CN113354800A - 一种peg嵌段聚乙丙交酯及其应用 - Google Patents
一种peg嵌段聚乙丙交酯及其应用 Download PDFInfo
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- 239000003814 drug Substances 0.000 claims abstract description 20
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229940079593 drug Drugs 0.000 claims abstract description 14
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims abstract description 13
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- 229920000954 Polyglycolide Polymers 0.000 claims description 7
- RSLNRVYIRDVHLY-UHFFFAOYSA-N Tulobuterol hydrochloride Chemical compound [Cl-].CC(C)(C)[NH2+]CC(O)C1=CC=CC=C1Cl RSLNRVYIRDVHLY-UHFFFAOYSA-N 0.000 claims description 6
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical group OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 206010040880 Skin irritation Diseases 0.000 abstract description 6
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- 239000000243 solution Substances 0.000 description 5
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 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
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
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- 210000004369 blood Anatomy 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010579 first pass effect Methods 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical compound [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000012641 Pigmentation disease Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/66—Polyesters containing oxygen in the form of ether groups
- C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
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- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
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Abstract
本发明属于化工医药技术领域,具体涉及一种PEG嵌段聚乙丙交酯及其应用。本发明所述的PEG嵌段聚乙丙交酯采用丙交酯单体、乙交酯单体和聚乙二醇为原料,在催化剂和引发剂作用下制得;其中,以摩尔比计,丙交酯单体:乙交酯单体:聚乙二醇=60:30:10~30:30:40。本发明获得的PEG嵌段聚乙丙交酯经过冷冻干燥,可相对长时间保存,在透皮给药区域,因为PEG嵌段PLGA具有生物相容性和生物降解性,它提高了药物的渗透性,皮肤刺激性低。
Description
技术领域
本发明属于化工医药技术领域,具体涉及一种PEG嵌段聚乙丙交酯及其应用。
背景技术
经皮给药系统是药物经由人体皮肤进入血液从而进入体循环来达到治疗目的的一种给药方式。经皮给药是一种新型给药方式,具有以下几点优势:一、解决了口服类药物给药方面的重大问题,即药物的首过效应问题。使用经皮给药,可以避免药物的首过效应及其他一些副作用问题。二、实用性,有些病情直接进行给药是不合适的,可能导致病人出现别的症状,而经皮给药则可以免去此问题。三、可减少或避免同源药物在口服或非口服给药过程中的限制。传统的给药方式会受到最高浓度和最低浓度的限制,而经皮给药系统同传统给药方式所引起的波定性相比,其释放更加平稳,两者联合使用有利于减少不良反应,并降低最低治疗量的血药浓度。
然而,经皮给药系统也存在很多局限性,最重要的一点是药物分子需要能通过皮肤最外层的角质层,解决该问题有效方法是在透皮贴剂中加入促渗剂,常用的促渗剂包括氮酮、脂肪酸及其酯类,醇类等,但是目前的这些促渗效果不理想,具有皮肤刺激性,而且促渗剂本身具有毒性,无形中对人体造成诸多伤害。因此,有必要开发一种安全且促渗效果好的促渗剂应用于经皮给药系统。
发明内容
针对上述问题,本发明提出了一种PEG嵌段聚乙丙交酯并将其用于透皮贴的促渗剂,提高了药物的渗透性,且皮肤刺激性低。
本发明所述的一种PEG嵌段聚乙丙交酯,采用丙交酯单体、乙交酯单体和聚乙二醇为原料,在催化剂和引发剂作用下制得;其中,以摩尔比计,丙交酯单体:乙交酯单体:聚乙二醇=60:30:10~50:50:10。本发明中丙交酯和乙交酯共聚物为脂溶性,添加聚乙二醇改性后具有了脂溶性和水溶性;本发明中乙交酯比例超过丙交酯会导致聚合物溶解性下降。
所述的聚乙二醇选自聚乙二醇1000或聚乙二醇1500或其混合物。
所述引发剂选自山梨醇或木糖醇。所述引发剂摩尔量为丙交酯单体、乙交酯单体和聚乙二醇总摩尔量的0.5%-1.5%。此类引发剂所制备聚合物为非线性聚合物,具有缓释作用。
本发明所述的PEG嵌段聚乙丙交酯用作透皮贴促渗剂的用途。
其具体步骤为:
(1)使用溶剂(水或乙醇)溶解PEG嵌段聚乙丙交酯,得混合溶液;
(2)向混合溶液中加入药物进行搅拌混合,将浆状物,制成湿品贴剂,经烘干、模切得到透皮贴。
所述的药物包括但不限于格列美脲或盐酸妥洛特罗或盐酸维拉帕米。
所述混合溶液中PEG嵌段聚乙丙交酯的质量分数为3%-5%。
本发明获得的PEG嵌段聚乙丙交酯经过冷冻干燥,可相对长时间保存,在透皮给药区域,因为PEG嵌段PLGA具有生物相容性和生物降解性,它提高了药物的渗透性,皮肤刺激性低。
具体实施方式
实施例1
称量15g丙交酯单体、10g乙交酯单体和10g聚乙二醇1000,加入三口烧瓶中,加入150mL二氯甲烷搅拌,常温下减压蒸馏除去溶剂,称取0.2%当量的辛酸亚锡和引发剂山梨醇(引发剂摩尔量为丙交酯单体、乙交酯单体和聚乙二醇总摩尔量的0.5%),加入三口烧瓶中,氮气置换3次,130~150℃下反应6~8小时后得到粘稠液体,用二氯甲烷溶解、乙醇沉淀三次,冷冻干燥至恒重即得白色粉末,收率为82.14%,Mw14009,Mn26531。
实施例2
称量60g丙交酯单体、40g乙交酯单体和30g聚乙二醇1500,倒入三口烧瓶中,加入200mL甲苯搅拌,80℃减压蒸馏除去溶剂,称取0.2%当量的辛酸亚锡和引发剂木糖醇(引发剂摩尔量为丙交酯单体、乙交酯单体和聚乙二醇总摩尔量的1.5%),加入三口烧瓶中,氮气置换3次,130~150℃下反应8~10小时后得到粘稠液体,经氯仿溶解、乙醚沉淀三次,冷冻干燥至恒重即得白色粉末,收率为76.84%,Mw42861,Mn33214。
实施例3
单次及多次皮肤刺激性实验
