprofen sodium in the external preparation of the present invention can be appropriately increased or decreased depending on the symptoms of the disease to be applied, but it is 0.5 to 10.0 w / v% of the total external preparation as loxoprofen sodium anhydride. It is preferably 1.0 to 5.0 w / v%. However, it can be appropriately changed depending on the dosage form.
本発明におけるＨＬＢ値が１２．５〜１６．５のポリオキシエチレン硬化ヒマシ油としては、ポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン硬化ヒマシ油５０、ポリオキシエチレン硬化ヒマシ油６０、ポリオキシエチレン硬化ヒマシ油８０、ポリオキシエチレン硬化ヒマシ油１００が挙げられる。好ましくはポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン硬化ヒマシ油５０、ポリオキシエチレン硬化ヒマシ油６０である。ＨＬＢ値が１２．５〜１６．５のポリオキシエチレン硬化ヒマシ油の配合濃度は、外用剤全体の０．２ｗ／ｖ％〜６．０ｗ／ｖ％であることが好ましく、溶解性の面から外用剤全体の１．０ｗ／ｖ％〜６．０ｗ／ｖ％であることが更に好ましい。 As polyoxyethylene hydrogenated castor oil having an HLB value of 12.5 to 16.5 in the present invention, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene Examples include hydrogenated castor oil 80 and polyoxyethylene hydrogenated castor oil 100. Polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60 are preferred. The blending concentration of the polyoxyethylene hydrogenated castor oil having an HLB value of 12.5 to 16.5 is preferably 0.2 w / v% to 6.0 w / v% of the entire external preparation, from the viewpoint of solubility. More preferably, it is 1.0 w / v% to 6.0 w / v% of the external preparation.
ＨＬＢ値とは、Ｈｙｄｒｏｐｈｉｌｅ−Ｌｉｐｏｐｈｉｌｅ−Ｂａｌａｎｃｅ値の略称であり、界面活性剤の親水性−親油性バランスを数値化したものを指す。 The HLB value is an abbreviation for Hydrophile-Lipophile-Balance value and refers to a value obtained by quantifying the hydrophilic-lipophilic balance of a surfactant.
また、本発明における外用剤のｐＨは、酸及び／又は酸性物質及び／又は塩基により調整し、３．５〜６．２であることが好ましく、３．５〜５．８であることが更に好ましい。 Moreover, the pH of the external preparation in the present invention is adjusted with an acid and / or an acidic substance and / or a base, and is preferably 3.5 to 6.2, and more preferably 3.5 to 5.8. preferable.
本発明における酸としては、特に制限されないが、通常外用剤に配合される適当な酸を使用することができる。そのような酸の例としては、例えば、塩酸、クエン酸、乳酸、リン酸、酒石酸、グルコン酸等を挙げることができる。 Although it does not restrict | limit especially as an acid in this invention, The suitable acid normally mix | blended with an external preparation can be used. Examples of such acids include hydrochloric acid, citric acid, lactic acid, phosphoric acid, tartaric acid, gluconic acid and the like.
本発明における酸性物質とは、通常外用剤に配合される外用剤のｐＨを低下させる物質のことであり、例えば、Ｌ−アスパラギン酸、Ｌ−グルタミン酸、グリチルレチン酸、Ｌ−アスコルビン酸、カルボキシビニルポリマー、イソステアリン酸、オレイン酸等を挙げることができる。 The acidic substance in the present invention is a substance that lowers the pH of an external preparation that is usually blended with an external preparation. For example, L-aspartic acid, L-glutamic acid, glycyrrhetinic acid, L-ascorbic acid, carboxyvinyl polymer , Isostearic acid, oleic acid and the like.
ｐＨ調節の際には、これらの酸及び／又は酸性物質及び／又は塩基を１種又は２種以上組み合わせて使用することができる。 In adjusting the pH, these acids and / or acidic substances and / or bases can be used alone or in combination of two or more.
