CN102205129B - Novel nasal mucosa absorption enhancer - Google Patents
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- CN102205129B CN102205129B CN 201110090720 CN201110090720A CN102205129B CN 102205129 B CN102205129 B CN 102205129B CN 201110090720 CN201110090720 CN 201110090720 CN 201110090720 A CN201110090720 A CN 201110090720A CN 102205129 B CN102205129 B CN 102205129B
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- 238000010521 absorption reaction Methods 0.000 title claims abstract description 52
- 210000002850 nasal mucosa Anatomy 0.000 title claims abstract description 19
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- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 3
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Abstract
本发明属于医药技术领域，涉及琥珀酰化壳聚糖作为鼻黏膜吸收促进剂的应用,该促进剂具有水溶性好、促吸收效果好、使用安全的特点。The invention belongs to the technical field of medicine and relates to the application of succinylated chitosan as a nasal mucosa absorption accelerator. The accelerator has the characteristics of good water solubility, good absorption promoting effect and safe use.
Description
技术领域 technical field
本发明涉及医药技术领域，涉及一种新型的鼻粘膜给药制剂的吸收促进剂，该促进剂具有水溶性好、促吸收效果好、使用安全的特点。 The invention relates to the technical field of medicine, and relates to a novel absorption accelerator for nasal mucosa administration preparations. The accelerator has the characteristics of good water solubility, good absorption promotion effect and safe use.
背景技术 Background technique
鼻黏膜给药途径由于具有吸收快、起效迅速、生物利用度高、副作用小等特点，受到药学研究者的广泛关注和重视。这主要是由于人鼻黏膜表面积为150㎝2，不但在呼吸区内粘膜表层上皮细胞有许多绒毛，与小肠绒毛相似，可大大增加药物吸收的有效面积，而且鼻黏膜上皮下层有丰富的毛细血管及淋巴毛细管，能使药物避免肝脏首过作用及在胃肠道中的降解，从而使药物从鼻腔吸收后迅速进入全身血液循环。但有些药物鼻黏膜给药时表示出较低的粘膜渗透性，致使药物的吸收受到极大限制。吸收促进剂的使用成为解决这一难题的最有效方法之一。常用的吸收促进剂有胆酸盐类、脂肪酸类、表面活性剂类等，但这些传统的吸收促进剂由于纤毛毒性较大且对鼻黏膜有不同程度的损伤，限制了其在药物制剂中的应用。因此，研究高效安全的新型鼻黏膜吸收促进剂成为解决该问题的关键。 Nasal drug delivery route has been widely concerned and valued by pharmaceutical researchers due to its characteristics of fast absorption, rapid onset of action, high bioavailability, and small side effects. This is mainly due to the fact that the surface area of the nasal mucosa is 150cm 2 . Not only are there many villi in the epithelial cells of the mucosal surface in the respiratory area, which are similar to the villi of the small intestine, which can greatly increase the effective area for drug absorption, but also the subepithelial layer of the nasal mucosa is rich in capillaries And lymphatic capillaries, which can make the drug avoid the first-pass effect of the liver and the degradation in the gastrointestinal tract, so that the drug can quickly enter the systemic blood circulation after being absorbed from the nasal cavity. However, some drugs exhibit low mucosal permeability when administered through the nasal mucosa, which greatly limits the absorption of the drug. The use of absorption enhancers has become one of the most effective ways to solve this problem. Commonly used absorption enhancers include cholates, fatty acids, surfactants, etc., but these traditional absorption enhancers have limited their use in pharmaceutical preparations due to the high toxicity of the cilia and the damage to the nasal mucosa in varying degrees. application. Therefore, it is the key to solve this problem to study efficient and safe new nasal mucosal absorption enhancers.
