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, x-ray 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 scanning calorimetry. No differences were observed in the physical state of pipemidic acid and in microsphere shape and surface between different size fractions of microspheres, prepared with different amounts of magnesium stearate. Additionally, no correlation between the physical state of the drug in different microspheres and their biopharmaceutical properties was found.     

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.     

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.     

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 µm and entrapment efficiency of ~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°C, for 12 weeks.     

Influence of magnesium stearate on the physicochemical and pharmacodynamic characteristics of insulin-loaded Eudragit entrapped mucoadhesive microspheres

Abstract

Effective oral insulin delivery has remained a challenge to the pharmaceutical industry. This study was designed to evaluate the effect of magnesium stearate on the properties of insulin-loaded Eudragit® RL 100 entrapped mucoadhesive microspheres. Microspheres containing Eudragit® RL 100, insulin, and varying concentrations of magnesium stearate (agglomeration-preventing agent) were prepared by emulsification-coacervation method and characterized with respect to differential scanning calorimetry (DSC), morphology, particle size, loading efficiency, mucoadhesive and micromeritics properties. The in vitro release of insulin from the microspheres was performed in simulated intestinal fluid (SIF, pH 7.2) while the in vivo hypoglycemic effect was investigated by monitoring the plasma glucose level of the alloxan-induced diabetic rats after oral administration. Stable, spherical, brownish, mucoadhesive, discrete and free flowing insulin-loaded microspheres were formed. While the average particle size and mucoadhesiveness of the microspheres increased with an increase in the proportion of magnesium stearate, loading efficiency generally decreased. After 12?h, microspheres prepared with Eudragit® RL 100: magnesium stearate ratios of 15:1, 15:2, 15:3 and 15:4 released 68.20?±?1.57, 79.40?±?1.52, 76.60?±?1.93 and 70.00?±?1.00 (%) of insulin, respectively. Reduction in the blood glucose level for the subcutaneously (sc) administered insulin was significantly (p?≤?0.05) higher than for most of the formulations. However, the blood glucose reduction effect produced by the orally administered insulin-loaded microspheres prepared with four parts of magnesium stearate and fifteen parts of Eudragit® RL 100 after 12?h was equal to that produced by subcutaneously administered insulin solution. The results of this study can suggest that this carrier system could be an alternative for the delivery of insulin.     

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.     

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.     

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.     

The stability of insulin in biodegradable microparticles based on blends of lactide polymers and polyethylene glycol

Abstract

Non-pareil cores were spray-coated with a chlorpheniramine maleate (an alkylamine antihistamine) layer and a Eudragit^R N overcoat in a Wurster air-suspension apparatus. In vitro dissolution studies demonstrated that drug release was a function of polymer membrane thickness. Polyethylene glycol 6000, as a hydrophillic additive, increased the in vitro release of chlorphenir amine maleate from the pellets. Pellets coated with 8 0% Eudragit^R N, 0 0% talc and 0% polyethylene glycol 6000 were found to display desirable controlled release characteristics for chlorpheniramine maleate over the 8-h testing period, which were also comparable with that of Dykatuss^R capsules. The controlled release pellets exhibited first-order release characteristics for chlorpheniramine maleate. Reproducibility of the manufacturing conditions employed in the study were confirmed thus ensuring reproducibility of drug release characteristics between batches of chlorpheniramine maleate pellets. Drug release from the pellets was shown to be independent of the dissolution method and medium used. Pellets displayed no significant change in drug release characteristics relative to the initial drug release data when stored for 12 weeks at room temperature (20+2) and for 8 weeks at a low temperature (5 + 1 °C). However, pellets stored at 37 °C with 80% relative humidity and at 40 + 2 showed a slower in vitro drug release after 8-week storage and therefore failed to maintain their initial drug release profile.     

硬脂酸镁过度润滑作用对盐酸二甲双胍缓释片的影响

目的 考察硬脂酸镁过度润滑作用对盐酸二甲双胍缓释片的影响。方法 通过改变硬脂酸镁的用量、改变硬脂酸镁的混合时间、改变加料器转速,制备不同盐酸二甲双胍缓释片。通过对比总混颗粒的粉体性质、片剂的溶出。综合评价硬脂酸镁过度润滑对盐酸二甲双胍缓释片的影响。结果 增加硬脂酸镁的用量、延长总混时间、加快加料器的转速均会导致硬脂酸镁过度润滑。表现为颗粒流动性并未明显改善,但可压性显著下降,盐酸二甲双胍缓释片溶出无明显减缓。结论 盐酸二甲双胍缓释片的可压性对硬脂酸镁的润滑作用敏感,需控制硬脂酸镁的用量、混合的时间以及加料器的转述,防止过度润滑,造成可压性变差的现象产生。     

Effects of fabrication conditions on the characteristics of etanidazole spray-dried microspheres

Etanidazole, a hypoxic radiosensitizer, has potential applications in radiotherapy. Due to its high solubility in water, common methods to encapsulate etanidazole into microspheres are not feasible. In this study, a spray-drying technique was employed to encapsulate etanidazole into the biodegradeable polymer, PLGA65:35. Different fabrication conditions, such as polymer concentration, inlet temperature, feed rate, compressed air flow rate, aspirator ratio, as well as drug-loading were investigated to understand their effects on the particle size and distribution, encapsulation efficiency, and release behaviour. The effect on the morphologies of microspheres were also observed by scanning electron microscopy (SEM) and atomic force microscopy (AFM). It was demonstrated that most of these fabrication conditions influence either the droplet formation process or its subsequent evaporation and particle shrinking process, thereby determining the properties of the microspheres obtained. In many cases, temperature seems to be more important among all the factors considered. The present study demonstrates good fabrication conditions for producing the etanidazole-PLGA65:35-microspheres by using DCM as a solvent. The release of etanidazole from the spray dried PLGA65:35 microspheres was very fast, with an initial burst of 47% within the first 30 min and a cumulative release of over 80% within the first 5.5 h. The encapsulation efficiency of the drug in the microspheres varied with operating conditions from 69-96%.     