本発明における可溶化とは、溶媒に溶解しない物質がミセル中に取り込まれることにより、透明かつ均一に溶解することを指し、本発明における乳化とは、溶媒に溶解しない物質を、界面活性剤により溶媒に小滴として分散させ、エマルションを生成することを指す。また、本発明の可溶化及び／又は乳化した外用剤とは、可溶化及び／又は乳化により、析出あるいは沈殿の生じていない外用剤を指す。 The solubilization in the present invention means that a substance that does not dissolve in a solvent is taken into the micelle and is dissolved transparently and uniformly, and the emulsification in the present invention refers to a substance that does not dissolve in a solvent by a surfactant. It refers to dispersing as a droplet in a solvent to form an emulsion. In addition, the solubilized and / or emulsified external preparation of the present invention refers to an external preparation that is not precipitated or precipitated by solubilization and / or emulsification.
本発明の外用剤の剤形は、特に限定されるものではないが、例えば、ローション剤、液剤、乳液、クリーム剤、軟膏剤、ゲル剤、エアゾール剤、チック剤等が挙げられ、これらは公知の方法で製造することができる。製造に際しては、本発明の効果を損なわない範囲で、他の非ステロイド性消炎鎮痛剤、局所刺激剤、清涼化剤、血行促進剤、抗炎症剤、抗ヒスタミン剤、生薬等の外用剤に用いる他の有効成分、ｐＨ調節剤、抗酸化剤、界面活性剤、紫外線吸収剤、経皮吸収促進剤等の添加物を適宜添加してもよい。 The dosage form of the external preparation of the present invention is not particularly limited, and examples thereof include lotions, liquids, emulsions, creams, ointments, gels, aerosols, tics, and the like. It can be manufactured by the method. In the production, other non-steroidal anti-inflammatory analgesics, topical stimulants, cooling agents, blood circulation promoters, anti-inflammatory agents, antihistamines, herbal medicines and other external preparations are used as long as the effects of the present invention are not impaired. You may add suitably additives, such as an active ingredient, a pH adjuster, an antioxidant, surfactant, a ultraviolet absorber, and a percutaneous absorption enhancer.
以下に、実施例、試験例を示し、本発明を詳細に説明する。なお、本発明はこれら実施例に限定されるものでは無い。 Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples. The present invention is not limited to these examples.
実施例１
ロキソプロフェンナトリウム １ｇ
ポリオキシエチレン硬化ヒマシ油６０ ４ｇ
エタノール １０ｇ
精製水 ８５ｇ
クエン酸 適量
ロキソプロフェンナトリウム１ｇを精製水８５ｇとエタノール１０ｇの混合物に溶解した。これにポリオキシエチレン硬化ヒマシ油６０を４ｇ溶解し、クエン酸適量を加え、ｐＨを４．８に調節し、ローション剤を得た。
Example 1
Loxoprofen sodium 1g
Polyoxyethylene hydrogenated castor oil 60 4g
Ethanol 10g
85g of purified water
Citric acid appropriate amount 1 g of loxoprofen sodium was dissolved in a mixture of 85 g of purified water and 10 g of ethanol. 4 g of polyoxyethylene hydrogenated castor oil 60 was dissolved therein, an appropriate amount of citric acid was added, and the pH was adjusted to 4.8 to obtain a lotion agent.
実施例２
ロキソプロフェンナトリウム ３ｇ
ポリオキシエチレン硬化ヒマシ油６０ ４ｇ
エタノール １０ｇ
精製水 ８３ｇ
希塩酸 適量
ロキソプロフェンナトリウム３ｇを精製水８３ｇとエタノール１０ｇの混合物に溶解した。これにポリオキシエチレン硬化ヒマシ油６０を４ｇ溶解し、希塩酸適量を加え、ｐＨを５．４に調節し、ローション剤を得た。
Example 2
Loxoprofen sodium 3g
Polyoxyethylene hydrogenated castor oil 60 4g
Ethanol 10g
83g of purified water
Dilute hydrochloric acid appropriate amount 3 g of loxoprofen sodium was dissolved in a mixture of 83 g of purified water and 10 g of ethanol. 4 g of polyoxyethylene hydrogenated castor oil 60 was dissolved therein, an appropriate amount of diluted hydrochloric acid was added, and the pH was adjusted to 5.4 to obtain a lotion agent.
