CN1248165A - 供局部应用的尼美舒利凝胶体系 - Google Patents
供局部应用的尼美舒利凝胶体系 Download PDFInfo
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- 229960000965 nimesulide Drugs 0.000 title claims abstract description 23
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- 238000002360 preparation method Methods 0.000 claims abstract description 34
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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Abstract
本发明涉及尼美舒利局部制剂,该制剂包括:作为胶凝剂中和了的羧乙烯基聚合物或聚丙烯酰胺—异链烷烃以及一种选自下组的溶剂:乙醇、异丙醇和二甘醇一乙基醚,并涉及其制备方法。所述制剂具有优点例如该体系更高的稳定性和活性成分更高的生物利用率。
Description
本发明涉及基于凝胶体系的尼美舒利局部制剂。
尼美舒利是一种已知的抗炎剂，它的疗效被证实已有一段时间了，但它具有不良化学-物理特性的缺点；将尼美舒利用于局部制剂的主要障碍实际上就是它在水中的不溶性，以及另一方面，它在常用于这类制剂的溶剂/原料中的溶解性差。
一些供外用的尼美舒利制剂被描述于WO 96/11002中；所述制剂由该活性成分粒子在一种组分中的分散体构成，在乳膏的情况下，所述制剂包括：一种亲水性聚合物、一种油状物质、一种表面活性剂、一种碱性物质和水。
该申请未提及凝胶体系，尤其是那些活性成分被分散于非水溶剂中的体系；此外，WO 96/11002中提出的制剂未解决一些与该体系的稳定性和活性成分的生物利用率相关的问题。
现已发现，基于羧乙烯基聚合物或其它合适的胶凝剂的凝胶与尼美舒利于选自乙醇、异丙醇或二甘醇一乙基醚的溶剂中的分散体的组合，给出该体系的稳定性方面以及活性成分的释放和吸收方面的显著优势，于是改善生物利用率。
胶凝作用是优选通过呈酸性形式的羧乙烯基聚合物树脂(它在化学上表现为弱酸)的中和而获得的；至于该中和作用应用的碱，弱碱例如三乙醇胺或二异丙醇胺(以1∶1的酸/碱当量比)的应用，被证实是特别成功的。
用于所述胶凝过程的羧乙烯基聚合物(例如卡波姆)是从丙烯酸/甲基丙烯酸开始获得的，并且它的用量范围是0.1wt％～5wt％，优选0.5％～2.5％。备选地，以商品名Sepigel(Sepic)已知的聚丙烯酰胺-异链烷烃(用量范围0.5～10wt％)可被有利地用作胶凝剂。
非水溶剂在本发明凝胶体系的制备中的应用，无疑包括尼美舒利的化学-物理特性方面的以及释放和吸收性能方面的优点。具体说来，本发明涉及乙醇、异丙醇和二甘醇一乙基醚这些溶剂的应用，证实后者在增大对活性成分的吸收方面特别有效，这是由于它对脂质皮肤屏障的溶解效果。
所述溶解效果(虽然它促进尼美舒利的吸收，但它会不利地影响皮肤的水合作用)通过基于羧乙烯基聚合物的凝胶的成膜性能和触觉形成性能而得以补偿。
本发明的组合物的粘度和pH可在宽范围内变动：粘度为数厘泊至100.000以上，而优选的pH范围则是5～7。水的量可在40wt％～95wt％范围内，而溶剂的量(还根据它对水相蒸发的影响作用)对乙醇和异丙醇来说是5wt％～20wt％，优选约10％；另一方面，就二甘醇一乙基醚而论，其扩散和渗透性能与5wt％～40wt％，优选约15％的浓度相关。
活性成分尼美舒利可在宽浓度范围内被分散，优选0.5wt％～7wt％。
本发明的组合物还可包含亲脂性赋形剂，例如辛酸酯或癸酸酯，或者甘油基(8)OE，它们既能改善吸收特性和最终的覆盖性，又能改善“皮肤感觉”特性。
可进一步应用适当防腐剂体系和适合限制由溶剂的脱脂质化(delipidization)在浅层引起的任何不希望有的效果的亲脂性原料。
所述防腐剂体系利用宽范围的抗菌剂(例如咪唑烷基脲和平衡对羟基苯甲酸酯类混合物)提供微生物保护作用；稳定性的进一步保障是存在螯合剂(例如EDTA)，它能螯合任何有害离子以保持合适的粘度指数。
考虑到存在的水的高百分含量，应提示EDTA保证对防腐剂体系抗微生物的增强效果。
本发明的组合物可进一步包括润肤剂/湿润剂，例如鲸蜡基酯1～15wt％，胆固醇0.3～0.5wt％，甘油1～30wt％，肉豆蔻酸异丙酯1～10wt％，棕榈酸异丙酯0.05～5.5wt％，卵磷脂1～20wt％，羊毛脂醇0.5～15wt％，凡士林4～95wt％，大豆脂质1～20wt％；以及皮肤吸收增强剂，例如2-吡咯烷酮0.1～10wt％，丙二醇5～50wt％，吡咯烷酮衍生物0.1～10wt％。
本发明的组合物可按一种方法制备，该方法包括：
-制备含羧乙烯基聚合物胶凝剂的分散相；
-添加所述醇溶剂，分散活性成分尼美舒利，添加防腐剂和稳定剂；
-用选定的碱中和所述树脂。
至于二甘醇一乙基醚是所述溶剂的体系，该方法的方案可列举如下：
-制备含水溶性防腐剂和均匀分散的羧乙烯基聚合物的水相；
-制备含处于二甘醇一乙基醚中的防腐剂(对羟基苯甲酸酯类)的相并分散所述活性成分，添加包括辛酸酯/癸酸酯和甘油基(8)OE的相；
-制备分散体，使含有所述活性成分的相悬浮于含所述羧乙烯基聚合物的水相中；
-制备适当地溶于所述水相的稳定剂；
