CN107028921A - 一种吡罗昔康巴布贴剂 - Google Patents

一种吡罗昔康巴布贴剂 Download PDF

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CN107028921A
CN107028921A CN201710343778.6A CN201710343778A CN107028921A CN 107028921 A CN107028921 A CN 107028921A CN 201710343778 A CN201710343778 A CN 201710343778A CN 107028921 A CN107028921 A CN 107028921A
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piroxicam
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蔡志浩
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BEIJING MINGZE ZHONGHE MEDICAMENT RESEARCH CO., LTD.
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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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates

Abstract

一种吡罗昔康巴布贴剂，由背衬层、药物储库和保护层组成，其特征是所述药物储库由以下重量百分比的组分组成：作为活性成分的吡罗昔康1％～2％；油相成分10～15％，所述油相成分由癸酸甘油酯、凡士林和月桂酸组成，癸酸甘油酯、凡士林和月桂酸的重量比为1～1.2:0.3～0.4：0.08～0.12，所述吡罗昔康分散于油相中；作为水相成分的部分中和聚丙烯酸钠5‑10％，丙三醇15‑20％，卡波姆934 1％～1.5％、羟丙基甲基纤维素(HPMC)1.5～2％，pH调节剂、甘羟铝0.2％～0.4％，依地酸钙钠0.1％～0.3％，二甲基亚砜(DMSO)0.2～0.3％，填充剂1～3％及余量的水。

