Application of hydrogel polymers for development of thyrotropin releasing hormone-loaded adhesive buccal patches

To utilize hydrogels for fabricating thyrotropin releasing hormone (TRH) adhesive buccal patches, type of hydrogels such as polyacrylic acids (Polycarbophil AA1, Carbopols 934P, 974P and 971P), celluloses (HPMC K4M, K4MCR and K15M), polysaccharide (sodium alginate) and polyacrylic acid combinations with either cellulose or polysaccharide were evaluated for adhesion force, water uptake and swelling capacity. Upon the characterization of hydrogel polymers, TRH-loading of patches fabricated from these hydrogels was evaluated at various polymer concentrations, combinations and ratios and then in vitro release kinetics of TRH from these patches were studied. Results indicated that maximum adhesion force was shown by polyacrylic acids. Adhesive force of polymer combination mainly resulted from combination of adhesive force, according to ratio proportion used, of each polymer without any superimposed effect of polymer combination. Polycarbophil AA1 showed highest water uptake and swelling capacity. Maximum TRH-loading was obtained with sodium alginate and Polycarbophil AA1 and sodium alginate combination. TRH release profiles revealed that release was sustained from Polycarbophil AA1 and its combination with celluloses or polysaccharide at 2:1 level of polymer ratio. Based on adhesion, loading and release characteristics, patches of Polycarbophil AA1 with K4M, K4MCR and sodium alginate were concluded to be suitable for further development.     

Preparation and evaluation of Eudragit gels. IV: Rectal gel preparations for sustained release and avoidance of first-pass metabolism of propentofylline.

Formulations of a high-viscosity acrylic resin gel (Eudispert hv) containing propentofylline, a new cerebral microcirculation-improving agent, were prepared and tested for avoidance of the first-pass metabolism of propentofylline through the liver and for sustained release of propentofylline. The absolute bioavailability of propentofylline after oral administration was only 4% in rabbits. The relative bioavailabilities of propentofylline from polyethylene glycol (M(r), 2000) and Witepsol H-15 suppositories were approximately 8- and 16-fold, respectively, compared with oral administration. Furthermore, the absolute bioavailability of propentofylline from Eudispert hv hydrogel and xerogel preparations was approximately 100%. The results indicate that, in principle, drug loss caused by first-pass metabolism may be avoided completely by placing Eudispert hv hydrogel and xerogel formulations in the lower part of the rectum for long periods.     

Preparation and evaluation of Eudragit gels. III: Rectal gel preparations for sustained release of pentoxifylline.

A novel method was established for the preparation of Eudragit S, Eudragit L, and Eudispert high-viscosity (hv) hydrogel and xerogel preparations containing a medicinal component such as pentoxifylline (an agent that improves cerebral microcirculation). A significant correlation was found between the in vitro mean dissolution time and the in vivo mean residence time of pentoxifylline after rectal administration of these preparations in rabbits. Staying properties of the hydrogel and xerogel preparations in the lower part of the rectum were compared with those of polyethylene glycol 2000 and Witepsol S-55 suppositories in rats, with water-insoluble dye. Eudispert hv hydrogel and xerogel preparations have excellent staying properties in the rectum. The efficacy of Eudispert hv xerogel preparations may be reduced by first passage through the liver after oral administration.     

Polyethylene glycol-coated liposomes for oral delivery of recombinant human epidermal growth factor

The present study was to investigate the feasibility of oral delivery of recombinant human epidermal growth factor (rhEGF). Polyethylene glycol (PEG)-coated liposomes containing rhEGF was prepared and evaluated for their stability and permeability in Caco-2 cells. In the animal study, we also determined plasma concentration and gastric ulcer healing effect after oral administration of rhEGF liposomes or the solution. Encapsulation of rhEGF into liposomes, suppressed the degradation in Caco-2 cell homogenate compared with the solution. The flux of rhEGF from dipalmitoylphosphatidylcholine (DPPC) liposome across Caco-2 cell monolayer from the apical to basolateral side was three times greater than that from phosphatidylcholine (PC) liposome or the solution. After oral administration of rhEGF liposomes or the solution in rats, the area under the concentration-time curve (AUC) of rhEGF increased 1.7- and 2.5-fold for PC and DPPC liposomes, respectively. The gastric ulcer healing effect was significantly increased in DPPC liposome compared with PC liposome and the solution. The enhanced curative ratio of rhEGF encapsulated into DPPC liposome may be due to the resistance to enzyme degradation, higher permeability and increased plasma AUC. Therefore, PEG-coated liposomes containing rhEGF could be used as an oral delivery formulation with enhanced encapsulation efficiency.     

