维生素C棕榈酸酯泡囊和固体脂质纳米粒作为维A酸经皮给药载体研究
摘要
目的:以维生素C棕榈酸酯泡囊和固体脂质纳米粒作为维A酸经皮给药载体,对其处方组成、制备工艺、包封率、稳定性、释放度、体外皮肤渗透性和皮肤贮留进行研究。期望通过这两种新型微粒给药系统用于皮肤局部给药,提高维A酸的稳定性,同时使更多的药物贮留在皮肤内,以增加局部药物浓度减少系统吸收。
方法:(1)维A酸维生素C棕榈酸酯泡囊和固体脂质纳米粒的制备。采用溶剂注入法制备维A酸维生素C棕榈酸酯泡囊,并进行了处方优化,采用透析法测定包封率。采用纳米乳法制备维A酸固体脂质纳米粒,通过相图研究确定处方组成,采用葡聚糖G50微型凝胶测定包封率。
(2)维A酸维生素C棕榈酸酯泡囊和固体脂质纳米粒的稳定性研究。稳定性研究中考查了维A酸维生素C棕榈酸酯泡囊和固体脂质纳米粒在光照(4500±500 lx)下药物降解的情况;以药物含量和包封率为指标,考查了泡囊在4℃和25℃,相对湿度75%,贮存6个月的稳定性;以药物含量、粒径、电位和包封率为指标考查了固体脂质纳米粒在4℃、25℃和40℃,相对湿度75%,贮存3个月的稳定性。
(3)维A酸维生素C棕榈酸酯泡囊和固体脂质纳米粒的体外释放度、皮肤渗透性和皮肤贮留的研究。用Franz扩散池测定维A酸从载体中的释放速度。扩散池与供给池之间为纤维素膜(截留分子量8000～14000),扩散池面积为2.92cm2。在第2、4、6、8、12、24h定时取样0.5ml,并补充等量新鲜介质,样品处理后用HPLC测定。体外经皮渗透试验同释放度,用小鼠、大鼠或家兔背部皮肤替代半透膜。皮肤贮留则在体外经皮渗透试验完结后,取下皮肤,剪碎匀浆,用50%异丙醇-生理盐水提取,提取液处理后用HPLC测定药物浓度。
结果:(1)维A酸维生素C棕榈酸酯泡囊优化处方及工艺。取0.1g L-半胱氨酸盐酸盐和0.05g EDTANa2溶于100ml PBS (pH 5.5)中,作为Ⅰ相;再取0.1g维A酸、2.1g维生素C棕榈酸酯、1.9g胆固醇和0.02g 2,6-二叔丁基对甲基苯酚加25ml乙醇-乙醚(3:2)完全溶解,作为Ⅱ相;1000r·min-1搅拌下将Ⅱ相慢慢滴至60℃的Ⅰ相中;滴毕后,继续60℃保温搅拌30min,去除有机溶剂,然后停止加热,继续搅拌30min。控制最终体积为100ml,即得。采用透析法测定其包封率>90%。4℃贮存6个月含量无明显变化,包封率略有下降;25℃贮存6个月含量和包封率有一定程度下降。
(2)维A酸固体脂质纳米粒优化处方及工艺。取0.5g单硬脂酸甘油酯、0.2g司盘60、4g吐温80、5g聚乙二醇400、0.04g维生素C棕榈酸酯、1g泊洛沙姆F-127、0.04g 2,6-二叔丁基对甲基酚,置70℃水浴加热使其熔化。在70℃,200r·min-1搅拌条件下加入0.025g维A酸,继续搅拌10min使维A酸完全溶解,得澄清透明黄色溶液。然后加入15ml,70℃的水,于200r·min-1搅拌20min,形成稳定均一乳液。然后将乳液倒入以1000r·min-1搅拌的78ml,2℃含0.01g EDTA的水中,搅拌5min后转速调至200r·min-1,搅拌2h,即得。采用葡聚糖G50微型凝胶测定包封率>92%。4℃、25℃和40℃贮存3个月,含量和包封率均无明显变化。
(3)释放速度、体外皮肤渗透性及皮肤贮留。释放度表明维A酸维生素C棕榈酸酯泡囊释放速度大于市售乳膏和维A酸固体脂质纳米粒。小鼠体外经皮渗透试验表明泡囊中维A酸累积经皮透过量高于市售乳膏和固体脂质纳米粒,但皮肤贮留量固体脂质纳米粒高于市售乳膏和泡囊。比较泡囊和固体脂质纳米粒在小鼠、大鼠及家兔皮肤的体外皮肤透过性,结果小鼠>大鼠>家兔。比较泡囊和固体脂质纳米粒在小鼠、大鼠及家兔皮肤的贮留量,结果家兔>大鼠>小鼠。
结论:采用注入法制备维A酸维生素C棕榈酸酯泡囊和纳米乳法制备维A酸固体脂质纳米粒,方法简单易行,优化处方的制品包封率均大于90%。稳定性方面脂质纳米粒优于泡囊。泡囊体外释放速度快,体外累积经皮透过量大于市售乳膏和固体脂质纳米粒,说明泡囊有增加药物经皮渗透作用。固体脂质纳米粒体外释放速度慢,皮肤贮留量大于市售乳膏和固体脂质纳米粒,说明其有助于增加局部药物浓度。泡囊和固体脂质纳米粒小鼠背部皮肤累积经皮渗透量高于大鼠和家兔,而皮肤贮留量低于大鼠和家兔。
Objective: Use ascorbyl palmitate vesicles and solid lipid nanoparticles as transdermal administration carrier for tretinoin, carry out studies on their formulation, preparation technology, entrapment efficiency, stability, release, in vitro skin penetration and retention .Expecting to improve the stability of tretinoin and increase the local concentration of drug when transdermal administration.