実施例３
ロキソプロフェンナトリウム ２ｇ
ポリオキシエチレン硬化ヒマシ油５０ ２ｇ
ポリオキシエチレン硬化ヒマシ油６０ ４ｇ
アジピン酸ジイソプロピル ２ｇ
トリ（カプリル・カプリン酸）グリセリル １０ｇ
セタノール ３ｇ
ステアリルアルコール ３ｇ
酢酸トコフェロール １ｇ
プロピレングリコール ５ｇ
精製水 ６８ｇ
リン酸 適量
ロキソプロフェンナトリウム２ｇ、ポリオキシエチレン硬化ヒマシ油５０ ２ｇ、ポリオキシエチレン硬化ヒマシ油６０ ４ｇを精製水６８ｇとプロピレングリコール５ｇの混合物に溶解した。これにリン酸適量を加え、ｐＨを５．３に調節し、水相とした。別に、アジピン酸ジイソプロピル２ｇ、トリ（カプリル・カプリン酸）グリセリル１０ｇ、セタノール３ｇ、ステアリルアルコール３ｇ、酢酸トコフェロール１ｇを約８０℃に加温し、撹拌して油相とした。約８０℃に加温した水相に油相を加え、攪拌しながら室温まで冷却し、これにリン酸適量を加え、ｐＨを５．０に調節して乳液を得た。
Example 3
Loxoprofen sodium 2g
2 g of polyoxyethylene hydrogenated castor oil 50
Polyoxyethylene hydrogenated castor oil 60 4g
Diisopropyl adipate 2g
Tri (capryl / capric acid) glyceryl 10g
Setanol 3g
Stearyl alcohol 3g
Tocopherol acetate 1g
5g propylene glycol
68g of purified water
Phosphoric acid appropriate amount Loxoprofen sodium 2g, polyoxyethylene hydrogenated castor oil 502g, polyoxyethylene hydrogenated castor oil 604g was dissolved in a mixture of purified water 68g and propylene glycol 5g. An appropriate amount of phosphoric acid was added thereto, and the pH was adjusted to 5.3 to obtain an aqueous phase. Separately, 2 g of diisopropyl adipate, 10 g of tri (capryl / capric acid) glyceryl, 3 g of cetanol, 3 g of stearyl alcohol and 1 g of tocopherol acetate were heated to about 80 ° C. and stirred to obtain an oil phase. The oil phase was added to the aqueous phase heated to about 80 ° C., cooled to room temperature with stirring, an appropriate amount of phosphoric acid was added thereto, and the pH was adjusted to 5.0 to obtain an emulsion.
実施例４
ロキソプロフェンナトリウム １ｇ
ｌ−メントール ３ｇ
ポリオキシエチレン硬化ヒマシ油４０ ２ｇ
ポリオキシエチレン硬化ヒマシ油５０ ４ｇ
ヒドロキシプロピルセルロース ２ｇ
１，３−ブチレングリコール １０ｇ
エタノール ５０ｇ
精製水 ２８ｇ
クエン酸 適量
ロキソプロフェンナトリウム１ｇ、ポリオキシエチレン硬化ヒマシ油４０ ２ｇ、ポリオキシエチレン硬化ヒマシ油５０ ４ｇを精製水２８ｇに溶解した。別に、ｌ−メントール３ｇを１，３−ブチレングリコール１０ｇとエタノール５０ｇの混合物に溶解したものをこれに加え混合した。これに、ヒドロキシプロピルセルロース２ｇを加え、攪拌した。これにクエン酸適量を加え、ｐＨを５．０に調節してゲル剤を得た。
Example 4
Loxoprofen sodium 1g
l-Menthol 3g
Polyoxyethylene hydrogenated castor oil 40 2g
Polyoxyethylene hydrogenated castor oil 50 4g
Hydroxypropylcellulose 2g
1,3-butylene glycol 10g
50g ethanol
28g of purified water
Citric acid appropriate amount Loxoprofen sodium 1g, polyoxyethylene hydrogenated castor oil 402g, polyoxyethylene hydrogenated castor oil 504g were dissolved in purified water 28g. Separately, 3 g of l-menthol dissolved in a mixture of 10 g of 1,3-butylene glycol and 50 g of ethanol was added thereto and mixed. To this, 2 g of hydroxypropylcellulose was added and stirred. An appropriate amount of citric acid was added thereto, and the pH was adjusted to 5.0 to obtain a gel.
