国产盐酸头孢他美酯的制备

盐酸头孢他美酯系-口服前体药,口服后在体内迅速水解为具有抗菌活性的头孢他美。本文报道头孢他美及其新戌酰氧甲酯的制备。以7-氨基-3-脱乙酰氧基头孢烷酸(7-ADCA)为原料．在C7-NH。位置上用活性酯法与侧链化合物2-(2-氨基-4-噻唑基)-2-甲氧亚胺基乙酸缩合得到头孢他美．然后在Cz—COOH位置上用新戌酰卤甲酯进行酯化得头孢他美酯．再制成盐酸盐以改善其口服吸收性。以7-ADCA为基准．总合成收率在80％在上,产物为高纯度结晶性粉末。国产头孢他美酯将在今年推向市场。     

LC method for the analysis of cefetamet pivoxil hydrochloride in drug substance and powder for oral suspension

A high-performance liquid chromatography isocratic procedure was developed for the assay of cefetamet pivoxil hydrochloride in drug substance and powder for oral suspension. The method validation yielded good results and included the range, linearity, precision intra- inter-day, accuracy, specificity, LOD and LOQ values. The chromatographic system consisted of a C(18) absorbosphere column (150 x 4.6 mm i.d., 5 microm particle size), a mobile phase composed of water-acetonitrile-methanol-phosphate buffer, pH 3.5 (50:35:10:5, v/v), flow rate of 1.5 ml min(-1) and UV detection at 254 nm. The relative standard deviation varied between 0.03 and 1.76%, and accuracy of 100.09% was found. Calibration curve was linear from 30.0-80.0 microg ml(-1); its correlation coefficient was 0.99989.     

Formulation,evaluation and 32 full factorial design-based optimization of ondansetron hydrochloride incorporated taste masked microspheres

Abstract

Context: Masking the bitter taste of Ondansetron hydrochloride (ONS) may improve palatability, acceptance and compliance of ONS products.

Objective: ONS-loaded, taste-masked microspheres were prepared with a polycationic pH-sensitive polymer and 3² full factorial design (FFD) was applied to optimize microsphere batches.

Materials and methods: Solvent evaporation, in acetone--methanol/liquid paraffin system, was used to prepare taste-masked ONS microspheres. The effect of varying drug/polymer (D/P) ratios on microspheres characteristics were studied by 3² FFD. Desirability function was used to search the optimum formulation. Microspheres were evaluated by FTIR, XRD and DSC to examine interaction and effect of microencapsulation process. In vitro taste assessment approach based on bitterness threshold and drug release was used to assess bitterness scores.

Results: Prepared ONS microspheres were spherical and surface was wrinkled. ONS was molecularly dispersed in microspheres without any incompatibility with EE100. In hydrochloric acid buffer pH 1.2, ONS released completely from microsphere in just 10?min. Contrary to this, ONS release at initial 5?min from taste-masked microspheres was less than the bitterness threshold.

Conclusion: Full factorial design and in vitro taste assessment approach, coupled together, was successfully applied to develop and optimize batches of ONS incorporated taste-masked microspheres.     

Design,statistical optimisation,characterisation and pharmacodynamic studies on Pioglitazone hydrochloride floating microparticles

Abstract

The purpose of this study was to develop floating microparticles containing Pioglitazone HCl, for controlled release and perform pharmacodynamic studies. The FTIR and DSC studies revealed that there is no interaction between drug and excipients used. The 2² factorial design was employed to evaluate the effect of drug: polymer (total) and Eudragit RS 100: Eudragit RL 100. The floating microparticles were prepared by solvent evaporation technique. The predicted and actual values of drug release at 1?h, 8?h and drug entrapment were 38.307%, 77.76%, 84.25% and 38.712%, 76.237% and 84.62%, respectively. XRD and SEM studies showed reduced crystallinity of drug and spherical microparticles. Buoyancy studies revealed good floating of particles for 12?h. Pharmacodynamic studies showed significant reduction in blood glucose levels in male New Zealand rabbits. The results demonstrate the feasibility of the factorial design in successfully developing floating microparticles of Pioglitazone HCl for controlled release.     

