难溶性多西紫杉醇的溶解微针制备及体外评价

目的:制备一种用于透皮给药的负载多西紫杉醇(DTX)的溶解微针,并进行体外评价。方法:考察不同材料及配方制备DTX溶解微针(DTX-MN),通过外观和力学性能指标对微针进行表征,测定微针针头载药量。使用猪皮肤考察微针溶解性能。剥离小鼠腹部皮肤,进行体外透皮吸收研究,初步考察DTX-MN给药后的皮肤药代动力学。结果:成功制备了针头完整、力学性能良好的DTX-MN,最佳工艺得到的微针针头载药量为(14.81±4.20)μg (n=5),微针能完整插入皮肤穿透角质层屏障,且在10 min内完全溶解。体外透皮实验显示,DTX-MN的初始透皮速率和累积透皮通量都高于药物溶液组,相比溶液组,DTX-MN在24 h后累积渗透量提高了3.27倍,其释放机制符合Fickian扩散。结论:制备的DTX-MN有良好的穿刺皮肤的性能,能够显著促进DTX的透皮递送,该类微针有望促进DTX的浅表皮肤递送,具有潜在的临床应用价值。     

尼莫地平贴剂体外渗透性及皮肤刺激性考察

尼莫地平经皮吸收贴剂选用丙烯酸酯为骨架材料 ,由背衬层、压敏胶层、覆盖层组成 .通过人体皮肤刺激性实验和体外经皮渗透实验对几组以不同浓度的油酸和月桂氮酮 (azone ,AZ)为渗透促进剂的处方进行了筛选 .结果表明含 5 %azone的尼莫地平贴剂对皮肤有轻度刺激性 ,其它处方对皮肤无刺激性 ;尼莫地平贴剂的体外经皮渗透符合零级动力学过程 ,含 10 %油酸的处方渗透性最好 .     

不锈钢微针经皮给药的研究

目的：将不锈钢微针阵列应用于经皮给药。考察离体大鼠皮肤经不同针形微针预处理相同时间、相同针形微针预处理不同时间后，模型药物鬼臼毒素经大鼠皮肤的透皮能力。方法：微针预处理大鼠皮肤后，用改进的Franz扩散池研究鬼臼毒素对皮肤的透皮速率。高效液相色谱法测定鬼臼毒素的含量。结果：皮肤经微针预处理后进行鬼臼毒素透皮，其透皮速率比未经微针处理时有明显提高。三角形微针、梯形微针、矛形微针对鬼臼毒素的促渗能力依次增强；三者所引起的鬼臼毒素在皮肤中的滞留量有显著差异。同种针形微针预处理皮肤时间越长，鬼臼毒素的透皮速率越大；但微针预处理时间对皮肤中的药物滞留量无显著影响。结论：微针用于药物经皮给药时，微针针形、微针的预处理时间对药物的经皮渗透具有重要影响。     

物理方法促进胰岛素经皮吸收的实验研究进展

目的胰岛素经皮吸收制剂是一种理想的胰岛素给药方式,但由于皮肤角质层的阻力、胰岛素分子在皮肤中的累积等因素限制了胰岛素的经皮给药。方法本文介绍了微针、电致孔、超声导入、离子导入等物理方法促进胰岛素经皮吸收实验研究进展。结果研究安全、有效、经济、方便的胰岛素透皮吸收物理促渗技术。结论随着对上述新技术、新方法实验研究的深入,物理促渗技术必将为胰岛素透皮吸收制剂的发展开辟更广阔的前景     

改装滚轮微针用于醋酸曲安奈德经皮给药的特性试验

目的:评价改装滚轮微针用于曲安奈德经皮给药的力度可控性、释药重现性和皮肤刺激性。方法:改装市售滚轮微针;石蜡切片、HE染色法观察不同微针使用力度(2.5,5.0,7.5,10.0,12.5,15.0,17.5,20.0 N)时的皮肤微孔深度,探讨改装前后其力度可控性;以离体裸鼠皮肤为屏障,Franz扩散池法考察改装前后曲安奈德经皮渗透特性;评分法测定皮肤刺激性。结果:皮肤微孔深度随微针使用力度的增加而加大,微孔深度范围由65.28~106.25 μm收窄为改装后的71.53~97.92 μm,其RSD范围由10.45%~19.69%显著下降至改装后的2.33%~9.21%。在相同微针使用力度下,曲安奈德的累积释药量RSD范围由改装前的34.75%~55.92%,显著下降至改装后的14.29%~29.73%。改装滚轮微针用药1 h时出现轻度皮肤刺激性,之后消失。结论:与市售滚轮微针相比,改装滚轮微针具有较好的力度可控性、释药重现性,以及较小的皮肤刺激性。     

