Preparation and evaluation of zolmitriptan submicron emulsion for rapid and effective nasal absorption in beagle dogs

Submicron emulsion was prepared for rapid and effective nasal absorption of zolmitriptan (ZT). The different charge inducers and pH values of the formulations were evaluated to optimize the formulations. Submicron emulsion prepared by using stearylamine as positive charge inducer with pH of 5.0 was stable and most of ZT was freely dispersed in the aqueous phase of the preparation. In vitro release study demonstrated that ZT from the submicron emulsion preparation could be released as fast as that from the solution preparation. The pharmacokinetics was studied after intranasal administration of the submicron emulsion and solution preparation of ZT to beagle dogs. ZT from the submicron emulsion was absorbed much more rapidly and the absolute availability of the submicron emulsion preparation was significantly higher compared with the solution preparation. The nasal ciliotoxicity of the preparations was evaluated by using in situ toad palate model, which indicated that the submicron emulsion of ZT did not exhibit any obvious nasal ciliotoxicity. These results demonstrated that the submicron emulsion preparation of ZT was a relatively safe dosage form for rapid and effective intranasal delivery of ZT.     

Preparation and evaluation of carfentanil nasal spray employing cyclodextrin inclusion technology

Carfentanil (CFTN), a derivative of fentanyl, is highly effective as an analgesic, but its relatively poor solubility in water has limited its nasal application. The objective of this study was to develop the new CFTN-CD inclusion technology to increase the solubility of CFTN. The inclusion compound CFTN–DM-β-CD was prepared by the ultrasonic method and characterized using X-ray powder diffraction and morphological shapes analysis (the scanning electron microscopy). The in vitro dissolution profiles of CFTN–DM-β-CD were assessed in hydrochloric acid and phosphate buffer. Nasal ciliotoxicity studies were carried out using isolated toad palate. Rats were treated with CFTN–DM-β-CD (250?µg/kg) by intravenous, intramuscular injection, oral, or nasal drops. The results showed that CFTN was successfully enveloped by DM-β-CD. The in vitro cumulative dissolution of CFTN–DM-β-CD was obviously enhanced compared to free CFTN in two buffers. Nasal ciliotoxicity studies have shown that the CFTN–DM-β-CD does not exhibit higher nasal ciliotoxicity than that of free CFTN. Pharmacokinetic studies demonstrated that CFTN–DM-β-CD by nasal administration was absorbed more rapidly and has higher C_max and bioavailability than that of either intramuscular injection or oral administration. In conclusion, the CFTN–DM-β-CD nasal spray was shown to be a relatively safe dosage form for the rapid and effective intranasal delivery of CFTN.     

Synthesis of fine sodium-free silica powder from sodium silicate using w/o emulsion

Fine silica powders were synthesized from sodium silicate at room temperature using w/o emulsion containing water, nonionic surfactant of Triton N-57, and cyclohexane. Submicron and sodium-free silica particles could be prepared at low cost using inexpensive starting material of aqueous sodium silicate solution and ion exchange of ammonium sulfate. The particle size and size distribution of the silica powders were affected by the factors of reaction time, and concentrations of surfactant and sodium silicate solutions. The particle size of silica powders could be controlled by the same factors to be ranged from submicron to micron sizes. The particle size of SiO₂ decreased with reaction time and concentration of surfactant, but increased with concentration of sodium silicate. The preparation conditions were experimentally determined for obtaining the silica powder with submicron size, narrow size distribution, sphere in shape, and high purity without sodium contamination.     

Box–Behnken experimental design for preparation and optimization of the intranasal gels of selegiline hydrochloride

