Surface Characterisation df Sucrose and Antibiotics Powder Mixes with Relevance to Mixing Theories

Adhesional ordered mixing is not applicable in real systems because ordered interaction between drug and excipient particles can not be achieved. In contrary, Interactive Mixture approach is more applicable because it allows the powder mixtures to be described according to the state of homogeneity achieved which is dependent on mixing variables.

Surface characteristics of powder mixture particles are important to study in order to understand the interparticulate interactions between drug and excipient particles.

Indentations on excipient particles act as mechanical entrapment sites for drug particles which result in areas containing highly localised drug content. Consequently, the state of homogeneity of powder mixtures is possibly affected. Furthermore, the release of particles which are entrapped will be different from those held by interparticulate forces on the plain surfaces of excipient particles. This is particularly important when the excipient particles are insoluble and drug particles are poorly soluble.     

In Vitro Evaluation of Polyisobutylcyanoacrylate Nanoparticles as a Controlled Drug Carrier for Theophylline

Theophylline nanoparticles were prepared by emulsifier-free emulsion polymerization technique in continuos aqueous phase. The polymerization process was carried out at a pH 3. Different concentrations of isobutylcyacoacrylate (IBCA) were used to investigate the effect of monomer concentration. The in vitro release of theophylline in phosphate buffer was studied. An HPLC assay was used to follow the release of the drug from the nanospheres. This polymerization technique was able to hold 2349% of the drug initially dissolved in the aqueous medium. The percentage drug loading is a monomer concentration dependent. Increasing the monomer concentration above 40 μL per mL resulted in a less significant increase in the percentage drug loading. The percentage of drug retained in nanospheres up to 24 hr followed first order kinetics (r = 0.94-0.98). The release rate constant of theophylline from nanoparticles is inversely related to the monomer concentration in the initial solution (r = 0.996). In the mean time the release rate constant of theophylline from the nanoparticles was directly related to the amount of the drug added initially (r = 0.990).     

中空聚合物乳胶粒子的合成与结构控制——(Ⅰ)核层乳胶粒的制备及其影响

以甲基丙烯酸/丙烯酸酯/苯乙烯为共聚单体,采用多步种子乳液聚合与碱溶胀的方法制备了中空聚合物乳液微球,通过透射电镜(TEM)和激光粒度仪表征了复合乳液的微相形态,着重研究了核层乳胶粒的制备过程及其影响规律,以及对中空聚合物微球结构的影响。结果表明,核层甲基丙烯酸(MAA)用量在10%~30%,乳化剂用量为单体用量的0.8%~1.2%,通过饥饿态进料的种子乳液聚合方法可制备粒径均一核层乳胶粒,可用于制备理想结构的中空聚合物微球。     

Mechanism of Transdermal Controlled Nitroglycerin Administration (III) Control of Skin Permeation Rate and Optimization

A mathematical model was developed to correlate the drug permeation rate through the skin with the drug release rate from a matrix-type drug delivery system. Experiments were carried out using hairless mouse abdominal skin mounted on a recently-developed and hydrodynamically well-calibrated Keshary-Chien skin permeation system. A matrix-type drug delivery system was designed to contain different loading doses of nitroglycerin and to study the effect of drug loading variation on the rate of drug release, the rate of skin permeation and the equilibrium concentration of nitroglycerin in the skin.

Results indicated that the stratum corneum plays a significant rate-limiting role in the skin permeation of nitroglycerin across the intact skin, yielding a constant skin permeation profile. The permeation rate across the intact skin was observed to increase with the increase in the drug release flux initially and then levelled off in a hyperbolic fashion. Various constants were obtained from the reciprocal plot of skin permeation rate vs. drug release flux. These constants could be used for the prediction of the skin permeation rate. A very good correlation between the predicted and the observed values of skin permeation rates was observed.

After the stratum corneum was removed by stripping technique, the mechanism and the rate of skin permeation became dominated by the mechanism and the release rate of the delivery system.

A linear correlation was observed between the drug permeation rate through the skin and the equilibrium concentration of drug in the skin. This correlation was observed in both intact and viable skins.     

Cellulose Acetate Trimellitate Microspheres Containing NSAIDS

Indomethacin and ketoprofen (non-steroidal anti-inflammatory drugs) were incapsulated with cellulose acetate trimellitate, enteric polymer, using a spray drying technique.