Development of luteinizing hormone releasing hormone (LHRH) delivery systems for vaginal mucosal route

The objective of this study was to find a rational dosage form for vaginal mucosal delivery of LHRH. Vaginal absorption of LHRH was estimated by measuring its ovulation inducing effect in rat and in vitro vaginal membrane permeation study in rabbit. The effectsof different hydrogel bases, such as Polycarbophil and Pemulen compared with solutions on vaginal membrane permeation of LHRH were investigated. Sodium laurate, disodium ethylenediamine tetraacetate (EDTA) and sodium tauro-24,25-dihydrofusidate (STDHF), which are effective peptidase inhibitors were chosen as additives to a LHRH hydrogel delivery system and LHRH solutions. A Polycarbophil hydrogel formulation showed 3.4 times increase in LHRH vaginal membrane permeability compared with a solution formulation. Vaginal membrane permeability from the Polycarbophil was greater than that from Pemulen hydrogels. This may be due to the larger bioadhesive values. LHRH solution with EDTA(2%), STDHF(1%) and sod. laurate(0.5%) showed 4.1 times, 4.8 times and 6.0 times of ovulation inducing activity compared with control. These results suggest that enzyme inhibition effect of EDTA, STDHF and sod. laurate may result in substantial enhancement of vaginal absorption. By administration of Polycarbophil hydrogels containing LHRH the ovulation inducing activity was 3.3 times greater than the solutions. This result indicates the bioadhesive hydrogels as well as peptidase inhibition significantly improved absorption of LHRH. By coadministration with these inhibitors the ovulation inducing activity of Polycarbophil hydrogel containing LHRH was comparable with subcutaneous administration in ovulation inducing activity.     

金因肽治疗手足口病并口腔溃疡132例临床观察

目的观察金因肽(重组人表皮细胞生长因子rhEGF)治疗手足口病并口腔溃疡的临床疗效。方法将256例手足口病并口腔溃疡患儿随机分成治疗组和对照组。两组均采用抗病毒治疗和对症支持治疗,治疗组同时给予rhEGF局部喷药一日一次,对照组给予维生素B2加利多卡因局部涂药,以疼痛消失及创面愈合时间为考察指标,比较rhEGF与维生素B2治疗手足口病口腔溃疡的疗效。结果两组比较用rhEGF治疗疼痛消失时间及创面愈合时间显著缩短,结果具有统计学意义。结论 rhEGF在儿童手足口病并口腔溃疡的改善进食和溃疡愈合等方面具有显著效果。     

Multivesicular liposomes for oral delivery of recombinant human epidermal growth factor

The purpose of the present study was to prepare multivesicular liposomes with a high drug loading capacity and to investigate its potential applicability in the oral delivery of a peptide, human epidermal growth factor (rhEGF). The multivesicular liposomes containing rhEGF was prepared by a two-step water-in-oil-in-water double emulsification process. The loading efficiency was increased as rhEGF concentration increased from 1 to 5 mg/mL, reaching approximately 60 % at 5 mg/mL. Approximately 47% and 35% of rhEGF was released from the multivesicular liposomes within 6 h in simulated intra-gastric fluid (pH 1.2) and intra-intestinal fluid (pH 7.4), respectively. rhEGF-loaded multivesicular liposomes markedly suppressed the enzymatic degradation of the peptide in an incubation with the Caco-2 cell homogenate. However, the transport of rhEGF from the multivesicular liposomes to the basolateral side of Caco-2 cells was two times lower than that of the rhEGF in aqueous solution. The gastric ulcer healing effect of rhEGF-loaded multivesicular liposomes was significantly enhanced compared with that of rhEGF in aqueous solution; the healing effect of the liposomes was comparable to that of the cimetidine in rats. Collectively, these results indicate that rhEGF-loaded multivesicular liposomes may be used as a new strategy for the development of an oral delivery system in the treatment of peptic ulcer diseases.     

