Preparation,characterization and in vitro drug release of isosorbide dinitrate microspheres

Microspheres of isosorbide dinitrate (ISDN) were prepared using the emulsification/solvent evaporation method. The impacts of different factors such as stirring rate, concentration of ethyl cellulose (EC) as matrix polymer, poly vinyl chloride (PVA) as stabiliser and ISDN on the characteristics of the microspheres were investigated. The morphology of microspheres was studied using optical and scanning electron microscopy and it was shown that microspheres had a spherical shape and smooth surface. The particle size distribution of microspheres, analysed by a sieving method, was affected by stirring rate and concentrations of EC, PVA and ISDN. Larger microspheres showed greater drug loading and smaller microspheres showed a faster drug release. The in vitro drug release from microspheres was predictable and reproducible, conforming to the Higuchi model of release kinetics.     

Encapsulation of antihypertensive drugs in cellulose-based matrix microspheres: characterization and release kinetics of microspheres and tableted microspheres

This study is an attempt to prepare microspheres loaded with two anti-hypertensive drugs viz., nifedipine (NFD) and verapamil hydrochloride (VRP) using cellulose-based polymers viz., ethyl cellulose (EC) and cellulose acetate (CA). Emulsification and solvent evaporation methods were optimized using ethyl acetate as a dispersing solvent. The particles are spherical in shape and have smooth surfaces, as evidenced by the scanning electron microscopy. The microspheres were characterized for their particle size and distribution, tapped density and encapsulation efficiency. Smaller sized particles with a narrow size distribution were produced with EC when compared to CA matrices. Molecular level drug distribution in the microspheres was confirmed by differential scanning calorimetry. The microspheres were directly compressed into tablets using different excipients. The drug release from CA was faster than EC microspheres and, also, the VRP release was faster than NFD. The excipients used in tableting showed an effect on the release as well as the physical properties of the tablets.     

In vitro modified release of acyclovir from ethyl cellulose microspheres

The aim of this study was to demonstrate a sustained-release microparticulate dosage form for acyclovir via an in vitro study. Ethyl cellulose was selected as a model encapsulation material. All of the microspheres were prepared by an oil-in-water solvent evaporation technique. A 2³ full factorial experiment was applied to study the effects of the viscosity of polymer, polymer/drug ratio, and polymer concentration on the drug encapsulation efficiency and the dissolution characteristics. The encapsulation efficiency of acyclovir in microspheres was in the range of 20.0-56.6%. Increase in the viscosity of ethyl cellulose and the ratio of CH₂Cl₂/ethyl cellulose increased drug encapsulation efficiency. The drug continuously released from microspheres for at least 12 h, and the release rate depended on the pH of the release medium. The sustained release characteristic was more prominent in the simulated intestine fluid than in the simulated gastric fluid. A faster release of drug was observed when a high viscosity polymer was used. The decomposition of acyclovir significantly decreased when encapsulated by ethyl cellulose, especially when stored at 37 and 50 °C.     

Study of processing parameters influencing the properties of diltiazem hydrochloride microspheres

Diltiazem hydrochloride-ethylcellulose microspheres were prepared by the water-in-oil emulsion-solvent evaporation technique. Small and spherical microspheres having a mean microsphere diameter in the range of 40-300 microm and entrapment efficiency of approximately 60-90% were obtained. Scanning electron micrographs of drug-loaded microspheres showed the presence of uniformly distributed small pores and absence of drug crystals on their surface, indicating simultaneous precipitation of drug and the polymer from the solvent during solvent evaporation. Differential scanning calorimetric analysis confirmed the absence of any drug-polymer interaction. The in vitro release profile could be altered significantly by changing various processing parameters to give a controlled release of drug from the microspheres. The stability studies of the drug-loaded microspheres showed that the drug was stable at storage temperatures, 5-55 degreesC, for 12 weeks.     

The influence of magnesium stearate on the characteristics of mucoadhesive microspheres

Microspheres containing the mucoadhesive polymer chitosan hydrochloride, with matrix polymer Eudragit RS, pipemidic acid as a model drug and agglomeration preventing agent magnesium stearate were prepared by the solvent evaporation method. The amount of magnesium stearate was varied and the following methods were used for microsphere evaluation: sieve analysis, drug content and dissolution determination, scanning electron microscopy, xray diffractometry, DSC and FTIR spectroscopy. The results showed that average particle size decreased with increasing amount of magnesium stearate used for microsphere preparation. This is probably a consequence of stabilization of the emulsion droplets with magnesium stearate. Higher pipemidic acid content in the microspheres was observed in larger particle size fractions and when higher amounts of magnesium stearate were used. It was also found that these two parameters significantly influenced the dissolution rate. The important reason for the differences in drug content in microspheres of different particle sizes is the diffusion of pipemidic acid from the acetone droplets in liquid paraffin during the preparation procedure. The physical state of pipemidic acid changed from crystalline to mostly amorphous with its incorporation in microspheres, as shown by x-ray diffractometry and differential     

