CN106924223B - 一种美洛昔康贴剂及其制备方法和应用 - Google Patents
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Abstract
本发明提供了一种美洛昔康贴剂及其制备方法和应用,所述美洛昔康贴剂包括背衬层、药物储库及防粘层；药物储库层包括活性成分美洛昔康或其可药用的盐、压敏胶、药物透皮吸收促进剂，其中美洛昔康或其可药用的盐和透皮吸收促进剂的用量分别占药物储库层固成分重量含量的0.5‑60％和0.1‑50％。美洛昔康贴剂制备方法是将美洛昔康或其可药用盐溶解在溶剂中，依次加入各药用辅料搅拌、混匀，静置脱气，涂膜，挥发溶剂，复合背衬层，根据剂量要求切割成合适大小的贴剂。该贴剂粘附性强、柔顺性好，既能避免口服对胃肠道的刺激，又能增加药物的经皮渗透，疗效持久平稳，并可随时中断给药。
Description
技术领域
本发明属于医药技术领域，涉及一种稳定性极佳的宽浓度范围的美洛昔康贴剂及其制备方法。
背景技术
美洛昔康作为第一个上市的环氧合酶-2(COX-2)抑制剂，大量临床试验表明美洛昔康具较强的镇痛消炎作用，对骨关节炎、类风湿性关节炎、坐骨神经痛患者的治疗效果与现今的NSAID相匹敌，甚至更好，而每天剂量比吡咯昔康、二氯芬酸、消炎痛及萘普生低得多，且胃肠道副反应发生率很低。该品自1996年上市以来，其剂型发展速度非常快。除了常用的7.5mg/15mg片剂及胶囊剂外，15mg栓剂和15mg注射剂的应用也很广。随着环氧合酶-2抑制剂的不断开发，最近有研究证实COX-2在调控肾功能中起重要作用，其在维持肾血液动力学和电解质平衡中起重要作用，故COX-2抑制剂可能产生危险的肾脏副作用，故肾功能不全病人、老年人及有胃肠疾病复发史的病人应慎用。由于无胃肠道保护作用且具潜在的肾毒性，加之需长期使用等特点限制了美洛昔康片剂、胶囊剂等口服剂型及注射剂、栓剂的应用，且注射剂还可能引起注射部位局部疼痛和轻度组织坏死。国内开发的凝胶剂受美洛昔康的水难溶性影响，使局部凝胶剂的载药量小(约为1％)，给药次数频繁(3～4次/天)，且易污染衣物，故使用不便。美洛昔康贴剂给药具有使用方便、经皮释药平稳，不污染衣物等优点，并可增加美洛昔康的适宜人群，显著提高患者用药的安全性和依从性。适应症：抗炎镇痛药物，用于关节炎的消肿止痛，还可用于扭伤、软组织挫伤等疼痛的缓解。
目前无上市的美洛昔康贴剂。目前已公开的关于美洛昔康透皮贴剂的专利中都是以美洛昔康为主药，如专利200410021122。但是皮肤屏障主要由亲脂性的角质层和亲水性的活性表皮组成，这表明具有适宜亲脂性的药物才能透过皮肤被人体吸收，美洛昔康具有较高脂溶性，在常用溶剂中的溶解性均较差，限制了美洛昔康的经皮吸收并且增大了美洛昔康外用制剂的制备难度。因此，考虑制备美洛昔康有机盐来解决上述问题。
发明内容
本发明的目的是提供一种美洛昔康贴剂及其制备方法，克服了现有技术中的局限性，且提供了稳定性更强、安全性更高、耐受性更好的局部给药制剂。
本发明所要解决的问题是通过以下技术方案来实现的：
本发明所述的美洛昔康透皮贴剂由背衬层、药物储库层及防粘层构成,所述药物储库层包括主药美洛昔康或其盐、压敏胶、经皮吸收促进剂，配方(重量百分比)如下：
美洛昔康或其可药用的盐 0.5-60％
压敏胶 10-98％
透皮吸收促进剂 0.1-50％
优选的，所述药物储库层含有，按药物储库层总重量计：
美洛昔康或其可药用的盐 1-45％
压敏胶 50-98％
透皮吸收促进剂 1-45％
其中，所述的美洛昔康盐为美洛昔康在药学上可接受的有机胺盐，为美洛昔康二乙胺、美洛昔康三乙胺、美洛昔康单乙醇胺、美洛昔康二乙醇胺、美洛昔康三乙醇胺、美洛昔康N-羟乙基吡咯烷、美洛昔康N-羟乙基哌啶、美洛昔康二甲基氨基乙醇和美洛昔康氨丁三醇中的一种或多种；