外用重组人表皮生长因子治疗慢性溃疡的效果观察

目的对比观察外用重组人表皮生长因子（rhEGF）啧雾荆治疗慢性浅表性溃疡的疗效。方法在经门诊诊断为慢性下肢溃疡的63例患者中随机分为治疗组和对照组。治疗组采用rhEGF喷湿创面，再敷盖庆大霉素浸湿纱布和凡士林纱布包扎；对照组只用庆大霉素浸湿纱布包扎。观察2组患者创面上皮、肉芽组织生长情况，创面愈合时间。结果治疗组47例患者的创面上皮、肉芽组织生长明显快于对照组，愈合时间缩短平均25d。结论rhEGF用于治疗慢性下肢溃疡有明显促进愈合作用，具有潜在的临床应用价值。     

Evaluation of physico-chemical properties of acrylic resin hydrogel and their application to transdermal delivery system

Recently, many attempts have been made to use hydrogels of various polumers as delivery systems of various drugs and bioactive materials to prolong and control their pharmacological activities. In this study, we have evaluated the physico-chemical properties of methacrylic acid-methacrylic acid methyl ester copolymer (Eudispert mv), a acrylic resin hydrogel, and its application to transdermal delivery system. In the dissolution tests, the release rate of salicylic acid (SA) and sodium salicylate (Sod. SA) were faster than lidocain (LD) and lidocain-HCl (LD-HCl). As the concentration of Eudispert mv polymer increased, the extensibility of Eudispert mv hydrogel decreased, whereas the swelling ratio increased. The more NaOH and polymer concentration increased, the more osmotic pressure linearly increased. The skin permeation of Sod. SA, an acidic model drug, was remarkably enhanced by Eudispert mv hydrogel. All fatty acids, except for Sod. glycolate, dramatically increased the skin permeation flux in Eudispert mv hydrogel containing LD-HCl, a basic model drug. Consequently, it is suggested that Eudispert mv hydrogel may be used as potential transdermal delivery vehicle.     

重组人表皮生长因子治疗外伤性鼓膜穿孔的临床研究

目的:对比传统治疗与加用药物治疗对外伤性鼓膜穿孔愈合的影响,研究重组人表皮生长因子(rhEGF)对外伤性鼓膜穿孔愈合的促进作用。方法:将90例外伤性鼓膜穿孔患者随机分成2组:传统治疗组给予消炎药物治疗及避免外耳道进水、鼻腔滴药的传统治疗方法;rhEGF治疗组给予传统治疗的基础上,加用rhEGF棉片贴补治疗。观察2组患者鼓膜穿孔愈合情况和听力提高程度。结果:rhEGF治疗组58例患者穿孔均愈合,愈合率100%,平均愈合时间为5.3d;传统治疗组32例中有25例愈合,7例穿孔未愈合,愈合率78%,平均愈合时间为28.4d。rhEGF治疗组鼓膜穿孔愈合时间较传统治疗组明显缩短,差异有统计学意义(P<0.01);2组愈合率有显著性差异(P<0.05)。结论:加用rhEGF治疗外伤性鼓膜穿孔能明显缩短鼓膜穿孔愈合时间,提高鼓膜穿孔愈合率。     