Selegiline hydrochloride (SL) is chosen as an adjunct for the control of clinical signs of Parkinsonian patients. The aim of the present work is to develop and optimize thermosensitive gels using Pluronic (F-127) for enhancing transport of SL into the brain through the nasal route. SL gels were prepared using a cold method and the Box–Behnken experimental design methodology. Drug (SL), gelling agent (F-127), and emulsifier (Propylene glycol, PG) were selected as independent variables, while the gelation temperature, gel strength, pH, gel content, and gel erosion were considered as dependent variables. For further understanding of the interaction between the various variables, contour plots and surface plots were also applied. Selected formulations, like S10 (contain 25?mg SL, 20?g F-127, and 1?g PG) and S14 (contain 50?mg SL, 18?g F-127 and 1?g PG), had a clear appearance in the sol form, with gelling temperature of the nasal gel ranging between 33 and 34, respectively. The gel strength of the formulations varied from 4.67 and 0.68?mm and the drug content was 100%. The pH of the formulations ranged between 6.71 and 7.11. Detachment force was acceptable (63.69–244.16 N/cm²) to provide prolonged adhesion. In vitro, drug release studies showed that the prepared formulations could release SL for up to 8?h. Permeation flux for the S10 gel was 0.0002?mg/min/cm². Results demonstrated that the potential use of SL gels can enhance the therapeutic effect of SL through the intranasal administration.     

Formulation and Characterization of Nanoemulsion-Based Drug Delivery System of Risperidone

Risperidone nanoemulsion (NE) and mucoadhesive NE formulations were successfully prepared by the spontaneous emulsification method (titration method) using Capmul MCM as the oily phase on the basis of solubility studies. The NE formulation containing 8%?oil, 44%?S_mix, 48%?(wt/wt) aqueous phase that displayed an optical transparency of 99.82%, globule size of 15.5?±?2.12 nm, and polydispersity of 0.172?±?0.02 was selected for the incorporation of mucoadhesive components. The mucoadhesive formulation that contained 0.5%?by weight of chitosan displayed highest diffusion coefficient that followed Higuchi model was free from nasal ciliotoxicity and stable for 3 months.     

Preparation of stabilized lidocaine particles by a combination of supercritical CO2 technique and particle surface control

Lidocaine particles were prepared by the rapid expansion of the supercritical fluids into aqueous solution (RESAS). About 150–300 nm lidocaine particles could be temporarily observed when collected in water at concentration of 10 mg/cc, but the particles developed into 50 μm needle crystals just 30 min later. To prevent the fast aggregation of the particles as well as further crystal growth, modifications on particle surfaces by adding surfactants and introduction of electrostatic repulsion between particles were conducted. When a surfactant (sucrose stearic acid ester S-1570) was added to the collecting aqueous solution, the particle growth was alleviated and no large needle crystals were formed. However, the long-term stability needs to be improved because the lidocaine particles tend to grow from submicron to a few microns in a few days even stored in the 1% S-1570 solution. Electrostatic repulsion between particles is found effective to stabilize the submicron particles during the storage. When the pH value of the aqueous solution with 1% S-1570 was adjusted to 8.5 by adding KOH, the lidocaine particles suspending in this solution showed good stability that the particle size was able to be controlled in submicron level in 3 months.     

Effects of poly(lactic-co-glycolic acid) on preparation and characteristics of plasmid DNA-loaded solid lipid nanoparticles

Poly(lactic-co-glycolic acid) (PLGA) was used as a polymeric emulsifier to encapsulate plasmid DNA into hydrogenated castor oil (HCO)-solid lipid nanoparticles (SLN) by w/o/w double emulsion and solvent evaporation techniques. The effects of PLGA on the preparation, characteristics and transfection efficiency of DNA-loaded SLN were studied. The results showed that PLGA was essential to form the primary w/o emulsion and the stability of the emulsion was enhanced with the increase of PLGA content. DNA-loaded SLN were spherical with smooth surfaces. The SLN had a negative charge in weak acid and alkaline environment but acquired a positive charge in acidic pH and the cationisation capacity of the SLN increased with the increase of PLGA/HCO ratio. Agarose gel electrophoresis demonstrated that the majority of the DNA maintained its structural integrity after preparation and being extracted or released from DNA-loaded SLN. When PLGA/HCO ratio increased from 5 to 15%, the encapsulation efficiency, loading capacity and transfection efficiency of the nanoparticles increased significantly, whereas the changes of particle size and polydispersity index were insignificant. Cytotoxicity study in cell culture demonstrated that the SLN was not toxic.     

