Formulation and evaluation of co-prodrug of flurbiprofen and methocarbamol

The current work envisages synthesis of an ester prodrug of flurbiprofen whereby its carboxylic group was condensed with a skeletal muscle relaxant methocarbamol, with the aim of synergistic activity of two drugs, avoid flurbiprofen mediated gastro-intestinal damage and minimize the ulceration tendency of flurbiprofen. The synthesized prodrug was characterized and confirmed by physicochemical and spectroscopic studies. Solubility and partition coefficient studies indicated an increased lipophilicity and thus better suitability for oral administration than the parent drugs and the protein binding studies revealed a low protein binding capacity of the mutual prodrug. Subsequently, in-vitro hydrolysis was studied in different pH, simulated gastric fluid, simulated intestinal fluid and plasma and quantitative evaluation was performed by high performance liquid chromatography. It was found that the prodrug remained unhydrolyzed in the stomach after absorption however, underwent rapid cleavage by the esterases in blood to give the parent drug. Furthermore, the mutual ester prodrug was evaluated for its anti-inflammatory, analgesic, skeletal muscle relaxation, ulcerogenic and total acid content activity and was found to possess comparable activity with that of the parent drugs. Microscopic structures of the stomach tissues revealed significant reduction in gastric ulcer formation of mice gastric mucosa as compared to parent carboxylic acid drug.     

Formulation and evaluation of an alternative triglyceride-free propofol microemulsion

A new triglyceride-free propofol microemulsion for intravenous injection was formulated using nonionic surfactants, poloxamers and polyethylene glycol 660 hydroxystearate. The aim of this investigation was to evaluate the formulation for storage stability, antimicrobial activity, toxicity and preclinical efficacy. The results were compared to the characteristics obtained for the most commonly used formulation of propofol (Diprivan®). The mean particle diameter of the microemulsion was less than 100 nm so that it could be readily sterilized using a 0.22 μm membrane at room temperature. The microemulsion formulation demonstrated enhanced stability compared to the marketed macroemulsion formulation. In a stress storage condition, it was physicochemically stable for at least 40 months. This new formulation showed higher antimicrobial activity, lower risk of hyperlipidemia and better tolerability than Diprivan®. In preclinical studies, the efficacy and pharmacokinetic profile of the microemulsion were similar to those of Diprivan®. Nevertheless, the administration of the microemulsion caused considerably low histamine release compared to the macroemulsion. Based on these results, the newly developed microemulsion of propofol appeared to have several advantages and, thus, could be an alternative to the fat macroemulsions of propofol.     

Formulation, evaluation and pharmacokinetics of colon targeted pulsatile system of flurbiprofen

Objective: The intent of the present investigation is to develop colon targeted compression coated flurbiprofen pulsatile release tablets that retard the drug release in the upper gastro intestinal system but progressively release in the colon. Materials and methods: Flurbiprofen core tablets were prepared by direct compression method and were compression coated with hydroxypropyl methylcellulose and Eudragit S100. The formulation is optimized based on the in vitro drug release study and further evaluated by X-ray imaging and pharmacokinetic studies in healthy humans for colonic delivery. Results and discussions: The optimized formulation showed negligible drug release (7.26?±?0.05%) in the initial lag period followed by progressive release (99.27?±?0.46%) for 24?h. The X-ray imaging study in human volunteers showed that the tablets reached the colon without disintegrating in the upper gastrointestinal tract. The C(max) of colon targeted tablets was 10792.62?ng/mL at T(max) 10?h where as in case of immediate release tablets the C(max) was 15684.79?ng/mL at T(max) 3?h signifies the ability of compression coated tablets to target the colon. Conclusion: Development of pulsatile release compression coated tablets using combination of time dependent and pH sensitive approaches was suitable to target the flurbiprofen to colon.     

Formulation,evaluation and pharmacokinetics of colon targeted pulsatile system of flurbiprofen

Objective: The intent of the present investigation is to develop colon targeted compression coated flurbiprofen pulsatile release tablets that retard the drug release in the upper gastro intestinal system but progressively release in the colon.

Materials and methods: Flurbiprofen core tablets were prepared by direct compression method and were compression coated with hydroxypropyl methylcellulose and Eudragit S100. The formulation is optimized based on the in vitro drug release study and further evaluated by X-ray imaging and pharmacokinetic studies in healthy humans for colonic delivery.