壳聚糖是由甲壳素脱乙酰基得到的碱性多糖，甲壳素广泛存在于甲壳类动物的贝壳中，是一个相当丰富的可再生资源。壳聚糖具有无毒、无味、耐碱、耐热、耐腐蚀、良好的生物相容性和生物降解性等优点，目前广泛应用于药物载体和组织工程。其可作为鼻腔给药的吸收促进剂，使用安全。但壳聚糖不溶于水和普通的有机溶剂，只能在酸性条件下溶解，这给实际应用带来了诸多不便。因此选择水溶性好、吸收促进作用强的壳聚糖衍生物作为鼻粘膜给药制剂的吸收促进剂具有重要意义。 Chitosan is an alkaline polysaccharide obtained by deacetylating chitin. Chitin widely exists in the shells of crustaceans and is a very abundant renewable resource. Chitosan has the advantages of non-toxic, odorless, alkali resistance, heat resistance, corrosion resistance, good biocompatibility and biodegradability, and is currently widely used in drug carriers and tissue engineering. It can be used as an absorption enhancer for nasal administration and is safe to use. However, chitosan is insoluble in water and common organic solvents, and can only be dissolved under acidic conditions, which brings a lot of inconvenience to practical applications. Therefore, it is of great significance to choose chitosan derivatives with good water solubility and strong absorption promotion as absorption promoters for nasal mucosal drug delivery preparations.
发明内容 Contents of the invention
本发明的目的是寻找水溶性好、吸收促进效果好、适应性广、使用安全的鼻粘膜吸收促进剂，将其应用于鼻黏膜给药系统，从而提高药物透过鼻黏膜吸收的速率及其吸收量。本发明涉及的新型鼻黏膜吸收促进剂为琥珀酰化壳聚糖。 The purpose of the present invention is to find a nasal mucosa absorption accelerator with good water solubility, good absorption promotion effect, wide adaptability and safe use, and apply it to the nasal mucosa drug delivery system, thereby improving the rate of drug absorption through the nasal mucosa and its absorption capacity. The novel nasal mucosa absorption accelerator involved in the present invention is succinylated chitosan.
所述的琥珀酰化壳聚糖包括不同分子量(Mw)、不同氨基取代度（DS）的壳聚糖。 The succinylated chitosan includes chitosan with different molecular weights (Mw) and amino substitution degrees (DS).
所述的琥珀酰化壳聚糖优选平均分子量为20kDa～100kDa，氨基取代度为54.0%~64.2%。 The succinylated chitosan preferably has an average molecular weight of 20kDa-100kDa and an amino substitution degree of 54.0%-64.2%.
所述的琥珀酰化壳聚糖，在鼻腔给药制剂中的使用浓度为0.1-1.0%，可显著增加亲脂性药物和亲水性药物的鼻粘膜吸收。 The succinylated chitosan can be used at a concentration of 0.1-1.0% in nasal administration preparations, which can significantly increase the nasal mucosal absorption of lipophilic drugs and hydrophilic drugs.
所述的琥珀酰化壳聚糖可应用于鼻腔给药制剂。 The succinylated chitosan can be applied to nasal cavity administration preparations.
所述的鼻腔给药制剂,包括鼻腔用溶液剂、混悬剂、乳剂、微球、脂质体、粉末制剂等。 The preparations for nasal administration include nasal solutions, suspensions, emulsions, microspheres, liposomes, powder preparations and the like.