雷贝拉唑对成人活动期胃溃疡患者的疗效及溃疡愈合质量的影响

目的 探讨雷贝拉唑在治疗成人活动期胃溃疡上的临床效果以及对溃疡愈合质量的影响.方法 将本院收治的124例成人活动期胃溃疡患者作为研究对象,按照入院治疗的先后将其分为治疗组(63例)和对照组(61例).治疗组采用雷贝拉唑进行治疗;对照组采用奥美拉唑进行治疗.治疗后从镜下溃疡恢复情况、临床症状变化及胃黏膜组织学三个方面对两组患者的治疗效果及溃疡愈合质量进行对比评价.并记录两组患者的不良反应发生情况,观察其用药安全性.结果 从溃疡恢复情况来看,治疗组的总有效率为92.06％,与对照组(83.61％)比较差异有统计学意义(P＜0.05).两组患者在临床上表现为腹痛、灼烧感、腹胀、反酸等症状,治疗结束后,治疗组的各症状积分均显著低于对照组,同时治疗组的各项胃黏膜组织学评分也均优于对照组,差异有统计学意义(P＜0.05).而治疗组的不良反应发生率为7.94％,与对照组(6.56％)比较差异无统计学意义(P＞0.05),临床用药较为安全.结论 雷贝拉唑在治疗成人活动期胃溃疡上的临床效果优于奥美拉唑,同时在缓解临床症状、促进溃疡炎症消退、促使胃黏膜组织快速恢复上效果更佳,能显著提高溃疡愈合质量,值得在临床应用上积极推广.     

Nonsteroidal anti-inflammatory drug ingestion interferes with cessation of apoptotic events during oral mucosal ulcer healing

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is a leading cause of gastrointestinal injury, but little is know about the effect of these agents on the integrity of soft oral tissue. We investigated the rate of buccal mucosal ulcer healing and the apoptotic processes in rats subjected to intragastric administration of NSAIDs. Groups of rats with acetic acid-induced buccal mucosal ulcers were administered orally twice daily for up to 10 days with indomethacin (5 mg/kg), or aspirin (20 mg/kg), or the vehicle, and their mucosal tissue was used for macroscopic assessment of ulcer healing rate and biochemical measurements. While in the control group the ulcer healed by the tenth day, the animals subjected to indomethacin showed only a 57.2% reduction in the ulcer area and a 54.8% reduction was attained in the presence of aspirin. The healing was reflected in a decrease in apoptosis and a decline in buccal mucosal expression of tumor necrosis factor- (TNF-) and endothelin-1 (ET-1), but the changes were significantly slower in the groups subjected to NSAIDs. The delay in healing in the presence of indomethacin was characterized on the tenth day by a 4.9-fold higher rate of apoptosis, a 4.6-fold higher level of TNF- and a 2.7-fold higher expression of ET-1, while the delay in healing by aspirin was manifested by a 5.6-fold higher rate of apoptosis, a 5.5-fold higher level of TNF- and a 2.9-fold higher expression of ET-1. Our findings are the first to demonstrate that NSAID ingestion leads to up-regulation of apoptotic events that interfere with soft oral tissue repair.     

云南白药气雾剂联合重组人表皮生长因子治疗放射性皮炎

目的：观察云南白药气雾剂联合重组人表皮生长因子（rhEGF）治疗Ⅱ、Ⅲ级放射性皮炎的临床疗效及安全性。方法：80例Ⅱ、Ⅲ级放射性皮炎患者随机分成两组,观察组予云南白药气雾剂联用金因肽喷雾治疗,对照组单用金因肽喷雾治疗,观察两组患者创面愈合、创面渗出、红肿消失时间、疼痛消失时间、瘙痒消失时间,比较两组临床疗效及药品不良反应。结果：观察组显效率72.5%,总有效率97.5%;对照组显效率40%,总有效率92.5%。两组比较差异统计学意义（P〈0.05）。两组红肿消失时间﹑疼痛消失时间、瘙痒消失时间等分布比较,差异均有统计学意义（P〈0.05）。结论：云南白药气雾剂联合rhEGF治疗Ⅱ﹑Ⅲ级放射性皮炎,能提高疗效,且安全性好。     

