CN117018211A - 一种睾酮-胆固醇前药及制备方法和应用 - Google Patents
一种睾酮-胆固醇前药及制备方法和应用 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
本发明公开了一种睾酮‑胆固醇前药及制备方法和应用,属于医药技术领域。本发明通过对睾酮进行胆固醇修饰,提高睾酮的脂溶性,采用湿法研磨技术制备了不同粒径的睾酮‑胆固醇前药混悬液,其具有良好的缓释效果,缓释时间至少达40天,且与十一酸睾酮油溶液(依据市售制剂配制)相比,其不会引起肺部损伤,为长效睾酮酯注射液的发展提供新的策略和选择。
Description
技术领域
本发明属于医药技术领域,涉及一种睾酮-胆固醇前药及制备方法和应用,尤其涉及一种可注射睾酮-胆固醇前药混悬液及制备方法及其在缓释药物递送系统中的应用。
背景技术
睾酮缺乏综合征,是一种常见的临床和生化疾病,约2-5.7%的40岁以上的男性有此困扰,睾酮缺乏症状随年龄的增长而加重,影响多个器官和系统,表现为代谢功能障碍、认知障碍、骨质疏松、贫血和性功能障碍,患者容易疲劳、出现情绪波动、肥胖、增加患糖尿病及阿尔兹海默症的发病率,对生活质量产生负面影响。
睾酮替代治疗是目前为止最行之有效的方案,已有多种睾酮相关制剂进入市场,例如,Andriol(十一酸睾酮口服片),规格80mg/片,每天2-3次,局限性为需要与食物同服,促进淋巴吸收;Androgel(睾酮凝胶),规格50-100mg/d,其局限为:(1)患者使用凝胶后,易被其他人接触,导致药物损失;(2)长期使用可能产生局部刺激;StriantTM(睾酮口腔贴片),规格30mg/次,每日2次;Natesto(鼻凝胶),规格11mg/次,每日3次,局限性为使用后引发刺激、牙龈炎。为延长药物的作用时间,开发出了多种睾酮缓释设计用于治疗睾酮缺乏综合征,例如,Androderm(睾酮透皮贴片),规格5mg/片,每周2次,局限性为使用会出现皮肤水泡、瘙痒或刺激;Testopel(睾酮植入片),规格3-4片/4-6个月,有一定局限,会产生部位感染、出血和植入部位纤维化;以及在睾酮17位碳原子-β羟基位酯化的相关药物,如Delastestryl(庚酸睾酮注射液),规格250mg/2-4周;Aveed(十一酸睾酮注射油溶液),规格750mg/3mL,局限性为:(1)具有引起患者肺部油微栓的风险;(2)在注射部位引起疼痛,炎症。基于以上局限性,如何开发缓释时间长,给药方便,副作用少,更加安全的睾酮药物长效缓释递送制剂是急切需要解决的难题。
胆固醇是哺乳动物体内最丰富的固醇类化合物,既为细胞生物膜的构成成分,且作为甾体类化合物,为体内多种类固醇激素的前体结构,如葡萄糖,维生素D,性激素,糖皮质激素,睾酮。胆固醇不溶于水,研究证实,使用胆固醇修饰药物,可使药物脂溶性增加,且具有较高的安全性。目前,针对胆固醇修饰睾酮合成脂溶性更低的前药还未见报道。
发明内容
鉴于现有技术的上述缺点、不足,本发明提供一种睾酮-胆固醇前药及制备方法和应用,解决了现有的长效睾酮制剂种类有限,且使用后导致的副作用和使用过程中的局限性的技术问题。
本发明通过如下技术方案实现:
第一方面,本发明提供一种用于治疗睾酮缺乏综合征的睾酮-胆固醇前药,包括式(Ⅰ)所示结构的化合物:
第二方面,本发明提供一种睾酮-胆固醇前药的制备方法,包括如下步骤:氮气保护下,在DMAP、三乙胺的催化作用下,将胆固醇氯甲酸酯与睾酮反应,反应结束,减压蒸馏除去溶剂,得到固体1;将固体1通过硅胶柱层析技术进行分离纯化,得到睾酮-胆固醇前药。
