Preparation, Characterization, and Anti-Ulcerative Colitis Efficacy of Cockroach Extract Liposomes
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摘要:
目的 探索制备蜚蠊提取物长效脂质体的最佳工艺, 并评价其对溃疡性结肠炎(UC)模型小鼠的治疗效果。 方法 采用薄膜分散法制备蜚蠊提取物长效脂质体(CE-Lip), 正交实验优化CE-Lip的处方及冻干工艺, 进行形态学表征并评价其体外释放速率, 并通过UC小鼠模型进行药效学评价。 结果 最佳制备工艺为胆固醇-磷脂质量比1 ∶ 5, 提取物-磷脂质量比1 ∶ 4, 水化时间0.75 h, 水化体积3 mL, 水化温度30 ℃; 最佳冻干工艺为采用5%甘露醇、10%海藻糖作为混合冻干保护剂; 所制得的CE-Lip平均粒径为(276.7±5.6)nm, 呈囊泡状结构, 冻干后稳定性良好, 在体外释放速率显著低于原料药。药效学结果显示CE-Lip可以显著降低UC小鼠的DAI评分、结肠长度、CMDI评分、TNF-α表达量、HS评分, 显著升高EGF表达量、杯状细胞中的黏液素表达量。 结论 获得简便、稳定、重现性良好的CE-Lip制备工艺。制得的CE-Lip, 大小分散均匀, 稳定性好, 具有缓释的效果, 相比于普通制剂, CE-Lip显著提高了CE对UC小鼠的治疗作用, 为CE-Lip的进一步开发研究奠定了基础。 Abstract:OBJECTIVE This study aimed to explore the optimal process for preparing long-acting liposomes loaded with cockroach extract (CE-Lip) and to evaluate their therapeutic efficacy against ulcerative colitis (UC). METHODS The CE-Lip was prepared using a thin film dispersion method. Orthogonal experiments were conducted to optimize the formulation and freeze-drying process of CE-Lip. Morphological characterization and in vitro release rate assessment were performed. The therapeutic efficacy of CE-Lip was evaluated using a mouse model of UC. RESULTS The optimal preparation process involved a cholesterol-phospholipid mass ratio of 1 ∶ 5, an extract-phospholipid mass ratio of 1 ∶ 4, hydration time of 0.75 h, hydration volume of 3 mL, and hydration temperature of 30 ℃. The optimal freeze-drying process utilized a mixture of 5% mannitol and 10% trehalose as protective agents. The resulting CE-Lip exhibited an average particle size of (276.7±5.6) nm, with a vesicular structure. The stability of CE-Lip after freeze-drying was excellent, and its in vitro release rate was significantly lower than that of the raw material. Pharmacological results demonstrated that CE-Lip significantly reduced DAI scores, colon length, CMDI scores, TNF-α expression, and HS scores in UC mice, while increasing EGF expression and mucin expression in goblet cells. CONCLUSION A simple, stable, and reproducible process for preparing CE-Lip is established. The resulting CE-Lip exhibits uniform size distribution, good stability, and sustained release effects. Compared to conventional formulations, CE-Lip significantly enhanced the therapeutic effect of CE against UC in mice. This study provides a foundation for further development and research of CE-Lip. -
Key words:
- cockroach extract /
- liposomes /
- orthogonal experiment /
- ulcerative colitis
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图 1 CE-Lip的制备单因素试验结果(x±s, n=3)
Figure 1. The results of the single factor test of CE-Lip preparation (x±s, n=3)
图 2 CE-Lip的形态学表征
注：A.外观; B.粒径; C.电位; D.TEM图像
Figure 2. Morphological characterization of CE-Lip
图 3 经冻干复溶后CE-Lip的形态学表征
注：A.外观; B.粒径; C.电位; D.TEM图像
Figure 3. Morphological characterization of CE-Lip after freeze-drying redissolving
图 5 CE-Lip对UC小鼠DAI评分(A)、结肠长度(B、C)、CMDI评分(D、E)的影响
注: 1.Control；2.Saline；3.Mesalazine；4.CE；5.CE-Lip。与Control组比较, *P < 0.05, * *P < 0.01;与Saline组比较, #P < 0.05, ##P < 0.01;与CE组比较, △P < 0.05, △△P < 0.01。
Figure 5. The effect of CE-Lip on DAI score(A), colon length(B, C), CMDI score(D, E) in UC mice
