CN1761462B - 含有非甾体类消炎镇痛剂的贴剂 - Google Patents
含有非甾体类消炎镇痛剂的贴剂 Download PDFInfo
- Publication number
- CN1761462B CN1761462B CN200480007150XA CN200480007150A CN1761462B CN 1761462 B CN1761462 B CN 1761462B CN 200480007150X A CN200480007150X A CN 200480007150XA CN 200480007150 A CN200480007150 A CN 200480007150A CN 1761462 B CN1761462 B CN 1761462B
- Authority
- CN
- China
- Prior art keywords
- acid
- analgesic agent
- patch
- nonsteroidal antiinflammatory
- adhesive phase
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 239000000730 antalgic agent Substances 0.000 title claims abstract description 49
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 title claims description 43
- 150000003839 salts Chemical class 0.000 claims abstract description 45
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- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 28
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 16
- 239000000853 adhesive Substances 0.000 claims description 44
- 230000001070 adhesive effect Effects 0.000 claims description 44
- 238000003475 lamination Methods 0.000 claims description 5
- 239000010410 layer Substances 0.000 abstract description 7
- 239000004820 Pressure-sensitive adhesive Substances 0.000 abstract 2
- 238000013329 compounding Methods 0.000 description 37
- -1 Grillocin P 176 Chemical compound 0.000 description 34
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
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- 241001597008 Nomeidae Species 0.000 description 4