The influence of stirring rate on biopharmaceutical properties of Eudragit RS microspheres

Eudragit RS microspheres containing pipemidic acid, as a model drug, were prepared by the solvent evaporation method using an acetone/liquid paraffin solvent system. The aim of the work was to evaluate the influence of stirring rate on the average particle size, particle morphology, drug content and release kinetics, as well as the influence of particle size on microsphere morphology, drug content and release kinetics. Stirring rate has been found to significantly influence the average diameter of microspheres. The average diameter decreases as the stirring rate increases. This can be explained by production of a finer dispersion of droplets when higher stirring rates are applied and, consequently, by the formation of smaller microspheres. With increasing stirring rate and increasing fraction particle size the drug content also increases. It is assumed that this dependence is a consequence of an uneven diffusion of the drug from the inner to the outer emulsion phase, and an uneven encapsulation of drug particles during the preparation. Drug release follows the Higuchi model. As seen from SEM photographs, larger microspheres are more porous and the microspheres produced at higher stirring rates are more porous than those produced at lower stirring rates. This explains the unexpected finding that the release rate increases as the fraction particle size and the stirring rate increase.     

Modelling of the solvent evaporation method for the preparation of controlled release acrylic microspheres using neural networks

The purpose of the present study was to model the solvent evaporation procedure for the preparation of acrylic microspheres by using artificial neural networks (ANNs) to obtain an understanding of the selected preparative variables. Three preparative variables, the concentration of the dispersing agent (sucrose stearate), the stirring rate of emulsion system, and the ratio of polymers (Eudragit RS-L) were studied, each at different levels, as input variables. The response (output) variables examined to characterize microspheres and drug release were the size of the microspheres and T 63.2%, the time at which 63.2% of drug is released. The results were also analysed by the multiple linear regression (MLR) to provide a comparison with the ANN methodology. Although both ANN and MLR methods were found to be similar in characterizing the process studied, the results showed that an ANN method gave a better prediction than the MLR method. For the size values of the microspheres, the predictability of the ANN model was quite high (R² = 0.9602) based on the input variables. A relationship between these variables and size values of microspheres was also obtained by the MLR model (R² = 0.9050). The performances of both models for the release data frommicrospheres based on the sameinput variables were at the level of 53%. According to the results, the ANN methodology can provide an alternative to the traditional regression methods, as a flexible and accurate method to study process and formulation factors.     

Ethyl acetate as a dispersing solvent in the production of poly(DL-lactide-co-glycolide) microspheres: effect of process parameters and polymer type

This study deals with the production of poly(DL-lactide-co-glycolide) (PLGA) microspheres using ethyl acetate as a dispersing solvent, a partially water soluble and less toxic solvent, by using emulsification and solvent diffusion/evaporation techniques. PLGA 50 : 50 was used, having molecular weights, 12 000 and 34 000 with the end group capped (RG502, 503) and uncapped (RG502H, 503H) biodegradable polymers. The microspheres were loaded with nifedipine (NFD) as a model drug. Solvent removal from the embryonic microspheres was manipulated by adopting different techniques. These methods have shown a significant effect on the physicochemical and release characteristics of the microspheres. Rapid removal of the solvent resulted in microspheres with a loose matrix and large size. Use of higher molecular weight polymers increased the size of the microspheres as well as delayed release of the drug. The uncapped polymer has given a higher rate of diffusion when compared to the capped polymers. Thermal analyses showed a uniform molecular distribution of the drug in the polymer matrix. The mechanism of drug release from the PLGA microspheres followed the Fickian diffusion.     

