本文選題：力度可控性滾輪微針 + 增生性瘢痕��； 參考：《寧夏醫(yī)科大學(xué)》2014年碩士論文

【摘要】：目的構(gòu)建力度可控性滾輪微針并研究其在大面積皮膚藥物吸收中的影響。 方法1.構(gòu)建力度可控性滾輪微針，采用石蠟切片、HE染色法考察其力度可控性，F(xiàn)ranz擴(kuò)散池法考察釋藥重現(xiàn)性，Score法測(cè)定皮膚刺激性；Franz擴(kuò)散池法、亞甲藍(lán)染色、CLSM法篩選微針密度、使用力度及不同處理次數(shù)；TEWL法、激光多普勒法考察微針對(duì)健康裸鼠、健康人體及瘢痕病人皮膚的刺激性。 2.采用洗脫法、組織勻漿法比較微針及注射針對(duì)地塞米松磷酸鈉在體不同時(shí)間的總吸收量、皮膚及血漿藥量；Franz擴(kuò)散池法研究其體外滲透特性；冰凍切片后進(jìn)行組織勻漿考察微針及注射針對(duì)地塞米松磷酸鈉均勻性的影響；SEM法、TEWL法、激光多普勒法考察皮膚刺激性。 3.采用激光多普勒法測(cè)定不同濃度川芎揮發(fā)油和去氧腎上腺素對(duì)健康裸鼠皮膚血流的影響，F(xiàn)ranz擴(kuò)散池法對(duì)比其對(duì)裸鼠離體皮膚的作用，洗脫法、組織勻漿法研究改變血流對(duì)地塞米松磷酸鈉在體吸收及分布的影響，Score法、組織學(xué)檢測(cè)皮膚刺激性。 結(jié)果1.滾輪微針改裝后有效的提高了力度可控性、釋藥重現(xiàn)性，且皮膚刺激性小。力度與深度實(shí)驗(yàn)結(jié)果為皮膚微孔深度隨微針使用力度的增加而加大，微孔深度范圍由65.28～106.25μm收窄為改裝后的71.53～97.92μm，其RSD范圍由10.45%～19.69%顯著下降至改裝后的2.33%～9.21%。在相同微針使用力度下，曲安奈德的累積釋藥量RSD范圍由改裝前的34.75%～55.92%，顯著下降至改裝后的14.29%～29.73%。改裝滾輪微針僅在用藥1h時(shí)出現(xiàn)輕度皮膚刺激性，之后消失。 微針密度、使用力度篩選實(shí)驗(yàn)結(jié)果為540針、3.5~4.0N效果較好。540針微針組維A酸的累積滲透量是對(duì)照組的6.8倍，較192針微針組的2.5倍促滲作用更強(qiáng)(P＜0.05)；2.5~3.0N使用力度時(shí)，給藥2h維A酸滲透深度為30μm，而3.5~4.0N與4.5~5.0N兩組的深度無(wú)顯著差異，滲透深度均為40μm。 微針處理次數(shù)結(jié)果顯示，微針使用次數(shù)越多促透作用越好，藥物吸收越均勻，但8次以后趨于平衡，皮膚刺激性實(shí)驗(yàn)結(jié)果顯示5次及以下處理次數(shù)較安全。處理10次時(shí)的48h累積滲透量和滲透速率均最高，分別為對(duì)照組的3.1倍和4.1倍（P0.05），較處理8次組的2.6倍和3.0倍增加不明顯；8、10次處理組的皮膚維A酸滯留量相近，約是對(duì)照組的3.0倍。亞甲藍(lán)染色與激光共聚焦結(jié)果顯示，微針孔數(shù)量隨微針使用次數(shù)的增加逐漸增多并趨于均勻，而使用8次與10次效果相似。TEWL與激光多普勒血流結(jié)果顯示，微針處理后TEWL和血流均迅速增加，并隨使用次數(shù)的增加對(duì)皮膚的刺激作用增大；處理10次時(shí)對(duì)TEWL和皮膚血流的影響均最大，且恢復(fù)時(shí)間也最長(zhǎng)；1、3、5次處理組TEWL恢復(fù)時(shí)間為24h，8、10次為48h；皮膚血流恢復(fù)時(shí)間除8、10次在120min外，其余處理組均在60min內(nèi)恢復(fù)基線。微針健康人體TEWL和血流影響均在90min內(nèi)完全恢復(fù)，而在瘢痕患者45min完全恢復(fù)。 