- QRZAKQDHEVVFRX-UHFFFAOYSA-N biphenyl-4-ylacetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1C1=CC=CC=C1 QRZAKQDHEVVFRX-UHFFFAOYSA-N 0.000 description 4
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Abstract
含有非甾体类消炎镇痛剂的贴剂,具备支持体和与该支持体上所层合的粘合剂层的贴剂,其特征在于在该粘合剂层中含有具有羧基或其盐的非甾体类消炎镇痛剂以及平均分子量为1000或以上的聚乙二醇。
Description
技术领域
本发明涉及含有非甾体类消炎镇痛剂的贴剂。
背景技术
关于非甾体类的消炎镇痛剂,虽已知从皮肤吸收为目的的许多经皮吸收型贴剂,但非甾体类消炎镇痛剂,尤其是具有羧基或其盐的非甾体类消炎镇痛剂仍有保存安定性低的问题。
因此,在国际公开WO96/08245号公报中,提出由在作为基础聚合物的苯乙烯-异戊二烯-苯乙烯嵌段聚合物以及聚异丁烯、作为溶解剂的左旋薄荷醇、作为增粘剂的松香脂衍生物、作为增塑剂的液体石蜡所形成的基剂中,配混分子中具有羧酸基的非甾体类消炎镇痛剂,进而配混防止上述的非甾体类消炎镇痛剂与左旋薄荷醇酯化的作为抗酯化剂的脂肪酸金属盐的贴剂。另外,在特开2002-226366号公报中,提出了配混防止分子中具有羧酸基的非甾体类消炎镇痛剂与左旋薄荷醇酯化的抗酯化剂的金属氧化物的贴剂。另外,在特开2002-193793号公报中,提出将分子中具有羧酸基的非甾体类消炎镇痛剂溶解于甘油以及碳原子数为3~30的乙二醇而更稳定化的方案。
发明内容
然而,本发明人等发现,即使上述专利文献所记载的传统的贴剂,含有作为药效成份的保存安定性低的具有羧基或其盐的非甾体类消炎镇痛剂时,在40℃或以上的高温的过苛条件下的保存安定性仍不够。
本发明是鉴于上述传统技术所存在的问题而提出的,其目的在于提供含有作为药效成份的具有羧基或其盐的非甾体类消炎镇痛剂的贴剂,即使在40℃或以上高温的过苛条件下,长期保存安定性也优良的贴剂。
本发明人等为达成上述目的,努力进行研究,结果发现通过在含有具有羧基或其盐的非甾体类消炎镇痛剂的贴剂中,含有平均分子量为1000或以上的聚乙二醇,不仅可提升非甾体类消炎镇痛剂的溶解性,并明显地提升在过苛条件下的长期保存性,从而完成本发明。
即,本发明是提供具备支持体和在支持体上所层合的粘合剂层的贴剂,其特征在于在粘合剂层中含有具有羧基或其盐的非甾体类消炎镇痛剂以及平均分子量为1000或以上的聚乙二醇。
本发明的含有非甾体类消炎镇痛剂的贴剂即使在40℃或以上高温的过苛条件下,长期保存安定性仍然优异。另外,不仅如此,非甾体类消炎镇痛剂的放出性也优异。可得到如此效果的原因并不是很清楚,但认为是由于粘合剂层含有聚乙二醇,而且其分子量为1000或以上,可使非甾体类消炎镇痛剂良好地分散在粘合剂层中,其溶解度也在适合的范围内。另外,还认为平均分子量为1000或以上的聚乙二醇,不仅每单位重量的羟基与低分子量的聚乙二醇(平均分子量为200~600左右)相比少,还因为在粘合剂层中分子的流动性低,使非甾体类消炎镇痛剂稳定化。
本发明的贴剂中,优选在粘合剂层中还含有脂肪酸金属盐,更优选作为脂肪酸金属盐含有选自十一碳烯酸锌、硬脂酸锌、硬脂酸铝、硬脂酸钙、硬脂酸镁、硬脂酸钠、棕榈酸锌、肉豆蔻酸锌、肉豆蔻酸镁、月桂酸锌及月桂酸钠的至少一种,其中特别优选硬脂酸锌。
另外,本发明的贴剂中,作为非甾体类消炎镇痛剂,优选含有选自酮洛芬(Ketoprofen)、双氯酚酸(diclofenac)、氟比洛芬(Flurbiprofen)、酮咯酸(Ketorolac)、联苯乙酸(Felbinac)、以及它们药学上所容许的盐的至少一种,更优选含有选自双氯酚酸以及其药学上所容许的盐的至少一种。