-用选定的碱中和所述树脂。
本发明的组合物具有如下优点：
-溶解尼美舒利的能力；
-快速性和凝胶载体的释放机制；
-促进吸收的能力；
-引起的脱水现象的减少。
既在动物(兔和豚鼠)中，也在临床研究中证实本发明的组合物被很好地耐受。
已应用熟知的药理试验(例如UV诱导的豚鼠红斑，巴豆油诱导的豚鼠耳的炎症，角叉胶诱导的大鼠肉芽肿)测试了本发明的组合物的效能。
应用14C尼美舒利在大鼠中和人志愿者中研究了皮肤吸收，在这些情况下都未观测到明显的尼美舒利系统浓度。
还按控制的双盲实验设计对200名患有上肢腱炎或者患有良性踝扭伤的患者临床测试了本发明的组合物。
证实本发明的组合物与安慰剂相比以统计上显著的方式有效。
下面是用本发明的方法得到的一些制剂的实施例：
实施例1
相 成分 ％w/w
A相 净化水 适量
咪唑烷基脲 0.20
EDTA四钠盐 0.10
B相 卡波姆(卡波泊尔(CARBOPOL)1382) 1.20
C相 混合的对羟基苯甲酸酯类 0.20
凡士林 1.00
D相 异丙醇 10.00
E相 尼美舒利 --
F相 净化水 10.00
三乙醇胺 0.60
在四个尼美舒利浓度(即2、3、4、5％w/w，每个浓度以3次不同的5kg分批)下制备了该制剂。
A+B相(即卡波帕尔在水和防腐剂的溶液中的分散体)是通过将所述凝胶在室温下溶胀两天直至达到均匀的分散体而获得的。C相是在水浴上加热的Gianke & Kunkel PM43型桨式混合机中制备的。
在添加异丙醇之后，应用Guarniero Mantelli F43CV2型均化器进行了均化。
备选地，可这样进行整个制备：在真空下通过透平机将卡波泊尔分散于水中，在添加C相后用桨叶混合，以及在添加异丙醇后再次用透平机在真空下均化。
“Paracombin”(一种对羟基苯甲酸甲酯、乙酯、丙酯、丁酯的粉状混合物)被用作防腐剂。对羟基苯甲酸甲酯、乙酯和丙酯在意大利药典(XI版)中被引述。对羟基苯甲酸丁酯在USP XXIII中被引述。
将该混合物与防腐剂咪唑烷基脲一起添加。
实施例2
％w/w
水 83.40
乙醇 10.00
尼美舒利 3.00
卡波姆(卡波泊尔1382) 1.40
凡士林 1.00
三乙醇胺 0.70
咪唑烷基脲 0.20对羟基苯甲酸甲酯、乙酯、丙酯 0.20
EDTA四钠 0.10
| 化学-物理特性 制备时 室温下 在40℃温度下45天后 45天后 |
| 外观 不透明 不透明 不透明白色凝胶 白色凝胶 白色凝胶 |
| pH 5.00 5.03 4.98 |
未观测到分离或粘度降低的迹象。
实施例3
％w/w
水 83.40
异丙醇 10.00
尼美舒利 3.00
卡波姆(卡波泊尔1382) 1.40
凡士林 1.00
三乙醇胺 0.60
咪唑烷基脲 0.20对羟基苯甲酸甲酯、乙酯、丙酯 0.20
EDTA四钠 0.10
| 化学-物理特性 制备时 室温下 在40℃温度下45天后 45天后 |
| 外观 不透明 不透明 不透明白色凝胶 白色凝胶 白色凝胶 |
| pH 5.00 5.03 5.01 |
未观测到分离或粘度降低的迹象。
实施例4相 成分 ％w/wA相 净化水 适量
甘油基(8)OE
辛酸酯/癸酸酯 2.00
咪唑烷基脲 0.20
EDTA四钠盐 0.10B相 卡波姆(卡波泊尔940) 1.00C相 混合的对羟基苯甲酸酯类 0.20
二甘醇一乙基醚 15.00
尼美舒利 --D相 净化水 10.00
三乙醇胺 0.50
在四个尼美舒利浓度(即2％、3％、4％、5％w/w，每个浓度以3次不同的5kg分批)下制备了该制剂。
实施例5
％w/w
水 83.40
二甘醇一乙基醚 15.00
尼美舒利 3.00
卡波姆(卡波泊尔940) 1.00PEG-8辛酸甘油酯/癸酸甘油酯 2.00
三乙醇胺 0.50
咪唑烷基脲 0.20对羟基苯甲酸甲酯、乙酯、丙酯 0.20
EDTA四钠 0.10
| 化学-物理特性 制备时 室温下 在40℃温度下45天后 45天后 |
| 外观 不透明 不透明 不透明白色凝胶 白色凝胶 白色凝胶 |
| pH 5.20 5.18 5.21 |
未观测到分离或粘度降低的迹象。
Claims (11)
1.呈凝胶体系形式的尼美舒利局部制剂，该制剂包括：用弱碱水溶液中和了的羧乙烯基聚合物或聚丙烯酰胺-异链烷烃以及一种选自乙醇、异丙醇、二甘醇一乙基醚的溶剂。
2.权利要求1的制剂，其中应用的乙醇和异丙醇浓度范围是5wt％～20wt％。
3.权利要求2的制剂，其中所述浓度是10wt％。
4.权利要求1的制剂，其中应用的二甘醇一乙基醚浓度范围是5％～40％。
5.权利要求4的制剂，其中所述浓度是15％。
6.权利要求1～5的制剂，其中用于中和羧乙烯基聚合物的弱碱是三乙醇胺或二异丙醇胺。
7.权利要求1～6的制剂，其中活性成分尼美舒利是在0.5～7wt％的浓度范围内被分散的。
8.上述权利要求任一项的制剂，该制剂进一步包括选自润肤剂、湿润剂、吸收增强剂、防腐剂的添加剂。
9.权利要求8的制剂，其中所述防腐剂是咪唑烷基脲、对羟基苯甲酸酯类和EDTA。
10.一种制备权利要求1～3的制剂的方法，该方法包括：
-制备含羧乙烯基聚合物胶凝剂的分散相；
-添加所述醇溶剂，分散活性成分尼美舒利，添加防腐剂和稳定剂；
-用选定的碱中和所述树脂。
11.一种制备权利要求4～5的制剂的方法，该方法包括：
-制备含水溶性防腐剂和均匀分散的羧乙烯基聚合物的水相；
-制备含处于二甘醇一乙基醚中的防腐剂(对羟基苯甲酸酯类)的相并分散所述活性成分，添加包括辛酸酯/癸酸酯和甘油基(8)OE的相；