Development of Controlled Release Formulations of Ketoprofen for Oral Use

Microencapsulated forms of ketoprofen were formulated using polymers and polymer combinations and their in-vitro release characteristics were evaluated against pure ketoprofen using Vanderkamp 600 dissolution test apparatus. Suspensions of cellulose acetate phthalate were prepared and various quantities of drug, glycerin, tween 80, span 80, methocel and avicel were added and the resulting solution was passed through a peristaltic pump into a hardening solution. Beads were formed, dried and the release of the drug was studied at various time intervals in a dissolution medium of simulated intestinal pH. The dissolution studies of the ketoprofen demonstrated differences in drug release properties depending on composition and method of preparation. A formulation of Methocel beads with equal proportions of the two surfactants released its drug content over a period of 12 hours in a zero-order fashion. Rapid drug dissolution was seen when the formulations contained Tween 80 as a surfactant. Varying the drug to CAP ratio in the suspension from 0.1 to 0.4 did not appear to alter dissolution. It is concluded that proper control of the formulation can give any desirable release from ketoprofen formulations.     

二水草酸钙晶体尺寸对非洲绿猴肾上皮细胞的损伤差异比较

采用扫描电子显微镜、激光扫描共聚焦显微镜、电感耦合等离子体发射光谱仪、流式细胞仪、酶标仪、细胞活性分析试剂盒和乳酸脱氢酶试剂盒(LDH)等方法比较研究了尺寸分别约为700 nm和15 μm的二水草酸钙(COD)晶体对非洲绿猴肾上皮细胞(Vero)损伤的差异。结果显示这两种不同尺寸的COD晶体都能引起Vero活力下降、LDH释放量升高以及碘化丙啶染色增强, 并表达带负电荷的骨桥蛋白, 说明它们对Vero都具有损伤作用, 且700 nm COD对Vero的细胞毒性及在细胞表面的粘附量均大于15 μm COD晶体。本研究从尺寸减小后COD的晶面变化、表面电荷变化、表面粘附位点、细胞与COD晶体间氢键作用等方面解释了亚微米COD毒性显著增强的原因。     

Novel surface modified polymer–lipid hybrid nanoparticles as intranasal carriers for ropinirole hydrochloride: in vitro, ex vivo and in vivo pharmacodynamic evaluation

Here we report fabrication and evaluation of novel surface modified polymer–lipid hybrid nanoparticles (PLN) as robust carriers for intranasal delivery of ropinirole hydrochloride (ROPI HCl). Sustained release, avoidance of hepatic first pass metabolism, and improved therapeutic efficacy are the major objectives of this experiment. PLN were fabricated by emulsification-solvent diffusion technique and evaluated for physicochemical parameters, in vitro mucoadhesion, in vitro diffusion, ex vivo permeation, mucosal toxicity and stability studies. Box-Behnken experimental design approach has been employed to assess the influence of two independent variables, viz. surfactant (Pluronic F-68) and charge modifier (stearylamine) concentration on particle size, ζ-potential and entrapment efficiency of prepared PLN. Numerical optimization techniques were used for selecting optimized formulation sample, further confirmed by three dimensional response surface plots and regression equations. Results of ANOVA demonstrated the significance of suggested models. DSC and SEM analysis revealed the encapsulation of amorphous form of drug into PLN system, and spherical shape. PLN formulation had shown good retention with no severe signs of damage on integrity of nasal mucosa. Release pattern of drug-loaded sample was best fitted to zero order kinetic model with non-Fickian super case II diffusion mechanism. In vivo pharmacodynamic studies were executed to compare therapeutic efficacy of prepared nasal PLN formulation against marketed oral formulation of same drug. In summary, the PLN could be potentially used as safe and stable carrier for intranasal delivery of ROPI HCl, especially in treatment of Parkinson’s disease.     

