Mucoadhesive buccal film containing ornidazole and dexamethasone for oral ulcers: in vitro and in vivo studies

A bilayered mucoadhesive buccal film containing a combination of ornidazole (OD) and dexamethasone sodium phosphate (DEX) was prepared using solvent casting to treat oral ulcers. Films were systematically evaluated in vitro to obtain the optimum formulation. The therapeutic effects of these films were investigated in the rabbit oral ulcer model and the in vivo release of OD and DEX in the human oral cavity was also evaluated. The backing layer contained ethyl cellulose and an optimal mucoadhesive layer containing both OD and DEX was produced. Films from the optimum formulation were 0.427?±?0.015?mm thick, weighed 55.89?±?0.79?mg, and had a surface pH of 6.34?±?0.01. The drug content of the optimum formulation approximated the theoretical value with good uniformity (2.959?±?0.106?mg/cm² for OD and 0.877?±?0.031?mg/cm² for DEX). The formulation showed favorable swelling characteristics and both drugs were released at >95% after 4?h. Moreover, the compound film had a statistically significant effect on mucosal repair and reduced ulcer inflammation without stimulating the human oral mucosa. C_max of OD in saliva was 37.04?μg/ml and that of DEX was 9.737?μg/ml. Given promising therapeutic effects, the compound film developed here could become a local drug delivery device for treating oral ulcers.     

Design and evaluation of bilayered buccal film preparations for local administration of lidocaine hydrochloride

Bilayered oromucosal film preparations (buccal films) offer a promising way to enable drug administration via the oral cavity. Adding a non-soluble or slowly eroding/dissolving backing layer to a mucoadhesive drug-loaded layer enables unidirectional drug delivery.The aim of this study was to investigate different approaches to the manufacture of bilayered films and to examine their properties by applying different characterization methods including an optimized experimental setup for the study of drug release from bilayered films. A solvent suitability study was performed screening over 15 polymers with respect to their feasibility for viscous film formation for film preparation by solvent casting method. Two methods (double-casting and pasting) were found as suitable methods for bilayered film manufacturing. Results from drug release experiments indicated that slowly eroding hypromellose backing layer films revealed the best shielding of the drug-loaded layer to enable unidirectional drug release. In summary, manufacturing of bilayered films using the described methods was feasible. Furthermore, the use of an optimized experimental setup for drug dissolution studies enabled monitoring of drug release without delays in sampling.     

Transbuccal delivery of chlorpheniramine maleate from mucoadhesive buccal patches

This article describes buccal permeation of chlorpheniramine maleate (CPM) and its transbuccal delivery using mucoadhesive buccal patches. Permeation of CPM was calculated in vitro using porcine buccal membrane and in vivo in healthy humans. Buccal formulations were developed with hydroxyethylcellulose (HEC) and evaluated for in vitro release, moisture absorption, mechanical properties, and bioadhesion, and optimized formulation was subjected for bioavailability studies in healthy human volunteers. In vitro flux of CPM was calculated to be 0.14 ± 0.03 mg.h^-1.cm^-2 and buccal absorption also was demonstrated in vivo in human volunteers. In vitro drug release and moisture absorbed were governed by HEC content and formulations exhibited good tensile and mucoadhesive properties. Bioavailability from optimized buccal patch was 1.46 times higher than the oral dosage form and the results showed statistically significant difference.     

Mucoadhesive buccal films containing phospholipid-bile salts-mixed micelles as an effective carrier for Cucurbitacin B delivery

Abstract

Cucurbitacin B (Cu B), a potent anti-cancer agent, suffers with the problems of water-insoluble, gastrointestinal side effects and non-specific toxicity via oral administration and drawbacks in patient’s compliance and acceptance through injections. An integration of nanoscale carriers with mucoadhesive buccal films drug delivery system would resolve these issues effectively with greater therapeutic benefits and clinical significance. Thus, the drug loaded mucoadhesive buccal film was developed and characterized in this study and the carboxymethyl chitosan (CCS) was chosen as a bioadhesive polymer, glycerol was chosen as a plasticizer and phospholipid-bile salts-mixed micelles (PL-BS-MMs) was selected as the nanoscale carriers. The CCS-films containing Cu B loaded PL-SDC-MMs was evaluated for the mechanical properties, mucoadhesion properties, in vitro water-uptake, in vitro release and morphological properties, respectively. The optimal CCS-films containing Cu B loaded PL-SDC-MMs was easily reconstituted in a transparent and clear solution with spherical micelles in the submicron range. The in vivo study revealed a greater and more extended release of Cu B from nanoscale CCS-films compared to that from a conventional CCS films (C-CCS-films) and oral marketed tablet (Hulusupian). The absorption of Cu B from CCS-films containing Cu B loaded PL-SDC-MMs resulted in 2.69-fold increased in bioavailability as compared to conventional tablet formulation and 10.46 times with reference to the C-CCS-films formulation. Thus, this kind of mucoadhesive buccal film might be an alternative safe route for delivery of Cu B with better patient compliance and higher bioavailability for the treatments.     