吸入粉雾剂的处方研究和制备工艺

吸入粉雾剂在治疗肺部疾病,如哮喘、慢性阻塞性肺病中应用广泛.文中广泛查阅欧盟、美国等国的吸入粉雾剂研发的要求,结合国内该剂型的研发和审批情况,对吸入粉雾剂的组成、处方筛选以及制备工艺进行详细的阐述.对吸入粉雾剂在处方筛选与制备过程中的影响因素加以详细讨论,为研发粉雾剂药学工作者提供有益的参考.     

盐酸头孢他美酯体内和体外抗菌作用研究

目的评价盐酸头孢他美对临床常见致病菌的体外和体内抗菌作用。方法采用试管二倍稀释法测定最低抑菌浓度（MIC）,同时与对照药头孢克洛进行对比。结果头孢他美对革兰氏阳性菌如乙型溶血性链球菌、肺炎链球菌有较强的抗菌活性,MICso均为0．25μg／mL;对革兰阴性菌如淋球菌、肺炎克雷伯杆菌、痢疾杆菌、流感嗜血杆菌也有较强的抗菌活性,MIC50分别为0．25、0．5、0．5和0．5μg／mL。头孢他美酯口服给药对金葡菌、大肠埃希菌感染小鼠有明显的保护作用,其ED50分别为24．6和9．3mg／kg,头孢他美酯对金葡菌的抗菌活性弱于头孢克洛,但对大肠埃希菌的抗菌活性强于头孢克洛。结论头孢他美和头孢他美酯对临床常见致病菌有良好的抗菌作用。     

布洛芬缓释干混悬剂的制备及大鼠体内药代动学研究

目的 制备布洛芬口服缓释干混悬剂,以期为一些吞咽困难的患者提供自主给药、方便的新剂型.方法 采用湿法制粒技术制备含药微粒,分别以累积释放度、沉降体积比和再分散性为评价指标筛选缓释载体种类及比例、助悬剂种类及用量,制备布洛芬口服缓释干混悬剂,并对其大鼠体内药动学进行研究.结果 布洛芬(ibuprofen,IBU)缓释干混...     

Preparation and characterization of a powder containing an oily liquid drug with Eudragit EPO or L100 copolymer

Oily liquid drugs are not convenient for oral administration. We developed a powder containing clofibrate (CF), a model of an oily drug, using aminoalkyl methacrylate copolymer (EPO) or methacrylic acid copolymer (L100). CF or a mixture of CF and soybean oil was emulsified with EPO or L100 aqueous solution. Using a high-pressure homogenizer, a stable emulsion was obtained, and a powder was then obtained by lyophilization of the emulsion. The content of CF in the powder depended on the formulation, with the highest contents being 24.6% and 27.1% for EPO and L100, respectively. The incorporation ratio of CF was higher for L100 than for EPO. The powder using EPO was sticky because of leaked CF and the low glass transition temperature of EPO. The powder using L100 was a typical powder obtained by lyophilization. The leakage of CF from the powder was <2%, lower than for EPO powder. The dissolution of CF from powder using EPO was fast, regardless of the pH of the medium, but the powder using L100 showed enteric-soluble characteristics, indicating that CF is well incorporated in L100.     

The influence of pH, temperature and buffers on the degradation kinetics of cefetamet pivoxil hydrochloride in aqueous solutions

The first-order hydrolysis kinetics of cefetamet pivoxil (CP) were investigated as a function of pH, temperature and buffers. The degradation was followed by HPLC. Buffer catalysis was observed in acetate and phosphate buffers. The pH–rate profiles for hydrolysis of cefetamet pivoxil were obtained at 333, 343, 353 and 363 K. The pH–rate expression was k_pH=k_H⁺a_H⁺+k_H2Ok_OH⁻a_OH⁻, where k_H⁺ and k_OH⁻ are the second-order rate constants (mol⁻¹ l s⁻¹) for hydrogen ion activity and for hydroxyl ion activity respectively, and k_H2O is the pseudo-first-order rate constant (s⁻¹) for spontaneous reaction under the influence of water. The pH–rate profile was characteristically U-shaped. Maximum stability was observed in the pH region from 3 to 5.     

