活性芦荟口疮缓释药膜对口腔溃疡的临床前实验研究
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摘要
研究背景：
口腔溃疡是口腔粘膜疾病中最常见的一种疾病,患病率为20%左右,是发生在口腔粘膜上的表浅性溃疡,大小可从小米粒至黄豆大小、成圆形或卵圆形,溃疡面为凹陷、周围充血。溃疡具有周期性、复发性及自限性等特点,好发于唇、颊、舌缘等。病因及致病机制仍不明确。诱因可能是局部创伤、精神紧张、食物、药物、激素水平改变及维生素或微量元素缺乏等。系统性疾病、遗传、免疫及微生物在其发生、发展中可能起重要作用。治疗主张全身和局部、中医和西医、生理和心理相结合。近年来国内外已报道多种治疗方法,但以局部治疗为主。局部治疗适合于健康的RAU患者。以消炎、止痛、防止继发感染、促进愈合为原则。局部皮质类固醇是目前世界各国治疗RAU最常用的方法,可减少RAU的症状,但在减少溃疡复发方面几乎无作用。抗菌类或杀菌类、含漱液、药膏、霜剂、药膜给药又减轻症状,促进愈合的作用。目前尚无较为理想的治疗药物,不能满足患者的治疗需求。
活性芦荟口疮缓释药膜采用理化性质稳定、亲水性大、透气性强的材料作为成膜材料,利用芦荟的抗溃疡性,直接作用于口腔粘膜、皮肤等部位。膜剂加强了药物与粘膜接触的紧密性及持续性,既可对粘膜起机械保护作用(保护溃疡面),又有利于药物的吸收、延长药物在患病局部的作用时间,且有定位、定向释放作用、局部药物浓度高、携带使用方便等优点。因此利用中药活性芦荟和西药达克罗宁配伍制成活性芦荟口疮缓释药膜,为口腔溃疡患者提供较理想的治疗药物。根据国家的相关政策法规,按照国家药品监督管理局颁发的《新药审批办法》中有关中药制剂的规定及《中药新药研究的技术要求》,进行新药活性芦荟口疮缓释药膜的临床前研究。临床前研究的主要内容包括：制备工艺、理化性质、纯度、检验方法、处方筛选、剂型、稳定性、质量标准、药理、毒理等研究。
实验目的：
1.活性芦荟口疮缓释药膜是局部治疗复发性口疮的药物之一。活性芦荟口疮缓释药膜是延边大学临床医学院研制而成的。它具有止痛、消炎、促进口腔溃疡愈合作用的药物。为了检测活性芦荟口疮缓释药膜的药物对细菌敏感性分析,做活性芦荟口疮缓释药膜药物敏感性实验。
2.活性芦荟口疮缓释药膜是近年来发展起来新剂型,其中膜剂能够通过粘附,牢固粘附在口腔粘膜表面,具有保护创面,提高局部药物浓度,迅速止痛,延长药物作用时间的作用。虽然有新鲜芦荟及芦荟干粉剂安全应用于临床的报道,但芦荟乙醇提取物能否安全应用于临床,是否对粘膜有刺激性尚未见报道。故进行活性芦荟口疮缓释药膜的急性毒理实验以确定药膜的安全性。
3.芦荟中的芦荟多糖具有免疫机能修复及细胞再生等功效。活性芦荟与达克罗宁配伍制成的口腔活性芦荟口疮缓释药膜安全、无毒,为观察其疗效制作创伤性口腔溃疡动物膜型实验,进行创伤性溃疡动物膜型愈合的研究,为今后的进一步的开发应用研究提供科学的依据。4.活性芦荟口疮缓释药膜是采用理化性质稳定、亲水性大、透气性强的材料作为成膜材料。现代研究表明芦荟具有抗癌、抗炎、抗病毒、抗菌杀虫、解热保肝、增强免疫等功效,广泛应用于医药工业、日用工业、美容化妆和食品保健等各个领域,因而芦荟是一种具有较高经济价值的药用植物。为了测定活性芦荟口疮缓释药膜中的有效含量并制定药膜制剂中含量标准,通过高效液相色谱法(HPLC)实验建立了活性芦荟口疮缓释药膜有效含量标准。实验方法：
1.活性芦荟口疮缓释药膜制备：0.5%芦荟药膜中活性芦荟0.5克,1.0%芦荟药膜中1.0克；1.5%芦荟药膜中1.5克,其余药品重量相同(达克罗宁0.5克,吐温-800.5ml,甘油2.Oml,加饱和羟丙基纤维素液至100ml)。空白膜：吐温-80：0.5ml；甘油：2.0ml；加饱和羟丙基纤维素液至1OOml。以上药物充分混匀,静置12小时,消除气泡,于玻璃板上涂膜,待自然风干后选择厚薄均匀的药膜切成2x2cm大小,消毒,装袋密封备用。
2.活性芦荟口疮缓释药膜药物敏感实验：活性芦荟口疮缓释药膜(延边大学临床医学院提供),所有菌株均来源为延边大学附属医院住院和门诊病人中分离的菌株。仪器为Microscan自动细菌鉴定、药物敏感分析仪及纸片扩散确证法进行检测。挑取菌落,在35℃,培养16-18h,按照Microscan自动分析仪及NCCLS标准来判读结果。
3.活性芦荟口疮缓释药膜急性毒理实验：实验采用双盲法。18只家兔,随机分为ab、c三组,每组6只,雌雄各半,每组左眼作为对照组,右眼作为实验组。a组：左眼空白膜(a1组),右眼0.5%芦荟药膜(a2组)；b组：左眼空白膜(b1组),右眼1.0%芦荟药膜(b2组)；c组：左眼空白膜(c1组),右眼1.5%芦荟药膜(c2组)；将芦荟药膜切成0.4cmx0.4cm大小,贴附于眼结膜,每日给药三次,连续给药7天,观察第6小时,24小时,48小时……至第14天眼结膜变化。观察内容及评分标准：角膜观察有无混浊；虹膜观察有无病理变化；结膜观察是否充血、水肿、有无分泌物等按眼刺激反应评分要求及眼刺激的评分标准,进行评分,最后计算平均分：0-3.9分—无刺激性；4-8.9分—轻度刺激性；9～12.9分—中度刺激性；13～16—重度刺激性。2统计处理：以上数据用SPSS13.0中General Linear Model(广义线性膜型)中的Repeated Measures...中的统计方法及多元方差分析方法进行统计学处理。
4.活性芦荟口疮缓释药膜动物溃疡膜型实验：活性芦荟口疮缓释药膜制备方法低剂量活性芦荟口疮缓释药膜：活性芦荟粉1.0克,达克罗宁0.5克,吐温-800.5ml,甘油1.0ml,加饱和羟丙甲基纤维素液至100ml；中剂量活性芦荟口疮缓释药膜：活性芦荟粉1.5克,其余同低剂量；高剂量活性芦荟口疮缓释药膜：活性芦荟粉2.0克,其余同低剂量；空白药膜：达克罗宁0.5克,吐温-800.5ml,甘油1.0ml,加饱和羟丙甲基纤维素液100ml,不含活性芦荟粉。制成膜剂,选择厚薄均匀的药膜切成3.0×3.0cm大小,紫外线消毒,装袋密封备用。建立大鼠人工口腔溃疡膜型：乙醚麻醉下,用含90%石炭酸棉球的塑料管(直径-6mm)置于大鼠左右两侧距口角1毫米处颊膜灼烧30秒,使局部成灰白色,于次日形成约直径约6mm的溃疡。实验分组及给药方法分为实验设计：于溃疡形成当日,将大鼠随机分成5组：A组(空白膜组)；B组(西瓜霜组)；C组(低剂量药膜组)；D(中剂量药膜组)；E(高剂量药膜组)。每组13只,其中5只用于疗效观察,另外8只作病理检查。给药方法：将活性芦荟药膜(高、中、低剂量)及空白膜切成0.7cm×0.7cm左右,覆盖溃疡创面；西瓜霜组将西瓜霜喷于溃疡表面,五组给药均为每日两次。给药前和每次给药后次日观察溃疡直径大小及溃疡愈合情况。组织病理学检查于用药后2、4、6、8天时采取溃疡区病理标本,常规处理、切片、HE染色、光镜下观察。统计学处理采用SPSS13.0统计软件中的方差分析和秩和检验进行统计分析。
5.活性芦荟口疮缓释药膜中有效成分含量及标准制定方法：高效液相色谱分析条件色谱柱：ZORBAX-SA-C18柱(5μm,200mm×4.6mm);流动相：甲醇-水(体积比70：30)；流速：1.0mL/min;柱温25℃；芦荟苷检测波长：360nm,芦荟大黄素检测波长：430nm；进样量：20μl。高效液相色谱分析条件的标准曲线建立、精密度实验、稳定性试验重现性实验、加样回收率实验、活性芦荟口疮缓释药膜中芦荟苷和芦荟大黄素的含量测定。活性芦荟口疮缓释药膜制备(延边大学临床医学院提供)。
实验结果：
1.活性芦荟口疮缓释药膜药物敏感实验结果：活性芦荟口疮缓释药膜对金黄色葡萄球菌类(68.57%)、表皮葡萄球菌(65.63%)、腐生葡萄球菌(66.67%)、溶血葡萄球菌(70.97%)、卡他布兰汉氏菌(72.73%)、绿脓杆菌(70.97)、大肠杆菌(75%)等细菌具有一定的敏感性。但洛菲氏不幼杆菌(33.33%)、海鱼弧菌(25.00%)、猪葡萄球菌(19.89%)等细菌敏感性较低。
2.活性芦荟口疮缓释药膜急性毒理实验结果：在整个实验过程中所有家兔均未出现角膜及虹膜反应,结膜无水肿反应,仅有结膜充血及少量分泌物产生,所有家兔最后计算平均分最高1.200分,最低0分,均小于3.9分。对组内因素进行的检验。组内随时间变化,刺激得分存在差异。分组因素对各时间段刺激作用没有影响。各组间两两比较(LSD法)的检验结果,说明这五组间刺激评分无统计学差异。