Lidocaine loaded gelatin/gelatinized tapioca starch films for buccal delivery and the irritancy evaluation using chick chorioallantoic membrane

The aim of this study was to confirm the feasibility of gelatin/gelatinized tapioca starch (α st) films for buccal delivery and to evaluate their irritancy. Lidocaine (LB) and lidocaine hydrochloride (LH) were used as model drugs and glycerin was used as the plasticizer. The scanning electron microscopy, atomic force electron microscopy, X-ray diffraction and thermogravimetric analysis results confirmed the compatibility of gelatin/α st/glycerin (Gαgly) films. Drug releases of LB- or LH-Gαgly films were evaluated. The drug release profiles of medicated films presented good patterns in both short time and 8 h drug release studies. The permeation study was examined through chick chorioallantoic membrane (CAM) by using modified Franz diffusion cells. Moreover, the irritancy study for buccal films was also examined by a hen’s egg test on CAM model (HET-CAM). The results revealed that LB and LH could permeate through CAM, and these Gαgly films created no irritation on HET-CAM. This indicates that the LB- and LH-Gαgly films are possible to use as buccal films.     

甲硝唑口颊片的释放度测定及不同测定方法的结果比较

建立测定甲硝唑口颊片释放度的方法，并对不同装置不同厂家测定的释放曲线进行比较。分别采用新建立的流通池法、篮法以及原标准的小杯法考察甲硝唑口颊片的体外释放特性，在规定时间点取样后采用HPLC测定。对测定结果进行释药曲线的相似性分析和威布尔参数的统计学分析。甲硝唑在3.012~50.20μg/mL内线性关系良好(r=0.9999)，样品溶液在24h内稳定。相同装置下，不同厂家释放曲线不相似。经Weibull方程拟合后，A厂样品在篮法和流通池法下，得到的特征溶出参数不存在显著性差异(P>0.05)，B厂样品在不同装置下得到的特征溶出参数存在显著性差异(P<0.01)。不同厂家甲硝唑口颊片的释放特性存在明显差异，本研究所建流通池法和篮法均可用于甲硝唑口颊片的释放度检查，对完善甲硝唑口颊片的质量控制有指导意义。     

新型茶碱口服结肠靶向给药系统的体内动力学

目的研究以时间为释药开关的结肠靶向给药系统。方法以非pH依赖型聚丙烯酸树脂Eu dragit NE 3 0D为膜材 ,制备茶碱薄膜衣片 ;用HPLC法进行体内血药浓度分析 ;以γ 闪烁照相研究该制剂体内胃肠道的转运情况。结果本制剂与参比制剂主要药代动力学参数分别为 :tlag( 8 67± 1 0 4 )h、( 0 67± 1 1 5 )h ;Cmax( 5 2 5± 1 2 1 )mg/L、( 4 0 9± 1 2 5 )mg/L ;AUC0 2 6 ( 2 7 5 0±7 2 0 )mg·h/L、( 3 9 0 4± 1 0 4 3 )mg·h/L ;体内γ 闪烁照相研究表明 ,体外 6 5h释放的制剂口服8 0h后到达升结肠处开始释药 ,且体内释药与体外释药有一定的相关性。结论本制剂能达到结肠靶向释药的设计要求     