另外,本发明的贴剂,特别优选在粘合剂层中含有1~25质量%的选自双氯酚酸以及其药学上所容许的盐的至少一种、1~6质量%的平均分子量为1000或以上的聚乙二醇、以及1~6质量%的上述脂肪酸金属盐。
具体实施方式
以下对本发明的含有非甾体类消炎镇痛剂的贴剂的适合实施方式进行说明。本发明的贴剂具备支持体和在支持体上所层合的粘合剂层(感敏性接合剂层),也可以再层合使用时可剥离的脱模薄膜。另外,本发明的贴剂的粘合剂层中含有具有羧基或其盐的非甾体类消炎镇痛剂和平均分子量为1000或以上的聚乙二醇。
首先,对本发明的含有非甾体类消炎镇痛剂的贴剂的粘合剂层进行说明。本发明的粘合剂层除了粘合基剂之外,还含有具有羧基或其盐的非甾体类消炎镇痛剂和平均分子量为1000或以上的聚乙二醇。
作为本发明的粘合基剂,可举出苯乙烯-异戊二烯-苯乙烯嵌段共聚物、苯乙烯-丁二烯-苯乙烯嵌段共聚物、苯乙烯-异戊二烯橡胶、苯乙烯-丁二烯橡胶、聚异戊二烯、聚异丁烯、聚丁二烯橡胶、硅橡胶、丙烯酸系聚合物(丙烯酸丁酯、2-乙基己基丙烯酸酯、醋酸乙烯酯、甲基丙烯酸酯、羟乙基丙烯酸酯、缩水甘油基甲基丙烯酸酯、甲氧基乙基丙烯酸酯及丙烯酸中的至少2种共聚物)、天然橡胶、以及聚氨酯类橡胶等,其中从凝集性、耐候性、耐老化性及耐药品性的观点出发,优选苯乙烯-异戊二烯-苯乙烯嵌段共聚物及聚异丁烯,特别优选苯乙烯-异戊二烯-苯乙烯嵌段共聚物与聚异丁烯的混合物。
作为这样的苯乙烯-异戊二烯-苯乙烯嵌段共聚物,可举出Cariflex TR-1107、TR-1111、TR-1112及TR-1117(商品名:Shell化学(股))、Quintac 3530、3421及3570C(商品名:日本Zeon(股))、JSR SIS-5229及5002(商品名:日本合成橡胶(股))、ClaytonD-KX401CS及D-1107CU(商品名:Shell化学(股))、Solprene 428(商品名:Phillips Petroleum(股))等,可1种或2种或以上组合使用。上述苯乙烯-异戊二烯-苯乙烯嵌段共聚物的配混量优选是粘合剂层(粘合制剂)全体的5~40质量%,更优选为10~35质量%。该配混量若低于上述下限,基剂的凝聚力或保型性等有降低的倾向,另一方面,若超过上述上限,基剂的凝聚力增加,容易导致粘合力降低或操作性降低等。
另外,作为聚异丁烯,可举出Oppanol B-3、B-10、B-15、B-50、B-100及B-200(商品名:BASF(股))、Bistanex LM-MS、LM-MH、MML-80、LLM-100、LLM-120及LLM-140(商品名:EXXON化学(股))、Tetrax 3T、4T、5T及6T(商品名:日本石油化学(股)等,可1种或2种或以上组合使用。上述聚异丁烯的配混量是粘合剂层(粘合制剂)全体的1~25质量%,更优选为2~20质量%。此配混量若低于上述下限,基剂的粘合力有降低的倾向,另一方面,若超过上述上限,长期保存时的基剂保型性有降低的倾向。
在本发明的粘合剂层中,与上述粘合基剂一起配混作为药效成份的具有羧基或其盐类的非甾体类消炎镇痛剂。作为所涉及的消炎镇痛剂,包括具有羧基的消炎镇痛剂(吲哚美锌、酮洛酚、氟比洛芬、联苯乙酸、双氯酚酸、氯索洛芬(Loxoprofen)、酮咯酸),以及该羧基的氢原子被药学上容许的盐所取代的消炎镇痛剂,其中优选酮洛酚、双氯酚酸、氟比洛芬、酮咯酸、联苯乙酸以及它们药学上所容许的盐,其中特别优选酮洛酚、双氯酚酸以及他们药学上所容许的盐。另外,作为构成上述药物的药学上所容许的盐的化合物,可举出碱金属、碱土金属及铵化合物等,具体地包括钠、钾、钙、镁、氨、二甲胺、二乙胺、三甲胺、四甲铵、单乙醇胺、二乙醇胺及三乙醇胺等。