Methods: (1)Study on the preparation of tretinoin ascorbyl palmitate vesicles and solid lipid nanoparticles. Prepare tretinoin ascorbyl palmitate vesicles by solvent-injection method, and optimize the formulation of vesicles, entrapment efficiency was determinated by dialysis method. Prepare tretinoin solid lipid nanoparticles by nanoemulsion method, formulation determined through study on phase diagram and entrapment efficiency was determinated by Sephadex G50 mini-column.
(2) Study on the stability of tretinoin ascorbyl palmitate vesicles and solid lipid nanoparticles. In the study of stability, we examen degradation of drug loaded in ascorbyl palmitate vesicles or solid lipid nanoparticles when exposure to illumination(4500±500 lx). The tretinoin ascorbyl palmitate vesicles were stored two different temperatures(4℃, 25℃) and relative humidity 75% for 6 mouths to carry through testing of stability, drug content and entrapment efficiency were measured. The solid lipid nanoparticles were stored three different temperatures(4℃, 25℃, 40℃) and relative humidity 75% for 3 mouths to carry through testing of stability, drug content, particle size , potential and entrapment efficiency were measured.
(3) Study on the release rate, in vitro skin penetration and retention of tretinoin ascorbyl palmitate vesicles and solid lipid nanoparticles. The in vitro release rate of tretinoin from carrier was determined by Franz diffusion cell. Between donor compartment and receptor compartment was cellulose membrane(cut-off molecules 8000～14000 ), the avaiable diffusion area of cell was 2.92 cm2. At appropriate intervals, namely, 2,4,6,8,12,24h, 0.5ml of the receptor medium were withdrawn and replaced by an equal volume of fresh receptor solution immediately. The sample was analyzed by HPLC after treatment .The in vitro skin penetration experiment was carry through by the same method as the in vitro release rate experiments except using the back skin of mouse, rats or rabbits instead of cellulose membrane. When in vitro skin penetration experiment completed, the skin were taken down from cells, cut and homogenated. After these treatment, extracted by 50% isopropanol-normal saline. The extracting solution was analyzed by HPLC after treatment .
Results: (1)Optimized formulation and preparation technology of tretinoin ascorbyl palmitate vesicles. 0.1g 1-cysteine hydrochloride and 0.05g EDTANa2 dissolved in 100ml PBS (pH 5.5), as phaseⅠ;0.1g tretinoin, 2.1g ascorbyl palmitate, 1.9g cholesterol and 0.02g BHT dissolved in ethanol-ether(3∶2), as phaseⅡ. PhaseⅡdrop into phaseⅠwhich heated to 60℃slowly at 1000r·min-1 stirring, after dropped, keep stirring 30min at 60℃in order to remove organic solvents, then stop heating and contuniue stirring 30min. The final volume was controlled to 100ml and the vesicles were obtained. The entrapment efficiency was over 90% and determinated by dialysis method . The products have no significant decrease on content and entrapment efficiency when stored at 4℃environment for 6 months but have some decrease when stored at 25℃environment.