所述的琥珀酰化壳聚糖可应用于各种鼻黏膜给药系统，具体方案为：将该琥珀酰化壳聚糖溶于水，配制质量比为0.1%~1.0%的琥珀酰化壳聚糖溶液，加入药物和其他辅料配制药物溶液。或者先将药物和其他辅料制成适宜剂型，再加入一定量的琥珀酰化壳聚糖，使其在处方中的终浓度为0.1%~1.0%。将制成的溶液应用于鼻腔粘膜表面，使溶液中具有生物活性的物质被鼻粘膜吸收的速度和药物吸收量比未添加吸收促进剂组及添加壳聚糖组明显提高，且对鼻黏膜无损伤，使用安全。在蛙纤毛毒性试验中，浓度为0.1%，氨基取代度为57.0%、60.7%和63.0%的琥珀酰化壳聚糖（Mw=50kDa）的纤毛抑制率（85.94%，85.37%和86.22%）与0.5%同分子量壳聚糖（Mw=50kDa）纤毛抑制率（77.60%）均大于70%，表明两者安全性较好；将其应用于大鼠体内研究，试验结果表明，与0.5%壳聚糖相比，0.1%琥珀酰壳聚糖能够显著提高药物在大鼠体内的吸收量（见表1，图8）。 The succinylated chitosan can be applied to various nasal mucosa drug delivery systems. The specific scheme is: dissolve the succinylated chitosan in water, and prepare a succinylated shell with a mass ratio of 0.1% to 1.0%. Polysaccharide solution, add drugs and other auxiliary materials to prepare drug solution. Or first make the drug and other auxiliary materials into a suitable dosage form, and then add a certain amount of succinylated chitosan so that the final concentration in the prescription is 0.1%~1.0%. Apply the prepared solution to the surface of the nasal mucosa, so that the speed and drug absorption of the biologically active substances in the solution by the nasal mucosa are significantly improved compared with the no absorption enhancer group and the chitosan group, and there is no effect on the nasal mucosa. Damage, safe to use. In the frog cilia toxicity test, the cilia inhibition rate of succinylated chitosan (Mw=50kDa) with a concentration of 0.1% and amino substitution degrees of 57.0%, 60.7% and 63.0% (85.94%, 85.37% and 86.22%) With 0.5% chitosan of the same molecular weight (Mw=50kDa), the cilia inhibition rate (77.60%) is greater than 70%, indicating that the safety of the two is better; it is applied to rats in vivo, and the test results show that, with 0.5% chitosan Compared with polysaccharide, 0.1% succinyl chitosan can significantly improve the drug absorption in rats (see Table 1, Figure 8).
所述的琥珀酰化壳聚糖对小分子的亲脂性药物和亲水性药物，如分子量小于1000的药物，其鼻黏膜吸收量均超过空白药物溶液，且与壳聚糖相比，其对药物产生鼻粘膜吸收促进作用的有效浓度显著降低，药物吸收量明显提高，且对鼻黏膜无损伤，对鼻内纤毛无抑制作用。 Described succinylated chitosan is to the lipophilic medicine of small molecule and hydrophilic medicine, as the medicine that molecular weight is less than 1000, its nasal mucosa absorption amount all surpasses blank drug solution, and compared with chitosan, its to The effective concentration of the drug to promote nasal mucosa absorption is significantly reduced, and the drug absorption is significantly increased, and there is no damage to the nasal mucosa, and no inhibitory effect on nasal cilia.
附图说明： Description of drawings:
[0013] 图 1不同时间磷酸川芎嗪对照组药物吸收量。0.1%壳聚糖（Mw=50kDa）组药物吸收量与0.1%氨基取代度为63.0%的琥珀酰壳聚糖（Mw=50kDa）组药物吸收量比较（实施例1）。 Fig . 1 different time ligustrazine phosphate control group drug absorption. The drug absorption of the 0.1% chitosan (Mw=50kDa) group was compared with that of the 0.1% succinyl chitosan (Mw=50kDa) group with an amino substitution degree of 63.0% (Example 1).
图2不同时间异丙嗪对照组药物吸收量。0.1%壳聚糖（Mw=50kDa）组药物吸收量与0.1%氨基取代度为63.0%的琥珀酰壳聚糖（Mw=50kDa）组药物吸收量（实施例2）。 Fig. 2 drug absorption amount of promethazine control group at different times. The drug absorption amount of the 0.1% chitosan (Mw=50kDa) group and the drug absorption amount of the 0.1% succinyl chitosan (Mw=50kDa) group with an amino substitution degree of 63.0% (Example 2).
图3不同时间硝酸异山梨酯对照组药物吸收量。0.1%壳聚糖（Mw=20kDa）组药物吸收量与0.1%氨基取代度为64.2%的琥珀酰壳聚糖（Mw=20kDa）组药物吸收量（实施例3）。 Figure 3 isosorbide dinitrate control group drug absorption at different times. The drug absorption amount of the 0.1% chitosan (Mw=20kDa) group and the drug absorption amount of the 0.1% succinyl chitosan (Mw=20kDa) group with an amino substitution degree of 64.2% (Example 3).