图 6 CE-Lip对UC小鼠TNF-α表达量(A)和EGF表达量(B)的影响
注: 与Control组比较, * *P < 0.01;与Saline组比较, ##P < 0.01;与CE组比较, △△P < 0.01。
Figure 6. The effect of CE Lip on TNF-α expression level (A) and EGF expression level (B) in UC mice
图 7 CE-Lip对UC小鼠结肠组织(A)、结肠组织黏液素生成(B)、HS评分(C)、黏液素表达量(D)的影响(×200)
注: 与Control组比较, * *P < 0.01;与Saline组比较, ##P < 0.01;与CE组比较, △△P < 0.01。
Figure 7. The effect of CE-Lip on colon tissue(A), mucin production in colon tissue (B), HS score(C), and mucin expression (D) of UC mice (×200)
表 1 CE-Lip复溶的外观及再分散性评价标准
Table 1. Appearance and redispersibility evaluation criteria of CE-Lip reconstituted
外观评价指标 再分散性评价指标 分值 保持原体积饱满、不皱缩、不塌陷、可整块脱落但不散碎 振摇30 s内能快速分散、无不溶颗粒或团块 5 松散、光滑、平整、饱满 振摇30s~1 min内能复溶成均匀混悬液, 无不溶颗粒或团块 3 轻度皱缩、塌陷 振摇1~3 min内能复溶成较均匀混悬液, 肉眼可见少量不溶颗粒 2 严重皱缩、塌陷 振摇5 min仍不能复溶成较均匀混悬液, 黏壁, 肉眼可见部分不溶颗粒或团块 1 不能成型 振摇10 min仍不能复溶成较均匀混悬液, 肉眼可见大量不溶颗粒或团块 0 
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表 2 UC小鼠的DAI评分标准细则
Table 2. Detailed rules for DAI scoring standards of UC mice
体质量减轻 粪便性状 大便隐血情况 计分 ≤1% 正常 隐血(-) 0 >1%且≤5% 介于正常与稀便之间 隐血(+) 1 >5%且≤10% 稀便 隐血(++) 2 >10%且≤15% 介于稀便与腹泻之间 血便(+++) 3 >15% 腹泻 肉眼血便 4 注: 正常=可成型的粪便; 稀便=不成型的稀状粪便; 腹泻=粘于肛门的液化粪便。体质量减轻=(造模后某时间的体质量-造模前体质量)/造模前体质量×100%。
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表 3 结肠黏膜损伤指数评分标准
Table 3. Scoring criteria for colonic mucosal injury index
分数 结肠特征的宏观观察 0 黏膜表面光滑, 平整无损坏 1 黏膜轻度充血、水肿、黏膜无糜烂或溃疡 2 黏膜充血、水肿、黏膜粗糙, 轻度糜烂或肠粘连 3 黏膜充血、水肿、中度糜烂和溃疡形成, 但溃疡直径 < 1 cm 4 黏膜充血、水肿、中度糜烂并形成溃疡, 但溃疡直径>1 cm
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表 4 HS评分标准
Table 4. HS Scoring Standards
分数 上皮细胞形态 炎性细胞浸润 0 正常形态 没有浸润 1 有杯形细胞丢失 浸润在隐窝基底层 2 杯形细胞大面积丢失 浸润达到黏膜肌层 3 隐窝细胞丢失 浸润深入黏膜肌层, 伴随黏膜增厚和明显水肿 4 隐窝细胞大面积丢失 浸润到达黏膜下层
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表 5 制备工艺正交试验因素水平表
Table 5. Orthogonal test factor level table of preparation process
水平 因素 A胆脂比/(g·g-1) B药脂比/(g·g-1) C水化时间/h D空白 1 1∶ 3 1∶ 3 0.5 - 2 1∶ 4 1∶ 4 0.75 - 3 1∶ 5 1∶ 5 1.0 -
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表 6 CE-Lip制备工艺相关检测指标统计表
Table 6. Statistical table of relevant detection indicators of CE-Lip preparation process
试验号 A胆脂比/(g·g-1) B药脂比/(g·g-1) C水化时间/h 包封率/% 平均粒径/nm 综合评分 1 1 1 1 38.57 437 61.50 2 1 2 2 47.98 371 80.77 3 1 3 3 43.95 326 80.53 4 2 1 2 43.05 302 82.01 5 2 2 3 50.67 295 92.54 6 2 3 1 48.88 286 91.23 7 3 1 3 40.36 274 81.64 8 3 2 1 54.71 280 99.34 9 3 3 2 53.81 278 98.41 K1 222.80 225.15 252.06 K2 265.78 272.65 261.20 K3 279.39 270.17 254.71 R 56.59 47.50 9.14
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表 7 CE-Lip制备工艺正交试验结果方差分析结果
Table 7. Orthogonal test results of CE-Lip preparation process results of variance analysis
来源 Ⅲ型均方根 df 均方值 F P A 581.609 8 2 290.804 9 39.48 0.017 B 476.597 2 2 238.298 6 32.35 0.039 C 17.646 1 2 8.823 0 1.20 0.877 误差 14.732 9 2 7.366 5
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表 8 CE-Lip最佳工艺验证结果
Table 8. The optimal process verification results of CE-Lip
CE-Lip样品 包封率/% 平均粒径/nm 综合评价 56.54 283 98.56 A3B2C2 54.97 277 97.28 54.45 270 97.41
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表 9 预冻温度、预冻时间、冻干时间对包封率、粒径、复溶后外观和再分散性的影响(x±s，n=3)