第三方面,本发明提供一种缓释药物组合物,以混悬液或者冻干粉末形式存在,包括睾酮-胆固醇前药、稳定剂、盐和冻干保护剂;所述睾酮-胆固醇前药的浓度为0.3%-6%(w/v);所述稳定剂与睾酮-胆固醇前药重量比为1:3-1:100;所述盐的浓度为1%-30%(w/v);所述冻干保护剂的浓度为2%-20%(w/v)。
进一步地,所述稳定剂包括吐温类、司盘类、泊洛沙姆类、纤维素类、聚酰胺类、硫酸酯类中的一种或两种以上;所述盐包括酒石酸盐或磷酸盐;所述冻干保护剂包括糖类、多羟基化合物类、聚合物类、氨基酸类、无机盐类中的一种或两种以上。
进一步地,所述吐温类包括吐温20(Tween 20)、吐温40(Tween 40)、吐温60(Tween60)、吐温80(Tween 80);所述司盘类包括司盘20(Span 20)、司盘40(Span 40)、司盘60(Span 60)、司盘80(Span 80);所述泊洛沙姆类包括泊洛沙姆188(Pluronic F68)、泊洛沙姆407(Pluronic F127);所述纤维类包括羧甲基纤维素钠(CMC-Na)、羟乙基纤维素(HEC);所述聚酰胺类包括聚乙烯吡咯烷酮(PVP K30);所述硫酸酯类包括十二烷基硫酸钠(SDS)。
优选地,所述稳定剂为泊洛沙姆407。
进一步地,所述糖类包括葡萄糖、蔗糖、乳糖、海藻糖;所述多羟基化合物类包括山梨醇、甘露醇;所述聚合物类包括聚氧乙烯吡咯烷酮、明胶;所述氨基酸类包括甘氨酸、色氨酸;所述无机盐类包括氯化钠、柠檬酸盐。
优选地,所述冻干保护剂为甘露醇。
第四方面,本发明提供一种缓释药物组合物的制备方法,所述混悬液的制备方法,包括介质研磨法、高压均质法、反溶剂沉淀法或超临界流体法。
进一步地,所述介质研磨法包括如下步骤:
(1)将睾酮-胆固醇前药、稳定剂、盐、冻干保护剂混合分散在水性介质中,得到混悬液;
(2)向步骤(1)的混悬液中加入研磨珠进行研磨,可得到粒径为100nm-50μm范围内的纳米晶/微米晶混悬液,即为所述缓释药物组合物。
第五方面,本发明提供所述的睾酮-胆固醇前药或者所述的缓释药物组合物在缓释治疗睾酮缺乏综合征中的应用。
进一步地,用于肌肉注射给药或皮下给药。
本发明的睾酮-胆固醇前药的可注射药物混悬液,其优势在于:(1)采用湿法研磨技术,制备工艺简单,温度可控,易于放大;(2)无需载体,稳定剂用量少,载药量高,安全性好;(3)混悬液分散均匀,稳定性好;(4)易于冻干,重复混悬后,再分散性好,有利于长期储存;(5)体内药动学行为较好,尤其粒径为300nm的睾酮-胆固醇前药纳米晶混悬液药动学性质最佳,血药浓度平稳,缓释时间长;(6)与市售制剂相比,睾酮-胆固醇前药混悬液并未引起肺部炎症,具有较大的应用潜力。
本发明具有以下优点和有益效果:
本发明通过对睾酮进行胆固醇修饰合成亲脂性的睾酮-胆固醇前药,进而,通过湿法研磨技术制备得到无需载体、稳定性好、安全性高的长效缓释纳米晶/微米晶混悬液,肌肉注射后,形成药物储库,产生长效缓释效果,缓释时间至少达40天,血药浓度平稳,可减少给药次数,提高患者依从性,且与十一酸睾酮油溶液相比,睾酮-胆固醇前药混悬液不会引起肺部血管栓塞的不良影响。为睾酮酯类药物开发提供新的思路,也为长效注射制剂的开发提供策略和选择。
附图说明
图1为实施例1的睾酮-胆固醇前药的高分辨质谱图(A)和1H-NMR谱图(B)。
图2为实施例1的睾酮-胆固醇前药、睾酮、胆固醇氯甲酸酯、睾酮和胆固醇氯甲酸酯的物理混合物的X粉末衍射图谱。
图3为睾酮(A)和实施例1的睾酮-胆固醇前药(B)的差示扫描量热分析图谱。