Description

一种吡罗昔康巴布贴剂
技术领域
本发明涉及一种吡罗昔康巴布贴剂。
背景技术
吡罗昔康(2-甲基-4-羟基-N-(2-吡啶基)-2H-1，2-苯并噻嗪-3-甲酰胺1，1-二氧化物,CAS:36322-90-4)是一种非甾体抗炎药，具有解热、镇痛作用，广泛应用于骨关节炎、风湿类风湿关节炎的镇痛治疗，可通过抑制环氧酶使组织局部前列腺素的合成减少及抑制白细胞的趋化性和溶酶体酶的释放而起到药理作用。但由于抑制环氧酶-2所需的浓度高于抑制环氧酶-1的浓度，因此胃肠道的不良反应较多，以传统的口服给药方式在治疗外伤及关节、软组织、肌肉的炎症产生的疼痛时，因需要服药量较大，造成副作用较大，且无法控制药物释放，难于对患处进行持久有效的镇痛消炎效果。现有的吡罗昔康外用制剂主要为凝胶剂与贴剂，但由于载药量较小，难于长时间的发挥镇痛抗炎作用。与常规外用制剂相比，水凝胶贴剂(巴布剂，Cataplasm)具有载药量大，促进药物经皮透过，且对皮肤无过敏反应和刺激作用，剥离时无拉痛感且无残留等优点。然而由于水凝胶贴剂的药物储库中载药量较大，且一般需要敷贴较长时间，其理想的释药特性应该是快速持续释放，在快速起效的同时在整个敷贴周期内都能持续稳定的释药。对于吡罗昔康这种胃肠副作用较大的抗炎药物来说，这点尤其重要，因此提供一种能够快速持续释药的吡罗昔康巴布贴剂成为现有技术中亟待解决的问题。
发明内容
为解决前述技术问题，本发明提供了一种吡罗昔康巴布贴剂，所述巴布贴剂由背衬层、药物储库和保护层组成，其特征是所述药物储库由以下重量百分比的组分组成：
作为活性成分的吡罗昔康1％～2％；
油相成分10～15％，所述油相成分由癸酸甘油酯、凡士林和月桂酸组成，癸酸甘油酯、凡士林和月桂酸的重量比为1～1.2:0.3～0.4：0.08～0.12，所述吡罗昔康分散于油相中；
作为水相成分的部分中和聚丙烯酸钠5-10％，丙三醇15-20％，卡波姆934 1％～1.5％、羟丙基甲基纤维素(HPMC)1.5～2％，pH调节剂、甘羟铝0.2％～0.4％，依地酸钙钠0.1％～0.3％，二甲基亚砜(DMSO)0.2～0.3％，填充剂1～3％及余量的水；所述部分中和聚乙烯酸钠优选为NP700。所述pH调节剂为将水相成分pH调节至5～6.5的氢氧化钠溶液。所述填充剂为高岭土。
在研究中发现，将吡罗昔康溶解在油相成分后再乳化分散于水凝胶中形成药物储库，既可以持续快速释药，又可以控制释药速度，从而显著提高水凝胶贴剂中作为活性成分的吡罗昔康的透皮吸收速度，能够实现有效成分的快速和持续稳定释放。且在研究中我们进一步发现，该效果依赖于油相成分的组成配比及水相成分中特定比例N-乙酰半胱氨酸与甘氨酸的加入，油相成分经过筛选采用了加入了少量月桂酸的月桂酸甘油酯，改变油相成分的成分及配比均会显著影响吡罗昔康的释放速度，，而水相成分中的特定比例的N-乙酰半胱氨酸与甘氨酸则可以使水凝胶贴剂在敷贴后期也保持较高的释放速度。三者匹配，使得到的吡罗昔康巴布贴剂能够兼顾快速与持续释药性能。在处方筛选时我们进一步发现，N-乙酰半胱氨酸与甘氨酸的选取与比例确定具有特定性，无论是减少其中任何一种成分，或者改变其用量，均会显著影响到的水凝胶贴剂的释药性能，且上述处方仅在活性成分为吡罗昔康时效果明显，改变活性成分时，其释药性能明显低于本发明提供的吡罗昔康巴布贴剂。
具体实施方式
本发明实施例中的一种吡罗昔康巴布贴剂按照以下方法制备
1)油相成分配制，将油相成分的原料加热至50-70℃，加入吡罗昔康微粉，搅拌分散得到油相液(1)
2)将水相成分散于水得到水凝胶，将水凝胶加热至50～70℃后在用均混器搅拌的同时加入温度为50-70℃的油相液(1)，油相加入后再加入填充剂后搅拌均匀；经静置真空脱气后得到膏状的药物储库；
3)将药物储库涂布于背衬层上，并在上表面贴附保护层。得到吡罗昔康巴布贴。得到的一种吡罗昔康巴布贴剂的规格为3g药物储库/34cm2背衬层
所有实施例及对照例中，部分中和聚丙烯酸钠为NP700(Showa Denko kk生产)，填充剂为2％高岭土。
实施例1～6的配方见下表
对照例1～6的配方见下表
与实施例1～6相比，对照例1～6的配方中部分改变油相成分配比(对照例1、2)，部分不加入DMSO(对照例3、4)，将DMSO替换为常用的溶剂丙二醇或N-甲基吡咯烷酮(NMP)(对照例5、6)
通过对实施例1～6得到的巴布剂进行考察，可知其外观平整、均匀，药物储库膏体光滑；成型性、含膏量、初粘力、粘附性以及膜残留量均符合要求。
药理实施例1体外释放实验
按照中国药典2010版第二部附录XD中释放度测定法中第三法(桨碟法，用于透皮贴剂)中提供的方法对实施例1～6得到的巴布贴紧急释放度测定。具体方法如下
试验以生理盐水为释放介质，将释放介质加入溶出杯内，预温至(32±0.5℃)将巴布剂除去保护层，裁剪成2.5cmx7.5cm大小，平放入透析袋(截留分子量14,000)中，释放面朝上,置于两层碟片之间，使碟片边缘夹住透析袋两端，再用皮筋缠绕固定,以固定碟片。于10min、20min、30min、45min、60min、90min、2h、2.5h、3h和4h分别从溶出杯内取样6mL，并补充等体积(32+0.5)℃新鲜释放介质，平行试验6片，取平均值计算。经过检测表明，本申请实施例中的巴布剂的体外释放度均在2h达到90％以上。
药理实施例2，体外透皮实验
采用改良Franz扩散池法，以离体3月龄大鼠腹部皮肤为屏障，用实施例1～6及对照例1～6制备得到的巴布贴剂进行进行体外透皮试验。具体实验方法为：
取3月龄健康大鼠麻醉处死后，用剪刀除尽腹部毛，取下无损伤的皮肤，除去皮下组织，洗净后分别固定于Franz扩散池的释放口，接受室中加入pH7.4磷酸缓冲液作释放介质，保持内皮层与溶液密切接触。将揭去保护层的巴布剂贴于皮肤上，调节水浴使外层套层温度恒定于(32±0.5)℃，搅拌速度为100rpm，分别于0、1h、2h、4h、6h、8h、12h小时吸取释放介质4ml，同时补加等量PBS液。计算累计吸收百分数(即累计透过的吡罗昔康占药物储库中吡罗昔康总量的百分比分数)结果如下表
上述结果表明，本发明提供的一种吡罗昔康巴布贴剂，在进行体外透皮吸收实验时，12h的累计药物透过率均高于75％，且药物释放率随时间增加速度较为均匀、说明本发明采用的技术方案中，通过分别优选油相成分与水相成分的组成，既提高了一种吡罗昔康巴布贴剂的透皮吸收速度，又能够控制药物在整个敷贴时间段内较为均匀的释放，实现了两种特性的平衡。在处方筛选时我们发现油相成分优选癸酸甘油酯、凡士林和月桂酸的组合，水相成分优选加入少量的DMSO，仅有同时具备处方范围内的上述成分，才能实现吡罗昔康快速均匀释放的效果。通过与对比例的对照实验表明，改变油相成分成分，不加入DMSO或将其替换为类似的丙二醇或NMP，均会影响吡罗昔康的释放效果，且在进一步实验中我们还发现，该辅料配方与吡罗昔康均有关联性，当改变活性成分时，即使采用同样的辅料配方，也会无法产生本发明提供的一种吡罗昔康巴布贴剂具有的快速均匀释药效果。