3.活性芦荟口疮缓释药膜本次试验结果：(1)中观察创伤性口腔溃疡膜型的溃疡面积的变化速度如下,活性芦荟口疮药膜治疗4天后B、C、D、E组的溃疡直径缩小明显快于A型组(P<0.01),且在治疗6天后开始D组溃疡直径缩小效果明显优于B组(P<0.01)。本试验结果(2)中观察创伤溃疡膜型的溃疡愈合时间如下,B、C、D、E组溃疡愈合时间均比A组短(P<0.01),溃疡愈合时间D组与B组比较具有显著差异(P<0.01)。本试验结果(3)组织病理学观察中也得出检查炎症的减轻,上皮组织的修复等均明显优于空白膜组及西瓜霜组。尤其是同空白膜比较可知活性芦荟发挥了主要作用。
4.高效液相色谱法测定活性芦荟口疮缓释药膜稳定性和有效成分含量标准实验结果：高效液相色谱法在一定浓度范围内与色谱峰面积线性良好,含量测定回收率高,重现性好,具有方法简便、快捷、准确、灵敏度高等特点。测得活性芦荟口疮缓释药膜1片(1cm×1cm)中芦荟苷和芦荟大黄素的含量标准规定为芦荟苷40.67μg、芦荟大黄素1.8μg。
结论：
1.活性芦荟口疮缓释药膜通过口腔细菌有抑菌作用。
2.活性芦荟口疮缓释药膜无毒性反应,是安全、无毒的药膜。
3.活性芦荟口疮缓释药膜对动物溃疡膜型治疗疗效确切。
4.活性芦荟口疮缓释药膜含量标准规定为芦荟苷40.67μg、芦荟大黄素1.8μg。
总之,以上的4个部分临床实验前实验结果得出：该药膜是安全、无毒性、动物实验疗效确切、药物质量稳定、质量标准可靠。将为临床应用提供可靠、科学的理论依据,同时在复发性口腔溃疡治疗方面具有临床前景广阔的药物,已达到中华人民共和国卫生部新中药开发与研制标准,可以进行临床应用研究实验。
Background:
The oral ulcers are the most common oral mucosal disease a disease, the prevalence rate of about20%, superficial ulcers on the oral mucosa, the size from the size of a grain of rice to soybeans, a round or oval,The ulcer surface is concave around congestion.Ulcers with periodic, recurrent and self-limiting and other features, occur in the lip, cheek, tongue edge.Etiology and pathogenic mechanism remains unclear.. Triggers may be local trauma, stress, foods, drugs, hormones and vitamins or trace element deficiency.Systemic disease, genetic, immune, and micro-organisms in which they arise, may play an important role in the development.The treatment advocated systemic and local, traditional Chinese medicine and Western medicine, physiology and psychology combined.In recent years at home and abroad have been reported in a variety of treatment methods, but with local treatment.The local treatment is suitable for the health of patients with RAU.In order to anti-inflammatory, analgesic, to prevent secondary infection, promote healing principle.. Topical corticosteroids are the most commonly used method of the world the treatment of RAU can reduce the symptoms of RAU, almost no effect in reducing ulcer recurrence.Antibacterial or bactericidal class gargle, ointments, creams, emulsion administration but also to reduce symptoms and promote healing.At present there is no ideal therapy, can not meet the treatment needs of patients
The stability of the physical and chemical properties of activity aloe sustained release membrane, hydrophilic large permeability material as a film-forming material, the use of aloe vera anti-ulcer, a direct role in the oral mucosa, skin and other parts。Film former to strengthen the drugs and mucous membranes close and continuing contact with both the mucosa from the mechanical protection role to protect the ulcer, and it helps the absorption of the drug to prolong the duration of action of drugs in patients with localized, and positioning.directed the release of the role of high local drug concentration, to bring the ease of use.So the use of traditional Chinese medicine and Western Medicine on activity of Aloe Vera Dyclonine made active aloe sustained-release film, for oral ulcer patients provide ideal therapeutic drug.In accordance with national policies and regulations, issued in accordance with the State Drug Administration approval of new drugs way the provisions of Chinese medicine preparations, and Traditional Chinese Drug Research, technical requirements, for new drugs active aloe aphthous membrane pre-clinical studies includepreparation process, physical and chemical properties, purity, methods of inspection, prescription screening, formulation, stability, quality standards, pharmacology, toxicology, etc.,