Preparation and characterization of a submicron lipid emulsion of docetaxel: submicron lipid emulsion of docetaxel

Docetaxel, a widely used anticancer agent, has sparingly low aqueous solubility, thus Tween 80 and ethanol need to be added into its formulation, probably resulting in the toxic effects. In this study, we aimed to utilize submicron lipid emulsions as a carrier of docetaxel to avoid these potential toxic vehicles. Preformulation study was performed for rational emulsions formulation design, including drug solubility, distribution between oil and water, and degradation kinetics. Supersaturated submicron lipid emulsion of docetaxel was prepared by temperature elevation method. Soya oil and Miglyol 812 can incorporate docetaxel up to 1.0% (drug to lipid ratio) and were used as the oil phase of emulsions. The optimal formulation of docetaxel is composed of 10% oil phase, 1.2% soybean lecithin, 0.3% Pluoronic F68, and 0.4 or 0.8 mg/mL docetaxel, with particle size in the nanometer range, entrapment efficiency more than 90%, and is physicochemically stable at 4 and 25 degrees C for 6 months. Animal studies showed that docetaxel emulsion has significantly higher area under the curve (AUC) and C(max) in rats compared to its micellar solution. The results suggested that the submicron lipid emulsion is a promising intravenous carrier for docetaxel in place of its present commercially available docetaxel micellar solution with potential toxic effects.     

Development of zolmitriptan transfersomes by Box–Behnken design for nasal delivery: in vitro and in vivo evaluation

The aim was to prepare an optimized zolmitriptan (ZT)-loaded transfersome formulation using Box–Behnken design for improving the bioavailability by nasal route for quick relief of migraine and further to compare with a marketed nasal spray. Here, three factors were evaluated at three levels. Independent variables include: amount of soya lecithin (X₁), amount of drug (X₂) and amount of tween 80 (X₃). The dependent responses were vesicle size (Y₁), flexibility index (Y₂) and regression coefficient of drug release kinetics (Y₃). Prepared formulations were evaluated for physical characters and an optimal system was identified. Further, in vivo pharmacokinetic study was performed in male wistar rats to compare the amount of drug in systemic circulation after intranasal administration. Optimized ZT-transfersome formulation containing 82.74?mg of lecithin (X₁), 98.37?mg of zolmitriptan (X₂) and 32.2?mg of Tween 80 (X₃) and had vesicle size of 93.3?nm, flexibility index of 20.25 and drug release regression coefficient of 0.992. SEM picture analysis revealed that the vesicles were spherical in morphology and had a size more than 1?µm. The formulations were found to be physically stable upon storage at room temperature up to 2?months period, as there were no significant changes noticed in size and ZP. The nasal bioavailability of optimized transfersome formulation was found to be increased by 1.72 times than that of marketed nasal spray (Zolmist^®). The design and development of zolmitriptan as transfersome provided improved nasal delivery over a conventional nasal spray for a better therapeutic effect.     

Heat denatured/aggregated albumin-based biomaterial: effects of preparation parameters on biodegradability and mechanical properties

Albumin-based biomaterials prepared using heat-aggregation or cross-linking agents have been used in various biomedical applications such as solder materials for laser-assisted tissue welding, anti-bacterial coatings and drug carriers. In this study, solid albumin-based materials were prepared via heat aggregation of albumin solution. The study aimed to determine the influences of the preparation parameters such as albumin concentration in solution, solution pH and temperature, on the mechanical properties as well as the biodegradation rate of heat-aggregated albumin-based materials. The results demonstrated that the materials prepared from the albumin solution with the pH of 8.5 had the highest mechanical strength. Augmenting the albumin concentration in solution led to an increase in mechanical strength, and the materials prepared from the solution with isoelectric albumin pH (pH 4.8) possessed the lowest biodegradation rate and those prepared at pH 12 showed the highest biodegradation rate.     

Preparation and Characterization of a Submicron Lipid Emulsion of Docetaxel: Submicron Lipid Emulsion of Docetaxel

Docetaxel, a widely used anticancer agent, has sparingly low aqueous solubility, thus Tween 80 and ethanol need to be added into its formulation, probably resulting in the toxic effects. In this study, we aimed to utilize submicron lipid emulsions as a carrier of docetaxel to avoid these potential toxic vehicles. Preformulation study was performed for rational emulsions formulation design, including drug solubility, distribution between oil and water, and degradation kinetics. Supersaturated submicron lipid emulsion of docetaxel was prepared by temperature elevation method. Soya oil and Miglyol 812 can incorporate docetaxel up to 1.0% (drug to lipid ratio) and were used as the oil phase of emulsions. The optimal formulation of docetaxel is composed of 10% oil phase, 1.2% soybean lecithin, 0.3% Pluoronic F68, and 0.4 or 0.8 mg/mL docetaxel, with particle size in the nanometer range, entrapment efficiency more than 90%, and is physicochemically stable at 4 and 25°C for 6 months. Animal studies showed that docetaxel emulsion has significantly higher area under the curve (AUC) and C_max in rats compared to its micellar solution. The results suggested that the submicron lipid emulsion is a promising intravenous carrier for docetaxel in place of its present commercially available docetaxel micellar solution with potential toxic effects.     