所述压敏胶所选用的基质材料为硅酮类、异丁烯类聚合物、丙烯酸酯类聚合物或纤维素类以及它们的衍生物中的一种或多种化合物，优选丙烯酸酯类聚合物。
所述药物透皮吸收促进剂选用油酸、月桂氮卓酮、薄荷醇、薄荷醇酯类、N-甲基吡咯烷酮中的一种或其混合物，优选月桂氮卓酮及N-甲基吡咯烷酮的混合物。月桂氮卓酮及N-甲基吡咯烷酮的重量比选自1:0.1-1，优选1:0.5-1。
所述美洛昔康贴剂还含有背衬层和防粘层，其中，背衬层选用含铝聚乙烯复合膜，或弹性无纺布；防粘层为表面经硅油防粘处理或含氟的聚酯膜或纸。
本发明的另一目的在于，提供一种美洛昔康贴剂的制备方法，包括如下步骤：
(1)将美洛昔康或其可药用盐，溶于溶剂中，并依次加入压敏胶、药物透皮吸收促进剂，溶解，搅拌，混匀，静置并脱气；
(2)涂膜，挥发溶剂，复合背衬层，根据剂量要求切割成合适大小的贴剂。
其中，步骤(1)中溶剂为乙醇和丙酮重量比2:1的混合溶剂。
与现有技术相比，本发明具有如下优点：通过美洛昔康成盐有效改善其经皮透过量，可通过给药面积的调整控制给药剂量，药物以零级释放，24小时内持续稳定释放药物，从而使疗效持久平稳；揭去贴剂即可中断给药，使用方便；本贴剂还具有粘附性、柔顺性好等优点。
具体实施方式
通过如下实例更详细阐释本发明，所述的实施例是为了进一步描述本发明，而不是限制本发明的保护范围。
实施例1
将7.5g美洛昔康加入小烧杯中，加入62.5g乙醇和31.25g丙酮，超声使药物溶解，加入3.5g月桂氮卓酮及3.5g N-甲基吡咯烷酮，搅拌使溶解，加入300g丙烯酸酯类聚合物，搅拌至混合均匀，静置并脱气，均匀涂布于防粘层上，挥发溶剂，然后用包括PVC或无纺布的背衬材料复合，冲切成贴剂1000片，即得。
实施例2
将7.5g美洛昔康二乙胺加入小烧杯中，加入62.5g乙醇和31.25g丙酮，超声使药物溶解，加入3.5g月桂氮卓酮及3.5g N-甲基吡咯烷酮，搅拌使溶解，加入300g丙烯酸酯类聚合物，搅拌至混合均匀，静置并脱气，均匀涂布于防粘层上，挥发溶剂，然后用包括PVC或无纺布的背衬材料复合，冲切成贴剂1000片，即得。
实施例3
将7.5g美洛昔康二乙胺加入小烧杯中，加入62.5g乙醇和31.25g丙酮，超声使药物溶解，加入7.0g油酸，搅拌使溶解，加入300g丙烯酸酯类聚合物，搅拌至混合均匀，静置并脱气，均匀涂布于防粘层上，挥发溶剂，然后用包括PVC或无纺布的背衬材料复合，冲切成贴剂1000片，即得。
实施例4
将7.5g美洛昔康二乙胺加入小烧杯中，加入62.5g乙醇和31.25g丙酮，超声使药物溶解，加入7.0g月桂氮卓酮及3.5g N-甲基吡咯烷酮，搅拌使溶解，加入300g异丁烯类聚合物，搅拌至混合均匀，静置并脱气，均匀涂布于防粘层上，挥发溶剂，然后用包括PVC或无纺布的背衬材料复合，冲切成贴剂1000片，即得。
实施例5
将7.5g美洛昔康二乙胺加入小烧杯中，加入62.5g乙醇和31.25g丙酮，超声使药物溶解，加入25g月桂氮卓酮，搅拌使溶解，加入300g硅酮类压敏胶，搅拌至混合均匀，静置并脱气，均匀涂布于防粘层上，挥发溶剂，然后用包括PVC或无纺布的背衬材料复合，冲切成贴剂1000片，即得。
实施例6
将7.5g美洛昔康二乙胺加入小烧杯中，加入62.5g乙醇和31.25g丙酮，超声使药物溶解，加入25g薄荷醇，搅拌使溶解，加入200g丙烯酸酯类聚合物，搅拌至混合均匀，静置并脱气，均匀涂布于防粘层上，挥发溶剂，然后用包括PVC或无纺布的背衬材料复合，冲切成贴剂1000片，即得。
实施例7