康复新液联合雷贝拉唑治疗老年消化性溃疡47例

目的观察康复新液联合雷贝拉唑治疗老年消化性溃疡的临床疗效。方法将94例胃溃疡、十二指肠球部溃疡患者随机分为研究组和对照组,其中研究组采用康复新液联合雷贝拉唑治疗,对照组单独采用雷贝拉唑治疗,对两组临床疗效和不良反应进行对比研究。结果治疗后溃疡径长两组均较本组治疗前明显下降,研究组下降更明显（P〈0．05）。研究组总有效率明显高于对照组（r=5．28,P〈0．05）,幽门螺旋杆菌（HP）清除率明显高于对照组（x2=5．05,P〈0．05）。两组不良反应发生率比较无明显差异（r=0．68,P〉0．05）。结论康复新液联合雷贝拉唑疗法能迅速改善老年人消化性溃疡的临床症状,既能增强胃黏膜的防御功能,加速溃疡愈合,又能有效根除HP感染,值得临床推广。     

复方足疡平促进糖尿病大鼠皮肤溃疡创面愈合及对RAGE/NF-κBp65/VEGF表达的影响

目的：探讨复方足疡平对糖尿病大鼠皮肤溃疡创面愈合的作用及其作用机制。方法：将50只SPF级SD大鼠分成正常对照组、皮肤溃疡模型组、凡士林组、足疡平组、rhEGF（重组人表皮生长因子外用溶液）组,每组10只。大鼠糖尿病模型通过高脂高糖饮食结合腹腔注射链脲佐菌素诱导。50只大鼠背部制造皮肤溃疡创面,各组给与相应药物外敷创面。观察创面愈合情况计算创面愈合率;分别在治疗第7,14天时采集创面肉芽组织制作HE染色切片,进行组织病理学观察;Western blot检测创面肉芽组织中晚期糖基化终末产物受体（RAGE）、核转录因子-κB p65（NF-κB p65）、血管内皮生长因子（VEGF）表达水平。结果：干预治疗第7,14天时,与皮肤溃疡模型组比较,足疡平组和rhEGF组能明显提高创面愈合率（P<0.01）,而凡士林组大鼠创面愈合率与皮肤溃疡模型组无显著性差异（P>0.05）;足疡平组和rhEGF组大鼠创面组织胶原纤维沉积、毛细血管、肉芽组织生长均明显增加;足疡平组能显著降低RAGE、NF-κB p65蛋白表达,升高VEGF蛋白表达（P<0.01）,rhEGF组在第7天时NF-κB p65蛋白表达与皮肤溃疡模型组比较差异无显著性（P>0.05）,其余指标均有显著性差异（P<0.01）。结论：复方足疡平可有效促进糖尿病大鼠皮肤溃疡创面愈合,其作用机制与抑制糖尿病大鼠皮肤溃疡创面中RAGE、NF-ΚB p65表达,促进VEGF的表达相关。     

口腔粘膜内酶对胰岛素口腔吸收的影响

目的　研究口腔粘膜内酶对胰岛素口腔吸收的影响。方法　用三氯醋酸沉淀法,考察胰岛素在仓鼠口腔粘膜匀浆物中不同条件下的降解情况。在胰岛素口腔喷雾剂中加入酶抑制剂(杆菌肽、屈来赛多)和去氧胆酸钠,考察了大鼠经口腔喷入胰岛素后的血糖降低情况。结果　小肠粘膜细胞内酶活性远高于口腔粘膜细胞中的酶的活性。杆菌肽、屈来赛多和去氧胆酸钠均能抑制口腔粘膜内胰岛素的降解。在相同浓度下,去氧胆酸钠的酶抑制作用比杆菌肽弱,但比屈来赛多强。胰岛素在正常仓鼠口腔内的降解显著大于糖尿病仓鼠。胰岛素溶液中加入杆菌肽、屈来赛多及去氧胆酸钠后,给正常大鼠口腔喷雾给药,药理相对生物利用度分别有不同程度的提高。只含胰岛素的喷雾液(胰岛素空白液) ,喷雾液中加入屈来赛多(0.1% ) ,加入杆菌肽(0.5% ) ,去氧胆酸钠(1% ) ,与sc胰岛素比较药理相对生物利用度分别为2.89% ,4.84% ,7.52 %和9.60%。结论　口腔粘膜中的酶可以限制胰岛素在口腔粘膜的吸收     