对本发明的粘合剂层中的非甾体类消炎镇痛剂的配混量没有特别的限制,但一般为粘合剂层全体的0.5~30质量%左右,尤其使用双氯酚酸或其药学上所容许的盐(特别优选双氯吩酸钠)时,优选为粘合剂层全体的1~25质量%。消炎镇痛剂的配混量若低于上述下限,有不能得到充分药效的倾向,另一方面,配混量若超过上述上限,因过度投予而出现皮肤刺激等的危害或在经济性方面上有不适当的倾向。另外,非甾体类消炎镇痛剂可1种或2种或以上组合使用。
另外,在本发明的粘合剂层中,对上述的具有羧基或其盐类的非甾体类消炎镇痛剂,可配混其溶解剂作用的聚乙二醇。而且,相对于作为传统溶解剂所使用的聚乙二醇的平均分子量为200~600左右,本发明中是使用平均分子量为1000或以上,优选使用1500~20000的聚乙二醇。聚乙二醇的平均分子量若低于1000,在过苛的保存下的长期保存安定性降低。另外,聚乙二醇的平均分子量若超过20000时,与药剂的亲和性增加,有放出性降低的倾向。另外,上述聚乙二醇的提高长期保存稳定性的效果是对于上述的具有羧基或其盐类的非甾体类消炎镇痛剂,可良好地发挥效果,对于双氯酚酸或其药学上所容许的盐(特别优选双氯吩酸钠),可更有效地发挥效果。
在本发明的粘合剂层中,上述聚乙二醇的配混量并无特别的限定,但一般为粘合剂层全体的0.5~20质量%左右,尤其使用双氯酚酸或其药学上所容许的盐(特别优选双氯吩酸钠)作为药效成份时,上述聚乙二醇的配混量优选是粘合剂层全体的1~6质量%。上述聚乙二醇的配混量若低于上述下限,有药剂对基剂的溶解性降低,结晶容易析出的倾向,另一方面,配混量若超过上述上限时,聚乙二醇将过剩,而有形成导致粘合力降低或经皮吸收性降低原因的倾向。另外,上述聚乙二醇是可1种或2种或以上组合使用。
另外,在本发明的粘合剂层中,除了上述的非甾体类消炎镇痛剂及聚乙二醇以外,优选还配混脂肪酸金属盐。脂肪酸金属盐是作为稳定化剂发挥功能,通过配混脂肪酸金属盐,有粘合剂层安定性进一步提高的倾向。作为这样的脂肪酸金属盐,可例举选自十一碳烯酸锌、硬脂酸锌、硬脂酸铝、硬脂酸钙、硬脂酸镁、硬脂酸钠、棕榈酸锌、肉豆蔻酸锌、肉豆蔻酸镁、月桂酸锌及月桂酸钠的至少一种,其中特别优选硬脂酸锌。另外,上述脂肪酸金属盐作为稳定化剂对上述的具有羧基或其盐类的非甾体类消炎镇痛剂,可良好地发挥其效果,对于双氯酚酸或其药学上所容许的盐(特别优选双氯吩酸钠),使用硬脂酸锌更有效。
在本发明的粘合剂层中的上述脂肪酸金属盐的配混量虽并无特别的限定,但一般为粘合剂层全体的0.5~10质量%左右,特别是使用双氯酚酸或其药学上所容许的盐(特别优选双氯酚酸钠)为药效成份时,上述脂肪酸金属盐(优选硬脂酸锌)的配混量优选是粘合剂层全体的1~6质量%。上述脂肪酸金属盐的配混量若低于上述下限时,不能充分地达成脂肪酸金属盐所起到的稳定化效果,粘合剂层中有容易发生结晶的倾向,另一方面,配混量若超过上述上限时,因粘合剂的凝聚力降低而有粘合性恶化的倾向。另外,上述脂肪酸金属盐可1种或2种或以上组合使用。
另外,在本发明的粘合剂层中,除了上述各成份以外,优选含有作为增粘剂的松香系树脂及/或石油系树脂。作为这样的松香系树脂,可举出天然树脂松香、改性松香、松香脂(松香甘油酯及松香季戊四醇酯等)、氢化松香酯(氢化松香甘油酯及氢化松香季戊四醇酯等),其中,从皮肤刺激性、耐老化性的观点考虑,优选氢化松香酯,特别优选氢化松香甘油酯。作为这样的松香系树脂,具体地可举出Estergum H(商品名:荒川化学工业(股))、Pinecrystal KE-100及KE-311(商品名:荒川化学工业(股))、Foral 85及105(商品名:理化Hercules(股))、Staybelite ester 7、10(商品名:理化Hercules(股))等,可1种或2种或以上组合使用。