Organic solutions of polymer and drug were prepared in different weight ratios and sprayed, achieving drug loaded microspheres.

The obtained spray dried microparticles were characterized in terms of yield of production, shape, size, morphological characteristics and drug content.

The in vitro drug release tests, carried out using a pH change method with a flow-through cell apparatus, show a typical delayed drug release due to the pH-dependent solubility of the polymer.     

In Vitro Evaluation of Polyisobutylcyanoacrylate Nanoparticles as a Controlled Drug Carrier for Theophylline

Abstract

Theophylline nanoparticles were prepared by emulsifier-free emulsion polymerization technique in continuos aqueous phase. The polymerization process was carried out at a pH 3. Different concentrations of isobutylcyacoacrylate (IBCA) were used to investigate the effect of monomer concentration. The in vitro release of theophylline in phosphate buffer was studied. An HPLC assay was used to follow the release of the drug from the nanospheres. This polymerization technique was able to hold 2349% of the drug initially dissolved in the aqueous medium. The percentage drug loading is a monomer concentration dependent. Increasing the monomer concentration above 40 μL per mL resulted in a less significant increase in the percentage drug loading. The percentage of drug retained in nanospheres up to 24 hr followed first order kinetics (r = 0.94-0.98). The release rate constant of theophylline from nanoparticles is inversely related to the monomer concentration in the initial solution (r = 0.996). In the mean time the release rate constant of theophylline from the nanoparticles was directly related to the amount of the drug added initially (r = 0.990).     

微波辐射乳液聚合制备磁性高分子微球

用化学共沉淀法制备了Fe3O4纳米粒子,并用油酸和十二烷基硫酸钠对Fe3O4纳米粒子进行表面修饰,得到了稳定的水分散性纳米Fe3O4磁流体。在Fe3O4磁流体存在下,以苯乙烯和丙烯酰胺为单体,采用微波辐射乳液聚合法制备了Fe3O4/聚(苯乙烯-丙烯酰胺)磁性高分子微球,表征了磁性高分子微球的形态与结构,研究了磁性高分子微球的粒径、热稳定性、磁含量与饱和磁化强度。研究发现,在选定合适的聚合条件下,通过微波辐射乳液聚合法可以制得粒径为70 nm~80 nm、磁含量为18.2%的磁性高分子微球。     

Effect of Granulating Method on Content Uniformity and Other Physical Properties of Granules and their Corresponding Tablets. II

Various properties of dexamethasone and sulfadiazine granules and tablets prepared by microgranulation, slugging, wet granulation and direct compression were compared.

The dexamethasone tablets showed comparable disintegration rates by all methods. The sulfadiazine tablets prepared by slugging did not meet the USP XIX limit, whereas those by microgranulating were satisfactory.

It was found that granule-homogeneity was not only dependent on the particle size and distribution, but also dependent on the granulating method. For either drug, the microgranulating procedure gave the best weight and content uniformity.     

梯度核壳结构硅丙乳液的聚合

采用单体浓度梯度加入法合成了具有梯度壳层的核壳结构,可用于木器涂料的硅丙乳液。考察了乳化体系、聚合工艺、有机硅预聚物的引入、软/硬单体比等因素对乳液和漆膜性能的影响,用透射电镜测定了乳胶粒子形态。研究表明:OP-10/SDS/MS-1为最佳乳化体系,有机硅预聚物与其他单体一次性混合引入,软/硬比为1∶2时,所制得乳液的综合性能良好。固含量为45%,成膜温度为48℃,附着力为1级,硬度为2H,乳胶粒子有明显的核壳结构。     

Evaluation of Spray-Drying as a Method to Prepare Microparticles for Controlled Drug Release

The possibility to obtain microcapsules or microspheres for controlled release by spray-drying is evaluated. Drugs of different solubilities like theophylline and sodium sulfamethazine, with Eudragit RS as coating polymer, are chosen.

The polymer is used, either dissolved in an hydroalcoholic solution or suspended (pseudolatex) in water, in different weight ratios with the drug. The obtained solution or suspension is spray-dried.