（酸性条件におけるロキソプロフェンの溶解性）
Ｈｅｎｄｅｒｓｏｎ−Ｈａｓｓｅｌｂａｌｃｈの式より、溶液中の分子型のロキソプロフェンの割合を求めると、ｐＨ６．２より高いｐＨでは分子型のロキソプロフェンはほとんど存在しない。そこで、希塩酸を適量加えてｐＨを６．２以下に調節し、分子型ロキソプロフェンの割合が増える酸性条件で、ロキソプロフェンの溶解性を確認した。溶解性の確認は、２５℃±５℃の室温で、ガラス容器にロキソプロフェンナトリウム水溶液を入れ、マグネチックスターラーで撹拌しながら、希塩酸を加え、数分撹拌した後、外観を目視で観察した。また、外観観察後にｐＨを測定した。試験液１〜１０の外観及びｐＨの結果を表１に示す。外観の欄の○は、澄明な状態、×は、析出あるいは沈殿が認められた状態を示す。
(Solubility of loxoprofen in acidic conditions)
When the ratio of molecular loxoprofen in the solution is determined from the Henderson-Hasselbalch equation, there is almost no molecular loxoprofen at a pH higher than pH 6.2. Accordingly, the appropriate amount of dilute hydrochloric acid was added to adjust the pH to 6.2 or less, and the solubility of loxoprofen was confirmed under acidic conditions in which the proportion of molecular loxoprofen increased. The solubility was confirmed by adding a loxoprofen sodium aqueous solution to a glass container at room temperature of 25 ° C. ± 5 ° C., adding dilute hydrochloric acid while stirring with a magnetic stirrer, stirring for several minutes, and visually observing the appearance. Moreover, pH was measured after appearance observation. Table 1 shows the appearance and pH results of the test solutions 1 to 10. ○ in the column of appearance indicates a clear state, and × indicates a state where precipitation or precipitation is observed.
（試験液１）
精製水にロキソプロフェンナトリウム１ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。
(Test solution 1)
After dissolving 1 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water.
（試験液２）
精製水にロキソプロフェンナトリウム１ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、希塩酸適量を加え、ｐＨを５．４に調節した。
(Test solution 2)
After dissolving 1 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. 10 mL of the solution was weighed out and an appropriate amount of diluted hydrochloric acid was added to adjust the pH to 5.4.
（試験液３）
精製水にロキソプロフェンナトリウム１ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、希塩酸適量を加え、ｐＨを５．０に調節した。
(Test solution 3)
After dissolving 1 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. 10 mL of the solution was weighed out and an appropriate amount of diluted hydrochloric acid was added to adjust the pH to 5.0.
（試験液４）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。
(Test solution 4)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water.
（試験液５）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、希塩酸適量を加え、ｐＨを５．７に調節した。
(Test solution 5)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed out and an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.7.
（試験液６）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、希塩酸適量を加え、ｐＨを５．５に調節した。
(Test solution 6)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed out and an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.5.
（試験液７）
精製水にロキソプロフェンナトリウム５ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。
(Test solution 7)
After dissolving 5 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water.
（試験液８）
精製水にロキソプロフェンナトリウム５ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、希塩酸適量を加え、ｐＨを６．４に調節した。
(Test solution 8)
After dissolving 5 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. 10 mL of the solution was weighed out and an appropriate amount of diluted hydrochloric acid was added to adjust the pH to 6.4.