双乳液体系在微胶囊制备中的应用研究进展

双乳液是一类多重乳状液体系,它具有保护物质并且可以控制这些物质从一个相释放到另一个相的能力。近年来这类乳液体系与传统微胶囊制备方法的结合在药物输送(如抗癌药物、激素等)、食品等领域得到了一定的应用,解决了传统微胶囊制备方法无法有效封装高度水溶性物质等问题。基于此,综述了双乳液体系与微胶囊制备方法结合延伸出的一些新方法,包括双乳液-复凝聚法、复乳溶剂挥发法以及膜乳化复乳法等;同时,评述了影响双乳液体系制备微胶囊的各种因素,展望了双乳液体系在农药微胶囊制备中的应用前景。     

In Vitro Release Studies of Piroxicam from Oil-in-Water Creams and Hydroalcoholic Gel Topical Formulations

The importance of piroxicam, a therapeutic anti-inflammatory drug, is well known. Because of gastrointestinal disorders, dermatological dosage forms are recommended most. In our first studies, oil-in-water (O/W) creams of piroxicam (1% concentration) were prepared using glyceryl monostearate (GMS), stearic acid, and triethanolamine as additive ingredients. In our second studies, hydroalcoholic transparent gel formulations of this drug in a 0.5% concentration were prepared using hydroxypropylcellulose (HPC) as the gelling agent. The release of piroxicam from all formulations via dialysis through a cellulose membrane into phosphate buffer pH 6.8 at 37°C was studied. The effects of additives such as propylene glycol and 2-propanol on the drug release were also investigated. The release profiles from the standpoint of diffusion-controlled processes, as well as zero-order and first-order kinetics, were evaluated, and relevant parameters, such as diffusion coefficient, permeability coefficient, and partition coefficient, were calculated. The release obeys both the diffusion mechanism and first-order kinetics. The drug release from gel formulations containing 10%, 20%, and 30% propylene glycol was decreased due to the enhancement of viscosity. However, the limpidity of these formulations was improved. Moreover, the release of drug from gel formulations containing 15% and 20% of 2-propanol was increased. These results show that a hydroalcoholic gel formulation with HPC is a more suitable preparation of piroxicam when compared with an O/W cream formulation.     

In vitro release studies of piroxicam from oil-in-water creams and hydroalcoholic gel topical formulations

The importance of piroxicam, a therapeutic anti-inflammatory drug, is well known. Because of gastrointestinal disorders, dermatological dosage forms are recommended most. In our first studies, oil-in-water (O/W) creams of piroxicam (1% concentration) were prepared using glyceryl monostearate (GMS), stearic acid, and triethanolamine as additive ingredients. In our second studies, hydroalcoholic transparent gel formulations of this drug in a 0.5% concentration were prepared using hydroxypropylcellulose (HPC) as the gelling agent. The release of piroxicam from all formulations via dialysis through a cellulose membrane into phosphate buffer pH 6.8 at 37°C was studied. The effects of additives such as propylene glycol and 2-propanol on the drug release were also investigated. The release profiles from the standpoint of diffusion-controlled processes, as well as zero-order and first-order kinetics, were evaluated, and relevant parameters, such as diffusion coefficient, permeability coefficient, and partition coefficient, were calculated. The release obeys both the diffusion mechanism and first-order kinetics. The drug release from gel formulations containing 10%, 20%, and 30% propylene glycol was decreased due to the enhancement of viscosity. However, the limpidity of these formulations was improved. Moreover, the release of drug from gel formulations containing 15% and 20% of 2-propanol was increased. These results show that a hydroalcoholic gel formulation with HPC is a more suitable preparation of piroxicam when compared with an O/W cream formulation.     