Scanning electron microscope analysis of the powders reveals no sign of microencapsulation. Moreover, only a fraction of the particles has a spherical shape.

For each spray-dried powder, a part of the obtained particles is compressed into tablets, and the rest is stored.

Dissolution studies in distilled water at 37 C are performed on powders and tablets.

While the uncompressed microparticles do not give any controlled release, the tablets show an ability in slowing down drug delivery greater than the one obtained with the traditional methods.     

Carbamazepine Modified Release Dosage Forms

The preparation of sustained release dosage forms of Carbamazepine (anti-epileptic drug characterized by a very low water solubility and by a short half life on chronique dosing) was carried out.

These formulations were obtained in two different steps:

a) modified release granules were prepared by the loading of cross-linked sodium carboxymethylcellulose (swellable polymer), with the drug and an enteric polymer. Cellulose acetate phthalate, methacrylic acid - methacrylic acid methyl ester copolymer (usually employed as enteric coating agents) and cellulose acetate trimellitate (a new enteric polymer) were used in different weight ratios.

b) some sustained release dosage forms were prepared tabletting physical mixtures of the modified release granules with different weight ratios of hydroxypropylmethylcellulose.

In vitro dissolution tests of modified release granules in gastric fluid (USP XXI) showed a modulation of the drug release, while in intestinal fluid (USP XXI) a quick drug dissolution was observed.

In vitro dissolution tests of sustained release dosage forms, performed varying during the test, the pH of the dissolution medium, (hydrochloric acid pH 1 from 0 to 2 hours and phosphate buffer pH 6.8 from 2 to 18 hours) showed that the determining factors in the controlling release of the drug are: the type and amount of enteric polymer constituting the granules and the amount of hydroxy-propylmethylcellulose mixed with them.     

Influence of Drug Loading and Gel Structure on in-Vitro Release Kinetics from Photopolymerized Gels

Precious work has shown that stabls and homogenous poly HEMA gels can be prepared using a visible light sensitive initiator system. Gels were prepared from solutions of water and poly-2-hydroxyethyl methacrylate monomer. At concentrations of water greater than 10% v/v, translucent gel resulted. However, polymerization solvents such as glycerol and tertiary butyl alcohol (T.B.T.A) gave transparent, flexible gels over a wider range of concentrations. Subsequent work showed that changes in polymerization solvent and monomer concentration brought about changes in the mechanical and structural properties of the gels.

In this work, the effects of drug loading and polymerization solvents on in vitro drug release rate from the photopolymerized polyHEMA gels were studied. Polymerization solvents used included glycerol and tertiary butyl alcohol. Results indicated that the release rate in vitro was a diffusion-controlled process except at high drug concentrations in poly HEMA - T.B.T.A. gels when a departure from root-time kinetics occurred. Poly HEMA T.B.T.A. gels presented greater hindeirance to the mobility of the drug than polyHEMA - glycerol gels. Higuch's model for release from incoluble homogenous matrices containing dispersed solute was found to be inappropriate for the analysis of the release of the drug from the gels. A simple equation based on the modelling of desorption in diffusion was found more appropriate. Estimates of drug release rates in vitro may be made from measurements of the physical crosslinking density of the polymer (if matrix-diffusion controlled release is operative). Quantitative drug loading was achieved in the gels as evidenced from variation in crosslinking density and in vitro release rate with drug loading.     

Preparation and In-Vitro Evaluation of Prolonged Release Tablets of Pheniramine Aminosalicylate

Prolonged release tablets of pheniramine aminosalicylate were prepared from co-precipitates of the drug in different types of Eudragit. The hardness of the tablet had a pronounced effect on the release rate of the drug. Tablets (500 mg, hardness 13 kg) and 375 mg tablets (hardness 6.5 kg) prepared from the co-precipitates containing 15% of the drug in Eudragit L 100, and 20% of the drug in Eudragit S 100 respectively, showed release rate patterns that were in agreement with Lang primary requirements for drug release from sustained release tablets.

Tablets (500 mg) prepared from the co-precipitates containing 15% of the drug in Eudragit L 100 or Eudragit S 100 and 375 mg tablets containing 20% of the drug in Eudragit S 100 showed release rate patterns that were best described by Higuchi equation, indicating that a diffusion controlled mechanism was mainly operative.     