另外,作为石油系树脂,可举出C5系合成石油树脂(异戊二烯、环戊二烯、1,3-戊二烯及1-戊烯中至少2种的共聚物;2-戊烯及二环戊二烯中至少2种的共聚物;1,3-戊二烯为主体的树脂等)、C9系合成石油树脂(茚、苯乙烯、甲基茚及α-甲基苯乙烯中至少2种的共聚物等)、二环戊二烯系合成石油树脂(以二环戊二烯为主体的异戊二烯及/或1,3-戊二烯的共聚物等)等,从耐候性、与粘合基剂的相溶性的观点,优选C9系合成石油树脂。另外,作为石油系树脂,就其它分类的观点,可举出脂环族系石油树脂(脂环族系烃树脂)、脂环族系氢化石油树脂、脂肪族系石油树脂(脂肪族系烃树脂)、脂肪族系氢化石油树脂及芳香族系石油树脂等,从粘合力、与粘合基剂的相溶性及耐老化性的观点,优选脂环族系石油树脂及脂环族系氢化石油树脂,特别优选脂环族系氢化石油树脂。作为这样的石油系树脂,具体地可举出Alcon P-70、Alcon P-90、Alcon P-100、Alcon P-115及Alcon P-125(商品名:荒川化学工业(股))、Escorets 8000(商品名:ESSO石油化学(股))等,可1种或2种或以上组合使用。
另外,在本发明的粘合剂层中,除了上述的松香系树脂及/或石油系树脂以外,还可以含有其它种类的增粘剂(萜系树脂、酚醛系树脂及二甲苯树脂等)。
在本发明的粘合剂层中,上述增粘剂的配混量优选为15质量%~50质量%,更优选为20质量%~45质量%。此配混量若低于上述下限时,有难以得到可长时间贴付的充分粘合力的倾向,另一方面,若超过上述上限时,发生药物放出性降低或剥离时的疼痛,以及有容易发生皮肤斑疹的倾向。
另外,所配混的药物若如双氯酚酸或其药学上所容许的盐这样的酸性药物时,优选粘合剂层中还含有碱性物质的加成盐化合物(例如碱性物质的酸加成盐)。另外,这样的碱性物质的加成盐化合物是在碱性物质上加成其它物质,形成盐的化合物,作为碱性物质优选路易斯碱,作为其它物质,优选路易斯酸等的电子对受体或有机卤化物所衍生的缺电子化合物等的物质。作为这样的碱性物质的加成盐化合物,具体地可举出铵化合物的盐类,优选氯化铵等的氨的酸加成盐或二乙基胺盐酸盐等的胺类的酸加成盐。添加碱性物质的加成盐化合物时,其阳离子部份与酸性药物的阳离子部份的一部份或全部形成离子交换或复合离子性物质,结果是所形成的离子交换体或复合离子性物质有改善药物的经皮吸收性的倾向。
在本发明的粘合剂层中,碱性物质的加成盐化合物的配混量是只要足够与酸性药物形成离子对的量即可,一般相对于酸性药物优选0.5~10倍摩尔的范围。另外,碱性物质的加成盐化合物可以1种或2种或以上组合使用。
本发明的贴剂中,粘合剂层中进一步可以含有有机酸。作为这样的有机酸,可举出脂肪族(单、二及三)羧酸(醋酸、丙酸、异丁酸、己酸、辛酸、乳酸、马来酸、丙酮酸、草酸、琥珀酸及酒石酸等)、芳香族羧酸(苯二甲酸、水杨酸、苯甲酸及乙酰水杨酸等)、烷基磺酸(甲磺酸、乙磺酸、丙磺酸、丁磺酸、聚氧亚乙基烷基醚磺酸等)、烷基磺酸衍生物(N-2-羟乙基哌啶-N’-2-乙磺酸等)以及胆酸衍生物(脱氢胆酸等),其中优选单羧酸类或烷基磺酸类,特别优选醋酸。另外,这些有机酸可以使用其盐或有机酸与其盐的混合物。
这样的有机酸及/或其盐,若考虑药物的皮肤透过性及对皮肤的刺激性时,基于构成粘合剂层的组合物全体的质量,适当进行配混,优选0.01~20质量%,进一步优选0.1~15质量%,特别优选0.1~10质量%。此配混量若低于0.01质量%,药物的皮肤透过性有不足的倾向,另一方面,若超过20质量%时,有容易发生皮肤刺激的倾向。
本发明的贴剂中,优选粘合剂层中还含有吸收促进剂。作为这样的吸收促进剂,只要是任一种传统上认为有对于皮肤的吸收促进作用的化合物均可,可举出