（試験液９）
精製水にロキソプロフェンナトリウム５ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、希塩酸適量を加え、ｐＨを６．０に調節した。
(Test solution 9)
After dissolving 5 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed out and an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 6.0.
（試験液１０）
精製水にロキソプロフェンナトリウム５ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、希塩酸適量を加え、ｐＨを５．８に調節した。
(Test solution 10)
After dissolving 5 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed out and an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.8.
表１に示すように、１％ロキソプロフェンナトリウムの場合はｐＨ５．０以下、３％ロキソプロフェンナトリウムの場合はｐＨ５．５以下、５％ロキソプロフェンナトリウムの場合はｐＨ５．８以下に調節すると、析出あるいは沈殿が認められた。 As shown in Table 1, when 1% loxoprofen sodium is adjusted to pH 5.0 or lower, 3% loxoprofen sodium is adjusted to pH 5.5 or lower, and 5% loxoprofen sodium is adjusted to pH 5.8 or lower to cause precipitation or precipitation. Admitted.
本試験を行った際に、生じた析出あるいは沈殿は分子型ロキソプロフェンと考えられる。本発明はまた、ロキソプロフェンナトリウムを配合した外用剤において、ロキソプロフェンナトリウムが分子型ロキソプロフェンとして析出あるいは沈殿を生じるｐＨ領域において、分子型ロキソプロフェンの析出あるいは沈殿の生成を防止するものである。 Precipitation or precipitation that occurs during this test is considered to be molecular loxoprofen. The present invention also prevents molecular loxoprofen precipitation or precipitation in a pH range where loxoprofen sodium precipitates or precipitates as molecular loxoprofen in an external preparation containing loxoprofen sodium.
（界面活性剤の比較）
分子型のロキソプロフェンが存在するｐＨ条件で、界面活性剤の効果を比較した。２５℃±５℃の室温で、ガラス容器に試験液を入れ、希塩酸を適量添加し、約１２時間マグネチックスターラーで撹拌後静置し、目視で外観を観察して比較した。また、外観観察後にｐＨを測定した。試験液１１〜２３の外観及びｐＨの結果を表２に示す。外観の欄の○は、析出あるいは沈殿が認められず、分子型のロキソプロフェンが可溶化及び／又は乳化していると考えられる状態、×は、析出あるいは沈殿が認められた状態を示す。
(Surfactant comparison)
The effect of the surfactant was compared under the pH condition where the molecular form of loxoprofen was present. At room temperature of 25 ° C. ± 5 ° C., the test solution was put in a glass container, an appropriate amount of diluted hydrochloric acid was added, and the mixture was stirred for about 12 hours and then left to stand. Moreover, pH was measured after appearance observation. Table 2 shows the appearance and pH results of the test solutions 11 to 23. ○ in the column of the appearance indicates a state where no precipitation or precipitation is observed and the molecular type loxoprofen is considered to be solubilized and / or emulsified, and x indicates a state where precipitation or precipitation is observed.
（試験液１１）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、ポリオキシエチレン硬化ヒマシ油４０を０．２ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．３に調節した。
(Test solution 11)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed, 0.2 g of polyoxyethylene hydrogenated castor oil 40 was added and stirred to obtain a test solution. To this, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.3.
（試験液１２）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、ポリオキシエチレン硬化ヒマシ油５０を０．２ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．４に調節した。
(Test solution 12)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed and 0.2 g of polyoxyethylene hydrogenated castor oil 50 was added and stirred to prepare a test solution. An appropriate amount of dilute hydrochloric acid was added thereto to adjust the pH to 5.4.
（試験液１３）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、ポリオキシエチレン硬化ヒマシ油６０を０．２ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．３に調節した。
(Test solution 13)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed and 0.2 g of polyoxyethylene hydrogenated castor oil 60 was added and stirred to prepare a test solution. To this, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.3.
（試験液１４）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、ポリオキシエチレン硬化ヒマシ油２０を０．２ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．３に調節した。
(Test solution 14)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed and 0.2 g of polyoxyethylene hydrogenated castor oil 20 was added and stirred to prepare a test solution. To this, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.3.