复方奥硝唑大黄口腔膜抑菌作用的实验室观察

目的:观察复方奥硝唑大黄口腔膜的抑菌、缓释和解吸附功能。方法:选择与牙周及龋病相关致病菌,用杯碟法进行复方奥硝唑大黄口腔膜的细菌敏感试验;用附着板法观察抑菌作用及解吸附作用。结果:复方奥硝唑大黄口腔膜对牙龈卟啉单胞菌等菌有明显抑菌作用;对变形链球菌有抗附着作用。结论:复方奥硝唑大黄口腔膜对牙周致病菌有稳定的抑制作用。     

Development and evaluation of buccal films impregnated with selegiline-loaded nanospheres

Poor peroral therapeutic efficiency of selegiline is primarily due to the extensive hepatic metabolism and hence the need for an alternative route of administration. The present study is based on evaluation of a buccal film which is impregnated with selegiline nanospheres to enhance the systemic bioavailability. Selegiline-loaded nanospheres prepared using poly(lactide-co-glycolide) was embedded into buccal films (F₁–F₄) with varying polymer composition [hydroxypropyl methylcellulose and eudragit]. The developed films were evaluated for their physicomechanical properties, hydration, mucoadhesive strength, in vitro drug release and ex vivo permeation in order to identify the ideal system suitable for further development. In vivo studies were carried out on rabbits to assess the comparative pharmacokinetics profile of the selected buccal film with oral solution. Preliminary studies indicated that the prepared films exhibited excellent physical properties, adequate mucoadhesive strength and moderate hydration. In vitro drug release data of the buccal films (F₁, F₂ and F₃) showed distinct profiles. Permeation studies indicated higher steady-state flux from film F₃ (p?<?0.0001) when compared to film F₂. In-vivo results of film (F₃) demonstrated significant increase in absorption (p?<?0.0001), C_max (～1.6-fold), T_max, AUC_0–α (～3-fold, p?<?0.0001) and improved bioavailability, when compared to control. This study concludes that the buccal delivery of selegiline using the developed buccal film (F₃) would be a promising alternative approach for the treatment of Parkinson's disease.     

Preparation and solid-state characterization of bupivacaine hydrochloride cyclodextrin complexes aimed for buccal delivery

Binary products of bupivacaine hydrochloride (BVP HCl), an amide type local anesthetic, with parent β-cyclodextrin (β-CD) and its soluble β-cyclodextrin-epichlorohydrin polymer (EPI-β-CD) were prepared and evaluated as a first phase in the development of a novel mucoadhesive formulation aimed for buccal delivery of this drug. The solid products were obtained by physical mixing, ball milling in high-energy mills, co-evaporation and lyophilisation, in order to rationally select the most effective preparation technique. The solid products obtained were carefully characterised by differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), Fourier transform infrared spectroscopy (FTIR) and environmental scanning electron microscopy (ESEM). The impact of the preparation techniques on the physicochemical properties of plain drug was also studied. Results of solid-state analysis revealed more intense interactions of BVP HCl with EPI-β-CD than with native β-CD, accompanied by stronger reduction of drug crystallinity in the samples, probably favoured by the amorphous nature of the polymeric carrier. While summarising the results of DSC and XRPD analyses, it seems that ball milling of drug/cyclodextrin binary mixtures was particularly efficient in inducing solid-state interaction between the components and it can be considered as the method of choice for preparation of complexes of BVP HCl with β-CD and EPI-β-CD. In vitro dissolution properties in artificial saliva of ball-milled BVP HCl and corresponding CD complexes were investigated by simulating the conditions present at the surface of the buccal mucosa. The obtained results confirmed that complexation of BVP HCl with β-CD and EPI-β-CD is a suitable tool for properly tailoring the dissolution properties of the drug and it can be favourably exploited for the development of an effective buccal drug delivery system.     

复方奥硝唑大黄口腔膜的安全性评价

目的:评价复方奥硝唑大黄口腔膜的安全性。方法:将口腔膜分别贴在健康豚鼠背部和口腔颊侧黏膜上,进行急性皮肤刺激实验和黏膜刺激实验;将药膜浸膏涂抹在牙周膜上,观察对牙周组织的毒性。结果:急性皮肤刺激反应及强度积分值均为0。黏膜刺激实验中未见充血、出血、肿胀、糜烂、溃疡等反应。牙周组织毒性实验中未出现细胞炎症反应。结论:该药膜对皮肤及口腔黏膜无刺激性,对牙周组织无毒性。     

Ex vivo buccal drug delivery of ropinirole hydrochloride in the presence of permeation enhancers: the effect of charge