Comparison of in vitro and in vivo release characteristics of sustained release ofloxacin microspheres

The sustained release nature of ofloxacin microspheres - to eradicate bacterial biofilm associated with chronic infections from sensitive strains of bacteria - was determined both in vitro and in vivo. Ofloxacin microspheres were prepared by emulsion solvent evaporation procedure using poly(glycolic acid-co-dl-lactic acid) (PLGA) as the biodegradable polymer. The microspheres were characterized by scanning electron microscopy, in vitro release in an incubator, and in vivo release in the rat subcutaneous model. The microspheres were highly spherical with a very smooth surface. Approximately 45% of the drug was released from microspheres in sizes of 125-250 mum and 250-425 mum in 2 days compared with 22% from microspheres of size range 37-125 mum indicating that surface area of the microspheres did not control the kinetics of in vitro release. However, about 96% of the drug was released from the three different size ranges in 35 days. The in vitro release profile of microspheres of size range 125-250 mum is not significantly different from microspheres in sizes of 250-425 mum. The peak plasma level of ofloxacin in animals that received the drug suspension occurred within 2 hr and was higher than that of the microspheres that occurred by the end of the second day. The plasma of animals that received the free drug was depleted of ofloxacin by the end of the first day, but the drug was sustained above 0.5 mug/mL in the plasma of animals that received the microspheres for about 3 weeks. The results suggest that biodegradable ofloxacin microspheres can be prepared that release the antibiotic in vivo for about 3 weeks. This should provide a means for continuous treatment of chronic infections in which bacterial biofilm can occur.     

盐酸地尔硫缓释片产业化研究

目的:探讨盐酸地尔硫缓释片的生产工艺、稳定性,了解临床验证研究结果。方法:分析比较不同工艺阶段影响释放度的因素,进而确定相关工艺参数;考察产品室温贮存的稳定性;采用开放自身对照试验观察本品对轻、中度原发性高血压的临床疗效和耐受性。结果:本品共生产20多批,室温下贮存2~3年,其各项质量指标均在规定范围内。临床验证表明,每日服用本品1次,剂量为1片,降压总有效率为70.37%;剂量为2片,降压总有效率为88.88%。结论:本品生产工艺可行,产品质量稳定,日服1次能获满意血压控制,有良好的耐受性和安全性。     

A Comparative Study of Controlled Release Matrix Tablets of Diclofenac Sodium,Ciprofloxacin Hydrochloride,and Theophylline

The need for controlled release formulations for diclofenac sodium, ciprofloxacin, and theophylline is well recognized. In our study, controlled release tablets of the three drugs were formulated by the matrix-embedding technique using ethyl cellulose as retardant. Tablets of all the drugs were of good physical quality with respect to appearance, drug content uniformity, hardness, weight variation, and friability. In vitro release rate studies showed that ethyl cellulose extended the release of the three drugs to 12 hr or more. Release patterns from formulations of the three drugs followed Higuchi's square root kinetics. At pH 6.8, the release rate was higher in all three drugs, probably due to increased solubility of the drugs and/or increased swelling of ethyl cellulose at the higher pH. The formulations were highly stable and possessed reproducible release kinetics across batches.     

Effects of solvent evaporation rate on the properties of protein-loaded PLLA and PDLLA microspheres fabricated by emulsion-solvent evaporation process

This paper investigated the effects of the rate of solvent removal by varying the ambient pressure at a fixed temperature on the morphology, particle size, encapsulation efficiency and release pattern of albumin-loaded PLLA and PDLLA microspheres, prepared by the W/O/W emulsion-solvent evaporation process. For PLLA microspheres prepared either with a fast rate of solvent evaporation (FRSE) or a normal rate of solvent evaporation (NRSE) process, the difference in morphology was minor. In contrast, the different processes did affect the morphology of PDLLA microspheres. Large (surface) pores were observed for PDLLA microspheres fabricated with a FRSE process, while a smooth surface was seen in those with a NRSE process. With the FRSE process, both PLLA and PDLLA microspheres showed smaller particle sizes and lower albumin encapsulation efficiencies than those prepared in the NRSE process. PLLA microspheres prepared with the NRSE process had higher drug encapsulation efficiencies than PDLLA ones, but this was not the case for the FRSE process. An initial burst release of albumin was observed for both PLLA and PDLLA microspheres prepared with the NRSE process, while a lesser burst release was seen for those prepared with the FRSE process. In subsequent stages of drug release, PLLA microspheres prepared with the two different processes showed differences, but this was not the case for PDLLA ones.     