（試験液１５）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、ポリソルベート６０を０．２ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．２に調節した。
(Test solution 15)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed, 0.2 g of polysorbate 60 was added and stirred to prepare a test solution. To this was added an appropriate amount of dilute hydrochloric acid to adjust the pH to 5.2.
（試験液１６）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、ポリソルベート８０を０．２ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．３に調節した。
(Test solution 16)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed and 0.2 g of polysorbate 80 was added and stirred to prepare a test solution. To this, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.3.
（試験液１７）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、ポリオキシエチレン（１０）ポリオキシプロピレン（４）セチルエーテルを０．２ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．３に調節した。
(Test solution 17)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed, 0.2 g of polyoxyethylene (10) polyoxypropylene (4) cetyl ether was added and stirred to prepare a test solution. To this, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.3.
（試験液１８）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、ポリオキシエチレン（２０）ポリオキシプロピレン（４）セチルエーテルを０．２ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．３に調節した。
(Test Solution 18)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed, 0.2 g of polyoxyethylene (20) polyoxypropylene (4) cetyl ether was added and stirred to prepare a test solution. To this, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.3.
（試験液１９）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、ポリオキシエチレン（２０）ポリオキシプロピレン（８）セチルエーテルを０．２ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．３に調節した。
(Test solution 19)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed, 0.2 g of polyoxyethylene (20) polyoxypropylene (8) cetyl ether was added and stirred to prepare a test solution. To this, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.3.
（試験液２０）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、モノラウリン酸ポリエチレングリコールを０．２ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．３に調節した。
(Test solution 20)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed, and 0.2 g of polyethylene glycol monolaurate was added and stirred to prepare a test solution. To this, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.3.
（試験液２１）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、モノステアリン酸ポリエチレングリコール（１０Ｅ．Ｏ．）を０．２ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．４に調節した。
(Test solution 21)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed, and 0.2 g of polyethylene glycol monostearate (10E.O.) was added and stirred to prepare a test solution. An appropriate amount of dilute hydrochloric acid was added thereto to adjust the pH to 5.4.
（試験液２２）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、モノステアリン酸ポリエチレングリコール（４０Ｅ．Ｏ．）を０．２ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．５に調節した。
(Test solution 22)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed, 0.2 g of polyethylene glycol monostearate (40E.O.) was added and stirred to obtain a test solution. To this, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.5.
(試験液２３)
精製水にロキソプロフェンナトリウム１ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、ポリオキシエチレン硬化ヒマシ油６０を０．１ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．０に調節した。
(Test Solution 23)
After dissolving 1 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed, 0.1 g of polyoxyethylene hydrogenated castor oil 60 was added and stirred to obtain a test solution. To this, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.0.
表２に示すように、ポリオキシエチレン硬化ヒマシ油２０及び他の界面活性剤では析出あるいは沈殿が認められ、ポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン硬化ヒマシ油５０、ポリオキシエチレン硬化ヒマシ油６０特異的に、析出あるいは沈殿の生成を防止する効果があった。 As shown in Table 2, precipitation or precipitation was observed in the polyoxyethylene hydrogenated castor oil 20 and other surfactants. Polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60 specifically had the effect of preventing precipitation or precipitation.
本発明により、皮膚透過性が良好な分子型のロキソプロフェンの割合が高いと考えられる酸性のｐＨ領域において、析出あるいは沈殿の生成を防止した外用剤を提供することが可能となった。 INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide an external preparation that prevents precipitation or formation of precipitates in an acidic pH region where the ratio of molecular type loxoprofen having good skin permeability is considered high.
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| JP2015061829A (en) * | 2013-08-23 | 2015-04-02 | 第一三共ヘルスケア株式会社 | Loxoprofen-containing external preparation composition |
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| JP2018021002A (en) * | 2016-01-29 | 2018-02-08 | 興和株式会社 | Pharmaceutical preparation containing loxoprofen |
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| JP2019206496A (en) * | 2018-05-30 | 2019-12-05 | 小林製薬株式会社 | External pharmaceutical composition |
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