The experiment:
1The activity of aloe sustained release membrane is one of the topical treatment of recurrent aphthous ulcer drug.The activity of aloe sustained release membrane is developed from the Clinical Medical College of Yanbian University.lt has analgesic, anti-inflammatory drugs promote the healing of mouth ulcers.In order to detect the drug of activity aloe sustained release membrane on bacterial sensitivity analysis, do the activity of aloe sustained-release film with drug sensitivity test.
2.Activity of aloe sustained release membrane in recent years developed the new formulation, which the release agent by adhesion, firmly adhere to the surface of the oral mucosa, with the time to protect the wound, increase local drug concentration, rapid pain relief, to extend the drug action.Although there are fresh aloe vera and aloe dry powder safety used in clinical reports, but the aloe ethanol extract can be safely used in clinical, if the mucous membrane irritant has not been reported.Therefore, the aloe membrane acute toxicological experiments to determine the emulsion side of security.
3.Aloe vera in aloe polysaccharides have the effect of immunodeficiency repair and cell regeneration.Activity of aloe vera and Dyclonine and made orally active aloe oral pellicles safe non-toxic, to observe the curative effect of the traumatic ulcer animal model experiment, for the further development and application of research to provide a scientific basis.
4.Activity of aloe sustained release membrane is the stability of the physical and chemical properties, hydrophilic large permeability material as a film-forming materials.Modern studies have shown that aloe vera has anti-cancer, anti-inflammatory, anti-virus, anti-bacterial insecticide, antipyretic and hepatoprotective, and enhance immune effects, widely used in various fields of the pharmaceutical industry, household industry, beauty make-up and food, health care, and thus the aloe isa higher economic value of medicinal plants.In order to determine the activity of aloe vera in the sustained-release film with an effective content and develop content standards in the membrane preparations, the sustained release membrane of activity aloe effective content standards established by high performance liquid chromatography (HPLC) experiments.
Experimental methods:
1.Activity aloe sustained release membrane preparation:0.5%aloe membrane activity of Aloe0.5g1.0g1.0%aloe pellicles。1.5g1.5%aloe membrane, the remaining drugs the same weight (0.5g Dyclonine Twain-800.5ml, the glycerol2.0ml, plus saturated hydroxypropyl cellulose solution to100ml).Blank film:Twain-80:0.5ml; glycerol:2.0ml; plus saturated hydroxypropyl cellulose solution to100ml.).These drugs are mixed fully, standing for12hours, elimination of bubbles in the glass plate, film, to be the natural air-dry after selecting the thickness uniformity of films into2x2cm size, disinfection, bagging backup seals.
2.Activity aloe sustained-release film with drug sensitivity test:Activity aloe sustained release membrane (Yanbian University School of Clinical Medicine, provided), all strains were sources of the strains isolated in the Yanbian University Hospital inpatients and outpatients.Apparatus for Microscan automatic bacterial identification, drug sensitivity analyzer and disk diffusion confirmatory assay.Picked colonies were cultured for16-18h at35℃C, in accordance with Microscan automatic analyzer and NCCLS standards to interpret the results.