(1)碳原子数为6~20的脂肪酸、脂肪族系醇、脂肪酰胺、脂肪酸醚(以上饱和及不饱和中的任一种均可,另外,环状、直链状及支链状中的任一种均可)、
(2)芳香族系有机酸、芳香族系醇、芳香族系有机酸酯或醚、
(3)乳酸酯类、醋酸酯类、单萜系化合物、倍半萜烯系化合物、Azone、Azone衍生物、甘油脂肪酸酯类、丙二醇脂肪酸酯类、山梨糖醇酐脂肪酸酯类(Span系)、聚山梨酸酯系(Tween系)、聚乙二醇脂肪酸酯类、聚氧亚乙基硬化蓖麻油系(HCO系)、聚氧亚乙基烷基醚类、蔗糖脂肪酸酯类及植物油等。
具体地优选辛酸、癸酸、己酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、异硬脂酸、油酸、亚油酸、亚麻酸、月桂醇、肉豆蔻醇、油醇、异硬脂醇、十六烷醇、月桂酸二乙醇酰胺、肉豆蔻酸肉豆蔻酯、肉豆蔻酸辛基十二烷基脂、棕榈酸十六酯、水杨酸甲酯、水杨酸乙二醇酯、肉桂酸、肉桂酸甲酯、甲酚、乳酸十六酯、乳酸月桂酯、醋酸乙酯、醋酸丙酯、香叶醇、百里香酚、丁子香酚、萜品烯醇、左旋薄荷醇、冰片(ボルネォロ-ル)、d-柠檬烯、异丁子香酚、异冰片、橙花醇、d1-樟脑、甘油单辛酸酯、甘油单癸酸酯、甘油单月桂酸酯、甘油单油酸酯、山梨糖醇酐单月桂酸酯、蔗糖单月桂酸酯、聚山梨酸酯20、丙二醇单月桂酸酯、聚乙二醇单月桂酸酯、聚乙二醇单异硬脂酸酯、聚氧亚乙基油醚、聚氧亚乙基月桂醚、HCO-60、焦性硫代癸烷及橄榄油,更特别优选油酸、月桂醇、肉豆蔻醇、油醇、异硬脂醇、月桂酸二乙醇酰胺、左旋薄荷醇、甘油单辛酸酯、甘油单癸酸酯、甘油单油酸酯、山梨糖醇酐单月桂酸酯、丙二醇单月桂酸酯、聚氧亚乙基油醚、聚氧亚乙基月桂醚及焦性硫代癸烷,特别优选油酸、油醇及左旋薄荷醇。所配混的药物是双氯酚酸或其药学上所容许的盐这样的酸性药物时,使用作为吸收促进剂的油酸、油醇、左旋薄荷醇时,有药物的皮肤透过性进一步提高的倾向,特别是使用左旋薄荷醇有提升的倾向。
这样的吸收促进剂,也可2种或以上混合使用,特别优选油酸与左旋薄荷醇的组合、或油醇与左旋薄荷醇的组合。通过这些组合,有特别明显地提升药物的皮肤透过性的倾向。另外,上述吸收促进剂是考虑作为贴剂的充分的渗透性及发红、浮肿等对皮肤的刺激性等,基于构成粘合剂层的组合物全体的质量,优选在0.01~20质量%,进一步优选在0.05~10质量%,特别优选在0.1~5质量%的范围内适当地配混。
本发明的贴剂中,粘合剂层中还可以含有增塑剂。作为这样的增塑剂,可举出液体石蜡、石油系油(石蜡系操作油、环烷系操作油及芳香族系操作油等)、三十碳烷、三十碳六烯、植物系油(橄榄油、椿油、蓖麻油、妥尔油及花生油等)、硅油、二碱式酸酯(邻苯二甲酸二丁基酯及邻苯二甲酸二辛基酯等)、液状橡胶(聚丁烯及异戊二烯橡胶等)、及水杨酸甘油酯等,其中特别优选液体石蜡及液状聚丁烯。
这样的增塑剂,也可2种或以上混合使用,基于构成粘合剂层的组合物全体的增塑剂的配混量,考虑充分的渗透性及维持作为贴剂的充分凝聚力,优选在5~70质量%,更优选在10~60质量%,特别优选在10~50质量%的范围内适当配混。
另外,本发明的贴剂中,粘合剂层根据需要,还可以配混抗氧化剂、充填剂、交联剂、防腐剂及紫外线吸收剂等。作为这样的抗氧化剂,希望为生育酚及其酯衍生物、抗坏血酸、抗坏血酸硬脂酸酯、降二氢愈疮木酸、二丁基羟基甲苯(BHT)、丁基羟基茴香醚等。作为充填剂,希望为碳酸钙、碳酸镁、硅酸盐(例如硅酸铝及硅酸镁等)、硅酸、硫酸钡、硫酸钙、锌酸钙、氧化锌及氧化钛等。作为交联剂,希望为氨基树脂、酚醛树脂、环氧树脂、醇酸树脂及不饱和聚酯等的热固化性树脂、异氰酸酯化合物、嵌段异氰酸酯化合物、有机系交联剂、金属或金属化合物等的无机系交联剂。作为防腐剂,希望为对羟基苯甲酸乙酯、对羟基苯甲酸丙酯及对羟基苯甲酸丁酯等。作为紫外线吸收剂,希望为对氨基苯甲酸衍生物、氨茴酸衍生物、水杨酸衍生物、香豆素衍生物、氨基酸类衍生物、咪唑啉衍生物、嘧啶衍生物及二噁烷衍生物等。