Results and discussions: The optimized formulation showed negligible drug release (7.26?±?0.05%) in the initial lag period followed by progressive release (99.27?±?0.46%) for 24?h. The X-ray imaging study in human volunteers showed that the tablets reached the colon without disintegrating in the upper gastrointestinal tract. The C_max of colon targeted tablets was 10792.62?ng/mL at T_max 10?h where as in case of immediate release tablets the C_max was 15684.79?ng/mL at T_max 3?h signifies the ability of compression coated tablets to target the colon.

Conclusion: Development of pulsatile release compression coated tablets using combination of time dependent and pH sensitive approaches was suitable to target the flurbiprofen to colon.     

氟比洛芬微乳的制备及其透皮吸收的研究

目的:制备氟比洛芬微乳,考察氟比洛芬微乳对离体大鼠皮的透皮能力.方法:Zetapals多功能电位/粒度分析仪测定氟比洛芬微乳的粒度及其分布.用改进的Franz扩散池研究氟比洛芬微乳的透皮速率,进一步优化处方.结果:微乳最优处方舍1.0%氟比洛芬,5.0%油酸乙酯,22.5%聚山梨醇酯80,7.5%丙二醇和64.0%水,微乳中药物经大鼠皮肤的稳态渗透速率为(19.8±3.1)μg·cm-2·h-1(r=0.998 5).结论:氟比洛芬微乳有很强的透皮能力,有望成为氟比洛芬的新型透皮给药制剂.     

Formulation and ex-vivo evaluation of metronidazole microemulsion loaded hydrogel for prevention of periodontitis

Periodontal disease comprises a group of inflammatory conditions of periodontal tissues with common etiologic agent (bacteria) in the form of dental plaque. The objective of this research was to prepare a water-in-oil type microemulsion comprising metronidazole and equate its potency towards the effective treatment of periodontitis. A pseudo ternary phase diagram for microemulsion investigated using quaternary system containing water/captex 500/ tween 80/acconon CC6. The microemulsion was preferred from the microemulsion area on the phase diagram. Stable water-in-oil type metronidazole microemulsion was prepared successfully using the quaternary system of water/captex 500/ tween 80/acconon CC6 at 4:1 ratio having droplet size in the range of 81 ± 12.91 to 196 ± 10.73 nm, conductivity 50.6 ± 0.8 to 330.7 ± 1.1 μs/cm. In-vitro drug release, in vitro and ex vivo antimicrobial activities by agar well diffusion were investigated. Metronidazole Microemulsion loaded hydrogel formulations (F9 and F10) were found to be optimized for maximum release and antimicrobial activity in terms of zone of inhibition. The in vitro release evidenced that metronidazole microemulsion loaded hydrogel release rate was maximum as compared to other plain metronidazole gels. Stability study proved that microemulsion persisted stable for at least 6 months; with no changes in clarity, characteristic properties, and no sign of crystallization of metronidazole. In ex vivo evaluation, microemulsion based hydrogels were effective against the microbial flora of the human oral cavity suffering from periodontitis. The system was found to be appropriate for application and more effective in reducing the clinical symptoms of periodontitis.     

Formulation of parenteral microemulsion containing itraconazole

The aim of this study was to develop an aqueous parenteral formulation containing itraconazole (ITZ) using an o/w microemulsion system. A mixture of benzyl alcohol and medium chain triglyceride (3/1) was chosen as the oil phase. Pseudoternary phase diagrams of the microemulsion formations were constructed in order to determine the optimum ratio of oils, the concentration range of surfactant and cosurfactant and the optimum ratio between them. Consequently, the suitability of the chosen microemulsion system as a parenteral formulation was evaluated using droplet size analysis and hemolysis tests. Among the surfactants and cosurfactants screened, a mixture of polyoxyethylene (50) hydrogenated castor oil and ethanol (3/1) showed the largest o/w microemulsion region in the phase diagram. The average droplet size of the microemulsions was < 150 nm, and the hemolysis test showed this formulation to be nontoxic to red blood cells. The pharmacokinetic profiles of the ITZ-microemulsion for itraconazole and its major metabolite, hydroxyitraconazole, were compared with those of a PEG 400 solution and cyclodextrin formulations in rats. Overall, these results highlight the potential of an ITZ-microemulsion formulation for the parenteral route.     