Claims (2)

1.一种吡罗昔康巴布贴剂，由背衬层、药物储库和保护层组成，其特征是所述药物储库由以下重量百分比的组分组成：作为活性成分的吡罗昔康1％～2％；油相成分10～15％，所述油相成分由癸酸甘油酯、凡士林和月桂酸组成，癸酸甘油酯、凡士林和月桂酸的重量比为1～1.2:0.3～0.4：0.08～0.12，所述吡罗昔康分散于油相中；作为水相成分的部分中和聚丙烯酸钠5-10％，丙三醇15-20％，卡波姆934 1％～1.5％、羟丙基甲基纤维素(HPMC)1.5～2％，pH调节剂、甘羟铝0.2％～0.4％，依地酸钙钠0.1％～0.3％，二甲基亚砜(DMSO)0.2～0.3％，填充剂1～3％及余量的水；所述部分中和聚乙烯酸钠为NP700。所述pH调节剂为将水相成分pH调节至5～6.5的氢氧化钠溶液。
2.如权利要求1所述一种吡罗昔康巴布贴剂，其特征是所述填充剂为高岭土。
CN201710343778.6A 2017-05-16 2017-05-16 一种吡罗昔康巴布贴剂 Pending CN107028921A (zh)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1548045A (zh) * 2003-05-23 2004-11-24 常州市第四制药厂有限公司 吡罗昔康外用制剂及制备方法
CN102065896A (zh) * 2008-06-16 2011-05-18 帝国制药株式会社 消炎镇痛外用剂
US20140046274A1 (en) * 2010-05-27 2014-02-13 Absize, Inc. Piroxicam-containing matrix patches and methods for the topical treatment of acute and chronic pain and inflammation therewith
CN105287361A (zh) * 2015-11-13 2016-02-03 北京泰德制药股份有限公司 含有非甾体抗炎药微乳的皮肤外用制剂

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1548045A (zh) * 2003-05-23 2004-11-24 常州市第四制药厂有限公司 吡罗昔康外用制剂及制备方法
CN102065896A (zh) * 2008-06-16 2011-05-18 帝国制药株式会社 消炎镇痛外用剂
US20140046274A1 (en) * 2010-05-27 2014-02-13 Absize, Inc. Piroxicam-containing matrix patches and methods for the topical treatment of acute and chronic pain and inflammation therewith
CN105287361A (zh) * 2015-11-13 2016-02-03 北京泰德制药股份有限公司 含有非甾体抗炎药微乳的皮肤外用制剂

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