In the current study, the ex vivo permeation of ropinirole hydrochloride (RH) across porcine buccal mucosa in the presence of three permeation enhancers, namely N-trimethyl chitosan (TMC) (positively charged) a chitosan derivative, sulfobutyl ether-β-cyclodextrin (SBE-β-CD) (negatively charged) and hydroxypropyl-β-cyclodextrin (HP-β-CD) (neutral), was investigated. Buccal permeation studies were conducted using Franz diffusion cells. Cumulative amounts of RH were plotted versus time. The presence of the permeation enhancers significantly increased the transport of the drug across the porcine buccal epithelium compared to its plain congener (RH solution). The rank order effect of the permeation enhancers for the transport of RH across buccal epithelium was TMC?≥?SBE-β-CD?>?HP-β-CD?>?RH solution. The presence of TMC increased 1.34-fold the transport of RH across buccal epithelium, whereas an increase of 1.23- and 1.28-fold was reported in the presence of HP-β-CD and SBE-β-CD, respectively. Infrared spectroscopy (IR) was employed to investigate the interaction of permeation enhancers with the epithelial lipids of porcine buccal mucosa corroborating the permeation results. Finally, light microscopy was performed to assess the histological changes in the porcine epithelium. Formation of vacuoles, spongiosis and acantholysis linear detachment and destruction of the epithelium resulted from the presence of the permeation enhancers. The data suggest that all enhancers tested, and particularly TMC, increase the transport of RH across buccal epithelium.     

复方奥硝唑大黄口腔膜对大鼠实验性口腔溃疡的治疗作用

目的:观察复方奥硝唑大黄口腔膜对Wistar大鼠实验性口腔溃疡的治疗作用。方法:建立Wistar大鼠口腔溃疡动物模型,将模型动物随机分成5组:复方奥硝唑大黄口腔膜高、中、低剂量组、奥硝唑膜阳性对照组和模型对照组,观察给药后溃疡面的愈合情况。结果:各剂量复方奥硝唑大黄口腔膜均能不同程度减小溃疡面直径。结论:复方奥硝唑大黄口腔膜对Wistar大鼠实验性口腔溃疡有较好的治疗作用。     

阿托伐他汀抗家兔内膜损伤后动脉粥样硬化的实验研究

目的探讨阿托伐他汀抗动脉粥样硬化的作用。方法将29只新西兰白兔随机分为正常组7例、病理组7例、用药5周组7例及用药9周组8例。实验前后抽血测定血脂全套,主动脉标本用作普通光镜、透射电镜及斑块面积检查。结果阿托伐他汀显著降低胆固醇(TC)、甘油三酯(TG)及低密度脂蛋白胆固醇(LDL-C),升高高密度脂蛋白胆固醇(HDL-C),组织病理学检查显示用药组血管内膜厚度、内膜中泡沫细胞、平滑肌细胞(SMC)明显减少,未见合成型SMC,用药9周组与病理组相比斑块面积减小。结论阿托伐他汀具有明显的抗动脉粥样硬化的作用。     

TR146 cells grown on filters as a model of human buccal epithelium: V. Enzyme activity of the TR146 cell culture model, human buccal epithelium and porcine buccal epithelium, and permeability of leu-enkephalin

The objective of the present study was to characterise the TR146 cell culture model as an in vitro model of human buccal mucosa with respect to the enzyme activity in the tissues. For this purpose, the contents of aminopeptidase, carboxypeptidase and esterase in homogenate supernatants of the TR146 cell culture model, and human and porcine buccal epithelium were compared. The esterase activity in the intact cell culture model and in the porcine buccal mucosa was compared. Further, the TR146 cell culture model was used to study the permeability rate and metabolism of leu-enkephalin. The activity of the three enzymes in the TR146 homogenate supernatants was in the same range as the activity in homogenate supernatants of human buccal epithelium. In the TR146 cell culture model, the activity of aminopeptidase (13.70±2.10 nmol/min per mg protein) was approx. four times the activity of carboxypeptidase (3.73±0.53 nmol/min per mg protein), whereas the level of esterase activity was significantly higher (223.39±69.82 nmol/min per mg protein). In the TR146 cell culture model, the apical esterase activity was found significantly higher than the basal activity, and found comparable to the porcine buccal mucosa. However, the esterase activity on the serosal side of the porcine buccal mucosa was higher than in the TR146 cell culture model. Approx. 1.5% of leu-enkephalin permeated the TR146 cell layers within 5 h (P_app 7.38±0.83×10⁻⁷ cm/s) and approx. 77% of intact peptide was still present in the donor phase after 5 h. The present study suggests that the TR146 cell culture model is a valuable in vitro model for permeability and metabolism studies with enzymatically labile drugs, such as leu-enkephalin, intended for buccal drug delivery.     