3.Activity aloe release membrane acute toxicological experiment:Experiments using double-blind method.In18rabbits, were randomly divided into a, B, C three group,6rats in each group, half of each group of male and female, the left eye as a control group, the right eye as the experimental group.a group:the left eye blank film (a group), the right eye and0.5%aloe membrane (a group);group b:left eye (b), the right eye and1.0%aloe membrane (b2); c:left blank film and (c), the right eye and1.5%aloe membrane blank film (c2);The aloe membrane cut into0.4cm×0.4cm size, attached to the conjunctiva, the daily dosing three times seven days of continuous administration to observe the first six hours,24hours,48hours... up to14days conjunctiva change.Observation of content and assessment criteria:Corneal opacities were observed; iris were observed with or without pathological changes; conjunctival hyperemia and edema, observe whether any discharge according to eye irritation response score requirements and eye irritation score, score, the final calculation of average:0-3.9-no irritation;4～8.9-mild irritation;9～12.9-moderate stimulation;13～16-severe stimulation.2.The statistical processing: The data above SPSS13.0in the General-Linear Model (generalized linear model) Repeated Measures... the statistical methods and multivariate analysis of variance for statistical analysis。
4.Sustained-release membrane of activity aloe animal ulcer model experiments:Activity of Aloe release membrane preparation method for the activity of aloe vera powder1.0g0.5g Dyclonine Twain-800.5ml, the glycerol1.0ml, add saturated hydroxyl C methy cellulose solution to100ml;Dose of activity aloe vera oral membrane:activity of aloe vere powder1.5g, and the rest with low-dose; High doses of activity aloe vera oral membrane activity of aloe vera powder2.0g, and the rest with low-dose; Blank membrane:0.5c Dyclonine, Twain-800.5ml, the glycerol1.0ml, plus saturated hydroxypropyl methy cellulose solution100ml, excluding the activity of aloe powder.Made of the film, selec uniform thickness of the membrane and cut into3.0×3.0cm size, UV disinfection bagging sealing spare.The establishment of the artificial mouth ulcer model in rats:undei ether anesthesia, the plastic tube containing90%phenol cotton balls (diameter-6mm' placed rats the right and left1mm away from the altercation at the buccal burning30seconds, the local into a grayabout a diameter of about6mm ulcer formation in the nex day.The experimental group and the administration method is:Ulceration of the day, the rats were randomly divided into five groups.Group A (blank membrane group); group E (watermelon cream group); membrane group of group C (low dose);(in doses o membrane group);(high dose membrane group).Each group of13, of which5is onl) used for observation, only another8for pathological examination..Delivery method:Activity aloe membrane (high, medium and low dose) and blank membrane an(?) cut into0.7cm x0.7cm or so, covering the ulcers;Watermelon Frost Group watermelor frost spray on the surface of the ulcer, five groups of drug delivery are twice daily.Administration before and after each dose the next day observed ulcer diamete and ulcer healing.Histopathological examination of pathological specimens of the ulce area to take in2,4,6,8days after treatment, conventional treatment, slices, HE staining and observed under light microscope.Statistical analysis using the software SPSS13.0the variance analysis and Wilcoxon rank sum test for statistical analysis.
5.Activity aloe sustained release membrane active ingredient content a(?) standard-setting methods:High performance liquid chromatography analysis condition(?) Column:ZORBAX-SA-C18column (5μm,200mm×4.6mm); mobile phase:methanol water (volume ratio70:30); flow rate:1.0mL/min,; column temperature was25℃;aloi(?) detection wavelength:360nm, aloe-emodin detection wavelength:430nm; injectio(?) volume:20μl.High performance liquid chromatographic analysis of conditions for the establishment of standard curve, precision test, stability test, the reproducibility of the experiments, sample recovery rate experiment, active aloe sustained-release film (?) Aloin and aloe emodin content determination.Active aloe release membrane preparation (Yanbian University, School of Clinical Medicine
Results:
1.Activity of aloe sustained-release film with drug sensitivity test results:Activity aloe release membrane on the Staphylococcus aureus class (68.57%), Staphylococcus epidermidis (65.63%), Staphylococcus saprophyticus (66.67%), Staphylococcus haemolyticus (70.97%), the card he Brandeis Han coli (72.73%), Pseudomonas aeruginosa (70.97), Escherichia coli (75%) and other bacteria have a certain sensitivity.But Loffi's not young bacilli (33.33%), fish Vibrio (25.00%), pigs aureus (19.89%) and other bacteria is less sensitive
2.Activity of aloe sustained-release film with acute toxicological experiment results:During the whole experiment all rabbits did not appear the cornea and iris reaction, no conjunctiva edema reaction, only conjunctival hyperemia and a small amount of secretions produced, all rabbits were calculated the average maximum1.200points, minimum0, were less than3.9minutes.On the factors in the test group. Within group variation with time, stimulate the score difference.Grouping factor did not affect the stimulation of the various time periods.Among the groups pairwise comparisons (LSD) test results, indicating that the five stimulus was no significant difference.
3.Activity of aloe sustained-release film with the test results:(1) the rate of change observed in traumatic ulcers of the oral ulcer model area are as follows, the membrane in the treatment of activity aloe aphthous four days after the B, C and D and E group ulcer diameter narrowing was significantly faster than the Type A group (P<0.01)ulcer diameter D, and in six days after treatment began to shrink better than group B (P <0.01).The results observed in ulcer healing traumatic ulcer model (2) hours are as follows, B, and C and D and Group E of ulcer healing time than Group A short (P<0.01), ulcer healing time in group D and group B with significantdifference (P<0.01).The results of this test (3) histopathological observation has drawn the check inflammation reduce the epithelial tissue repair and so much better than the blank film group, and Watermelon Frost Group. In particular, played a major role with blank film shows the activity of aloe.
4.HPLC determination of activity aloe release membrane stability and active ingredient content standard experimental results:High performance liquid chromatography chromatographic peak area in a certain concentration range with good linearity, determination of recovery, good reproducibility, with the method is simple, fast, accurate, and high sensitivity.Measured the activity of aloe sustained-release film with a content standard requirements of the aloin and aloe-emodin (1cm×1cm) aloin40.67μg, aloe-emodin1.8μg.
Conclusion:
1. Active aloe oral sustained-release membrane by oral bacteria have a bacteriostatic effect.
2. Active aloe oral sustained-release membrane no toxicity reaction, is safe, non-toxic pellicles.
3. Active aloe oral sustained-release membrane on the membrane type animal ulcer treatment curative effect.
4. Active aloe oral sustained-release membrane with content standards provisions of the aloin40.67μg and aloe-emodin1.8μg.
In short, the above4parts before clinical trials from the experiment result, the drug is safe, non-toxic, animal experiment, curative effect of drug quality, quality standard is complete scientific method for clinical application, will provide reliable scientific experiments, theoretical basis, at the same time with recurrent oral ulcer clinical prospects of drug, has reached the people's Republic of China Ministry of health research and development of new traditional Chinese medicine standard, can be clinical application study..