Formulation and evaluation of a sustained-release tablets of metformin hydrochloride using hydrophilic synthetic and hydrophobic natural polymers

Metformin hydrochloride has relatively short plasma half-life, low absolute bioavailability. The need for the administration two to three times a day when larger doses are required can decrease patient compliance. Sustained release formulation that would maintain plasma level for 8-12 h might be sufficient for daily dosing of metformin. Sustained release products are needed for metformin to prolong its duration of action and to improve patient compliances. The overall objective of this study was to develop an oral sustained release metformin hydrochloride tablet by using hydrophilic Eudragit RSPO alone or its combination with hydrophobic natural polymers Gum copal and gum damar as rate controlling factor. The tablets were prepared by wet granulation method. The in vitro dissolution study was carried out using USP 22 apparatus I, paddle method and the data was analysed using zero order, first order, Higuchi, Korsmeyer and Hixson-Crowell equations. The drug release study revealed that Eudragit RSPO alone was unable to sustain the drug release. Combining Eudragit with gum Copal and gum Damar sustained the drug release for more than 12 h. Kinetic modeling of in vitro dissolution profiles revealed the drug release mechanism ranges from diffusion controlled or Fickian transport to anomalous type or non-Fickian transport. Fitting the in vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release.     

Formulation development and evaluation of lidocaine hydrochloride loaded in chitosan-pectin-hyaluronic acid polyelectrolyte complex for dry socket treatment

The main purpose of this study was to assess a lidocaine hydrochloride-loaded chitosan-pectin-hyaluronic polyelectrolyte complex for rapid onset and sustained release in dry socket wound treatment. Nine formulations (LCs) of lidocaine hydrochloride (LH) loaded into a chitosan–pectin–hyaluronic polyelectrolyte complex (PEC) were assessed using full factorial design (two factors × three levels). The formulations ranged between 4 and 10% w/w LH and 0.5–1.5% w/w HA. The following physicochemical properties of LCs were characterized: size, zeta potential, % entrapment efficiency, viscosity, mucoadhesiveness, % drug release, morphology, storage stability, and cytotoxicity. The particle size, zeta potential, % EE, viscosity, and % mucoadhesion increased with increasing LH and HA concentrations. Rapid release of LH followed a zero-order model, and a steady-state percentage of the drug was released over 4 h. LCs were found to be non-cytotoxic compared to LH solution. LH loaded into PEC demonstrated appropriate characteristics—including suitable rate of release—and fit a zero-order model. Furthermore, it was not cytotoxic and showed good stability in a high-HA formula, making it a promising candidate for future topical oral formulations.     

Formulation and Evaluation of Controlled Release Floating Microballoons of Stavudine

The aim of this study was to formulate and evaluate stavudine floating microballoons for controlled drug release. Initially, the drug-loaded low-density granular pellets were prepared with hydroxypropyl methylcellulose E5 grade and by using isopropyl alcohol as a granulating fluid. Further, the low-density granular pellets were subjected to microencapsulation by an emulsion evaporation technique using ethyl cellulose 7 cps and Eudragit S 100 as coating polymers and 1% w/v polyethylene glycol 400 as aqueous phase. The prepared microballoons were characterized for their particle size analysis, angle of repose, and compressibility index. The in vitro release studies were performed in 0.1 N HCl as medium. The prepared microballoons were free-flowing and spherical in shape. From all the formulations, F5E and F5F can be considered as promising controlled release floating microballoons of stavudine providing first-order release over a period of 12 hours, with a minimum floating lag time of 1 minute. It was found that the ratio of the drug & polymer, stirring speed, and concentration of surfactant were the most significant variables which influenced the size of the stavudine microballoons under the applied experimental conditions.     

Formulation development and evaluation of pioglitazone hydrochloride self-emulsifying drug delivery systems

As a widely prescribed anti diabetic drug, pioglitazone belongs to class IΙ under BCS and exhibits low and variable oral bioavailability due to its poor aqueous solubility. Its oral absorption is dissolution rate limited, and its solubility and dissolutionrate need to be enhanced in order to increase its oral bioavailability. In the present study, we aimed to screen various oils, surfactantsand cosolvents. The highest solubility was observed in Labrafac, Tween-80 and propylene glycol. Then the feasibility of formulatingpioglitazone SEDDS was evaluated, and the effect of dilution on the dissolution rate and dissolution efficiency of pioglitazone was also analyzed. A comparative evaluation of pioglitazone from SEDDS was made in SGF and 1% SLS. Dissolution of pioglitazone from SEDDS was rapid and higher compared with pure drug. The rate and extent of release of pioglitazone hydrochloride from stable SEDDS (F1) were higher in 1% SLS compared with SGF. The FTIR spectra proved that there was on chemical interaction between excipients and drug. SEM studies confirmed that the size was small and spherical.     