-制备分散体，使含有所述活性成分的相悬浮于含所述羧乙烯基聚合物的水相中；
-制备适当地溶于所述水相的稳定剂；
-用选定的碱中和所述树脂。
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| Application Number | Priority Date | Filing Date | Title |
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| ITMI97A000408 | 1997-02-25 | ||
| IT97MI000408A IT1289973B1 (it) | 1997-02-25 | 1997-02-25 | Sistemi gelificati di nimesulide per uso topico |
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| CN1148174C CN1148174C (zh) | 2004-05-05 |
Family
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| CN (1) | CN1148174C (zh) |
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| CU (1) | CU22836A3 (zh) |
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| DE (2) | DE69802913T2 (zh) |
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| HK (1) | HK1025265A1 (zh) |
| HU (1) | HU226122B1 (zh) |
| ID (1) | ID22668A (zh) |
| IL (1) | IL131128A (zh) |
| IS (1) | IS2090B (zh) |
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| AU718356B2 (en) * | 1998-01-12 | 2000-04-13 | Panacea Biotec Limited | A parenteral water-miscible non-intensely coloured injectable composition of non-steroidal anit-inflammatory drugs |
| GB2340751B (en) * | 1998-08-12 | 2003-11-05 | Edko Trading Representation | Pharmaceutical compositions |
| AU1888900A (en) * | 1999-05-31 | 2000-12-18 | Shashikant Prabhudas Kurani | A novel formulation of n-(4-nitro-2-phenoxyphenyl)methanesulfonamide |
| ES2283425T3 (es) | 2000-08-03 | 2007-11-01 | Antares Pharma Ipl Ag | Nueva composicion para la administracion transdermica y/o transmucosa de compuestos activos que asegura niveles terapeutiocos adecuados. |
| US8980290B2 (en) | 2000-08-03 | 2015-03-17 | Antares Pharma Ipl Ag | Transdermal compositions for anticholinergic agents |
| US7198801B2 (en) | 2000-08-03 | 2007-04-03 | Antares Pharma Ipl Ag | Formulations for transdermal or transmucosal application |
| ES2222817B1 (es) * | 2003-07-25 | 2007-03-01 | Luis Ucelay Sanz | Gel frio. |
| MXPA06003316A (es) | 2003-10-10 | 2006-06-08 | Antares Pharma Ipl Ag | Formulacion farmaceutica transdermica para minimizar los residuos en la piel. |
| US7425340B2 (en) | 2004-05-07 | 2008-09-16 | Antares Pharma Ipl Ag | Permeation enhancing compositions for anticholinergic agents |
| WO2007124250A2 (en) | 2006-04-21 | 2007-11-01 | Antares Pharma Ipl Ag | Methods of treating hot flashes with formulations for transdermal or transmucosal application |