口腔溃疡是口腔粘膜疾病中最常见的一种疾病,患病率为20%左右,是发生在口腔粘膜上的表浅性溃疡,大小可从小米粒至黄豆大小、成圆形或卵圆形,溃疡面为凹陷、周围充血。溃疡具有周期性、复发性及自限性等特点,好发于唇、颊、舌缘等。病因及致病机制仍不明确。诱因可能是局部创伤、精神紧张、食物、药物、激素水平改变及维生素或微量元素缺乏等。系统性疾病、遗传、免疫及微生物在其发生、发展中可能起重要作用。治疗主张全身和局部、中医和西医、生理和心理相结合。近年来国内外已报道多种治疗方法,但以局部治疗为主。局部治疗适合于健康的RAU患者。以消炎、止痛、防止继发感染、促进愈合为原则。局部皮质类固醇是目前世界各国治疗RAU最常用的方法,可减少RAU的症状,但在减少溃疡复发方面几乎无作用。抗菌类或杀菌类、含漱液、药膏、霜剂、药膜给药又减轻症状,促进愈合的作用。目前尚无较为理想的治疗药物,不能满足患者的治疗需求。
活性芦荟口疮缓释药膜采用理化性质稳定、亲水性大、透气性强的材料作为成膜材料,利用芦荟的抗溃疡性,直接作用于口腔粘膜、皮肤等部位。膜剂加强了药物与粘膜接触的紧密性及持续性,既可对粘膜起机械保护作用(保护溃疡面),又有利于药物的吸收、延长药物在患病局部的作用时间,且有定位、定向释放作用、局部药物浓度高、携带使用方便等优点。因此利用中药活性芦荟和西药达克罗宁配伍制成活性芦荟口疮缓释药膜,为口腔溃疡患者提供较理想的治疗药物。根据国家的相关政策法规,按照国家药品监督管理局颁发的《新药审批办法》中有关中药制剂的规定及《中药新药研究的技术要求》,进行新药活性芦荟口疮缓释药膜的临床前研究。临床前研究的主要内容包括：制备工艺、理化性质、纯度、检验方法、处方筛选、剂型、稳定性、质量标准、药理、毒理等研究。
实验目的：
1.活性芦荟口疮缓释药膜是局部治疗复发性口疮的药物之一。活性芦荟口疮缓释药膜是延边大学临床医学院研制而成的。它具有止痛、消炎、促进口腔溃疡愈合作用的药物。为了检测活性芦荟口疮缓释药膜的药物对细菌敏感性分析,做活性芦荟口疮缓释药膜药物敏感性实验。
2.活性芦荟口疮缓释药膜是近年来发展起来新剂型,其中膜剂能够通过粘附,牢固粘附在口腔粘膜表面,具有保护创面,提高局部药物浓度,迅速止痛,延长药物作用时间的作用。虽然有新鲜芦荟及芦荟干粉剂安全应用于临床的报道,但芦荟乙醇提取物能否安全应用于临床,是否对粘膜有刺激性尚未见报道。故进行活性芦荟口疮缓释药膜的急性毒理实验以确定药膜的安全性。
3.芦荟中的芦荟多糖具有免疫机能修复及细胞再生等功效。活性芦荟与达克罗宁配伍制成的口腔活性芦荟口疮缓释药膜安全、无毒,为观察其疗效制作创伤性口腔溃疡动物膜型实验,进行创伤性溃疡动物膜型愈合的研究,为今后的进一步的开发应用研究提供科学的依据。4.活性芦荟口疮缓释药膜是采用理化性质稳定、亲水性大、透气性强的材料作为成膜材料。现代研究表明芦荟具有抗癌、抗炎、抗病毒、抗菌杀虫、解热保肝、增强免疫等功效,广泛应用于医药工业、日用工业、美容化妆和食品保健等各个领域,因而芦荟是一种具有较高经济价值的药用植物。为了测定活性芦荟口疮缓释药膜中的有效含量并制定药膜制剂中含量标准,通过高效液相色谱法(HPLC)实验建立了活性芦荟口疮缓释药膜有效含量标准。实验方法：
1.活性芦荟口疮缓释药膜制备：0.5%芦荟药膜中活性芦荟0.5克,1.0%芦荟药膜中1.0克；1.5%芦荟药膜中1.5克,其余药品重量相同(达克罗宁0.5克,吐温-800.5ml,甘油2.Oml,加饱和羟丙基纤维素液至100ml)。空白膜：吐温-80：0.5ml；甘油：2.0ml；加饱和羟丙基纤维素液至1OOml。以上药物充分混匀,静置12小时,消除气泡,于玻璃板上涂膜,待自然风干后选择厚薄均匀的药膜切成2x2cm大小,消毒,装袋密封备用。
2.活性芦荟口疮缓释药膜药物敏感实验：活性芦荟口疮缓释药膜(延边大学临床医学院提供),所有菌株均来源为延边大学附属医院住院和门诊病人中分离的菌株。仪器为Microscan自动细菌鉴定、药物敏感分析仪及纸片扩散确证法进行检测。挑取菌落,在35℃,培养16-18h,按照Microscan自动分析仪及NCCLS标准来判读结果。
3.活性芦荟口疮缓释药膜急性毒理实验：实验采用双盲法。18只家兔,随机分为ab、c三组,每组6只,雌雄各半,每组左眼作为对照组,右眼作为实验组。a组：左眼空白膜(a1组),右眼0.5%芦荟药膜(a2组)；b组：左眼空白膜(b1组),右眼1.0%芦荟药膜(b2组)；c组：左眼空白膜(c1组),右眼1.5%芦荟药膜(c2组)；将芦荟药膜切成0.4cmx0.4cm大小,贴附于眼结膜,每日给药三次,连续给药7天,观察第6小时,24小时,48小时……至第14天眼结膜变化。观察内容及评分标准：角膜观察有无混浊；虹膜观察有无病理变化；结膜观察是否充血、水肿、有无分泌物等按眼刺激反应评分要求及眼刺激的评分标准,进行评分,最后计算平均分：0-3.9分—无刺激性；4-8.9分—轻度刺激性；9～12.9分—中度刺激性；13～16—重度刺激性。2统计处理：以上数据用SPSS13.0中General Linear Model(广义线性膜型)中的Repeated Measures...中的统计方法及多元方差分析方法进行统计学处理。
4.活性芦荟口疮缓释药膜动物溃疡膜型实验：活性芦荟口疮缓释药膜制备方法低剂量活性芦荟口疮缓释药膜：活性芦荟粉1.0克,达克罗宁0.5克,吐温-800.5ml,甘油1.0ml,加饱和羟丙甲基纤维素液至100ml；中剂量活性芦荟口疮缓释药膜：活性芦荟粉1.5克,其余同低剂量；高剂量活性芦荟口疮缓释药膜：活性芦荟粉2.0克,其余同低剂量；空白药膜：达克罗宁0.5克,吐温-800.5ml,甘油1.0ml,加饱和羟丙甲基纤维素液100ml,不含活性芦荟粉。制成膜剂,选择厚薄均匀的药膜切成3.0×3.0cm大小,紫外线消毒,装袋密封备用。建立大鼠人工口腔溃疡膜型：乙醚麻醉下,用含90%石炭酸棉球的塑料管(直径-6mm)置于大鼠左右两侧距口角1毫米处颊膜灼烧30秒,使局部成灰白色,于次日形成约直径约6mm的溃疡。实验分组及给药方法分为实验设计：于溃疡形成当日,将大鼠随机分成5组：A组(空白膜组)；B组(西瓜霜组)；C组(低剂量药膜组)；D(中剂量药膜组)；E(高剂量药膜组)。每组13只,其中5只用于疗效观察,另外8只作病理检查。给药方法：将活性芦荟药膜(高、中、低剂量)及空白膜切成0.7cm×0.7cm左右,覆盖溃疡创面；西瓜霜组将西瓜霜喷于溃疡表面,五组给药均为每日两次。给药前和每次给药后次日观察溃疡直径大小及溃疡愈合情况。组织病理学检查于用药后2、4、6、8天时采取溃疡区病理标本,常规处理、切片、HE染色、光镜下观察。统计学处理采用SPSS13.0统计软件中的方差分析和秩和检验进行统计分析。
5.活性芦荟口疮缓释药膜中有效成分含量及标准制定方法：高效液相色谱分析条件色谱柱：ZORBAX-SA-C18柱(5μm,200mm×4.6mm);流动相：甲醇-水(体积比70：30)；流速：1.0mL/min;柱温25℃；芦荟苷检测波长：360nm,芦荟大黄素检测波长：430nm；进样量：20μl。高效液相色谱分析条件的标准曲线建立、精密度实验、稳定性试验重现性实验、加样回收率实验、活性芦荟口疮缓释药膜中芦荟苷和芦荟大黄素的含量测定。活性芦荟口疮缓释药膜制备(延边大学临床医学院提供)。
实验结果：
1.活性芦荟口疮缓释药膜药物敏感实验结果：活性芦荟口疮缓释药膜对金黄色葡萄球菌类(68.57%)、表皮葡萄球菌(65.63%)、腐生葡萄球菌(66.67%)、溶血葡萄球菌(70.97%)、卡他布兰汉氏菌(72.73%)、绿脓杆菌(70.97)、大肠杆菌(75%)等细菌具有一定的敏感性。但洛菲氏不幼杆菌(33.33%)、海鱼弧菌(25.00%)、猪葡萄球菌(19.89%)等细菌敏感性较低。
2.活性芦荟口疮缓释药膜急性毒理实验结果：在整个实验过程中所有家兔均未出现角膜及虹膜反应,结膜无水肿反应,仅有结膜充血及少量分泌物产生,所有家兔最后计算平均分最高1.200分,最低0分,均小于3.9分。对组内因素进行的检验。组内随时间变化,刺激得分存在差异。分组因素对各时间段刺激作用没有影响。各组间两两比较(LSD法)的检验结果,说明这五组间刺激评分无统计学差异。