Encapsulation of immunoglobulin G by solid-in-oil-in-water: Effect of process parameters on microsphere properties

Antibodies (Abs) are prone to a variety of physical and chemical degradation pathways, which require the development of stable formulations and specific delivery strategies. In this study, injectable biodegradable and biocompatible polymeric particles were employed for controlled-release dosage forms and the encapsulation of antibodies into polylactide-co-glycolide (PLGA) based microspheres was explored. In order to avoid stability issues which are commonly described when water-in-oil (w/o) emulsion is used, a solid-in-oil-in-water (s/o/w) method was developed and optimized. The solid phase was made of IgG microparticles and the s/o/w process was evaluated as an encapsulation method using a model Ab molecule (polyclonal bovine immunoglobulin G (IgG)). The methylene chloride (MC) commonly used for an encapsulation process was replaced by ethyl acetate (EtAc), which was considered as a more suitable organic solvent in terms of both environmental and human safety. The effects of several processes and formulation factors were evaluated on IgG:PLGA microsphere properties such as: particle size distribution, drug loading, IgG stability, and encapsulation efficiency (EE%). Several formulations and processing parameters were also statistically identified as critical to get reproducible process (e.g. the PLGA concentration, the volume of the external phase, the emulsification rate, and the quantity of IgG microparticles). The optimized encapsulation method has shown a drug loading of up to 6% (w/w) and an encapsulation efficiency of up to 60% (w/w) while preserving the integrity of the encapsulated antibody. The produced microspheres were characterized by a d(0.9) lower than 110 μm and showed burst effect lower than 50% (w/w).     

A comparative study of controlled release matrix tablets of diclofenac sodium, ciprofloxacin hydrochloride, and theophylline

The need for controlled release formulations for diclofenac sodium, ciprofloxacin, and theophylline is well recognized. In our study, controlled release tablets of the three drugs were formulated by the matrix-embedding technique using ethyl cellulose as retardant. Tablets of all the drugs were of good physical quality with respect to appearance, drug content uniformity, hardness, weight variation, and friability. In vitro release rate studies showed that ethyl cellulose extended the release of the three drugs to 12 hr or more. Release patterns from formulations of the three drugs followed Higuchi's square root kinetics. At pH 6.8, the release rate was higher in all three drugs, probably due to increased solubility of the drugs and/or increased swelling of ethyl cellulose at the higher pH. The formulations were highly stable and possessed reproducible release kinetics across batches.     

Effect of adding non-volatile oil as a core material for the floating microspheres prepared by emulsion solvent diffusion method

Eudragit® microspheres, to float in the gastrointestinal tract, were prepared to prolong a gastrointestinal transit time. To enhance their buoyancy, non-volatile oil was added to the dispersed phase. When an oil component was not miscible with water, over 90% was entrapped within the microspheres and prolonged the floating time of the microspheres. Depending on the solvent ratio, the morphologies of the microspheres were different and the best result was obtained when the ratio of dichloromethane:ethanol:isopropanol was 5:6:4. As the isopropanol portion increased, the time to form microspheres was delayed and the amount of fibre-like substance produced was decreased, due to the slow diffusion rate of the solvent. Compared with microspheres prepared without non-volatile oil, the release rate of the drug from microspheres was faster in all cases tested, except the microspheres containing mineral oil. The solubility of the drug in the non-volatile oil affected the release profiles of the drugs. The non-volatile oil tends to decrease the glass transition temperature of prepared microspheres and change the release profile. The internal morphology of the microspheres was slightly different depending on the entrapped oil phase used. Tiny spherical objects were present at the inner surface of microspheres and the inside of the shell.     

Particle size and loading efficiency of poly(D,L-lactic-coglycolic acid) multiphase microspheres containing water soluble substances prepared by the hydrous and anhydrous solvent evaporation methods

PLGA multiphase microspheres were prepared by the multiple emulsion solvent evaporation method using acetonitrile as the polymer solvent and mineral oil as the evaporation medium. The preparation process was further developed in the present study to reduce the particle size and to increase the loading capacity of brilliant blue, bovine serum albumin (BSA) and tumour necrosis factor-alpha (TNF-alpha) which were used as water soluble model drug substances. Sorbitan sesqui-oleate (SO-15EX), present at the 1% w/w level in the evaporation medium, prevented agglomeration of the microspheres containing a solid-in-oil (S/O) suspension as the core phase. This S/O suspension core provided significantly higher loading efficiency of the proteins to the W/O emulsion core. The W/O emulsion system resulted in agglomeration of the protein-loaded microspheres and the loading efficiency decreased significantly. When brilliant blue was included as the model compound, the loading efficiencies were not influenced by the core type. Heavy mineral oil was employed to stabilize the dispersed unhardened microspheres rather than light mineral oil that was reported previously. This anhydrous emulsion system employing the S/O suspension core and containing a dispersion of TNF-alpha enabled the encapsulation of this protein without loss of activity. It was concluded that the anhydrous emulsion system is asuitable approach toprepare multiple microspheres as an alternative to the W/O emulsion system, especially when solvent sensitive proteins are incorporated into the microspheres.     