薄荷醇衍生物对荜茇提取物贴剂中胡椒碱体外经皮通透性的影响

目的研究薄荷醇衍生物对荜茇提取物贴剂中胡椒碱体外经皮通透性的影响,探讨将荜茇提取物制成贴剂的可行性。方法采用卧式双室扩散池,以离体大鼠皮肤作为通透屏障进行体外透皮实验,用HPLC法测定接收池中胡椒碱的浓度。结果戊酸薄荷醇酯、己酸薄荷醇酯、丁酸薄荷醇酯和乳酸薄荷醇酯对胡椒碱经皮吸收有明显的促透效果,其中以戊酸薄荷醇酯的促透效果最好;庚酸薄荷醇酯、十四酸薄荷醇酯和油酸薄荷醇酯的促透作用不明显;薄荷醇对胡椒碱的经皮吸收有抑制作用。结论在含有化学促进剂的贴剂中,胡椒碱的累积透过量及稳态通透速率均显著增加,说明将荜茇提取物制成贴剂是可行的。     

山茶油对非甾体抗炎药经皮渗透的促进作用

目的考察山茶油对5种非甾体抗炎药体外经皮渗透的促进作用及其与药物油水分配系数的关系。方法采用两室扩散池装置,以离体大鼠腹部皮肤为渗透屏障,用预处理皮肤法考察山茶油的促渗透作用;用HPLC法测定非甾体抗炎药不同时间在接受池药物浓度,计算累积渗透量及其他渗透动力学参数;用摇瓶法测定药物正辛醇介质分配系数以拟合其与山茶油促渗活性关系。结果山茶油可有效促进非甾体抗炎药的经皮渗透率(除双氯芬酸钠外),尤其对氟比洛芬,促渗效果最明显(P<0.01),其增渗倍数达到3.51;山茶油的促渗活性与非甾体抗炎药的正辛醇介质分配系数呈类似抛物线关系。结论山茶油作为一种低毒、无刺激性的渗透促进剂,能够有效提高药物的经皮渗透效果,具有良好的开发应用前景。     

微针经皮给药技术

微针是介于皮下注射和透皮贴剂之间的一种给药方式,利用在皮肤角质层产生的微小孔道来显著增加药物的经皮吸收。综述微针经皮给药技术的研究进展,介绍制造微针的材料和方法、微针的给药方式及其在经皮给药系统中的应用。     

巴布膏剂中双氯芬酸钠的体外经皮渗透性考察

目的 研究巴布膏剂中双氯芬酸钠体外经皮吸收情况。方法 经皮装置采用改进型Pranz扩散池，以离体大鼠皮肤为经皮屏障，生理盐水为接受液，用725紫外分光光度计进行测定。结果与结论 巴布膏剂中双氯芬酸钠能够经皮吸收。     

电致孔-离子导入技术对胰岛素经皮给药促渗作用的研究

目的:以胰岛素为模型药物,大鼠的离体皮肤为皮肤模型,采用电致孔-离子导入联合物理促渗新技术,进行体外经皮导入生物大分子药物的研究。方法:以胰岛素为实验药物,采用经皮被动扩散方法,分别考察人体、家兔、小鼠、大鼠离体皮肤的透皮速率,从而进行皮肤模型的筛选;在预实验的基础上,选择pH值分别为4.0、6.0、7.4的三种渗透介质,采用离子导入法,考察渗透介质对胰岛素经皮渗透量的影响,从而确定渗透介质最适pH;应用电致孔-离子导入并用、电致孔、离子导入技术,在生理pH7.4、阴极转运条件下,对胰岛素的经皮渗透量进行考察,并与胰岛素的被动扩散经皮给药进行比较。结果:胰岛素对人体、家兔、小鼠、大鼠皮肤的透皮速率分别为0.78±0.03×10-1u/cm2·h、2.25±0.18×10-1u/cm2·h、2.02±0.19×10-1u/cm2·h、1.12±0.14×10-1u/cm2·h;在pH值分别为4.0、6.0、7.4的三种渗透介质中,胰岛素的经皮渗透速率分别为18.28±1.06×10-1u/cm2·h、9.42±0.29×10-1u/cm2·h、8.66±0.40×10-1u/cm2·h;采用电致孔-离子导入并用、离子导入、电致孔技术对胰岛素经皮促渗时,胰岛素的渗透速率分别达到19.63±6.37×10-1u/cm2·h、8.66±0.40×10-1u/cm2·h、1.83±0.07×10-1u/cm2·h。结论:电致孔-离子导入并用技术能够显著地促进生物大分子体外经皮给药的渗透速率。     