3.活性芦荟口疮缓释药膜本次试验结果：(1)中观察创伤性口腔溃疡膜型的溃疡面积的变化速度如下,活性芦荟口疮药膜治疗4天后B、C、D、E组的溃疡直径缩小明显快于A型组(P<0.01),且在治疗6天后开始D组溃疡直径缩小效果明显优于B组(P<0.01)。本试验结果(2)中观察创伤溃疡膜型的溃疡愈合时间如下,B、C、D、E组溃疡愈合时间均比A组短(P<0.01),溃疡愈合时间D组与B组比较具有显著差异(P<0.01)。本试验结果(3)组织病理学观察中也得出检查炎症的减轻,上皮组织的修复等均明显优于空白膜组及西瓜霜组。尤其是同空白膜比较可知活性芦荟发挥了主要作用。
4.高效液相色谱法测定活性芦荟口疮缓释药膜稳定性和有效成分含量标准实验结果：高效液相色谱法在一定浓度范围内与色谱峰面积线性良好,含量测定回收率高,重现性好,具有方法简便、快捷、准确、灵敏度高等特点。测得活性芦荟口疮缓释药膜1片(1cm×1cm)中芦荟苷和芦荟大黄素的含量标准规定为芦荟苷40.67μg、芦荟大黄素1.8μg。
结论：
1.活性芦荟口疮缓释药膜通过口腔细菌有抑菌作用。
2.活性芦荟口疮缓释药膜无毒性反应,是安全、无毒的药膜。
3.活性芦荟口疮缓释药膜对动物溃疡膜型治疗疗效确切。
4.活性芦荟口疮缓释药膜含量标准规定为芦荟苷40.67μg、芦荟大黄素1.8μg。
总之,以上的4个部分临床实验前实验结果得出：该药膜是安全、无毒性、动物实验疗效确切、药物质量稳定、质量标准可靠。将为临床应用提供可靠、科学的理论依据,同时在复发性口腔溃疡治疗方面具有临床前景广阔的药物,已达到中华人民共和国卫生部新中药开发与研制标准,可以进行临床应用研究实验。
Background:
The oral ulcers are the most common oral mucosal disease a disease, the prevalence rate of about20%, superficial ulcers on the oral mucosa, the size from the size of a grain of rice to soybeans, a round or oval,The ulcer surface is concave around congestion.Ulcers with periodic, recurrent and self-limiting and other features, occur in the lip, cheek, tongue edge.Etiology and pathogenic mechanism remains unclear.. Triggers may be local trauma, stress, foods, drugs, hormones and vitamins or trace element deficiency.Systemic disease, genetic, immune, and micro-organisms in which they arise, may play an important role in the development.The treatment advocated systemic and local, traditional Chinese medicine and Western medicine, physiology and psychology combined.In recent years at home and abroad have been reported in a variety of treatment methods, but with local treatment.The local treatment is suitable for the health of patients with RAU.In order to anti-inflammatory, analgesic, to prevent secondary infection, promote healing principle.. Topical corticosteroids are the most commonly used method of the world the treatment of RAU can reduce the symptoms of RAU, almost no effect in reducing ulcer recurrence.Antibacterial or bactericidal class gargle, ointments, creams, emulsion administration but also to reduce symptoms and promote healing.At present there is no ideal therapy, can not meet the treatment needs of patients
The stability of the physical and chemical properties of activity aloe sustained release membrane, hydrophilic large permeability material as a film-forming material, the use of aloe vera anti-ulcer, a direct role in the oral mucosa, skin and other parts。Film former to strengthen the drugs and mucous membranes close and continuing contact with both the mucosa from the mechanical protection role to protect the ulcer, and it helps the absorption of the drug to prolong the duration of action of drugs in patients with localized, and positioning.directed the release of the role of high local drug concentration, to bring the ease of use.So the use of traditional Chinese medicine and Western Medicine on activity of Aloe Vera Dyclonine made active aloe sustained-release film, for oral ulcer patients provide ideal therapeutic drug.In accordance with national policies and regulations, issued in accordance with the State Drug Administration approval of new drugs way the provisions of Chinese medicine preparations, and Traditional Chinese Drug Research, technical requirements, for new drugs active aloe aphthous membrane pre-clinical studies includepreparation process, physical and chemical properties, purity, methods of inspection, prescription screening, formulation, stability, quality standards, pharmacology, toxicology, etc.,