Development of matrix type transdermal patches of lercanidipine hydrochloride: physicochemical and in-vitro characterization

Background and the purpose of the study

Lercanidipine hydrochloride (LRDP) is used in the treatment of hypertension because of its selectivity and specificity on the smooth vascular cells. The pharmacokinetic parameters make LRDP a suitable candidate for transdermal delivery. The purpose of the study was to select a suitable formulation for the development of transdermal drug-delivery system (TDDS) of LRDP and to determine the effect of penetration enhancer, limonene on drug permeation

Methods

The matrix type TDDS of LRDP were prepared by solvent evaporation technique. Formulations A1, A2, A3, A4, A5 and A6 were composed of Eudragit RL100 (ERL) and hydroxypropyl methyl cellulose (HPMC) in 1.5:8.5, 3:7, 4:6, 6:4, 7:3 and 8.5:1.5 ratios respectively. All the six formulations carried 10 mg of LRDP/patch area, 8% v/w of d-limonene as a penetration enhancer, 20% v/w of propylene glycol as plasticizer in methanol and dichloromethane as solvent system. The prepared TDDS were evaluated for physicochemical characteristics, in-vitro release, ex-vivo permeation and skin irritation. The ex-vivo permeation studies were carried out across excised rat skin using Franz diffusion cell.

Results

All the formulations exhibited satisfactory physicochemical characteristics. Cumulative percentage of the drug released in 24 hrs from the six formulations were 82.0%, 74.9%, 63.2%, 63.5%, 59.8% and 53.5% respectively. Corresponding values for the cumulative amounts of the drug permeated across the rat skin for the above matrix films were 2644.5, 2347.2, 2249.5, 1933.4, 2021.5 and 1663.4 µg/cm² respectively. By fitting the data into zero order, first order and Higuchi model, it was concluded that drug release from matrix films followed Higuchi model and the mechanism of the drug release was diffusion mediated. The patches were seemingly free of potentially hazardous skin irritation.

Conclusions

The patches composed of ERL, HPMC (1.5:8.5) with 8% v/w limonene as penetration enhancer may be selected for the development of TDDS of LRDP for potential therapeutic use by using a suitable adhesive layer and backing membrane.     

Formulation of novel dry powder inhalation for fluticasone propionate and salmeterol xinafoate with capsule-based device

The aim of this study was to develop a novel fluticasone propionate (FP) and salmeterol xinafoate (SX)-loaded dry powder inhaler (DPI) system, which was composed of powder formulation and performance. The air flow resistances were determined with various types of DPI device, showing that the modified RS01 device gave the specific resistance similar to the commercial DPI device. The particle properties of FP, SX, and inhalation grade lactose particles, such as particle size, size distribution, and fine content, were assessed. Subsequently, the aerodynamic behaviors of the DPI powder formulations were evaluated by the in vitro deposition of drugs in the DPI products using Andersen cascade impactor. Amongst the DPI powder formulations tested, the formulation composed of FP, SX, Respitose^® SV003, Respitose^® SV010, and Respitose^® ML006 at the weight ratio of 0.5/0.145/19/19/2 gave depositions, emitted dose, fine particle dose, fine particle fraction, and mass median aerodynamic diameter of drugs similar to the commercial product, suggesting that they had similar aerodynamic behaviors. Furthermore, it gave excellent content uniformity. Thus, this DPI using the modified RS01 device would be recommended as a candidate for FP and SX-loaded pharmaceutical DPI products.     

Formulation development and systematic optimization of stabilized ziprasidone hydrochloride capsules devoid of any food effect

Context and objective: The objective of the study was to develop a stable capsule formulation of ziprasidone hydrochloride which can be administered without regards to food intake.