图4为实施例5的不同粒径的睾酮-胆固醇前药混悬液的粒径分布图;其中,A为睾酮-胆固醇前药混悬液1,B为睾酮混悬液1,C为睾酮-胆固醇前药混悬液2,D为睾酮混悬液2,E为睾酮-胆固醇前药混悬液3,F为睾酮混悬液3。
图5为实施例5的稳定剂泊洛沙姆407、睾酮-胆固醇前药混悬液冻干粉末与泊洛沙姆407的物理混合物、睾酮混悬液冻干粉末与泊洛沙姆407的物理混合物、实施例6的睾酮-胆固醇前药混悬液冻干粉末、睾酮混悬液冻干粉末、的X粉末衍射图谱。
图6为在大鼠中肌肉注射16.6mg睾酮/kg的实施例5不同粒径的睾酮-胆固醇前药混悬液、睾酮混悬液及十一酸睾酮油溶液(依据市售制剂配制)后睾酮的平均血浆浓度。
图7为在大鼠腿部肌肉注射16.6mg睾酮/kg的实施例5的睾酮-胆固醇前药混悬液、睾酮混悬液及十一酸睾酮油溶液(依据市售制剂配制)后的大鼠肺部组织病理切片。
具体实施方式
列举下列实施例对本发明进一步说明,而不是以任何方式限制本发明。
实施例1睾酮-胆固醇前药的合成
精密称取胆固醇氯甲酸酯(1.868g,4.16mmol),用10mL无水二氯甲烷溶解,置于反应瓶中,冰浴搅拌,再依次精密称取DMAP(0.508g,4.16mmol),三乙胺(289.2μL,2.08mmol),睾酮(0.6g,2.08mmol),用10mL二氯甲烷溶解,缓慢滴加至反应瓶中,冰浴搅拌2h,温度升至室温,反应8h,薄层色谱法监测反应进程。反应结束后,减压蒸馏除去溶剂,即得粗产物。用硅胶柱梯度层析技术对粗产物进行分离纯化(淡黄色固体,收率57%)。
采用高分辨质谱(A)和1H-NMR谱(B)对目标化合物进行结构确证,结果如图1所示,核磁共振波谱解析结果如下:δ5.73(s,1H,H-1),5.39(d,J=4.5Hz,1H,H-2’),4.56 4.47(m,1H,H-2),4.51 4.39(m,1H,H-1’),1.19(s,3H,H-3),1.01(s,3H,H-6’),0.91(d,J=6.5Hz,3H,H-3’),0.86(dd,J=6.2,1.9Hz,9H,H-4,4’,5’),0.68(s,3H,H-7’).
经验证,目标化合物的结构式如下:
实施例2X射线衍射谱分析
各样品在扫描范围10-90°(2θ)之间进行扫描,步长0.05°,管电压40kV。
以X射线衍射图表征睾酮、胆固醇氯甲酸酯、睾酮和胆固醇氯甲酸酯的物理混合物、睾酮-胆固醇前药的结晶形式,其结果如图2所示。
结果可知,物理混合物在2θ角7.85°、8.43°、12.26°、14.10°、14.42°、14.89°、17.25°、17.88°、19.98°、23.24°、27.55°处具有强衍射峰,包含了原料药睾酮和胆固醇氯甲酸酯的特征峰,说明二者物理混合过程中,药物晶型没有发生改变;睾酮-胆固醇前药图谱在2θ角4.91°、9.79°、14.05°、14.84°、15.47°、17.09°、19.04°、20.51°有明显的衍射峰,与物理混合物特征峰位置不同,说明睾酮和睾酮-胆固醇前药均为晶型药物。
实施例3差示扫描量热分析
分别称定睾酮粉末、睾酮-胆固醇前药粉末各6mg于坩埚内,加盖压紧,氧化铝作为参比,在氮气保护的条件下,升温速率为10℃/min,扫描范围分别为30-210℃和30-230℃,结果如图3所示。
由图3可知,睾酮粉末在114.7℃有较小的吸热峰,在155.80℃有明显的吸热峰,说明睾酮为结晶状态;睾酮-胆固醇前药粉末在225.36℃一个明显的吸热峰,说明睾酮-胆固醇前药粉末为结晶状态。
实施例4睾酮-胆固醇前药和睾酮在不同水性介质中的溶解度