黄芪提取物联合重组人表皮生长因子对大鼠烫伤创面愈合和血管形成的影响

目的:观察黄芪提取物联合重组人表皮生长因子(rhEGF)对大鼠烫伤创面组织愈合和血管形成的影响.方法:Wistar大鼠80只,于背部2处制备直径2.8 cm深Ⅱ度烫伤创面,将大鼠随机分为:生理盐水对照组、黄芪提取物组、rhEGF组、黄芪提取物+ rhEGF组,每组20只.分别于创面形成后当日和第3、7、14、21天,观察创面并计算创面愈合率;计算微血管密度以及痂下组织pH,组织学检查大鼠创面皮肤并进行新生血管评分.结果:与黄芪提取物组及rhEGF组比较,黄芪提取物+ rhEGF组大鼠皮肤创面愈合时间显著缩短(P＜0.05),微血管密度、痂下组织的pH和新生血管的形成也明显增加(P＜0.01或0.05).结论:黄芪提取物联合rhEGF能显著增加创面愈合过程中的血管形成,显著缩短创面愈合时间.     

Spray-dried Amioca starch/Carbopol 974P mixtures as buccal bioadhesive carriers

In the present study, spray-dried Amioca starch/Carbopol 974P mixtures were evaluated as potential buccal bioadhesive tablets. Carbopol (C 974P) concentrations from 5 to 75% were tested. All spray-dried mixtures showed a comparable or better bioadhesive capacity compared to a reference formulation (DDWM/C 974P 95/5). The bioadhesive capacities of Amioca/Carbopol 974P mixtures were improved by spray-drying. All spray-dried mixtures showed significantly higher work of adhesion values compared to their equivalent physical mixtures. The influence of Carbopol concentration on the in vivo adhesion time of placebo tablets and in vitro miconazole nitrate release was tested. The ratio Amioca/C 974P 70/30 showed the longest in vivo adhesion time (24.5+/-8.5 h). Lower and higher C 974P concentrations had a shorter in vivo adhesion time. The mixtures containing between 15 and 30% C 974P could all sustain the in vitro miconazole nitrate release over 20 h. Again, lower and higher C 974P concentrations showed a faster in vitro miconazole release. The drug loading capacity of a spray-dried mixture containing 20% C 974P was investigated in vivo in dogs using testosterone as model drug. The spray-dried mixture could be loaded with 60% drug without loosing its in vivo bioadhesive and pharmacokinetic properties.     

Effect of peptide loading and surfactant concentration on the characteristics of physically crosslinked hydrogel

The purpose of this study was to investigate the effect of varying drug load and concentration of a surfactant (sodium lauryl sulfate [SLS]) on the release characteristics of a model peptide (bovine serum albumin [BSA]), and study the net effects of the swelling properties of the hydrogel matrix [poly(vinyl alcohol) (PVA)]. The PVA hydrogel was prepared by a freeze-thaw process in the absence of a chemical crosslinking agent. The effect of protein loading on drug release was examined at three levels (0.65, 1.3, and 2%), whereas the effect of SLS was studied at four levels (0, 0.07, 0.13, and 0.26%). The baseline time for reaching equilibrium swelling was 48 hr for the hydrogel containing 0.65% BSA, and the equilibrium swelling time decreased significantly as the protein load was increased to 2%. The net effect of increased BSA concentrations resulted in faster BSA dissolution from the hydrogel matrix. The equilibrium-swelling ratio decreased from 21 to 10% when SLS was added to the PVA solution, which resulted in a reduction in the extent of equilibrium swelling; however, the time to reach equilibrium swelling was increased. The investigation provided a mechanistic basis toward the development of a hydrogel formulation by altering the concentration of two fundamental components, i.e., drug and surfactant, within the delivery system.