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.     

Cross-linked starch microspheres: Effect of cross-linking condition on the microsphere characteristics

Cross-linked starch microspheres were prepared using different kinds of cross-linking agents. The influence of several parameters on morphology, size, swelling ratio and drug release rate from these microspheres were evaluated. These parameters included cross-linker type, concentration and the duration of cross-linking reaction. Microspheres cross-linked with glutaraldehyde had smooth surface compared with those prepared with epichlorhydrine or formaldehyde. The particle size increased with increasing the cross-linking time and increasing the drug loading. Swelling ratio of the particles was a function of cross-linker type but not the concentration or time of cross-linking. Drug release from starch microspheres was measured in phosphate buffer and also in phosphate buffer containing alpha-amylase. Results showed that microspheres cross-linked with epichlorhydrine released all their drug content in the first 30 minutes. However, cross-linking of the starch microspheres with glutaraldehyde or formaldehyde decreased drug release rate. SEM and drug release studies showed that cross-linked starch microspheres were susceptible to the enzymatic degradation under the influence of alpha-amylase. Changing the enzyme concentration from 5000 to 10,000 IU/L, increased drug release rate but higher concentration of enzyme (20,000 IU/L) caused no more acceleration.     

The influence of magnesium stearate on the Hiestand Tableting Indices and other related mechanical properties of maltodextrins

Magnesium stearate is widely used as a lubricant in pharmaceutical dosage forms. A film of magnesium stearate, or other lubricant, around individual granules is generally considered to cause the softening of tablets. Maltodextrins were chosen as model excipients since maltodextrins possessing a series of molecular weights showed systematically changing consolidation mechanisms. As maltodextrin molecular weight increases, the plasticity of the material increases. The Hiestand Tableting Indices and other related mechanical properties were used to study the effect of magnesium stearate addition on the mechanical properties and consolidation mechanisms of single component maltodextrins. Magnesium stearate was shown to lower the tensile strengths of maltodextrin compacts. Additionally, magnesium stearate addition lowered both the Hiestand Bonding Index and the Hiestand Brittle Fracture Index. The lower values of the Hiestand Brittle Fracture Index indicate that magnesium stearate promotes greater plastic behavior in maltodextrin compacts.     

Effects of solvent selection and fabrication method on the characteristics of biodegradable poly(lactide-co-glycolide) microspheres containing ovalbumin

To demonstrate the effect of formulation conditions on the controlled release of protein from poly(lactide-co-glycolide) (PLGA) microspheres for use as a parenteral drug carrier, ovalbumin (OVA) microspheres were prepared using the W/O/W multiple emulsion solvent evaporation and extraction method. Methylene chloride or ethyl acetate was applied as an organic phase and poly(vinyl alcohol) as a secondary emulsion stabilizer. Low loading efficiencies of less than 20% were observed and the in vitro release of OVA showed a burst effect in all batches of different microspheres, followed by a gradual release over the next 6 weeks. Formulation processes affected the size and morphology, drug content, and the controlled release of OVA from PLGA microspheres.     

The effect of distribution of magnesium stearate on the penetration of a tablet by water

Magnesium carbonate powder and granules were compressed and the tablets characterized by their permeability to air and penetration by liquids. To the same materials, magnesium stearate was added, its distribution being varied by varying its concentration, the size of the base material and the method of mixing. The inhibition of penetration by liquids is roughly proportional to the concentration of magnesium stearate and very susceptible to the method of mixing. The influence of granule size on its distribution was seen mainly as a change in the uniformity of penetration.     

布地奈德联合硫酸镁对支气管哮喘急性期患儿血清免疫球蛋白E和白细胞介素-17的影响

目的 观察布地奈德联合硫酸镁对支气管哮喘急性期患儿血清免疫球蛋白E（IgE）和白细胞介素-17 （IL-17）的影响.方法 86例支气管哮喘急性发作患儿采用随机数字表法分为两组,观察组43例,对照组43例,对照组采用常规治疗加用静脉激素,观察组采用常规治疗加用雾化吸入布地奈德联合硫酸镁治疗,共治疗7d.测定患者血清IgE和IL-17.结果 治疗后观察组总有效率为97.7％,高于对照组的88.4％（x2=5.24,P＜0.01）.两组治疗后患者血清IgE和IL-17均有明显降低（t=21.7119、13.0190、11.2647、7.1588,均P＜0.01）,与对照组治疗后比较,观察组降低更明显（t=13.8141、5.1214,均P＜0.05）.结论 布地奈德联合硫酸镁可以明显减少支气管哮喘急性发作患儿血清IgE和IL-17表达.     

生脉注射液联合镁治疗充血性心力衰竭的疗效观察

目的评价生脉注射液联合镁治疗充血性心力衰竭的临床疗效。方法选择慢性充血性心力衰竭患者60例,随机分对照组30例和治疗组30例。对照组应用常规抗心衰药物血管紧张素转换酶抑制剂、利尿剂、洋地黄制剂、β受体阻制剂治疗。治疗组在常规抗心衰治疗基出上加用生脉注射液和氯化镁。每组疗程21d。所有患者治疗前后测血清镁浓度,行超声心动图评价心脏收缩功能的改善情况。结果治疗后治疗组心衰疗效优于对照组,治疗组LVEF较治疗前明显增加,也明显高于对照组治疗后水平,血清镁浓度高于对照组。结论在常规心衰治疗的基础上加用生脉注射液和氯化镁能改善充血性心力衰竭患者的心脏收缩功能。