(2)Optimized formulation and preparation technology of tretinoin solid lipid nanoparticles. 0.5g glycerin monostearate, 0.2g span60, 4g tween80, 5g PEG400, 0.04g ascorbyl palmitate,1g poloxamer F-127, 0.04g butylated hydroxytoluene, mixed and melted in 70℃water bath heating to form a clear solution. Then 0.025g tretinoin was added to this solution at 70℃and 200r·min-1 stirring until it was complete dissolved and another yellow clear solution was obtained. After that 15ml, 70℃water was added to this solution and stirred at 200r·min-1 for 20min to form a stable nanoemulsion. Then pour the nanoemulsion into 78ml, 2℃water(contains 0.01g EDTA) with 1000r·min-1 stirring. The stirring speed reduced to 200r·min-1 after 5min and keep this speed for 2h, and the nanoparticles were obtained. The entrapment efficiency was over 92% and determinated by Sephades G50 mini-column. The products have no significant decrease on content and entrapment efficiency when stored at 4℃, 25℃and 40℃environment for 3 months.
(3) Release rate, in vitro skin penetration and retention. The in vitro release rate of tretinoin ascorbyl palmitate vesicles was higher than cream and tretinoin solid lipid nanoparticles. The in vitro tretinoin cumulative penetration quantity indicated higher levels in ascorbyl palmitate vesicles than cream and solid lipid nanoparticles in mouse back skin, but solid lipid nanoparticles had more drug retention in mouse back skin than cream and ascorbyl palmitate vesicles . The result of diffierent animal back skin cumulative penetration quantity of vesicles and solid lipid nanoparticles was mouse>rats>rabbits. The result of diffierent animal back skin retention quantity of vesicles and solid lipid nanoparticles was rabbits >rats> mouse.
Conclusions: Prepare tretinoin ascorbyl palmitate vesicles by solvent-injection method and tretinoin solid lipid nanoparticles by nanoemulsion method were simple and reliable. The entrapment efficiency of optimized formulation were over 90%. Solid lipid nanoparticles had better stability than vesicles. Vesicles had higher in vitro release rate and in vitro cumulative penetration quantity than cream and solid lipid nanoparticles, this indicated vesicles can increase the skin penetration quantity of drugs. Solid lipid nanoparticles had lower in vitro release rate than cream and vesicles but had the highest skin retention quantity, this indicated solid lipid nanoparticles can increase local concentration of drugs. Back skin cumulative penetration quantity in vitro of vesicles and solid lipid nanoparticles in mouse was higher than that from rats and rabbits. on the contrary, back skin retention quantity in vitro of vesicles and solid lipid nanoparticles in mouse was lower than rats and rabbits.
方法:(1)维A酸维生素C棕榈酸酯泡囊和固体脂质纳米粒的制备。采用溶剂注入法制备维A酸维生素C棕榈酸酯泡囊,并进行了处方优化,采用透析法测定包封率。采用纳米乳法制备维A酸固体脂质纳米粒,通过相图研究确定处方组成,采用葡聚糖G50微型凝胶测定包封率。
(2)维A酸维生素C棕榈酸酯泡囊和固体脂质纳米粒的稳定性研究。稳定性研究中考查了维A酸维生素C棕榈酸酯泡囊和固体脂质纳米粒在光照(4500±500 lx)下药物降解的情况;以药物含量和包封率为指标,考查了泡囊在4℃和25℃,相对湿度75%,贮存6个月的稳定性;以药物含量、粒径、电位和包封率为指标考查了固体脂质纳米粒在4℃、25℃和40℃,相对湿度75%,贮存3个月的稳定性。