In vivo assessment of safety of microneedle arrays in human skin

Microneedle arrays are promising devices for the delivery of drugs and vaccines into or the skin. However, little is known about the safety of the microneedles. In this study we obtained insight in the ability of microneedles to disrupt the skin barrier, which was evaluated by transepidermal water loss (TEWL). We also determined the safety in terms of skin irritation (skin redness and blood flow) and pain sensation. We applied microneedle arrays varying in length and shape on the ventral forearms of 18 human volunteers. An effect of needle length was observed, as TEWL and redness values after treatment with solid microneedle arrays of 400mum were significantly increased compared to 200mum. The blood flow showed a similar trend. Needle design also had an effect. Assembled microneedle arrays induced higher TEWL values than the solid microneedle arrays, while resulting in less skin irritation. However, for all microneedles the irritation was minimal and lasted less than 2h. In conclusion, the microneedle arrays used in this study are able to overcome the barrier function of the skin in human volunteers, are painless and cause only minimal irritation. This opens the opportunity for dermal and transdermal delivery of drugs and vaccines.     

微针与新型经皮给药载体结合的研究进展

经皮给药系统具有给药方便、血药浓度稳定、无首过效应等优点,但皮肤的屏障作用使得药物难以透过皮肤。近年来,出现了很多新型经皮给药的药物载体,如脂质体、醇质体、囊泡等,这些能通过化学方法促进药物的经皮渗透。而微针能穿透皮肤角质层形成微孔通道,通过物理方法促进药物的渗透,将微针与新型经皮给药载体结合能显著提高药物的经皮吸收的速率。本文对微针与新型经皮给药载体结合的最新研究进行了综述,并展望了微针辅助新型药物载体经皮给药的发展前景。     

Direct Microneedle Array Fabrication Off a Photomask to Deliver Collagen Through Skin

Purpose

To fabricate microneedle arrays directly off a photomask using a simple photolithographical approach and evaluate their potential for delivering collagen.

Methods

A simple photolithographical approach was developed by using photomask consisting of embedded micro-lenses that govern microneedle geometry in a mould free process. Microneedle length was controlled by use of simple glass scaffolds as well as addition of backing layer. The fabricated arrays were tested for their mechanical properties by using a force gauge as well as insertion into human skin with trypan blue staining. Microneedle arrays were then evaluated for the delivery of fluorescent collagen, which was evaluated using a confocal laser scanning microscope.

Results

Microneedles with sharp tips ranging between 41.5?±?8.4 μm and 71.6?±?13.7 μm as well as of two different lengths of 1336?±?193 μm and 957?±?171 μm were fabricated by using the photomasks. The microneedles were robust and resisted fracture forces up to 25 N. They were also shown to penetrate cadaver human skin samples with ease; especially microneedle arrays with shorter length of 957 μm penetrated up to 72% of needles. The needles were shown to enhance permeation of collagen through cadaver rat skin, as compared to passive diffusion of collagen.

Conclusions

A simple and mould free approach of fabricating polymeric microneedle array is proposed. The fabricated microneedle arrays enhance collagen permeation through skin.     

Transdermal Delivery of Insulin Using Microneedles in Vivo

PURPOSE: The purpose of this study was to design and fabricate arrays of solid microneedles and insert them into the skin of diabetic hairless rats for transdermal delivery of insulin to lower blood glucose level. METHODS: Arrays containing 105 microneedles were laser-cut from stainless steel metal sheets and inserted into the skin of anesthetized hairless rats with streptozotocin-induced diabetes. During and after microneedle treatment, an insulin solution (100 or 500 U/ml) was placed in contact with the skin for 4 h. Microneedles were removed 10 s, 10 min, or 4 h after initiating transdermal insulin delivery. Blood glucose levels were measured electrochemically every 30 min. Plasma insulin concentration was determined by radioimmunoassay at the end of most experiments. RESULTS: Arrays of microneedles were fabricated and demonstrated to insert fully into hairless rat skin in vivo. Microneedles increased skin permeability to insulin, which rapidly and steadily reduced blood glucose levels to an extent similar to 0.05-0.5 U insulin injected subcutaneously. Plasma insulin concentrations were directly measured to be 0.5-7.4 ng/ml. Higher donor solution insulin concentration, shorter insertion time, and fewer repeated insertions resulted in larger drops in blood glucose level and larger plasma insulin concentrations. CONCLUSIONS: Solid metal microneedles are capable of increasing transdermal insulin delivery and lowering blood glucose levels by as much as 80% in diabetic hairless rats in vivo.     