Formulation and stability of silkworm pupae oil microemulsion

Because of the instability, perishable odor and peculiar smell, a microemulsion system was designed to safely and effectively supply α-linolenic acid from silkworm pupae oil. Microemulsion-loaded silkworm pupae oil was prepared from isoamyl acetate, castor oil polyoxyethylene ether 35 (EL-35), ethanol and water. The optimal microemulsion formulation was a 4% composite oil phase (silkworm pupae oil: isoamyl acetate, 1:2), 16% composite surfactant (EL-35: ethanol, 2:1) and 80% water, with uniformly dispersed spherical particles with diameters of 16.25 nm. The color of the microemulsion was transparent and had no peculiar smell. The investigation results of environmental stress show that the transmittance is 86%–99%, and there is no significant difference from the control group (p > 0.05). Compared with silkworm pupae oil, the total antioxidant capacity of the microemulsion was increased by 7.70 times. Microemulsion-loaded silkworm pupae oil exhibited good physical and antioxidation stability. This work provides a feasible new scheme for ensuring the nutritional and health functions of silkworm pupae oil and supplying α-linolenic acid safely and effectively.     

氟比洛芬酯微乳注射液大鼠组织分布及靶向性研究

摘 要 目的： 研究自制的氟比洛芬酯（FA）微乳注射液在大鼠体内的组织分布并评价其在手术切口创伤炎症部位靶向性。方法: 建立大鼠手术切口创伤模型,随机分成2组,分别经尾静脉注射氟比洛芬酯微乳和氟比洛芬溶液注射液,在给药后15,30,60,120,240 min处死大鼠,取血清、心、肝、脾、肺、肾、创伤肌肉组织及正常肌肉组织,HPLC法测定样本氟比洛芬浓度。结果:微乳注射液组在体内血液及各组织脏器消除速度较溶液组慢,5个时间点氟比洛芬酯微乳注射液组手术侧创伤肌肉组织中药物浓度均高于非手术侧正常肌肉组织（P<0.05）,而溶液注射液组差异无统计学意义（P>0.05）。微乳组药物创伤肌肉组织靶向效率T_e=12.21%,而溶液组T_e=3.97%,微乳注射液对普通溶液注射液创伤肌肉组织相对摄取率R_e=4.15。结论: 氟比洛芬酯微乳注射液静脉注射后在大鼠手术切口创伤炎症部位有靶向性,具有靶向消炎镇痛的作用。     

Formulation,characterization, and in vitro/ex vivo evaluation of quercetin-loaded microemulsion for topical application

The aim of this study was to develop a new microemulsion formulation for topical application of poorly soluble drug named quercetin. In order to design suitable microemulsion system, the pseudo-ternary phase diagrams of microemulsion systems were constructed at different surfactant/co-surfactant ratios using tween 80 as surfactant, transcutol^® P as a co-surfactant and oleic acid as an oil phase. Some physicochemical properties such as droplet size, density, refractive index, electrical conductivity, pH, surface tension, and viscosity of the microemulsion systems were measured at 298.15 K. The average hydrodynamic droplet size of the optimized microemulsions was obtained by dynamic light scattering method. Morphology assessment of the optimized quercetin-loaded microemulsion by transmission electron microscopy analysis indicated that the particles have the size of about 25?nm and spherical with narrow size distribution. Equilibrium solubility, in vitro drug release at a 24?h time period, release kinetic evaluation as well as ex vivo permeation and retention of quercetin-loaded microemulsions through rat skin has been investigated. The obtained results showed a slow release behavior without any transdermal delivery. Most of the formulations fitted best with zero-order kinetic model with a non-Fickian mechanisms. This study illustrated that the proposed QU-microemulsion has a good potential for use in sunscreen formulations.

     

Formulation design of microemulsion for dermal delivery of penciclovir

The purpose of the present study was to evaluate the potential application of microemulsions as a dermal drug delivery loading penciclovir. The pseudo-ternary phase diagrams were developed for various microemulsion formulations composed of oleic acid (oil phase), Cremorphor EL (surfactant) and ethanol (cosurfactant). Composition of microemulsion systems was optimized using simplex lattice mixture design including the concentrations of surfactant, cosurfactant and water (independent variables) and the solubility and the cumulative amount of penciclovir permeated through excised mouse skins per unit area (response variables). The physicochemical properties of the optimized microemulsion and the permeating ability of penciclovir from microemulsions were also investigated. The results showed that the optimized microemusion formulation was composed of oleic acid (5%, w/w), Cremorphor EL (20%, w/w), ethanol (30%, w/w) and water (45%, w/w). The mean particle diameter was 36.5nm and solubility of penciclovir in the emulsion was 7.41 mg g(-1). The cumulative amount of penciclovir permeated through excised mouse skins from microemulsion was about 3.5 times that of the commercial cream. The conclusion was that the permeating ability of penciclovir was significantly increased from the microemulsion formulation compared with commercial cream.     