2.微針給藥技術(shù)較皮內(nèi)注射給藥的優(yōu)點(diǎn)在于皮膚促透作用高效持續(xù)、皮膚中藥物分布量反而高于皮內(nèi)注射組，且分布更加均勻，皮膚刺激性相對(duì)較小。皮內(nèi)注射組裸鼠體外快速滲透，4h透皮累積藥量高達(dá)83.76%，而后緩慢釋藥；而微針組則體外釋藥緩慢，4h透皮累積藥量?jī)H為25.75%，但相對(duì)持續(xù)。皮內(nèi)注射組皮膚滯留藥量較微針組少，12h皮膚滯留藥量?jī)H為微針組的36.14%。皮內(nèi)注射組裸鼠體內(nèi)1h皮膚滯留藥量為微針組的94.52%，隨后皮膚滯留藥量逐漸下降，至12h僅為1h的18.96%；而微針組皮膚滯留藥量隨時(shí)間逐步增加，12h皮膚滯留藥量是皮內(nèi)注射組的6.92倍。此外，給藥12h，微針組血漿藥物濃度是對(duì)照組的3.16倍，是皮內(nèi)注射組的2.25倍。皮內(nèi)注射組注射點(diǎn)處皮膚滯留藥量較高，注射點(diǎn)外藥量較少，峰谷值相差286.21%；而微針組皮膚滯留藥量相對(duì)均衡，峰谷值相差僅為114.61%。TEWL顯示微針對(duì)皮膚表面失水量影響較注射組大，但24h后刺激消除；而激光多普勒血流量法顯示皮內(nèi)注射對(duì)皮膚血流的影響更大。 3.川芎揮發(fā)油和去氧腎上腺素對(duì)微針離體皮膚促透沒(méi)有影響，但能通過(guò)改變?cè)隗w皮膚血流達(dá)到對(duì)微針給藥的調(diào)控作用。離體實(shí)驗(yàn)各處理組12h累積滲透量、滲透速率和12h皮膚內(nèi)藥物滯留量均無(wú)顯著差異；在體實(shí)驗(yàn)中，含10%川芎揮發(fā)油組的給藥部位皮膚藥量最低，為1.45±0.42μg，，僅為對(duì)照組的0.5倍（P0.05），而含0.15%去氧腎上腺素組給藥部位皮膚含藥量為3.89±1.52μg，為對(duì)照組的1.32倍（P0.05）；血漿中藥物含量規(guī)律相反，含3%川芎揮發(fā)油組和含10%川芎揮發(fā)油組分別是對(duì)照組的5.39倍和6.39倍（P0.05），而含0.15%去氧腎上腺素組僅為對(duì)照組的0.61倍（P0.05）；含10%川芎揮發(fā)油組藥物總吸收量最高，為對(duì)照組的2.05倍，含0.15%去氧腎上腺素組總吸收量最��；皮膚刺激性實(shí)驗(yàn)各組1h時(shí)表現(xiàn)為輕度刺激強(qiáng)度，48h所有實(shí)驗(yàn)裸鼠均完全恢復(fù)。皮膚組織學(xué)檢查結(jié)果顯示，微針處理后6h，皮膚僅現(xiàn)輕微角質(zhì)層剝離和缺失，加入川芎揮發(fā)油和去氧腎上腺素后刺激性均未增加，未現(xiàn)炎細(xì)胞等炎癥反應(yīng)。 結(jié)論制備力度可控性滾輪微針后，有效提高了其力度可控性、釋藥重現(xiàn)性及給藥均勻性，通過(guò)篩選滾輪微針的使用方法，增強(qiáng)了對(duì)增生性瘢痕大面積給藥的可操作性。構(gòu)建滾輪微針在解決了皮內(nèi)注射給藥存在的疼痛、給藥不便等問(wèn)題的同時(shí)，起到高效促透、皮膚藥物濃集及分布均勻的作用。皮膚血流影響透皮藥物在皮膚和血液中的分布，適當(dāng)?shù)娜パ跄I上腺素能降低局部皮膚血流有效增加給藥病灶部位藥量，降低藥物入血。
[Abstract]:Objective to construct a dynamic controllable roller microneedle and study its effect on the absorption of large area skin drugs.