将7.5g美洛昔康二乙胺加入小烧杯中，加入62.5g乙醇和31.25g丙酮，超声使药物溶解，加入35g月桂氮卓酮及35g N-甲基吡咯烷酮，搅拌使溶解，加入90g丙烯酸酯类聚合物，搅拌至混合均匀，静置并脱气，均匀涂布于防粘层上，挥发溶剂，然后用包括PVC或无纺布的背衬材料复合，冲切成贴剂1000片，即得。
实施例8
将7.5g美洛昔康加入小烧杯中，加入62.5g乙醇和31.25g丙酮，超声使药物溶解，加入25g月桂氮卓酮及25g N-甲基吡咯烷酮，搅拌使溶解，加入42.5g丙烯酸酯类聚合物，搅拌至混合均匀，静置并脱气，均匀涂布于防粘层上，挥发溶剂，然后用包括PVC或无纺布的背衬材料复合，冲切成贴剂1000片，即得。
对比例1
将7.5g美洛昔康加入小烧杯中，加入100g氯仿中，超声使药物溶解，加入300g丙烯酸酯类聚合物，搅拌至混合均匀，静置并脱气，均匀涂布于防粘层上，挥发溶剂，然后用包括PVC或无纺布的背衬材料复合，冲切成贴剂1000片，即得。
对比例2
将7.5g美洛昔康二乙胺加入小烧杯中，加入62.5g乙醇和31.25g丙酮，超声使药物溶解，加入300g压敏胶，搅拌至混合均匀，静置并脱气，均匀涂布于防粘层上，挥发溶剂，然后用包括PVC或无纺布的背衬材料复合，冲切成贴剂1000片，即得。
透皮吸收试验：
本发明采用改进的Franz卧式扩散池，采用大鼠腹部皮肤作为屏障，试验结果如表1。
表1.不同处方贴剂透过结果
| Q<sub>24</sub>(μg/cm<sup>2</sup>) | Js(μg/cm<sup>2</sup>/h) | T<sub>lag</sub>(h) | |
| 对比例1 | 10.79±0.31 | 0.2369 | 0.4756 |
| 对比例2 | 11.10±2.49 | 0.2762 | 0.5173 |
| 实施例1 | 38.60±2.19 | 2.993 | 3.4980 |
| 实施例2 | 53.48±7.39 | 3.8756 | 4.2185 |
| 实施例3 | 41.08±7.44 | 3.1992 | 4.0606 |
| 实施例4 | 36.30±5.43 | 2.6661 | 2.9496 |
| 实施例5 | 36.10±2.49 | 2.7992 | 2.5573 |
| 实施例6 | 30.12±3.32 | 2.1147 | 2.0742 |
| 实施例7 | 27.60±2.19 | 1.8962 | 1.9606 |
| 实施例8 | 24.10±4.90 | 1.7563 | 1.8247 |
Claims (3)
1.美洛昔康透皮贴剂，由背衬层、药物储库及防粘层构成，其特征在于，所述药物储库层含有活性成分美洛昔康可药用的盐、压敏胶、药物透皮吸收促进剂，其重量百分比如下：
美洛昔康可药用的盐 1-45％
压敏胶 50-98％
透皮吸收促进剂 1-约2.23％
所述压敏胶选用的基质材料为丙烯酸酯类聚合物；
所述透皮吸收促进剂为月桂氮卓酮与N-甲基吡咯烷酮重量比为1:1的混合物；
所述的美洛昔康可药用的盐为美洛昔康二乙胺。
2.根据权利要求1所述的美洛昔康透皮贴剂，其特征在于，背衬层选用含铝聚乙烯复合膜，或弹性无纺布；防粘层为表面经硅油防粘处理或含氟的聚酯膜或纸。
3.权利要求1所述的美洛昔康透皮贴剂的制备方法，其特征在于，该方法包括如下步骤：
(1)将美洛昔康可药用盐，溶于溶剂中，并依次加入压敏胶、药物透皮吸收促进剂，溶解，搅拌，混匀，静置并脱气；
(2)涂膜，挥发溶剂，复合背衬层，根据剂量要求切割成合适大小的贴剂；
其中，步骤(1)中溶剂为乙醇和丙酮重量比2:1的混合溶剂。
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