Preparation of ethyl cellulose pseudolatex and studies on suitability of it as a binder for granulation

Ethyl cellulose pseudolatices were prepared by an emulsion-solvent evaporation technique, which consisted of dissolving the polymer in a blend of benzene and ethyl alcohol, followed by the addition of adjuvants. The organic, solvents were removed from the emulsion using vacuum distillation. Physical evaluation of the dispersions and the cast films was carried out.

On the basis of characteristics of cast films selected formulations were fused as granulating agents for preparing chlorpheniramine maleate tablets. Good correlation was observed between total solid in the granulating dispersion and the drug release. The possible mechanisms for the drug release from the tablets are suggested.     

去甲斑蝥素PLA-PEG纳米微球的制备研究

采用复乳法和相分离法两种方法制备去甲斑蝥素的聚乳酸-聚乙二醇嵌段共聚物(PLA-PEG)纳米微球.对比了两种不同方法对制得的含药微球在粒径、包封率以及缓释性能方面的差异.用激光粒度分析仪表征了微球的粒径及其分布,并用透射电镜观察了微球的形貌,其结果表明:复乳法与相分离法制备的微球粒径均在100nm左右,并且成球性好;相对于复乳法,相分离法制备的微球分布较宽,包封率较高,可达到50%左右;体外释放实验表明两种方法制备的微球都具有缓释作用.     

阳离子无皂含氟核壳苯丙乳液的制备及成核机理

在水溶性阳离子单体甲基丙烯酰氧基乙基三甲基氯化铵(DMC)存在下,以乙醇为助溶剂,通过种子半连续核壳乳液聚合法制备阳离子无皂含氟核壳苯丙乳液。考察了水溶性阳离子单体DMC和乙醇用量对乳液聚合过程的影响;用透射电镜(TEM)和X射线光电子能谱(XPS)对聚合物乳液乳胶粒形貌及涂膜化学组成进行表征,并讨论了无皂乳液聚合的成核机理和聚合过程。结果表明,采用种子半连续乳液聚合法,当DMC的质量分数为6.0%,乙醇的质量分数为7.5%(釜液)时,可以得到稳定的阳离子核壳结构含氟乳液,无皂乳液聚合的成核机理是先以均相成核方式后继续以低聚物成核方式进行,最终形成核壳结构。     

Research Papers: Preparation of Indobufen Pellets by Using Centrifugal Rotary Fluidized Bed Equipment Without Starting Seeds

ABSTRACT

Pellets containing Indobufen as model drug were prepared by using the centrifugal-rotary fluidized bed equipment without employing non-pareil seeds.

The influence of different amounts of spheronization enhancer (microcrystalline cellulose) and of different fillers (lactose, mannitol, calcium carbonate) on both processing and physical properties of the pellets were evaluated.

The preparation reproducibility was also investigated. The use of 30% w/w of microcrystalline cellulose was essential to produce a good quality pellets; the incorporation of filler decreased the qualitative characteristics of the pellets.

The water feeding rate proved to be an important parameter for the pellet growth.

Therefore, the results showed that this technology based on the rotary fluidized bed is a promising and alternative method in producing pellets.     

Preparation of codeine-resinate and chlorpheniramine-resinate sustained-release suspension and its pharmacokinetic evaluation in beagle dogs

Using ion exchange resins (IERs) as carriers, a dual-drug sustained release suspension containing codeine, and chlorpheniramine had been prepared to elevate drug safety, effectiveness and conformance. The codeine resinate and chlorpheniramine resinate beads were prepared by a batch process and then impregnated with Polyethylene glycol 4000 (PEG 4000), respectively. The PEG impregnated drug resinate beads were coated with ethylcellulose as the coating polymer and di-n-butyl-phthalate as plasticizer in ethanol and methylene chloride mixture by the Wurster process. The coated PEG impregnated drug resinate beads were dispersed in an aqueous suspending vehicle containing 0.5% w/w xanthan gum and 0.5% w/w of hydroxypropylmethylcellulose of nominal viscosity of 4000 cps, obtaining codeine resinate and chlorpheniramine resinate sustained-release suspension (CCSS).