The experiment:
1The activity of aloe sustained release membrane is one of the topical treatment of recurrent aphthous ulcer drug.The activity of aloe sustained release membrane is developed from the Clinical Medical College of Yanbian University.lt has analgesic, anti-inflammatory drugs promote the healing of mouth ulcers.In order to detect the drug of activity aloe sustained release membrane on bacterial sensitivity analysis, do the activity of aloe sustained-release film with drug sensitivity test.
2.Activity of aloe sustained release membrane in recent years developed the new formulation, which the release agent by adhesion, firmly adhere to the surface of the oral mucosa, with the time to protect the wound, increase local drug concentration, rapid pain relief, to extend the drug action.Although there are fresh aloe vera and aloe dry powder safety used in clinical reports, but the aloe ethanol extract can be safely used in clinical, if the mucous membrane irritant has not been reported.Therefore, the aloe membrane acute toxicological experiments to determine the emulsion side of security.
3.Aloe vera in aloe polysaccharides have the effect of immunodeficiency repair and cell regeneration.Activity of aloe vera and Dyclonine and made orally active aloe oral pellicles safe non-toxic, to observe the curative effect of the traumatic ulcer animal model experiment, for the further development and application of research to provide a scientific basis.
4.Activity of aloe sustained release membrane is the stability of the physical and chemical properties, hydrophilic large permeability material as a film-forming materials.Modern studies have shown that aloe vera has anti-cancer, anti-inflammatory, anti-virus, anti-bacterial insecticide, antipyretic and hepatoprotective, and enhance immune effects, widely used in various fields of the pharmaceutical industry, household industry, beauty make-up and food, health care, and thus the aloe isa higher economic value of medicinal plants.In order to determine the activity of aloe vera in the sustained-release film with an effective content and develop content standards in the membrane preparations, the sustained release membrane of activity aloe effective content standards established by high performance liquid chromatography (HPLC) experiments.
Experimental methods:
1.Activity aloe sustained release membrane preparation:0.5%aloe membrane activity of Aloe0.5g1.0g1.0%aloe pellicles。1.5g1.5%aloe membrane, the remaining drugs the same weight (0.5g Dyclonine Twain-800.5ml, the glycerol2.0ml, plus saturated hydroxypropyl cellulose solution to100ml).Blank film:Twain-80:0.5ml; glycerol:2.0ml; plus saturated hydroxypropyl cellulose solution to100ml.).These drugs are mixed fully, standing for12hours, elimination of bubbles in the glass plate, film, to be the natural air-dry after selecting the thickness uniformity of films into2x2cm size, disinfection, bagging backup seals.
2.Activity aloe sustained-release film with drug sensitivity test:Activity aloe sustained release membrane (Yanbian University School of Clinical Medicine, provided), all strains were sources of the strains isolated in the Yanbian University Hospital inpatients and outpatients.Apparatus for Microscan automatic bacterial identification, drug sensitivity analyzer and disk diffusion confirmatory assay.Picked colonies were cultured for16-18h at35℃C, in accordance with Microscan automatic analyzer and NCCLS standards to interpret the results.