Formulation of microemulsion systems for transdermal delivery of aceclofenac

An ONW microemulsion system was developed to enhance the skin permeability of aceclofenac. Of the oils studied, Labrafil M 1944 CS was chosen as the oil phase of the microemulson, as it showed a good solubilizing capacity. Pseudo-ternary phase diagrams were constructed to obtain the concentration range of oil, surfactant, Cremophor ELP, and co-surfactant, ethanol, for micoemulsion formation. Eight different formulations with various values of oil of 6-30%, water of 0-80%, and the mixture of surfactant and co-surfactant (at the ratio of 2) of 14-70%. The in vitro transdermal permeability of aceclofenac from the microemulsions was evaluated using Franz diffusion cells mounted with rat skin. The level of aceclofenac permeated was analyzed by HPLC and the droplet size of the microemulsions was characterized using a Zetasizer Nano-ZS. Terpenes were added to the microemulsions at a level of 5%, and their effects on the skin permeation of aceclofenac were investigated. The mean diameters of the microemulsions ranged between approximately 10-100 nm, and the skin permeability of the aceclofenac incorporated into the microemulsion systems was 5-fold higher than that of the ethanol vehicle. Of the various terpenes added, limonene had the best enhancing ability. These results indicate that the microemulsion system studied is a promising tool for the percutaneous delivery of aceclofenac.     

Preparation and evaluation of andrographolide-loaded microemulsion

Andrographolide has a low aqueous solubility and oral bioavailability, which limits its clinical application. Reform the dosage forms of andrographolide to improve its aqueous solubility and oral bioavailability. The formulation, characterisation, stability, anti-inflammatory effect, pharmacokinetics and oral toxicity of andrographolide-loaded microemulsion, were studied. An formulation of O/W microemulsion consisting of an oil phase of isopropyl myristate, a surfactant phase of Tween 80, a co-surfactant of alcohol, and water was found to be ideal, with mean droplet size of 15.9?nm, a high capacity of solubilisation for andrographolide (8.02?mg?mL^?1). Such an andrographolide-loaded microemulsion is stable by monitoring the time, temperature and gravity-dependent change, and has a much better anti-inflammatory effect and a higher biological availability than andrographolide tablets. Besides, it also shows a very low acute oral toxicity. The andrographolide-loaded microemulsion is a promising dosage form of andrographolide.     

双黄连微乳质量评价研究

目的:探讨双黄连微乳的质量评价方法与指标的合理性与适用性.方法:以自制"双黄连微乳"为样品,观察和测定制剂的外观性状、pH值、粒径和粒径分布、电导率、黏度等指标,采用HPLC方法测定制剂中黄芩苷、绿原酸和连翘苷的含量,进行3个月的初步稳定性实验,并与普通双黄连口服液作比较.结果:外观性状、pH值、相对密度、粒径和有效成分的含量测定可作为双黄连微乳口服液的质量评价指标.其中粒径的测定是微乳的重要指标.结论:双黄连微乳的质量评价指标应以物理指标与化学成分(或有效成分)相结合比较合理.     

Development and evaluation of artemether parenteral microemulsion

The objective of the present investigation was to develop a parenteral microemulsion delivering artemether, a hydrophobic antimalarial drug and to evaluate antimalarial activity of the microemulsion in comparison to the marketed oily injection of artemether (Larither^®). The microemulsion was evaluated for various parameters such as globule size, ability to withstand centrifugation and freeze-thaw cycling and effect of sterilization method on the drug content and globule size. The in vivo antimalarial activity of the microemulsion was evaluated in P. berghei infected mice in comparison to the Larither^;. The stability of the microemulsion was evaluated at 5º for 1 month. The microemulsion exhibited globule size of 113 nm and it could successfully withstand centrifugation and freeze-thaw cycling. The method of sterilization did not have any significant effect on the artemether content and globule size of the microemulsion. The microemulsion showed around 1.5-fold higher antimalarial activity and higher survival as compared to that of marketed artemether injection Larither^® and it showed a good stability at the end of 1 month.     

