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首页> 外文学位 >Development of locally- and systemically effective methotrexate transdermal therapeutic system: Formulation development and in vitro/in vivo evaluation.
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Development of locally- and systemically effective methotrexate transdermal therapeutic system: Formulation development and in vitro/in vivo evaluation.

机译：局部和全身有效的甲氨蝶呤透皮治疗系统的开发：制剂开发和体外/体内评估。

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摘要

A folic acid derivative, methotrexate (MTX) solution was found to be very unstable in the hydrophilic and lipophilic vehicles with the Hildebrand solubility parameter range of 5.9–23.4 (cal/cc)1/2 and extremely impermeable through the skin because of its polar nature. In the present study, the ion-pair formation of the anionic carboxylic functionality (pKa1 = 3.76 and pKa2 = 4.83) of MTX in the presence of protonated counter ions of basic amino acids was studied to evaluate its effect on the chemical stability and skin transport characteristics of the immunosuppressant. The cationic counter ions examined in the study include basic amino acids such as L-arginine (pKa1 = 2.17, pK a2 = 9.04, pKR = 12.48), L-lysine (pKa1 = 2.18, pKa2 = 8.95, pKR = 10.53), and L-histidine (pK a1 = 2.82, pKa2 = 9.17, pKR = 6.00), and an inorganic base, sodium hydroxide. The influence of various hydrophilic and lipophilic vehicles in single and binary mixtures on the epidermal permeation of MTX was also investigated in vitro using the hairless mouse (HLM) skin. Among the neat solvents examined, a lipophilic carrier, isopropyl myristate (IPM) provided the most enhancing effect on the permeation of MTX, followed by N-methylpyrrolidone (NMP), and a short-chain alkanol, isopropyl alcohol. The binary cosolvents consisting of IPM and NMP, in particular, in a 2:8 combination, produced a marked synergistic enhancement of MTX permeation, achieving the steady-state flux value of 39 μg/cm2/hr with a short lag time of 0.8 hrs. The inclusion of ion-paired MTX with a basic amino acid, in particular, with L-arginine in a 1:3 molar ratio into a simple aqueous solution and NMP/IPM cosolvent based microemulsion provided a marked improvement of chemical stability of the easily hydrolysable drug and also produced a significant enhancement of transdermal flux of a polar compound, MTX. The rank order of stabilizing and skin permeation enhancing potency of the basic amino acids obtained with aqueous MTX solutions was L-arginine > L-lysine > L-histidine, which conforms to the order of ionic strength of basic group functionality (pKR) of the amino acids.; An attempt was made to improve the viscosity of ME reservoir systems with a view to reducing the solvent leaching effect through the microporous rate controlling membrane. The two polymer materials, i.e. methyl vinyl ether-maleic anhydride (Grantrez®/GTZ) and polyoxyethylene-polyoxypropylene-polyoxyethylene (Poloxamer®) polymers were evaluated in the study. The permeation results clearly indicated that the HLM skin was 10–12 times more permeable for MTX than the HC skin. The 3% MTX ME prepared with NMP/IPM cosolvent produced a steady state flux value of 2.4 μg/cm2/hr across human skin, which is approximately 41% greater flux than the target delivery rate of 1.7 μg/cm2/hr.; The results of skin irritation study in New Zealand white rabbits indicated that 1 MTX suspension in water appeared to be no evidence of irritation while 1% MTX solution in NMP showed a mild irritation score. In addition, 2.6% MTX gel formulation prepared with IPM-NMP-TW80-SP20-1%GTZ 139-Water exhibited a mild irritation (3.3 score) while its placebo produced an irritation score of 1.3. The formulation development studies with ion-paired MTX in microemulsion and gel structures showed the feasibility of designing a stable and effective MTX topical and transdermal therapeutic system for use in the treatment of rheumatoid arthritis, psoriasis, and other proliferative disorders of the skin. (Abstract shortened by UMI.)
机译：发现叶酸衍生物甲氨蝶呤（MTX）在亲水和亲脂性介质中非常不稳定，其Hildebrand溶解度参数范围为5.9–23.4（cal / cc） 1/2 ，并且极不渗透通过皮肤，因为它的极性。在本研究中，MTX的质子化抗衡离子存在下，MTX的阴离子羧酸官能团（pK a1 = 3.76和pK a2 = 4.83）的离子对形成研究了碱性氨基酸以评估其对免疫抑制剂化学稳定性和皮肤运输特性的影响。研究中检查的阳离子抗衡离子包括碱性氨基酸，例如L-精氨酸（pK a1 = 2.17，pK a2 = 9.04，pK R = 12.48），L-赖氨酸（pK a1 = 2.18，pK a2 = 8.95，pK R = 10.53）和L-组氨酸（pK a1 = 2.82，pK a2 = 9.17，pK R = 6.00），和无机碱氢氧化钠。还使用无毛小鼠（HLM）皮肤在体外研究了单一和二元混合物中各种亲水性和亲脂性媒介物对MTX的表皮渗透的影响。在所检查的纯溶剂中，亲脂性载体肉豆蔻酸异丙酯（IPM）对MTX的渗透作用最强，其次是N-甲基吡咯烷酮（NMP）和短链烷醇异丙醇。由IPM和NMP组成的二元助溶剂，特别是2：8组合，显着协同增强了MTX的渗透性，达到39μg/ cm 2 / hr的稳态通量值延迟时间仅为0.8小时。在简单的水溶液和NMP / IPM助溶剂型微乳液中加入离子配对的MTX与碱性氨基酸，特别是与L-精氨酸以1：3的摩尔比，显着改善了易水解的化学稳定性药物，还显着增强了极性化合物MTX的透皮通量。用MTX水溶液获得的碱性氨基酸稳定和增强皮肤渗透能力的等级顺序为L-精氨酸> L-赖氨酸> L-组氨酸，与碱性基团官能团的离子强度顺序一致（pK R ）的氨基酸。为了降低通过微孔速率控制膜的溶剂浸出效果，已尝试提高ME储库系统的粘度。在研究中评估了两种聚合物材料，即甲基乙烯基醚-马来酸酐（Grantrez ®/ GTZ）和聚氧乙烯-聚氧丙烯-聚氧乙烯（Poloxamer ®）聚合物。渗透结果清楚地表明HLM皮肤对MTX的渗透性比HC皮肤高10到12倍。使用NMP / IPM助溶剂制备的3％MTX ME在人体皮肤上产生的稳态通量值为2.4μg/ cm 2 / hr，比目标递送速率1.7高约41％。 μg/ cm 2 /小时。新西兰白兔皮肤刺激性研究的结果表明，水中1份MTX悬浮液似乎没有刺激性迹象，而NMP中1％的MTX溶液显示出轻度的刺激性评分。另外，用IPM-NMP-TW80-SP20-1％GTZ 139-水制备的2.6％MTX凝胶制剂显示出轻度刺激性（3.3分），而其安慰剂产生的刺激性分值为1.3。在微乳液和凝胶结构中使用离子对MTX进行配方开发研究表明，设计稳定，有效的MTX局部和透皮治疗系统用于治疗类风湿性关节炎，牛皮癣和其他皮肤增生性疾病的可行性。 （摘要由UMI缩短。）

著录项

  • 作者

    Nandi, Indranil.;

  • 作者单位

    St. John's University (New York), School of Pharmacy.;

  • 授予单位 St. John's University (New York), School of Pharmacy.;
  • 学科 Chemistry Pharmaceutical.; Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2002
  • 页码 223 p.
  • 总页数 223
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药物化学;药剂学;
  • 关键词

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