Codeine phosphate and chlorpheniramine maleate were respectively loaded onto AMBERLITE® IRP 69, and PEG 4000 was used to impregnate drug resinate beads to maintain their geometry. Ethylcellulose with di-n-butyl-phthalate in ethanol and methylene chloride mixture for the coating of drug resinate beads was performed in Glatt fluidized bed coater, where the coating solution flow rate was 8-12 g/min, the inlet air temperature was 50-60°C, the outlet air temperature was 32-38°C, the atomizing air pressure was 2.0 bar and the fluidized air pressure was adjusted as required. Few significant agglomeratation of circulating drug resinate beads was observed during the operation. The film weight gained 20% w/w and 15% w/w were suitable for the PEG impregnated codeine resinate and chlorpheniramine resinate beads, respectively. Residual solvent content increased with coating level, but inprocess drying could reduce residual solvent content.

In the present study, the rates of drug release from both drug resinate beads were measured in 0.05M and 0.5M KCl solutions. The increased ionic strength generally accelerated the release rate of both drugs. But the release of codeine from its resinate beads was much more rapid than chloropheneramine released from its resinate beads in the same ionic strength release medium. The drug release specification of the CCSS, where release mediums were 0.05M KCl solution for codeine and 0.5M KCl solution for chlorpheniramine, was established to be in conformance with in vivo performance.

Relative bioavailability and pharmacokinetics evaluation of the CCSS, using commercial immediate-release tablets as the reference preparation, were performed following a randomized two-way crossover design in beagle dogs. The drug concentrations in plasma were measured by a validated LC-MS/MS method to determine the pharmacokinetic parameters of CCSS. This LC-MS/MS method demonstrated high accuracy and precision for bioanalysis, and was proved quick and reliable for the pharmacokinetic studies. The results showed that the CCSS had the longer value of T_max and the lower value of C_max, which meant an obviously sustained release effect, and its relative bioavailability of codeine and chlorpheniramine were (103.6 ± 14.6)% and (98.1 ± 10.3)%, respectively, compared with the reference preparation. These findings indicated that a novel liquid sustained release suspension made by using IERs as carriers and subsequent fluidized bed coating might provide a constant plasma level of the active pharmaceutical ingredient being highly beneficial for various therapeutic reasons.     

单分散聚苯乙烯乳胶粒的制备及其二维胶体晶体的自组装

以自合成的平均粒径为95.7 nm、粒径分布指数为0.047的聚苯乙烯乳胶粒为种子,采用种子乳液聚合方法制备出单分散的聚苯乙烯乳胶粒,探讨了控制胶粒粒径大小及分布的方法及制备条件.结果表明,在种子乳液聚合中,通过控制单体加入量和乳化剂的补加速度,可以得到单分散聚苯乙烯乳胶粒;当没有新的胶束生成且乳胶粒子没有发生聚结时,乳胶粒尺寸和分布有自身变窄的倾向,得到了平均粒径为261.6 nm、粒径分布指数为0.021的单分散乳胶粒.采用毛细管作用力驱动的微粒自组装技术进行单分散胶粒的组装,获得了二维有序聚苯乙烯胶体晶体,并用场发射扫描电子显微镜表征了其二维有序结构.     

Influence of extrusion-spheronization processing on the physical properties of d-Indobufen pellets containing pH adjusters

d-Indobufen pellets containing pH adjusters (acids, buffer, salt) were prepared by extrusion-spheronization technology.

The interaction effect between some processing variables (feeding/agitator speeds of extruder, plate speed and residence time of spheronizer) was evaluated by comparing the basic formulation pellets with the pellets in which the soluble filler (lactose) was substituted by fumaric, tartaric and citric acids and also sodium citrate.

The criteria of formulation and process evaluation were the reproducibility of the particle size distribution, the density, the hardness and morphological properties, in addition to the reproducibility of the drug dissolution rates.

In all cases, the physical/technological characteristics were not influenced very much by pH adjuster incorporation, but the drug dissolution profiles showed some significant variations in the first hour. As a logical extension of this work, wet granulations with aqueous ethylcellulose and acrylic resin dispersions instead of only water were tested to evaluate the wetting effect of the release modifier inclusion. The results confirmed the validity of polymeric systems in the preparation of pellets and their ability to produce a further delay of d-Indobufen release.