杨梅素微乳的制备及质量评价

目的制备杨梅素微乳,并评价其质量。方法选择适宜的油相、表面活性剂和助表面活性剂,利用伪三元相图筛选微乳处方,研制出适合经口给药的微乳制剂;采用HPLC法测定杨梅素的含量,并对微乳的类型、载药量、体外释放等进行考察。结果优选处方为聚山梨酯80-聚山梨酯20-乙醇-油酸-pH 6.5磷酸缓冲液的质量比20∶10∶15∶5∶50,杨梅素质量分数为2%。所制微乳外观透明,平均粒径为(56.3±8.7)nm,zeta电位为-2.73 mV,电导率为13.27 mS.m-1。载药微乳在不同pH值环境下对药物有良好的释放效果。结论通过优化处方制备的杨梅素微乳具有较稳定的理化性质,HPLC法可以有效、准确的测定杨梅素微乳的含量,并且微乳载药系统有良好的释药效果。     

酮康唑微乳的制备及其质量评价

目的制备酮康唑微乳并进行质量评价。方法以肉豆蔻酸异丙酯(isopropyl myristate,IPM),中链甘油三酯(medium chain triglycerides,MCT)为油相,以聚氧乙烯蓖麻油(polyoxyethylenated castor oil,EL-40)或Tween80为乳化剂,分别以乙醇、1,2-丙二醇、聚乙二醇400(polyethylene glycol400,PEG400)、甘油为助乳化剂,采用加水滴定法,绘制伪三元相图,以所形成的微乳区域大小为评价指标,筛选出酮康唑微乳的最佳处方。考察所制微乳的形态、粒径及其分布、稳定性和体外经皮透过性。结果最优处方为:按质量分数取IPM 12.0%、EL-40 27.0%、PEG400 9.0%、水50.5%、酮康唑1.5%。所制备的酮康唑微乳澄清透明,透射电子显微镜下呈圆整的球形,平均粒径为36.7nm、黏度为141 mPa·s、pH值为6.66,对热、光照稳定;其透皮速率显著大于酮康他索乳膏。结论酮康唑微乳质量稳定,此微乳体系对酮康唑的透皮具有促渗作用。     

微乳型丙泊酚纳米注射液的制备与评价

目的:制备微乳型丙泊酚纳米注射液,并对其进行体内外评价,为新型微乳型纳米注射液研究提供参考。方法:使用可注射用乳化剂和油制备丙泊酚纳米注射液,旋转黏度计测定其黏度,动态光散射法测定其粒径和Zeta电位,透射电镜测定其显微外观,透析法测定其游离药物浓度,并研究其体外溶血性和Beagle犬体内药动学性质。结果:黏度为1.5×10-3 Pa.s,粒径为(22.7±10.2)nm,Zeta电位为-5.82 mV;透射电镜照片显示微乳粒子外观近球状,游离药物浓度为(17.9±0.8)μg.mL-1(n=3),不引起溶血的发生;微乳与脂肪乳主要药动学参数t1/2α分别为(1.506±0.994)和(2.512±2.122)min,t1/2β分别为(42.221±43.878)和(49.095±42.521)min,V1分别为(1.947±1.17)和(3.546±3.836)L.kg-1,CL分别为(0.218±0.07)和(0.219±0.068)L.min-1.kg-1,AUC0～t分别为(17.916±6.772)和(16.968±5.395)mg.min.L-1,AUC0～∞分别为(20.488±7.729)和(...     

Formulation and evaluation of niosomes

Span 20-based niosome was prepared by lipid film hydration technique and loaded with Newcastle disease vaccine. Three batches with Span 20, cholesterol and dicetyl phosphate in micro molar ratios of 10:10:1; 15:15:1 and 20:20:1 were prepared and evaluated for encapsulation efficiency using haemagglutination test. The morphology of the vesicles was studied by means of transmission electron microscopy. Particle size, zeta potential and polydispersity index were determined by photon correlation spectroscopy using a nanosizer. Adjuvanticity was assessed using haemagglutination inhibition test. The vesicles of Span 20-based niosomes were distinct, near spherical large unilamellar vesicles. The vesicles were of varied sizes (<1000 nm) with the entrapped Newcastle disease vaccine in the core of the vaccine. The zeta potential had a peak at -50 mV. The polydispersity index was 0.68. Haemagglutination inhibition test showed a 71% increment in immune response over that of the marketed La Sota^® vaccine which had a 60% increment in immune response. The niosomal vaccine did not alter but rather enhanced the immunogenicity of the Newcastle disease vaccine.