Method 1. the dynamics controllable roller microneedles were constructed. The strength controllability was examined by paraffin section and HE staining. The reproducibility of drug release was investigated by the Franz diffusion pool method. Score method was used to determine the irritation of the skin. Franz diffusion pool, methylene blue staining, and CLSM method were used to screen the density of microneedles, use intensity and different treatment times; TEWL method and laser Doppler method were used to investigate the micropin density. For healthy nude mice, skin irritation of healthy and scarred patients.
2. the method of elution and tissue homogenate were used to compare the total absorption of dexamethasone sodium phosphate and the dosage of dexamethasone sodium phosphate at different time in the body and the dosage of the skin and plasma; the Franz diffusion pool method was used to study the osmosis in vitro; the effect of microneedle and injection on the homogeneity of sodium phosphate of dexamethasone was investigated by tissue homogenate after frozen section; SEM method, TEWL Method, laser Doppler method was used to examine skin irritation.
3. the effects of different concentrations of volatile oil and epinephrine on the skin blood flow of healthy nude mice were measured by laser Doppler method. The effect of the Franz diffusion pool method on the skin of nude mice was compared. The effect of blood flow on the absorption and distribution of dexamethasone sodium phosphate in the body was studied by the elution method and tissue homogenate method. Score method and histological examination of skin were used. Skin irritation.
Results after the 1. roller microneedles were modified, the dynamic controllability, reproducibility and irritation of the skin were effectively improved. The results of strength and depth were increased with the increase of micropin intensity. The range of micropore depth was narrowed from 65.28 to 106.25 mu m to 71.53 to 97.92 mu m, and the range of RSD was from 10.45% to 19.69%. Under the use of the same micro needle, the cumulative release amount of Cu Ann Ned's RSD range from 2.33% to 9.21%. after the modification was 34.75% ~ 55.92% before the modification, which was significantly reduced to 14.29% ~ 29.73%. modified roller microneedles for mild skin irritation only at 1H.
Microneedle density, the results of the use of the strength screening test were 540 needles, and the effect of 3.5~4.0N was better than that of the control group. The cumulative permeability of the.540 needle microneedle group was 6.8 times more than that of the control group, and the infiltration effect was stronger than that of the 192 needle microneedle group (P < 0.05). The penetration depth of 2H vitamin A was 30 u m, while the depth of 3.5~4.0N and 4.5~5.0N two was not obvious when 2.5~3.0N was used. The depth of penetration is 40 u M.
The results of microneedle treatment showed that the better the use of microneedles, the better the penetration effect, the better the absorption of the drugs, but the more balanced after 8 times. The results of the skin irritation test showed that the 5 times and the following treatment times were more safe. The 48h cumulative permeability and the penetration rate of the 10 times were the highest, 3.1 times and 4.1 times of the control group (P0.05), respectively. The increase of 2.6 times and 3 times of the treatment in the 8 group was not obvious; the amount of A acid retention in the skin of the 8,10 treatment group was similar, about 3 times that of the control group. The methylene blue staining and laser confocal results showed that the number of micropinholes increased gradually with the increase of the number of microneedles, and the effect of the 8 and 10 times was similar to that of the laser Doppler. The blood flow results showed that the TEWL and blood flow increased rapidly after the microneedle treatment, and increased with the increase of use times. The effects on TEWL and skin blood flow were the largest and the recovery time was the longest when treated 10 times; the TEWL recovery time of the 1,3,5 treatment group was 24h, 8,10 was 48h, and the time of skin blood flow recovery was 1 except 8,10 times in 8,10. At 20min, the rest of the treatment groups were all restored to the baseline in 60min. The effects of TEWL and blood flow on the healthy human body were all recovered within the 90min, while the 45min in the scar patients recovered completely.