将过量的睾酮原料药和睾酮-胆固醇前药分别置于10mL的具塞试管内,分别加入适量的水,生理盐水,pH6.8或pH7.4的磷酸盐缓冲溶液,将具塞试管置于37℃恒温摇床中,保证睾酮原料药和睾酮-胆固醇前药在上述水性介质中达到过饱和,连续振摇72h,取各溶液上层清液过0.22μm微孔滤膜,高效液相进样测定不同介质中睾酮和睾酮-胆固醇前药的浓度,结果见表1,表明睾酮-胆固醇前药的水性溶解度明显小于睾酮,易制备出缓释效果更好的混悬液。
表1睾酮-胆固醇前药和睾酮在不同介质中的溶解度
实施例5不同粒径的睾酮-胆固醇前药纳米/微米晶混悬液的制备
将睾酮-胆固醇前药、稳定剂均匀分散在蒸馏水,加入研磨珠分别研磨一定时间。
不同粒径的睾酮-胆固醇前药混悬液、睾酮混悬液的组成和制备方法如表2、表3所示以及马尔文粒度仪、BT-9300s型激光粒度分布仪测定的粒径和粒径分布结果如表4、表5所示,分布图如图4所示,结果表明通过介质研磨技术可以分别制备得到粒径均匀、粒径分布范围窄的睾酮-胆固醇前药混悬液和睾酮混悬液。
表2睾酮-胆固醇前药混悬液的组成和研磨过程
表3睾酮混悬液的组成和研磨过程
表4睾酮-胆固醇前药混悬液的粒径和粒径分布
表5睾酮混悬液的粒径和粒径分布
实施例6睾酮-胆固醇前药混悬液的制剂冻干
于睾酮-胆固醇前药混悬液中均匀加入10%(w/v)的甘露醇进行冻干,睾酮-胆固醇前药混悬液冻干粉末表面平整,为疏松的圆饼状结构。加入蒸馏水,轻轻振摇,容易分散,复混悬后的粒径及分布与冻干前相比,几乎没有变化,说明此冻干技术制备的混悬液冻干粉末性质优良,不同粒径的混悬液冻干前后的粒径见表6、表7。
表6睾酮-胆固醇前药混悬液冻干前后的粒径和粒径分布
表7睾酮混悬液冻干前后的粒径和粒径分布
实施例7粉末X射线衍射谱分析
各样品在扫描范围10-90°(2θ)之间扫描,步长0.05°,管电压40kV。
以X射线衍射图表征稳定剂泊洛沙姆407、实施例6的睾酮-胆固醇前药混悬液1冻干粉末、睾酮混悬液1冻干粉末(制备方法为将实施例6的睾酮-胆固醇前药混悬液替换为睾酮混悬液,其余步骤相同)、泊洛沙姆407和睾酮混悬液1冻干粉末的物理混合物(1:1,w:w)、泊洛沙姆407和睾酮-胆固醇前药混悬液1冻干粉末的物理混合物(1:1,w:w),其结果如图5所示。
泊洛沙姆407在19.27°、23.42°处有特征衍射峰,泊洛沙姆407与睾酮混悬液冻干粉末的物理混合物、泊洛沙姆407与睾酮-胆固醇前药混悬液冻干粉末的物理混合物分别包含泊洛沙姆407和各自药物的特征峰,说明药物和稳定剂没有发生相互作用。睾酮混悬液冻干粉末和睾酮-胆固醇前药混悬液冻干粉末中存在泊洛沙姆407和各自药物的特征衍射峰,说明混悬液经研磨、冻干,依然以晶体形式存在。
实施例8睾酮-胆固醇前药混悬液的药代动力学研究
取35只雌性健康大鼠,体重200-220g,随机分为7组,每组5只,分别肌肉注射粒径为300nm,12μm,20μm的睾酮-胆固醇前药混悬液、300nm,12μm,20μm的睾酮混悬液(对照)以及根据市售处方配制的十一酸睾酮油溶液,等效给药剂量为16.6mg/kg(按所含睾酮计)。于规定时间点进行大鼠眼眶取血,涡旋3min,13000rpm离心5min,得到血浆。利用高效液相色谱-质谱联用仪测定血浆中睾酮的浓度,药动曲线如图6所示,DAS软件处理药动学参数见表8。
结果显示,粒径为300nm的睾酮-胆固醇前药混悬液的AUCTst与十一酸睾酮油溶液相当;Cmax为120ng/mL,说明肌肉注射300nm的Tst-Chol混悬液缓释时间至少可达40天,且不会产生很大的血药浓度突跃,安全性高。
表8三种粒径的睾酮-胆固醇前药混悬液、睾酮混悬液以及十一酸睾酮油溶液(根据市售处方配制)的药动学参数