门静脉灌注胶原酶逆转四氯化碳致实验兔肝硬化

目的观察门静脉灌注胶原酶对逆转兔实验性肝硬化的作用。方法实验动物分4组,1组:四氯化碳注射12周后行门静脉置管,1周后开始门静脉灌注胶原酶4周;2组:四氯化碳注射12周后行门静脉置管,1周后开始门静脉灌注生理盐水4周;3组:橄榄油注射12周后行门静脉置管,1周后开始门静脉灌注胶原酶4周;4组:橄榄油注射12周后行门静脉置管,1周后开始门静脉灌注生理盐水4周。以上各组取肝组织,用氯胺T法检测门静脉灌注实验前后肝组织的羟脯氨酸含量及肝组织的病理检查。结果经过的四氯化碳(CCL4)注射和胶原酶门静脉灌注后,应用胶原酶灌注的动物肝羟脯氨酸含量显著低于用生理盐水灌注的对照组,肝组织学检查也显示胶原酶治疗后肝硬化消退,肝肾功能检查未发现胶原酶的毒性反应。结论门静脉灌注胶原酶可以促进已形成的肝硬化向正常肝组织结构逆转,并未发现对肝、肾组织毒性反应。     

Micronucleus frequency in buccal mucosa cells of mobile phone users

Mobile phones are being used extensively throughout the world, with more than four billion accounts existing in 2009. This technology applies electromagnetic radiation in the microwave range. Health effects of this radiation have been subject of debate for a long time, both within the scientific community and within the general public. This study investigated the effect of mobile phone use on genomic instability of the human oral cavity's mucosa cells. 131 Individuals donated buccal mucosa cells extracted by slightly scraping the oral cavity with a cotton swab. Every participant filled out a questionnaire about mobile phone use including duration of weekly use, overall period of exposure and headset usage. 13 Individuals did not use mobile phones at all, 85 reported using the mobile phone for three hours per week or less, and 33 reported use of more than three hours per week. Additionally, information on age, gender, body weight, smoking status, medication and nutrition was retrieved. For staining of the cells a procedure using α-tubulin-antibody and chromomycin A₃ was applied. Micronuclei and other markers were evaluated in 1000 cells per individual at the microscope. A second scorer counted another 1000 cells, resulting in 2000 analyzed cells per individual. Mobile phone use did not lead to a significantly increased frequency of micronuclei.     

The effect of pectin on swelling and permeability characteristics of free films containing Eudragit RL and/or RS as a coating formulation aimed for colonic drug delivery

BACKGROUND AND THE PURPOSE OF THE STUDY: The potential of pectin as a bacterially degradable polysaccharide for colon drug delivery has been demonstrated. Due to the high solubility and swelling properties of pectin in aqueous media, it is frequently used in combination with water insoluble polymers for targeting drugs to the colon. The aim of this study was to evaluate free films containing pectin as a bacterially-degradable polysaccharide in combination with Eudragit RL (ERL) and/or RS (ERS) as a coating formulation for colonic drug delivery. METHODS: Isolated free films comprising 20% pectin and 80% ERL or ERS and their combination in 1:1 ratio were prepared by casting method. Then, free films were evaluated by water vapor transmission (WVT), swelling and permeability experiments for theophylline and indomethacin in different media. RESULTS: Formulations containing ERL exhibited higher WVT, swelling and permeability compared with formulations containing ERS. The permeability of theophylline through free films composed of pectin and eudragit polymers in simulated colonic media was not significantly different from those obtained in other media. However indomethacin free films containing pectin and ERL showed higher permeation in simulated colonic fluid (SCF) compared to the other media. MAJOR CONCLUSION: Formulation containing pectin and ERL may be suitable as a coating formulation for colon targeted delivery of drugs of low solubility such as indomethacin.