The advantage of 2. microneedle therapy is that the effect of intradermal injection is more efficient and continuous. The distribution of drugs in the skin is higher than that in the intradermal injection group, and the distribution is more uniform and the skin irritation is relatively small. The intradermal injection group is fast permeable in the nude mice in vitro, the 4H transdermal cumulative dosage is up to 83.76%, and then slowly release the drug; and the microneedle group The drug release in vitro was slow, and the cumulative dose of 4H was only 25.75%, but it was relatively sustained. The amount of skin retention in the intradermal injection group was less than that in the microneedle group. The amount of 12h retention in the 36.14%. intradermal injection group was only 94.52% in the nude mice of the group of microneedles, and the dosage of the skin stagnation gradually decreased to 12h only 18.96% of the 1H. The dosage of skin retention in the microneedle group increased gradually with time, and the amount of 12h skin retention was 6.92 times as high as that in the intradermal injection group. In addition, the drug concentration in the microneedle group was 3.16 times more than that of the control group and 2.25 times that of the intradermal injection group. The dosage of the injection point at the intradermal injection group was higher, the dosage of the injection point was less and the difference of peak and valley value was 286.21%. The amount of skin retention in the microneedle group was relatively balanced, and the difference of peak and valley value was only 114.61%.TEWL, but the effect of the skin water loss was larger than that of the injection group, but the stimulation after 24h was eliminated, while the laser Doppler blood flow method showed that intradermal injection had more effect on the skin blood flow.
3. the volatile oil of Ligusticum chuanxiong and deoxyadrenaline did not affect the penetration of microneedles in vitro, but it could regulate the effects of microneedle therapy on the blood flow in the body skin. There was no significant difference in the cumulative 12h permeability, the rate of osmosis and the drug retention in the 12h skin in the experimental group. In the body experiment, the volatile oil group of 10% Ligusticum chuanxiong was found. The dosage of the skin was the lowest, 1.45 + 0.42 mu g, only 0.5 times of the control group (P0.05), while the dosage of the 0.15% deoxyadrenaline group was 3.89 + 1.52 g, which was 1.32 times (P0.05) of the control group, and the drug content in the plasma was opposite, 3% of the volatile oil group and 10% Ligusticum chuanxiong volatile oil group were 5.3 of the control group. 9 times and 6.39 times (P0.05), and 0.15% deoxyadrenaline group was only 0.61 times of the control group (P0.05), and the total absorption of the volatile oil group containing 10% Ligusticum chuanxiong was the highest, which was 2.05 times of the control group, and the total absorption of 0.15% deoxyadrenaline group was the smallest. The 1H in the skin irritation test group was mild stimulation intensity, and all the experimental nude mice of 48h were finished. The results of skin histological examination showed that the skin was only slight cuticle dissection and deletion in 6h after microneedle treatment. After adding Ligusticum chuanxiong volatile oil and deoxyadrenaline, the irritation did not increase, and there was no inflammatory reaction.
Conclusion the controllability, reproducibility and uniformity of drug delivery are effectively improved after the preparation of the dynamics controllable roller microneedles. By screening the use of roller microneedles, the maneuverability of large area drug delivery for hypertrophic scars is enhanced. The construction of roller microneedles is a solution to the pain and inconvenience of intradermal injection. At the same time, the skin blood flow affects the distribution of the skin and blood in the skin and blood. The appropriate deoxyadrenaline can reduce the local skin blood flow effectively and reduce the dose of the focus on the focus of the focus, and reduce the entry of the drug into the blood.

【學(xué)位授予單位】：寧夏醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R96

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