Development of a novel self-dissolving microneedle array of alendronate, a nitrogen-containing bisphosphonate: evaluation of transdermal absorption, safety, and pharmacological effects after application in rats

Alendronate is a nitrogen-containing bisphosphonate that is widely used for the treatment of osteoporosis. In this study, we developed a novel self-dissolving micron-size needle array (microneedle array) containing alendronate, which was fabricated by micromodeling technologies using hyaluronic acid as a basic material. Micron-scale pores in the skin were seen after the application of the alendronate-loaded microneedle array, verifying establishment of transdermal pathways for alendronate. The absorption of alendronate after the application of alendronate-loaded microneedle array was almost equivalent to that after subcutaneous administration, and the bioavailability of alendronate was approximately 90% in rats. Furthermore, delivery of alendronate via this strategy effectively suppressed the decrease in the width of the growth plate in a rat model of osteoporosis. Although mild cutaneous irritation was observed after the application of the alendronate-loaded microneedle array, it resolved by day 15. These findings indicate that this alendronate-loaded microneedle array is a promising transdermal formulation for the treatment of osteoporosis.     

葫芦素B水-醇凝胶的体外经皮通透性

目的考察处方因素对葫芦素B水-醇凝胶的体外通透性的影响。方法建立了HPLC法测定葫芦素B的方法。采用Franz扩散池,以大鼠离体皮肤为通透膜,研究葫芦素B水-醇凝胶体外经皮通透性。结果选择的3种通透促进剂中,质量分数(w)为1%的油酸溶液具有最佳的促透效果,含葫芦素B质量分数为0.2%的凝胶经大鼠皮肤24 h累积通透量Qt达(410.39±33.75)μg.cm-2。结论水-醇凝胶是葫芦素B经皮给药的有效载体。     

Transdermal delivery of relatively high molecular weight drugs using novel self-dissolving microneedle arrays fabricated from hyaluronic acid and their characteristics and safety after application to the skin

The purpose of this study was to develop novel dissolving microneedle arrays fabricated from hyaluronic acid (HA) as a material and to improve the transdermal permeability of relatively high molecular weight drugs. In this study, fluorescein isothiocyanate-labeled dextran with an average molecular weight of 4 kDa (FD4) was used as a model drug with a relatively high molecular weight. The microneedle arrays significantly increased transepidermal water loss (TEWL) and reduced transcutaneous electrical resistance (TER), indicating that they could puncture the skin and create drug permeation pathways successfully. Both TEWL and TER almost recovered to baseline levels in the microneedle array group, and relatively small pathways created by the microneedles rapidly recovered as compared with those created by a tape stripping treatment. These findings confirmed that the microneedle arrays were quite safe. Furthermore, we found that the transdermal permeability of FD4 using the microneedle arrays was much higher than that of the FD4 solution. Furthermore, we found that the microneedle arrays were much more effective for increasing the amount of FD4 accumulated in the skin.These findings indicated that using novel microneedle arrays fabricated from HA is a very useful and effective strategy to improve the transdermal delivery of drugs, especially relatively high molecular weight drugs without seriously damaging the skin.     

多肽透皮给药研究进展

针对近年来多种多肽类药物的透皮给药系统进行综述。通过查阅国内外多种相关期刊文献。将多肽类药物透皮给药方法分为化学促渗剂、多种物理促渗技术,以及透皮肽、微针技术并对其进行论述。反向离子导入技术应用前景广阔,微针给药系统研究逐步深入,出现了胰岛素智能化微针给药系统,透皮肽的研究发展迅速,相信未来多种蛋白质及多肽的透皮给药方式将应用于临床,极大地促进医疗事业的发展。     

Enhanced delivery of hydrophilic peptides in vitro by transdermal microneedle pretreatment

The aims of this study were to investigate the utility of solid microneedle arrays (150 µm in length) in enhancing transdermal delivery of peptides and to examine the relationship between peptide permeation rates and D₂O flux. Four model peptides were used (Gly–Gln–Pro–Arg [tetrapeptide-3, 456.6 Da], Val–Gly–Val–Ala–Pro–Gly [hexapeptide, 498.6 Da], AC–Glu–Glu–Met–Gln–Arg–Arg–NH₂ [acetyl hexapeptide-3, 889 Da] and Cys–Tyr–Ile–Gln–Asn–Cys–Pro–Leu–Gly–NH₂ [oxytocin, 1007.2 Da]). The influence of microneedle pretreatment on skin permeation was evaluated using porcine ear skin with Franze diffusion cell. Peptide permeation across the skin was significantly enhanced by microneedle pretreatment, and permeation rates were dependent on peptide molecular weights. A positive correlation between D₂O flux and acetyl hexapeptide-3 clearances suggests that convective solvent flow contributes to the enhanced transdermal peptide delivery. It is concluded that solid microneedle arrays are effective devices to enhance skin delivery of peptides.KEY WORDS: Microneedle, Peptide, Transdermal, Convective solvent flow