Artesunate-loaded chitosan/lecithin nanoparticles: Preparation,characterization, and in vivo studies

Artesunate (AST), the most widely used artemisnin derivative, has poor aqueous solubility and suffers from low oral bioavailability (~40%). Under these conditions, nanoparticles with controlled and sustained released properties can be a suitable solution for improving its biopharmaceuticals properties. This work reports the preparation and characterization of auto-assembled chitosan/lecithin nanoparticles loaded with AST and AST complexed with β-cyclodextrin (β-CD) to boost its antimalarial activity. The nanoparticles prepared by direct injection of lecithin alcoholic solution into chitosan/water solution have shown the particle size distribution below 300?nm. Drug entrapment efficiency was found to be maximum (90%) for nanoparticles containing 100?mg of AST. Transmission electron microscopy images show spherical shape with contrasted corona (chitosan) surrounded by a lipidic core (lecithin + isopropyl myristate). Differential scanning calorimeter thermograms demonstrated the presence of drug in drug-loaded nanoparticles along with the disappearance of decomposition exotherm suggesting the increased physical stability of drug in prepared formulations. Negligible changes in the characteristic peaks of drug in Fourier-transform infrared spectra indicated the absence of any interaction among the various components entrapped in the nanoparticle formulation. In vitro drug release behavior was found to be influenced by pH value. Increased in vivo antimalarial activity in terms of less mean percent parasitemia was observed in infected Plasmodium berghei mice after the oral administration of all the prepared nanoparticle formulations.     

Solid lipid nanoparticles of ondansetron HCl for intranasal delivery: development, optimization and evaluation

The present investigation deals with the development and statistical optimization of solid lipid nanoparticles (SLNs) of ondansetron HCl (OND) for intranasal (i.n.) delivery. SLNs were prepared using the solvent diffusion technique and a 2(3) factorial design. The concentrations of lipid, surfactant and cosurfactant were independent variables in this design, whereas, particle size and entrapment efficiency (EE) were dependent variables. The particle size of the SLNs was found to be 320-498?nm, and the EE was between 32.89 and 56.56?%. The influence of the lipid, surfactant and cosurfactant on the particle size and EE was studied. A histological study revealed no adverse response of SLNs on sheep nasal mucosa. Transmission electron microscopic analysis showed spherical shape particles. Differential scanning calorimetry and X-ray diffraction studies indicated that the drug was completely encapsulated in a lipid matrix. In vitro drug release studies carried out in phosphate buffer (pH 6.6) indicated that the drug transport was of Fickian type. Gamma scintigraphic imaging in rabbits after i.n. administration showed rapid localization of the drug in the brain. Hence, OND SLNs is a promising nasal delivery system for rapid and direct nose-to-brain delivery.     

Valproic acid-hydrophilic cyclodextrin complexes and valproic acid-solid dispersions: evaluation of their potential pharmaceutical use

The purpose of this study was to evaluate the potential use of two novel solid formulations of valproic acid (VPA) prepared by complexation with hydrophilic cyclodextrins (CDs) as hydroxypropyl-β- and sulfobutylether-β-cyclodextrin and by solid dispersion (SD) in hydrophilic carriers as polyethylene glycol 6000 (PEG 6000) and polyvinylpyrrolidone K-30 (PVP K-30). The corresponding cyclodextrin-based complexes were prepared by the freeze-drying method while the solid dispersions were obtained by the solvent method. Valproic acid solubility improved by CDs complexation and solid dispersion techniques. Comparison of dissolution profiles with that of VPA sodium salt (NaVP) was made by using release parameters such as dissolution efficiency, percent of drug dissolved after 60 min, and difference and similarity factors. Based on difference and similarity factors, it can be concluded that all the VPA formulations possess dissolution profiles essentially equivalent to those of NaVP at pH 6. However, this conclusion is not confirmed by using the analysis of variance (ANOVA) approach, indicating some significant differences between some SD-based formulations and NaVP at that pH value. Preliminary pharmacological studies in the pentylenetetrazole test in rats showed some important differences among the SD-based formulations, NaVP, and VPA as oil/water emulsion. Some implications and limitations of the investigated formulations are discussed.