(3)维A酸维生素C棕榈酸酯泡囊和固体脂质纳米粒的体外释放度、皮肤渗透性和皮肤贮留的研究。用Franz扩散池测定维A酸从载体中的释放速度。扩散池与供给池之间为纤维素膜(截留分子量8000～14000),扩散池面积为2.92cm2。在第2、4、6、8、12、24h定时取样0.5ml,并补充等量新鲜介质,样品处理后用HPLC测定。体外经皮渗透试验同释放度,用小鼠、大鼠或家兔背部皮肤替代半透膜。皮肤贮留则在体外经皮渗透试验完结后,取下皮肤,剪碎匀浆,用50%异丙醇-生理盐水提取,提取液处理后用HPLC测定药物浓度。
结果:(1)维A酸维生素C棕榈酸酯泡囊优化处方及工艺。取0.1g L-半胱氨酸盐酸盐和0.05g EDTANa2溶于100ml PBS (pH 5.5)中,作为Ⅰ相;再取0.1g维A酸、2.1g维生素C棕榈酸酯、1.9g胆固醇和0.02g 2,6-二叔丁基对甲基苯酚加25ml乙醇-乙醚(3:2)完全溶解,作为Ⅱ相;1000r·min-1搅拌下将Ⅱ相慢慢滴至60℃的Ⅰ相中;滴毕后,继续60℃保温搅拌30min,去除有机溶剂,然后停止加热,继续搅拌30min。控制最终体积为100ml,即得。采用透析法测定其包封率>90%。4℃贮存6个月含量无明显变化,包封率略有下降;25℃贮存6个月含量和包封率有一定程度下降。
(2)维A酸固体脂质纳米粒优化处方及工艺。取0.5g单硬脂酸甘油酯、0.2g司盘60、4g吐温80、5g聚乙二醇400、0.04g维生素C棕榈酸酯、1g泊洛沙姆F-127、0.04g 2,6-二叔丁基对甲基酚,置70℃水浴加热使其熔化。在70℃,200r·min-1搅拌条件下加入0.025g维A酸,继续搅拌10min使维A酸完全溶解,得澄清透明黄色溶液。然后加入15ml,70℃的水,于200r·min-1搅拌20min,形成稳定均一乳液。然后将乳液倒入以1000r·min-1搅拌的78ml,2℃含0.01g EDTA的水中,搅拌5min后转速调至200r·min-1,搅拌2h,即得。采用葡聚糖G50微型凝胶测定包封率>92%。4℃、25℃和40℃贮存3个月,含量和包封率均无明显变化。
(3)释放速度、体外皮肤渗透性及皮肤贮留。释放度表明维A酸维生素C棕榈酸酯泡囊释放速度大于市售乳膏和维A酸固体脂质纳米粒。小鼠体外经皮渗透试验表明泡囊中维A酸累积经皮透过量高于市售乳膏和固体脂质纳米粒,但皮肤贮留量固体脂质纳米粒高于市售乳膏和泡囊。比较泡囊和固体脂质纳米粒在小鼠、大鼠及家兔皮肤的体外皮肤透过性,结果小鼠>大鼠>家兔。比较泡囊和固体脂质纳米粒在小鼠、大鼠及家兔皮肤的贮留量,结果家兔>大鼠>小鼠。
结论:采用注入法制备维A酸维生素C棕榈酸酯泡囊和纳米乳法制备维A酸固体脂质纳米粒,方法简单易行,优化处方的制品包封率均大于90%。稳定性方面脂质纳米粒优于泡囊。泡囊体外释放速度快,体外累积经皮透过量大于市售乳膏和固体脂质纳米粒,说明泡囊有增加药物经皮渗透作用。固体脂质纳米粒体外释放速度慢,皮肤贮留量大于市售乳膏和固体脂质纳米粒,说明其有助于增加局部药物浓度。泡囊和固体脂质纳米粒小鼠背部皮肤累积经皮渗透量高于大鼠和家兔,而皮肤贮留量低于大鼠和家兔。
Objective: Use ascorbyl palmitate vesicles and solid lipid nanoparticles as transdermal administration carrier for tretinoin, carry out studies on their formulation, preparation technology, entrapment efficiency, stability, release, in vitro skin penetration and retention .Expecting to improve the stability of tretinoin and increase the local concentration of drug when transdermal administration.
Methods: (1)Study on the preparation of tretinoin ascorbyl palmitate vesicles and solid lipid nanoparticles. Prepare tretinoin ascorbyl palmitate vesicles by solvent-injection method, and optimize the formulation of vesicles, entrapment efficiency was determinated by dialysis method. Prepare tretinoin solid lipid nanoparticles by nanoemulsion method, formulation determined through study on phase diagram and entrapment efficiency was determinated by Sephadex G50 mini-column.
(2) Study on the stability of tretinoin ascorbyl palmitate vesicles and solid lipid nanoparticles. In the study of stability, we examen degradation of drug loaded in ascorbyl palmitate vesicles or solid lipid nanoparticles when exposure to illumination(4500±500 lx). The tretinoin ascorbyl palmitate vesicles were stored two different temperatures(4℃, 25℃) and relative humidity 75% for 6 mouths to carry through testing of stability, drug content and entrapment efficiency were measured. The solid lipid nanoparticles were stored three different temperatures(4℃, 25℃, 40℃) and relative humidity 75% for 3 mouths to carry through testing of stability, drug content, particle size , potential and entrapment efficiency were measured.