3.Activity aloe release membrane acute toxicological experiment:Experiments using double-blind method.In18rabbits, were randomly divided into a, B, C three group,6rats in each group, half of each group of male and female, the left eye as a control group, the right eye as the experimental group.a group:the left eye blank film (a group), the right eye and0.5%aloe membrane (a group);group b:left eye (b), the right eye and1.0%aloe membrane (b2); c:left blank film and (c), the right eye and1.5%aloe membrane blank film (c2);The aloe membrane cut into0.4cm×0.4cm size, attached to the conjunctiva, the daily dosing three times seven days of continuous administration to observe the first six hours,24hours,48hours... up to14days conjunctiva change.Observation of content and assessment criteria:Corneal opacities were observed; iris were observed with or without pathological changes; conjunctival hyperemia and edema, observe whether any discharge according to eye irritation response score requirements and eye irritation score, score, the final calculation of average:0-3.9-no irritation;4～8.9-mild irritation;9～12.9-moderate stimulation;13～16-severe stimulation.2.The statistical processing: The data above SPSS13.0in the General-Linear Model (generalized linear model) Repeated Measures... the statistical methods and multivariate analysis of variance for statistical analysis。
4.Sustained-release membrane of activity aloe animal ulcer model experiments:Activity of Aloe release membrane preparation method for the activity of aloe vera powder1.0g0.5g Dyclonine Twain-800.5ml, the glycerol1.0ml, add saturated hydroxyl C methy cellulose solution to100ml;Dose of activity aloe vera oral membrane:activity of aloe vere powder1.5g, and the rest with low-dose; High doses of activity aloe vera oral membrane activity of aloe vera powder2.0g, and the rest with low-dose; Blank membrane:0.5c Dyclonine, Twain-800.5ml, the glycerol1.0ml, plus saturated hydroxypropyl methy cellulose solution100ml, excluding the activity of aloe powder.Made of the film, selec uniform thickness of the membrane and cut into3.0×3.0cm size, UV disinfection bagging sealing spare.The establishment of the artificial mouth ulcer model in rats:undei ether anesthesia, the plastic tube containing90%phenol cotton balls (diameter-6mm' placed rats the right and left1mm away from the altercation at the buccal burning30seconds, the local into a grayabout a diameter of about6mm ulcer formation in the nex day.The experimental group and the administration method is:Ulceration of the day, the rats were randomly divided into five groups.Group A (blank membrane group); group E (watermelon cream group); membrane group of group C (low dose);(in doses o membrane group);(high dose membrane group).Each group of13, of which5is onl) used for observation, only another8for pathological examination..Delivery method:Activity aloe membrane (high, medium and low dose) and blank membrane an(?) cut into0.7cm x0.7cm or so, covering the ulcers;Watermelon Frost Group watermelor frost spray on the surface of the ulcer, five groups of drug delivery are twice daily.Administration before and after each dose the next day observed ulcer diamete and ulcer healing.Histopathological examination of pathological specimens of the ulce area to take in2,4,6,8days after treatment, conventional treatment, slices, HE staining and observed under light microscope.Statistical analysis using the software SPSS13.0the variance analysis and Wilcoxon rank sum test for statistical analysis.
5.Activity aloe sustained release membrane active ingredient content a(?) standard-setting methods:High performance liquid chromatography analysis condition(?) Column:ZORBAX-SA-C18column (5μm,200mm×4.6mm); mobile phase:methanol water (volume ratio70:30); flow rate:1.0mL/min,; column temperature was25℃;aloi(?) detection wavelength:360nm, aloe-emodin detection wavelength:430nm; injectio(?) volume:20μl.High performance liquid chromatographic analysis of conditions for the establishment of standard curve, precision test, stability test, the reproducibility of the experiments, sample recovery rate experiment, active aloe sustained-release film (?) Aloin and aloe emodin content determination.Active aloe release membrane preparation (Yanbian University, School of Clinical Medicine
Results:
1.Activity of aloe sustained-release film with drug sensitivity test results:Activity aloe release membrane on the Staphylococcus aureus class (68.57%), Staphylococcus epidermidis (65.63%), Staphylococcus saprophyticus (66.67%), Staphylococcus haemolyticus (70.97%), the card he Brandeis Han coli (72.73%), Pseudomonas aeruginosa (70.97), Escherichia coli (75%) and other bacteria have a certain sensitivity.But Loffi's not young bacilli (33.33%), fish Vibrio (25.00%), pigs aureus (19.89%) and other bacteria is less sensitive
2.Activity of aloe sustained-release film with acute toxicological experiment results:During the whole experiment all rabbits did not appear the cornea and iris reaction, no conjunctiva edema reaction, only conjunctival hyperemia and a small amount of secretions produced, all rabbits were calculated the average maximum1.200points, minimum0, were less than3.9minutes.On the factors in the test group. Within group variation with time, stimulate the score difference.Grouping factor did not affect the stimulation of the various time periods.Among the groups pairwise comparisons (LSD) test results, indicating that the five stimulus was no significant difference.
3.Activity of aloe sustained-release film with the test results:(1) the rate of change observed in traumatic ulcers of the oral ulcer model area are as follows, the membrane in the treatment of activity aloe aphthous four days after the B, C and D and E group ulcer diameter narrowing was significantly faster than the Type A group (P<0.01)ulcer diameter D, and in six days after treatment began to shrink better than group B (P <0.01).The results observed in ulcer healing traumatic ulcer model (2) hours are as follows, B, and C and D and Group E of ulcer healing time than Group A short (P<0.01), ulcer healing time in group D and group B with significantdifference (P<0.01).The results of this test (3) histopathological observation has drawn the check inflammation reduce the epithelial tissue repair and so much better than the blank film group, and Watermelon Frost Group. In particular, played a major role with blank film shows the activity of aloe.
4.HPLC determination of activity aloe release membrane stability and active ingredient content standard experimental results:High performance liquid chromatography chromatographic peak area in a certain concentration range with good linearity, determination of recovery, good reproducibility, with the method is simple, fast, accurate, and high sensitivity.Measured the activity of aloe sustained-release film with a content standard requirements of the aloin and aloe-emodin (1cm×1cm) aloin40.67μg, aloe-emodin1.8μg.
Conclusion:
1. Active aloe oral sustained-release membrane by oral bacteria have a bacteriostatic effect.
2. Active aloe oral sustained-release membrane no toxicity reaction, is safe, non-toxic pellicles.
3. Active aloe oral sustained-release membrane on the membrane type animal ulcer treatment curative effect.
4. Active aloe oral sustained-release membrane with content standards provisions of the aloin40.67μg and aloe-emodin1.8μg.
In short, the above4parts before clinical trials from the experiment result, the drug is safe, non-toxic, animal experiment, curative effect of drug quality, quality standard is complete scientific method for clinical application, will provide reliable scientific experiments, theoretical basis, at the same time with recurrent oral ulcer clinical prospects of drug, has reached the people's Republic of China Ministry of health research and development of new traditional Chinese medicine standard, can be clinical application study..
引文
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