这样的抗氧化剂、充填剂、交联剂、防腐剂及紫外线吸收剂,基于构成贴剂的粘合剂层的组合物全体的质量,优选在10质量%以下,更优选在5质量%以下,特别优选在2质量%以下更的范围内适当配混。
使用上述各成份所调制的本发明的粘合剂层厚度(不包含后述的支持体及剥离被覆物的厚度)优选为50~300μm,更优选为80~200μm。另外,上述厚度若低于50μm时,有粘合性或付着性的持续力降低的倾向,另一方面,上述厚度若超过300μm时,有凝聚力或保型性降低的倾向。
作为本发明的含有非甾体类消炎镇痛剂的贴剂的支持体希望不影响药物的放出,可使用伸缩性或非伸缩性的。作为可用于本发明的支持体,可举出聚乙烯、聚丙烯、聚丁二烯、乙烯-乙酸乙烯酯共聚物、聚氯乙烯、聚酯、尼龙及聚氨酯等的合成树脂的薄膜、薄片、薄片状多孔物、薄片状发泡体、织布或不织布;纸;它们的层合物等。
其次,对本发明的含有非甾体类消炎镇痛剂的贴剂的制造方法的适合一例进行说明。首先,将构成上述粘合剂层的各成份(药物以外),以分别设定的比例,在氮气等的惰性环境下加热混合,添加药物后再搅拌,得到均匀的溶解物。另外,在己烷、甲苯及醋酸乙酯等有机溶剂中添加上述各成份及药物而配成各自设定的比例,搅拌得到均匀溶解物。
然后,将此溶解物以通常的方法,直接延展在支持体上,以剥离被覆物被覆后,切断成所需形状,或也可暂时将此溶解物延展在剥离被覆物上,再被覆在支持体上,将溶解物压合转印在支持体上后,切断成所需形状。另外,使用有机溶剂而得到均匀溶解物时,优选在支持体上延展后,用干燥机干燥,挥发除去有机溶剂后,以剥离被覆物被覆,或也可在剥离被覆物上延展后,用干燥机干燥,挥发除去有机溶剂后,压合转印在支持体。
作为这样的剥离被覆物,可举出施以剥离处理(如硅处理)的剥离纸、玻璃纸或合成树脂薄膜(聚乙烯、聚丙烯、聚酯、聚氯乙烯及聚偏氯乙烯等)。
另外,在上述制造方法中,配混各基剂成份、药物及其它添加成份的顺序是仅叙述其中的一例,贴剂的制造方法并不局限于此配混顺序的方法。
实施例
以下是基于实施例及比较例而更具体地说明本发明,但本发明并不局限于这些实施例,在不逸脱本发明的技术思想的范围内,可有各种变化。
实施例1
在甲苯中混合如下述配方所示的各成份,作为混合物,搅拌得到均匀溶解物。然后,将此溶解物延展在剥离被覆物(聚酯薄膜)上,使干燥后的厚度成为100μm,用干燥机挥发除去甲苯后,被覆在支持体(厚度约为550μm的聚酯布)上,将粘合剂层压合转印在支持体上而得到含有非甾体类消炎镇痛剂的贴剂。另外,下述配方的数值是指「质量%」。
(配方)
SIS 10
PIB 15
液体石蜡 31
脂环族系石油树脂 30
氯化铵 1
油酸 2
左旋薄荷醇 2
聚乙二醇 2
硬脂酸锌 4
双氯酚酸钠 3。
另外,上述配方所示的各成份是使用如下所述的物质。
SIS(苯乙烯-异戊二烯-苯乙烯嵌段共聚物):日本合成橡胶(股)社制,商品名:SIS-5229;
PIB(聚异丁烯):BASF社制,商品名:Oppanol B-200;
液体石蜡:Kaneda(股)社制,商品名:HI-CALL M-352;
脂环族系石油树脂:荒川化学工业(股)社制,商品名:Alcon P-100;
聚乙二醇:三洋化成工业(股)社制,商品名:Macrogol 1500,平均分子量:1300~1600。
实施例2~3及比较例1~3
除了作为聚乙二醇使用如下所述的物质以外,与实施例1同样地操作,而得含有非甾体类消炎镇痛剂的贴剂。