(3) Study on the release rate, in vitro skin penetration and retention of tretinoin ascorbyl palmitate vesicles and solid lipid nanoparticles. The in vitro release rate of tretinoin from carrier was determined by Franz diffusion cell. Between donor compartment and receptor compartment was cellulose membrane(cut-off molecules 8000～14000 ), the avaiable diffusion area of cell was 2.92 cm2. At appropriate intervals, namely, 2,4,6,8,12,24h, 0.5ml of the receptor medium were withdrawn and replaced by an equal volume of fresh receptor solution immediately. The sample was analyzed by HPLC after treatment .The in vitro skin penetration experiment was carry through by the same method as the in vitro release rate experiments except using the back skin of mouse, rats or rabbits instead of cellulose membrane. When in vitro skin penetration experiment completed, the skin were taken down from cells, cut and homogenated. After these treatment, extracted by 50% isopropanol-normal saline. The extracting solution was analyzed by HPLC after treatment .
Results: (1)Optimized formulation and preparation technology of tretinoin ascorbyl palmitate vesicles. 0.1g 1-cysteine hydrochloride and 0.05g EDTANa2 dissolved in 100ml PBS (pH 5.5), as phaseⅠ;0.1g tretinoin, 2.1g ascorbyl palmitate, 1.9g cholesterol and 0.02g BHT dissolved in ethanol-ether(3∶2), as phaseⅡ. PhaseⅡdrop into phaseⅠwhich heated to 60℃slowly at 1000r·min-1 stirring, after dropped, keep stirring 30min at 60℃in order to remove organic solvents, then stop heating and contuniue stirring 30min. The final volume was controlled to 100ml and the vesicles were obtained. The entrapment efficiency was over 90% and determinated by dialysis method . The products have no significant decrease on content and entrapment efficiency when stored at 4℃environment for 6 months but have some decrease when stored at 25℃environment.
(2)Optimized formulation and preparation technology of tretinoin solid lipid nanoparticles. 0.5g glycerin monostearate, 0.2g span60, 4g tween80, 5g PEG400, 0.04g ascorbyl palmitate,1g poloxamer F-127, 0.04g butylated hydroxytoluene, mixed and melted in 70℃water bath heating to form a clear solution. Then 0.025g tretinoin was added to this solution at 70℃and 200r·min-1 stirring until it was complete dissolved and another yellow clear solution was obtained. After that 15ml, 70℃water was added to this solution and stirred at 200r·min-1 for 20min to form a stable nanoemulsion. Then pour the nanoemulsion into 78ml, 2℃water(contains 0.01g EDTA) with 1000r·min-1 stirring. The stirring speed reduced to 200r·min-1 after 5min and keep this speed for 2h, and the nanoparticles were obtained. The entrapment efficiency was over 92% and determinated by Sephades G50 mini-column. The products have no significant decrease on content and entrapment efficiency when stored at 4℃, 25℃and 40℃environment for 3 months.
(3) Release rate, in vitro skin penetration and retention. The in vitro release rate of tretinoin ascorbyl palmitate vesicles was higher than cream and tretinoin solid lipid nanoparticles. The in vitro tretinoin cumulative penetration quantity indicated higher levels in ascorbyl palmitate vesicles than cream and solid lipid nanoparticles in mouse back skin, but solid lipid nanoparticles had more drug retention in mouse back skin than cream and ascorbyl palmitate vesicles . The result of diffierent animal back skin cumulative penetration quantity of vesicles and solid lipid nanoparticles was mouse>rats>rabbits. The result of diffierent animal back skin retention quantity of vesicles and solid lipid nanoparticles was rabbits >rats> mouse.
Conclusions: Prepare tretinoin ascorbyl palmitate vesicles by solvent-injection method and tretinoin solid lipid nanoparticles by nanoemulsion method were simple and reliable. The entrapment efficiency of optimized formulation were over 90%. Solid lipid nanoparticles had better stability than vesicles. Vesicles had higher in vitro release rate and in vitro cumulative penetration quantity than cream and solid lipid nanoparticles, this indicated vesicles can increase the skin penetration quantity of drugs. Solid lipid nanoparticles had lower in vitro release rate than cream and vesicles but had the highest skin retention quantity, this indicated solid lipid nanoparticles can increase local concentration of drugs. Back skin cumulative penetration quantity in vitro of vesicles and solid lipid nanoparticles in mouse was higher than that from rats and rabbits. on the contrary, back skin retention quantity in vitro of vesicles and solid lipid nanoparticles in mouse was lower than rats and rabbits.
引文
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