图4不同时间硝酸异山梨酯对照组药物吸收量。0.5%壳聚糖（Mw=50kDa）组药物吸收量与0.5%氨基取代度为60.7%的琥珀酰壳聚糖（Mw=50kDa）组药物吸收量（实施例4）。 Figure 4 isosorbide dinitrate control group drug absorption at different times. The drug absorption amount of the 0.5% chitosan (Mw=50kDa) group and the drug absorption amount of the 0.5% succinyl chitosan (Mw=50kDa) group with an amino substitution degree of 60.7% (Example 4).
图5不同时间硝酸异山梨酯对照组药物吸收量。0.1%壳聚糖（Mw=100kDa）组药物吸收量与0.1%氨基取代度为54.0%的琥珀酰壳聚糖（Mw=100kDa）组药物吸收量（实施例5）。 Figure 5 isosorbide dinitrate control group drug absorption at different times. The drug absorption amount of the 0.1% chitosan (Mw=100kDa) group and the drug absorption amount of the 0.1% succinyl chitosan (Mw=100kDa) group with an amino substitution degree of 54.0% (Example 5).
图6不同时间硝酸异山梨酯对照组药物吸收量。0.1%壳聚糖（Mw=50kDa）组药物吸收量与0.1%、氨基取代度为57.0%的琥珀酰壳聚糖（Mw=50kDa）组药物吸收量（实施例6）。 Figure 6 isosorbide dinitrate control group drug absorption at different times. The drug absorption of the 0.1% chitosan (Mw=50kDa) group and the drug absorption of the 0.1% succinyl chitosan (Mw=50kDa) group with an amino substitution degree of 57.0% (Example 6).
图7不同时间硝酸异山梨酯对照组药物吸收量。1.0%壳聚糖（Mw=50kDa）组药物吸收量与1.0%氨基取代度为60.7%的琥珀酰壳聚糖（Mw=50kDa）组药物吸收量（实施例7）。 Figure 7 isosorbide dinitrate control group drug absorption at different times. The drug absorption of the 1.0% chitosan (Mw=50kDa) group and the drug absorption of the 1.0% succinyl chitosan (Mw=50kDa) group with an amino substitution degree of 60.7% (Example 7).
图8 实施例8中不同处方、不同途径给药后的血药浓度时间曲线(mean ± SD, n=5)。 Fig. 8 Plasma concentration-time curves (mean ± SD, n = 5) of different prescriptions and different routes of administration in Example 8.
具体实施方式： Specific implementation methods :
实例1：氨基取代度63.0%的琥珀酰化壳聚糖（50kDa）对磷酸川芎嗪鼻粘膜吸收促进作用 Example 1: Succinylated chitosan (50kDa) with an amino substitution degree of 63.0% promotes nasal mucosal absorption of ligustrazine phosphate
雄性大鼠（180g～220g）经食管插管手术后置于贮药池上方，贮药池内加入5mL磷酸川芎嗪溶液(4.0mg/mL)并不断搅拌，通入37±0.5℃的循环水浴，最后加入0.1%氨基取代度为63.0%的琥珀酰化壳聚糖（Mw=50kDa），搅拌溶解（对照组不加）。药液从贮药池经蠕动泵进入大鼠鼻腔后又从鼻孔返回至贮药池，在2小时内不同时间间隔从贮药池取样进行含量测定。同法考察0.1%壳聚糖(Mw=50kDa)的吸收促进效果，结果见图1。 Male rats (180g-220g) were placed above the drug storage pool after esophageal intubation. Add 5mL ligustrazine phosphate solution (4.0mg/mL) into the drug storage pool and keep stirring. Finally, 0.1% succinylated chitosan (Mw=50kDa) with an amino substitution degree of 63.0% was added and stirred to dissolve (the control group was not added). The drug solution enters the nasal cavity of the rats through the peristaltic pump from the drug storage pool and then returns to the drug storage pool from the nostrils. Samples are taken from the drug storage pool at different time intervals within 2 hours for content determination. In the same way, the absorption-promoting effect of 0.1% chitosan (Mw=50kDa) was investigated, and the results are shown in Figure 1.