单次实验组:将12只家兔雌雄各半随机分为2组,并在其背部依次按脊柱两侧分区域(3cm×3cm),左侧涂抹生理盐水为对照组,右侧按组别分别涂抹2%PEG嵌段聚乙丙交酯溶液、5%PEG嵌段聚乙丙交酯溶液,实验本身采用自身对照。按照上述的分组,分别对不同区域涂抹不同受试物0.5ml。给药1d后,用蒸馏水将药物擦除,去除药物后的2,12,24,48h观察受试区域皮肤变化情况,打分评价刺激性强度。
多次给药组实验动物及动物皮肤受试区域处理方法同单次皮肤刺激性实验,同样按照对应区域涂抹上述3组溶液,固定受试区,每1d涂抹1次药物,连续给药7d。每次给药后2h,涂药前观察皮肤情况(有无色素沉淀、皮肤红斑、水肿、皮肤粗糙等),最终次涂抹药物后,除去受试物,之后分别于2,12,24,48h观察记录皮肤状况并打分评价刺激性强度。
实验结果表明,2%PEG嵌段聚乙丙交酯溶液、5%PEG嵌段聚乙丙交酯溶液均未表现出刺激性。
实施例4
PEG嵌段聚乙丙交酯用作透皮贴促渗剂的用途,其具体步骤为:
(1)使用溶剂溶解PEG嵌段聚乙丙交酯,得混合溶液;
(2)向混合溶液中加入药物进行搅拌混合,将浆状物,制成湿品贴剂,经烘干、模切得到透皮贴。
所述的药物包括但不限于格列美脲或盐酸妥洛特罗或盐酸维拉帕米。
实施例5
参照实施例4,分别以3%PEG嵌段聚乙丙交酯、3%油酸、3%氮酮为促渗剂制备格列美脲透皮贴剂,并进行体外透皮试验,8小时累计透皮数据如表1,结果表明PEG嵌段聚乙丙交酯具有更好的促渗效果。
表1含不同种类促渗剂的格列美脲透皮贴剂的透皮试验结果
促渗剂种类 | 8小时累积透过量(ug/cm<sup>2</sup>) |
PEG嵌段聚乙丙交酯 | 26.6±3.7 |
油酸 | 16.6±3.1 |
氮酮 | 18.2±4.3 |
实施例6
参照实施例4,分别以5%PEG嵌段聚乙丙交酯、5%丙二醇、5%L-薄荷醇为促渗剂制备盐酸妥洛特罗透皮贴剂,并进行体外透皮试验,8小时累计透皮数据如表2,结果表明PEG嵌段聚乙丙交酯具有更好的促渗效果。
表2含不同种类促渗剂的盐酸妥洛特罗透皮贴剂的透皮试验结果
促渗剂种类 | 8小时累积透过量(ug/cm<sup>2</sup>) |
PEG嵌段聚乙丙交酯 | 55.5±5.8 |
丙二醇 | 42.3±6.1 |
L-薄荷醇 | 38.8±4.9 |
实施例7
分别以4%PEG嵌段聚乙丙交酯、4%丙二醇、4%氮酮为促渗剂制备盐酸维拉帕米透皮贴剂,并进行体外透皮试验,8小时累计透皮数据如表3,结果表明PEG嵌段聚乙丙交酯促渗效果与丙二醇相当,优于氮酮。
表3含不同种类促渗剂的盐酸妥洛特罗透皮贴剂的透皮试验结果
促渗剂种类 | 8小时累积透过量(ug/cm<sup>2</sup>) |
PEG嵌段聚乙丙交酯 | 331.5±25.2 |
丙二醇 | 328.8±29.8 |
氮酮 | 259.4±33.5 |
Claims (7)
1.一种PEG嵌段聚乙丙交酯,其特征在于,采用丙交酯单体、乙交酯单体和聚乙二醇为原料,在催化剂和引发剂作用下制得;其中,以摩尔比计,丙交酯单体:乙交酯单体:聚乙二醇=60:30:10~30:30:40。
2.根据权利要求1所述的一种PEG嵌段聚乙丙交酯,其特征在于,所述的聚乙二醇选自聚乙二醇1000或聚乙二醇1500或其混合物。
3.根据权利要求1所述的一种PEG嵌段聚乙丙交酯,其特征在于,所述引发剂选自山梨醇或木糖醇。
4.权利要求1或2或3所述的一种PEG嵌段聚乙丙交酯用作透皮贴促渗剂的用途。
5.根据权利要求4所述的PEG嵌段聚乙丙交酯用作透皮贴促渗剂的用途,其特征在于,其具体步骤为:
(1)使用溶剂溶解PEG嵌段聚乙丙交酯,得混合溶液;
(2)向混合溶液中加入药物进行搅拌混合,将浆状物,制成湿品贴剂,经烘干、模切得到透皮贴。
6.根据权利要求5所述的PEG嵌段聚乙丙交酯用作透皮贴促渗剂的用途,其特征在于,所述的药物包括但不限于格列美脲或盐酸妥洛特罗或盐酸维拉帕米。
7.根据权利要求5所述的PEG嵌段聚乙丙交酯用作透皮贴促渗剂的用途,其特征在于,所述混合溶液中PEG嵌段聚乙丙交酯的质量分数为3%-5%。
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