实施例9肌肉注射睾酮-胆固醇前药混悬液的肺部组织病理研究
将SD大鼠随机分为四组,分别于大腿外侧肌肉注射生理盐水、睾酮-胆固醇前药混悬液、睾酮混悬液、以及根据市售处方配制的十一酸睾酮油溶液各0.3mL。于给药后的第2、7、14天分别对各组大鼠肺部组织进行取材,用生理盐水洗净,将其浸泡于4%多聚甲醛组织固定液48h。固定后的肺部组织包埋切片、苏木精-曙红染色后,置于显微镜下观察,如图7所示。
肌肉注射生理盐水,肺部纤维未见病理性改变,分别肌肉注射睾酮-胆固醇前药混悬液、睾酮混悬液2天、7天、14天后,肺部切片与生理盐水组相比并无明显差异。肌肉注射十一酸睾酮油溶液2天、7天、14天后,均观察到肺部病理改变(箭头所示),说明肌肉注射十一酸睾酮油溶液会引起肺部炎症,相比之下,睾酮-胆固醇前药混悬液安全性较高,没有发现对肺部产生不良反应。
最后应说明的是:以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (10)
1.一种用于治疗睾酮缺乏综合征的睾酮-胆固醇前药,其特征在于,包括式(Ⅰ)所示结构的化合物:
2.权利要求1所述的睾酮-胆固醇前药的制备方法,其特征在于,包括如下步骤:
氮气保护下,在DMAP、三乙胺的催化作用下,将胆固醇氯甲酸酯与睾酮反应,反应结束,减压蒸馏除去溶剂,得到固体1;将固体1通过硅胶柱层析技术进行分离纯化,得到睾酮-胆固醇前药。
3.一种缓释药物组合物,其特征在于,以混悬液或者冻干粉末形式存在,包括权利要求1所述的睾酮-胆固醇前药、稳定剂、盐和冻干保护剂;所述睾酮-胆固醇前药的浓度为0.3%-10%(w/v);所述稳定剂与睾酮-胆固醇前药重量比为1:3-1:100;所述盐的浓度为1%-30%(w/v);所述冻干保护剂的浓度为2%-20%(w/v)。
4.根据权利要求3所述的缓释药物组合物,其特征在于,所述稳定剂包括吐温类、司盘类、泊洛沙姆类、纤维素类、聚酰胺类、硫酸酯类中的一种或两种以上;所述盐包括酒石酸盐或磷酸盐;所述冻干保护剂包括糖类、多羟基化合物类、聚合物类、氨基酸类、无机盐类中的一种或两种以上。
5.根据权利要求4所述的缓释药物组合物,其特征在于,所述吐温类包括吐温20、吐温40、吐温60、吐温80;所述司盘类包括司盘20、司盘40、司盘60、司盘80;所述泊洛沙姆类包括泊洛沙姆188、泊洛沙姆407;所述纤维类包括羧甲基纤维素钠、羟乙基纤维素;所述聚酰胺类包括聚乙烯吡咯烷酮;所述硫酸酯类包括十二烷基硫酸钠。
6.根据权利要求4所述的缓释药物组合物,其特征在于,所述糖类包括葡萄糖、蔗糖、乳糖、海藻糖;所述多羟基化合物类包括山梨醇、甘露醇;所述聚合物类包括聚氧乙烯吡咯烷酮、明胶;所述氨基酸类包括甘氨酸、色氨酸;所述无机盐类包括氯化钠、柠檬酸盐。
7.权利要求3-6中任一项所述的缓释药物组合物的制备方法,其特征在于,所述混悬液的制备方法,包括介质研磨法、高压均质法、反溶剂沉淀法或超临界流体法。
8.根据权利要求7所述的制备方法,其特征在于,所述介质研磨法包括如下步骤:
(1)将睾酮-胆固醇前药、稳定剂、盐、冻干保护剂混合分散在水性介质中,得到混悬液;
(2)向步骤(1)的混悬液中加入研磨珠进行研磨,可得到粒径为100nm-50μm范围内的纳米晶/微米晶混悬液,即为所述缓释药物组合物。
9.权利要求1所述的睾酮-胆固醇前药或者权利要求3-6中任一项所述的缓释药物组合物在缓释治疗睾酮缺乏综合征中的应用。
10.根据权利要求9所述的应用,其特征在于,用于肌肉注射给药或皮下给药。
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