实例2：氨基取代度63.0%的琥珀酰化壳聚糖（Mw=50kDa）对异丙嗪鼻粘膜吸收促进作用 Example 2: Succinylated chitosan (Mw=50kDa) with an amino substitution degree of 63.0% promotes the nasal mucosal absorption of promethazine
雄性大鼠（180g～220g）经食管插管手术后置于贮药池上方，贮药池内加入5mL异丙嗪溶液(0.35mg/mL)并不断搅拌，通入37±0.5℃的循环水浴，最后加入0.1%氨基取代度为63.0%的琥珀酰化壳聚糖（Mw=50kDa），搅拌溶解（对照组不加）。药液从贮药池经蠕动泵进入大鼠鼻腔后又从鼻孔返回至贮药池，在2小时内不同时间间隔从贮药池取样进行含量测定。同法考察0.1%壳聚糖Mw= (50kDa)的吸收促进效果，结果见图2。 Male rats (180g-220g) were placed above the drug storage pool after esophageal intubation, and 5mL of promethazine solution (0.35mg/mL) was added to the drug storage pool and stirred continuously, and then passed into a circulating water bath at 37±0.5°C. Finally, 0.1% succinylated chitosan (Mw=50kDa) with an amino substitution degree of 63.0% was added and stirred to dissolve (the control group was not added). The drug solution enters the nasal cavity of the rats through the peristaltic pump from the drug storage pool and then returns to the drug storage pool from the nostrils. Samples are taken from the drug storage pool at different time intervals within 2 hours for content determination. Investigate the absorption promoting effect of 0.1% chitosan Mw=(50kDa) with the same method, the results are shown in Fig. 2.
实例3：氨基取代度64.2%的琥珀酰化壳聚糖（Mw=20kDa）对硝酸异山梨酯鼻粘膜吸收促进作用 Example 3: The effect of succinylated chitosan (Mw=20kDa) with amino substitution degree of 64.2% on nasal mucosal absorption of isosorbide dinitrate
雄性大鼠（180g～220g）经食管插管手术后置于贮药池上方，贮药池内加入5mL硝酸异山梨酯溶液（0.5mg/mL）并不断搅拌，通入37±0.5℃的循环水浴，最后加入0.1%氨基取代度为64.2%的琥珀酰化壳聚糖（Mw=20kDa），搅拌溶解（对照组不加）。药液从贮药池经蠕动泵进入大鼠鼻腔后通过鼻孔返回至贮药池，在2小时内不同时间间隔从贮药池取样进行含量测定。同法考察0.1%壳聚糖(Mw=20kDa)的吸收促进效果，结果见图3。 Male rats (180g-220g) were placed above the drug storage pool after esophageal intubation, and 5mL of isosorbide dinitrate solution (0.5mg/mL) was added to the drug storage pool and stirred continuously, and then passed into a circulating water bath at 37±0.5°C , and finally add 0.1% succinylated chitosan (Mw=20kDa) with an amino substitution degree of 64.2%, and stir to dissolve (the control group is not added). The drug solution enters the nasal cavity of the rats through the peristaltic pump from the drug storage pool, and then returns to the drug storage pool through the nostrils. Samples are taken from the drug storage pool at different time intervals within 2 hours for content determination. In the same way, the absorption-promoting effect of 0.1% chitosan (Mw=20kDa) was investigated, and the results are shown in Figure 3.
实例4：取代度60.7%的琥珀酰化壳聚糖（50kDa）对硝酸异山梨酯鼻粘膜吸收促进作用 Example 4: Succinylated chitosan (50kDa) with a degree of substitution of 60.7% promotes the nasal mucosal absorption of isosorbide dinitrate
雄性大鼠（180g～220g）经食管插管手术后置于贮药池上方，贮药池内加入5mL硝酸异山梨酯溶液（0.5mg/mL）并不断搅拌，通入37±0.5℃的循环水浴，最后加入0.5%氨基取代度为60.7%的琥珀酰化壳聚糖（Mw=50kDa），搅拌溶解（对照组不加）。药液从贮药池经蠕动泵进入大鼠鼻腔后又从鼻孔返回至贮药池，在2小时内不同时间间隔从贮药池取样进行含量测定。同法考察0.5%壳聚糖(Mw=50kDa)的吸收促进效果，结果见图4。 Male rats (180g-220g) were placed above the drug storage pool after esophageal intubation, and 5mL of isosorbide dinitrate solution (0.5mg/mL) was added to the drug storage pool and stirred continuously, and then passed into a circulating water bath at 37±0.5°C , and finally add 0.5% succinylated chitosan (Mw=50kDa) with an amino substitution degree of 60.7%, and stir to dissolve (the control group is not added). The drug solution enters the nasal cavity of the rats through the peristaltic pump from the drug storage pool and then returns to the drug storage pool from the nostrils. Samples are taken from the drug storage pool at different time intervals within 2 hours for content determination. In the same way, the absorption-promoting effect of 0.5% chitosan (Mw=50kDa) was investigated, and the results are shown in Figure 4.