In vitro and In vivo characterization of the transdermal delivery of sertraline hydrochloride Films

Background and the purpose of the study

Sertraline hydrochloride is a selective serotonin reuptake inhibitor principally used in the treatment of major depressive disorder. To maintain the therapeutic plasma drug concentration of the drug for prolonged period, the transdermal drug delivery has been chosen as an alternative route of drug delivery. The pharmacokinetic properties of sertraline hydrochloride make it suitable for transdermal delivery. The purpose of the study was to investigate the effect of polymers and penetration enhancers on the transdermal delivery of the drug in order to improve its therapeutic efficacy.

Methods

In the preparation of films, Eudragit RL 100, Eudragit RS 100, hydroxy propyl methyl cellulose (HPMC) and ethyl cellulose were used as polymers. The films were characterized for thickness, tensile strength, drug content, moisture uptake, moisture content, water vapor transmission rate and drug release. The films exhibiting higher rates of drug release were subjected to study the effect of oleic acid and propylene glycol as penetration enhancers on skin permeation of sertraline hydrochloride. In vivo and skin irritation studies were performed for the optimized film.

Results

Films containing Eudragit RL 100, Eudragit RL 100 and HPMC showed the highest drug release of 94.34% and 96.90% respectively in a period of 42 hrs. The release data fitted into kinetic equations, yielded zero-order and fickian mechanism of drug release. There was a two-fold increase in skin permeation of sertraline hydrochloride in the presence of penetration enhancers in the film. The physical evaluation indicated the formation of smooth, flexible and translucent films. No skin irritation occurred on rabbit skin and the infrared studies showed the compatibility of the drug with the formulation excipients. The in vivo study revealed a constant plasma concentration of drug for long periods and the films containing penetration enhancers had achieved adequate plasma levels of the drug.

Conclusions

The obtained results indicated the feasibility for transdermal delivery of sertraline hydrochloride using eudragit RL 100 and HPMC.     

Effects of the permeability characteristics of different polymethacrylates on the pharmaceutical characteristics of verapamil hyhdrochloride-loaded microspheres

Microspheres containing verapamil hydrochloride (VRP) were prepared with various polymethacrylates, with different permeability characteristics (Eudragit RS 100, Eudragit RL 100, Eudragit L 100 and Eudragit L 100-55) and also with mixtures of these polymers in a 1:1 ratio using the solvent evaporation method. The aim was to investigate the effects of the permeability of the polymers on drug release rates and the characteristics of the microspheres. To achieve these aims, yield, incorporation efficiency, particle size and the distribution of microspheres were determined, and the influence of the inner phase viscosities prepared with different polymer and polymer mixtures on particle size and the distribution of microspheres were evaluated. Surface morphologies of microspheres were observed by scanning electron microscope. Drug release rates from microspheres were determined by the half-change method using a flow-through cell. The results indicate that microspheres with different surface morphologies and statistically different yields and incorporation efficiencies could be prepared and their particle size and distribution variances resulted from the viscosity of the inner phase. Dissolution profiles showed that the drug release rate could be modified depending on the permeability characteristics of polymethacrylates.     

盐酸普罗帕酮注射液在2种注射器中稳定性研究

目的考察盐酸普罗帕酮注射液的稳定性。方法观察盐酸普罗帕酮注射液在常规和避光两种注射器中0 h2、h4、h6、h8、h1、2 h2、4 h的pH值和含量变化情况。结果盐酸普罗帕酮在两种注射器中12 h内的pH值符合药典3.5~5.0范围的规定;其含量在避光注射器中8 h内无显著性变化,而在常规注射器中4h后含量即显著下降。结论盐酸普罗帕酮注射液在避光注射器中较稳定,建议ICU使用避光注射器,并在8 h内用完。     

盐酸地尔硫革缓释片产业化研究

目的：探讨盐酸地尔硫Zhuo缓释片的生产工艺、稳定性，了解临床验证研究结果。方法：分析比较不同工艺阶段影响释放度的因素，进而确定相关工艺参数；考察产品室温贮存的稳定性；采用开放自身对照试验观察本品对轻、中度原发性高血压的临床疗效和耐受性。结果：本品共生产20多批，室温下贮存2－3年，其各项质量指标均在规范范围内。临床验证表明，每日服用本品1次，剂量为1片，降压总有效率为70．37％；剂量为2片，降压总有效率为88．88％。结论：本品生产工艺可行，产品质量稳定，日服1次能获满意血压控制，有良好的耐受性和安全性。