Materials and methods: The unstable anhydrous form of ziprasidone hydrochloride was stabilized employing hot-melt extrusion and further optimized by 3² central composite design. The formulation was optimized after establishing acceptable ranges for response variables like disintegration time, dissolution and impurity profile. A crossover fasted and fed in vivo study was conducted in human volunteers to assess the food-effect of optimized formulation vis-à-vis the marketed brand.

Results and discussion: The optimized formulation met in-house specifications for various response variables. Further, high values of correlation coefficient vouch the adequate selection of experimental design and its high prognostic ability. In our study, no significant difference was observed between the C_max and AUC values after administration of the optimized formulation in fasted and fed states. On the contrary, there was a statistically significant increase in the C_max and AUC values after oral administration of Zeldox in fed state in comparison to fasted state.

Conclusions: The present study describes the successful development of a stable formulation of 20?mg of ziprasidone devoid of any food-effects.     

Formulation and process development of (recombinant human) deoxyribonuclease I as a powder for inhalation

A formulation and process development study was performed to formulate recombinant human deoxyribonuclease I as a powder for inhalation. First, excipient compatibility (with bovine DNase as a model substance) was examined with a stability study at stressed conditions (60 and 85°C) while monitoring for occurrence of the Maillard reaction. Next, powders for inhalation were prepared by spray drying and spray freeze drying. We found that spray drying with inulin as stabilizer resulted in the best powder for inhalation. Finally, an ex-vivo test with the spray dried rhDNase I/inulin powder significantly decreased elastic and viscous moduli of sputum from five cystic fibrosis patients.     

Equilibrium and release properties of aqueous dispersions of non-steroidal anti-inflammatory drugs complexed with polyelectrolyte eudragit e 100

Equilibria and release properties of aqueous systems consisting of a set of five non-steroidal anti-inflammatory drugs (AH) complexed with the cationic polymethacrylate Eudragit E 100 (EU) are reported in this study. The composition (EU(AH)(50) (HCl)(50)) having fifty mole percent of each counterion (A(-) and Cl(-)) produces clear, stable aqueous dispersions in which a remarkably high proportion of AH (higher than 98%) is condensed with the PE under the form of ion pairs. This property expands the interval of pH in which AH are aqueous soluble. The set of AH contains members with and without an alpha methyl group (-(CH(3))CH-COOH: Flurbiprofen, Naproxen, Ketoprofen) and (-CH(2)-COOH: Diclofenac, Indomethacin). The proportion of ion pairs in the complexes was lower in the former group. Release of AH from the complexes toward a saline (NaCl 0.9%) solution was assayed in Franz cells. The five complexes behaved as drug carriers that exhibited a slow drug release with a remarkable zero order. In line with the percentages of counterionic condensation observed, release rates from -(CH(3))CH-COOH complexes were clearly higher than those of -CH(2)-COOH ones.     

Air classifier technology (ACT) in dry powder inhalation Part 3. Design and development of an air classifier family for the Novolizer multi-dose dry powder inhaler

In this study, the design of a multifarious classifier family for different applications is described. The main design and development steps are presented as well as some special techniques that have been applied to achieve preset objectives. It is shown by increasing the number of air supply channels to the classifier chamber (from 2 to 8), that the fine particle losses from adhesion onto the classifier walls can be reduced from 75% to less than 5% of the real dose for soft (spherical) agglomerates. By applying a bypass flow that is arranged as a co-axial sheath of clean air around the aerosol cloud from the classifier, the airflow resistance of the classifier can be controlled over a relatively wide range of values (0.023-0.041 kPa(0.5) min l(-1)). This, without affecting the fine particle dose or increasing the fine particle losses in the inhaler. Moreover, the sheath flow can be modelled to reduce the depositions in the induction port to the cascade impactor or in the patient's mouth, which are the result of back flows in these regions. The principle of powder induced pressure drop reduction across a classifier enables assessment of the amount of powder in the classifier at any moment during inhalation, from which classifier loading (from the dose system) and discharge rates can be derived. This principle has been applied to study the residence time of a dose in the classifier as function of the carrier size fraction and the flow rate. It has been found that this residence time can be controlled in order to obtain an optimal balance between the generated fine particle fraction and the inhalation manoeuvre of the patient. A residence time between 0.5 and 2 s at 60 l/min is considered favourable, as this yields a high fine particle dose (depending on the type of formulation used) and leaves sufficient inhaled volume for particle transport into the deep lung.