Table 9. Effect of pre-freezing temperature, pre-freezing time, lyophilization time on encapsulation efficiency, particle size, appearance and redispersibility of CE-Lip reconstituted (x±s, n=3)
条件 包封率/% 粒径/nm 外观 再分散性 预冻温度 -20℃ 14.50±2.06 368±8.43 0 3 -40℃ 20.60±3.15 375±5.82 1 3 -80℃ 26.10±3.23 353±7.78 3 3 预冻时间 6 h 18.80±2.12 367±9.65 0 2 12 h 25.50±3.32 348±8.66 1 2 24 h 27.30±3.58 353±6.54 2 3 48 h 26.70±3.84 365±6.68 3 3 冻干时间 12 h 23.00±2.66 387±5.36 2 2 24 h 27.30±1.86 353±10.28 3 3 48 h 25.50±3.02 362±7.92 3 3 72 h 24.80±2.76 367±10.60 3 3
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表 10 甘露醇比例、海藻糖比例、乳糖比例对包封率、粒径、复溶后外观和再分散性的影响(x±s，n=3)
Table 10. Effect of mannitol ratio, trehalose ratio, lactose ratio on encapsulation efficiency, particle size, appearance and redispersibility of CE-Lip reconstituted (x±s, n=3)
条件 包封率/% 粒径/nm 外观 再分散性 甘露醇比例/% 5 29.00±2.35 433±7.86 5 3 10 35.50±2.15 487±8.54 5 2 20 39.20±1.65 360±7.75 3 2 海藻糖比例/% 5 42.40±2.34 453±9.86 3 3 10 45.60±3.12 332±5.78 5 3 20 48.80±1.68 302±7.95 3 3 乳糖比例/% 5 26.7±3.25 536±11.85 1 1 10 0 0 0 0 20 0 0 0 0
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表 11 冻干工艺正交试验因素水平
Table 11. Orthogonal test factor level table of freeze-drying process
水平 因素 A冻干时间/h B甘露醇/% C海藻糖/% D空白 1 12 5 5 - 2 24 8 8 - 3 48 10 10 -
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表 12 CE-Lip冻干工艺相关检测指标统计表
Table 12. Statistical table of detection indicators related to CE-Lip freeze-drying process
试验号 A冻干时间/h B甘露醇/% C海藻糖/% 包封率/% 平均粒径/nm 外观 再分散性 综合评分 1 1 1 1 36.44 409 3 3 73.00 2 1 2 2 42.67 513 3 3 75.86 3 1 3 3 38.22 580 5 2 71.03 4 2 1 2 47.11 441 2 5 86.91 5 2 2 3 48.00 369 2 2 81.88 6 2 3 1 44.89 468 5 2 83.25 7 3 1 3 47.11 366 2 5 89.98 8 3 2 1 43.56 391 5 3 87.88 9 3 3 2 45.78 417 5 2 86.36 K1 219.89 249.89 244.13 K2 252.04 245.62 249.14 K3 264.23 240.64 242.88 R 44.34 9.24 6.25
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表 13 CE-Lip冻干工艺正交试验结果方差分析结果
Table 13. Orthogonal test results of CE-Lip freeze-drying process analysis of variance results
来源 Ⅲ型均方根 df 均方值 F P A 349.827 0 2 174.913 5 47.96 0.001 B 14.264 3 2 7.132 1 1.96 0.237 C 10.397 8 2 5.198 9 1.43 0.864 error 7.294 4 2 3.647 2
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表 14 冻干脂质体的稳定性考察
Table 14. Stability study of freeze-dried liposomes
条件 外观 再分散性 粒径/nm 电位/mV 包封率/% 0 d 5 5 304.5±2.3 -15.9±0.4 48.60±2.85 -20℃ 5 d 5 3 318.4±1.6 -13.6±2.1 47.37±2.94 10 d 5 3 326.8±2.5 -20.2±1.7 46.98±3.68 30 d 5 3 349.8±2.7 -19.8±1.5 44.85±2.09 4℃ 5 d 5 5 305.8±2.1 -16.5±1.5 47.89±1.81 10 d 5 5 310.4±0.9 -16.6±2.6 47.23±2.34 30 d 5 5 314.8±2.9 -16.9±1.9 47.20±1.37 25℃ 5 d 5 3 318.9±3.9 -14.7±4.1 47.56±3.77 10 d 5 3 354.0±4.6 -17.8±1.3 47.01±3.97 30 d 5 2 389.9±5.5 -18.4±2.3 44.78±1.23
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表 15 CE-Lip体外释放拟合结果
Table 15. In vitro release fitting results of CE-Lip
模型 CE CE-Lip(冻干前) CE-Lip(冻干后) 拟合方程 R2 拟合方程 R2 拟合方程 R2 零级释放 Q=1.82T+65.13 0.6021 Q=2.01T+35.82 0.885 1 Q=1.74T+44.27 0.857 5 一级释放 Q=92.15(1-e-1.02T) 0.771 6 Q=64.75(1-e-0.62T) 0.7260 Q=67.05(1-e-1.04T) 0.712 6 Higuchi Q=11.80T1/2+51.011 0.760 7 Q=11.89T1/2+22.91 0.977 4 Q=10.36T1/2+32.97 0.955 5
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