实例5：取代度54.0%的琥珀酰化壳聚糖（Mw=100kDa）对硝酸异山梨酯鼻粘膜吸收促进作用 Example 5: Succinylated chitosan (Mw=100kDa) with a substitution degree of 54.0% promotes the nasal mucosal absorption of isosorbide dinitrate
雄性大鼠（180g～220g）经食管插管手术后置于贮药池上方，贮药池内加入5mL硝酸异山梨酯溶液（0.5mg/mL）并不断搅拌，通入37±0.5℃的循环水浴，最后加入0.1%氨基取代度为54.0%的琥珀酰化壳聚糖（Mw=100kDa），搅拌溶解（对照组不加）。药液从贮药池经蠕动泵进入大鼠鼻腔后又从鼻孔返回至贮药池，在2小时内不同时间间隔从贮药池取样进行含量测定。同法考察0.1%壳聚糖(Mw=100kDa)的吸收促进效果，结果见图5。 Male rats (180g-220g) were placed above the drug storage pool after esophageal intubation, and 5mL of isosorbide dinitrate solution (0.5mg/mL) was added to the drug storage pool and stirred continuously, and then passed into a circulating water bath at 37±0.5°C , and finally add 0.1% succinylated chitosan (Mw=100kDa) with an amino substitution degree of 54.0%, and stir to dissolve (the control group is not added). The drug solution enters the nasal cavity of the rats through the peristaltic pump from the drug storage pool and then returns to the drug storage pool from the nostrils. Samples are taken from the drug storage pool at different time intervals within 2 hours for content determination. In the same way, the absorption-promoting effect of 0.1% chitosan (Mw=100kDa) was investigated, and the results are shown in Figure 5.
实例6：氨基取代度57.0%的琥珀酰化壳聚糖（Mw=50kDa）对硝酸异山梨酯鼻粘膜吸收促进作用 Example 6: Succinylated chitosan (Mw=50kDa) with a degree of amino substitution of 57.0% promotes the nasal mucosal absorption of isosorbide dinitrate
雄性大鼠（180g～220g）经食管插管手术后置于贮药池上方，贮药池内加入5mL硝酸异山梨酯溶液（0.5mg/mL）并不断搅拌，通入37±0.5℃的循环水浴，最后加入0.1%氨基取代度为57.0%的琥珀酰壳聚糖（Mw=50kDa），搅拌溶解（对照组不加）。药液从贮药池经蠕动泵进入大鼠鼻腔后又从鼻孔返回至贮药池，在2小时内不同的时间间隔从贮药池取样进行含量测定。同法考察0.1%壳聚糖(Mw=50kDa)的吸收促进效果，结果见图6。 Male rats (180g-220g) were placed above the drug storage pool after esophageal intubation, and 5mL of isosorbide dinitrate solution (0.5mg/mL) was added to the drug storage pool and stirred continuously, and then passed into a circulating water bath at 37±0.5°C , and finally add 0.1% succinyl chitosan (Mw=50kDa) with an amino substitution degree of 57.0%, and stir to dissolve (the control group is not added). The drug liquid enters the nasal cavity of the rats through the peristaltic pump from the drug storage pool, and then returns to the drug storage pool from the nostrils. Samples are taken from the drug storage pool at different time intervals within 2 hours for content determination. In the same way, the absorption-promoting effect of 0.1% chitosan (Mw=50kDa) was investigated, and the results are shown in Figure 6.