实施例2:三洋化成工业(股)社制,商品名:Macrogol 4000,平均分子量:2600~3800;
实施例3:三洋化成工业(股)社制,商品名:Macrogol 6000,平均分子量:7300~9300;
比较例1:三洋化成工业(股)社制,商品名:Macrogol 200,平均分子量:190~210;
比较例2:三洋化成工业(股)社制,商品名:Macrogol 400,平均分子量:380~420;
比较例3:三洋化成工业(股)社制,商品名:Macrogol 600,平均分子量:570~630。
实施例4
除了未配混硬脂酸锌以外,与实施例1同样地操作,而得含有非甾体类消炎镇痛剂的贴剂。
试验例1(过苛条件下的药物稳定性试验)
将实施例1~3及比较例1~3所得含有非甾体类消炎镇痛剂的贴剂的药物稳定性试验如下所述进行评价。即,将贴剂在40℃下,保存2个月、3个月及6个月,以及在50℃下,保存2个月及3个月后,保存后的贴剂中药物(双氯酚酸)的残存量由液相色谱法测定,算出药物残存率(%)。另外,测定是重复3次进行,所得结果的平均值如表1所示。
(表1)
40℃-2个月保存 | 40℃-3个月保存 | 40℃-6个月保存 | 50℃-2个月保存 | 50℃-3个月保存 | |
实施例1 | 99.2 | 98.5 | 97.5 | 97.3 | 96.0 |
实施例2 | 98.9 | 98.8 | 98.2 | 98.0 | 96.8 |
实施例3 | 99.0 | 99.0 | 98.2 | 98.1 | 97.2 |
比较例1 | 94.0 | 93.2 | 88.1 | 89.3 | 84.8 |
比较例2 | 95.2 | 94.7 | 90.2 | 90.2 | 85.3 |
比较例3 | 96.1 | 95.3 | 90.3 | 90.5 | 86.0 |
如表1所示的结果显示,确认使用平均分子量为1000或以上的聚乙二醇的本发明的含有非甾体类消炎镇痛剂的贴剂(实施例1~3)与平均分子量不满足该条件的含有非甾体类消炎镇痛剂的贴剂(比较例1~3)相比较,在过苛条件下的长期保存安定性明显地优异。另外,药物残存率90%或以下,一般不适合作为商品。
试验例2(观察贴剂层中有无结晶)
由显微镜观察实施例1及4中所得的含有非甾体类消炎镇痛剂的贴剂的贴剂层中有无结晶而进行评价。其结果确认,实施例1中所得的贴剂层中完全没有发生结晶,相对于此,实施例4中所得的贴剂层中仅发生极少量的结晶。
如以上说明,依据本发明,含有具有羧基或其盐的非甾体类消炎镇痛剂作为药效成份的贴剂,可得到即使在40℃或以上高温的过苛条件下,长期保存安定性仍然优异的含有非甾体类消炎镇痛剂的贴剂。
Claims (1)
1.含有非甾体类消炎镇痛剂的贴剂,具备支持体和与该支持体上所层合的粘合剂层的贴剂,其特征在于在该粘合剂层中含有具有羧基或其盐的非甾体类消炎镇痛剂以及平均分子量为1000或以上的聚乙二醇。
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EP1611884A4 (en) | 2010-02-24 |
KR20050107804A (ko) | 2005-11-15 |
CA2519195A1 (en) | 2004-09-30 |
EP1611884A1 (en) | 2006-01-04 |
TWI321470B (zh) | 2010-03-11 |
BRPI0408457A (pt) | 2006-04-04 |
BRPI0408457B8 (pt) | 2021-05-25 |
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