| WO2006125642A1 (en) | 2005-05-27 | 2006-11-30 | Antares Pharma Ipl Ag | Methods and apparatus for transdermal or transmucosal application of testosterone |
| TR200906775A1 (tr) * | 2009-09-02 | 2011-03-21 | Sanovel İlaç San.Ve Ti̇c.A.Ş. | Nimesulid ve kas gevşetici kombinasyonları |
| CN102068404A (zh) * | 2009-11-25 | 2011-05-25 | 中国人民武装警察部队医学院 | 一种尼美舒利温度敏感水凝胶及其制备方法 |
| RU2711090C2 (ru) * | 2015-01-23 | 2020-01-15 | Др. Редди'С Лабораториз Лимитед | Неокрашивающая гелевая композиция, содержащая нимесулид, для местного применения |
| RU2593777C1 (ru) * | 2015-04-20 | 2016-08-10 | Общество с ограниченной ответственностью "Трейдсервис" | Гелевая форма нимесулида, обладающая противовоспалительным и анальгетическим действием |
| CN108158993A (zh) * | 2018-01-12 | 2018-06-15 | 连云港本草美汇医药科技有限公司 | 一种祛痘控油微乳凝胶剂及其制备方法与应用 |
| EP4297765A4 (en) * | 2021-02-25 | 2025-02-19 | Alphyn Biologics Llc | COMPOSITION FOR THE TREATMENT OF TOPICAL DERMATOLOGICAL BACTERIAL SKIN CONDITIONS |
| PL244577B1 (pl) | 2021-12-16 | 2024-02-12 | Univ Gdanski | Sole nimesulidu i sposób otrzymywania kryształów soli nimesulidu |
| PL444224A1 (pl) | 2023-03-28 | 2024-09-30 | Uniwersytet Gdański | Sól potasowa nimesulidu oraz sposób otrzymywania kryształów soli potasowych nimesulidu |
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| IT1251838B (it) * | 1991-09-20 | 1995-05-26 | Lpb Ist Farm | Uso della nimesulide nel trattamento della cataratta |
| BR9509183A (pt) * | 1994-10-05 | 1997-12-30 | Helsinn Healthcare Sa | Agente antiinflamatório para uso externo |
| HUP9601442A3 (en) * | 1995-07-25 | 1999-03-29 | Panacea Biotec Ltd | Nes antinflammatory and analgetic pharmaceutical compositions, containing nimesulid for transdermal use, and process for producing them |
| EE03419B1 (et) * | 1995-10-05 | 2001-06-15 | Helsinn Healthcare S.A. | Välispidiselt kasutatav põletikuvastane vahend |
| HUP9601443A3 (en) * | 1996-05-29 | 1999-03-29 | Panacea Biotec Ltd | Injectable analgetic pharmaceutical compositions for intramuscular use containing nimesulid, and process for producing them |
| IT1291278B1 (it) * | 1996-07-05 | 1999-01-07 | Errekappa Euroterapici S P A | Preparazione farmaceutica a base di nimesulide per uso topico |
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