实例7：氨基取代度60.7%的琥珀酰化壳聚糖（Mw=50kDa）对硝酸异山梨酯鼻粘膜吸收促进作用 Example 7: The effect of succinylated chitosan (Mw=50kDa) with amino substitution degree of 60.7% on nasal mucosal absorption of isosorbide dinitrate
雄性大鼠（180g～220g）经食管插管手术后置于贮药池上方，贮药池内加入5mL硝酸异山梨酯溶液（0.5mg/mL）并不断搅拌，通入37±0.5℃的循环水浴，最后加入1.0%氨基取代度为60.7%的琥珀酰化壳聚糖（Mw=50kDa），搅拌溶解（对照组不加）。药液从贮药池经蠕动泵进入大鼠鼻腔后又从鼻孔返回至贮药池，在2小时内不同时间间隔从贮药池取样进行含量测定。同法考察1.0%壳聚糖(Mw=50kDa)的吸收促进效果，结果见图7。 Male rats (180g-220g) were placed above the drug storage pool after esophageal intubation, and 5mL of isosorbide dinitrate solution (0.5mg/mL) was added to the drug storage pool and stirred continuously, and then passed into a circulating water bath at 37±0.5°C , and finally add 1.0% succinylated chitosan (Mw=50kDa) with an amino substitution degree of 60.7%, and stir to dissolve (the control group is not added). The drug solution enters the nasal cavity of the rats through the peristaltic pump from the drug storage pool and then returns to the drug storage pool from the nostrils. Samples are taken from the drug storage pool at different time intervals within 2 hours for content determination. In the same way, the absorption-promoting effect of 1.0% chitosan (Mw=50kDa) was investigated, and the results are shown in Figure 7.
实例8：应用动物实验比较琥珀酰化壳聚糖对硝酸异山梨酯鼻粘膜吸收促进效果 Example 8: Application of animal experiments to compare the effect of succinylated chitosan on nasal mucosal absorption of isosorbide dinitrate
取180～220g的雄性大鼠15只，随机分成三组，分别给予剂量为1.04 mg·kg-1的硝酸异山梨酯（对照组）、硝酸异山梨酯-壳聚糖溶液（0.5%，Mw=50kDa）和硝酸异山梨酯-琥珀酰化壳聚糖溶液（0.1%，Mw=50kDa，DS=63.0%）双侧鼻孔给药，每鼻孔20μL，于2，5，10，15，20，30，60，120，180min眼眶取血0.3mL，血样处理，取20μL高效液相色谱法测定含量；另取180～220g的雄性大鼠10只，随机分成两组，分别给予灌胃剂量为2.58 mg·kg-1和尾静脉注射剂量为0.64mg·kg-1，于2，5，10，20，30，60，120，180min眼眶取血0.3mL，血样处理，取20μL高效液相色谱法测定含量。实验数据见表1，图8为相应的体内血药浓度时间曲线。 Fifteen male rats weighing 180-220 g were randomly divided into three groups, and given a dose of 1.04 mg·kg -1 isosorbide dinitrate (control group), isosorbide dinitrate-chitosan solution (0.5%, Mw =50kDa) and isosorbide dinitrate-succinylated chitosan solution (0.1%, Mw=50kDa, DS=63.0%) bilateral nostril administration, 20μL per nostril, at 2, 5, 10, 15, 20, At 30, 60, 120, and 180 minutes, 0.3 mL of blood was taken from the orbit, processed, and 20 μL was taken to determine the content by high-performance liquid chromatography; another 10 male rats of 180-220 g were randomly divided into two groups, and the dose of 2.58 mg·kg -1 and the tail vein injection dose is 0.64 mg·kg -1 , 0.3 mL of blood is collected from the orbit at 2, 5, 10, 20, 30, 60, 120, and 180 min. Determination of content. The experimental data are shown in Table 1, and Fig. 8 is the corresponding time curve of blood drug concentration in vivo.
表1 主要药代动力学参数 (mean ± SD, n=5) Table 1 Main pharmacokinetic parameters (mean ± SD, n =5)
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| 汪琴等.N-琥珀酰壳聚糖的合成和性能研究.《功能高分子学报》.2004,第17卷(第01期), * |
| 陶露丝等.N-琥珀酰壳聚糖制备及理化特性研究.《现代食品科技》.2007,第23卷(第07期), * |
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