Streptomycin sulphate microspheres: formulation and in vivo distribution

Abstract

Albumin and gelatin microspheres of streptomycin sulphate were formulated and their potential as a drug delivery system for a tuberculostatic agent in vivo was evaluated. Biodistribution was determined by i.v. administration of a ^99mTc-labelled microsphere suspension to mice. The radioactivity of the lungs was compared with the radioactivity of the liver, spleen, kidney and heart at 10min, 60min, 4h and 24 h post-injection. The percentage accumulated was higher in the lungs than in the other organs for both albumin and gelatin microspheres.     

Streptomycin sulphate microspheres: formulation and in vivo distribution

Albumin and gelatin microspheres of streptomycin sulphate were formulated and their potential as a drug delivery system for a tuberculostatic agent in vivo was evaluated. Biodistribution was determined by i.v. administration of a 99mTc-labelled microsphere suspension to mice. The radioactivity of the lungs was compared with the radioactivity of the liver, spleen, kidney and heart at 10 min, 60 min, 4 h and 24 h post-injection. The percentage accumulated was higher in the lungs than in the other organs for both albumin and gelatin microspheres.     

去甲斑蝥素白蛋白微球的制备

目的:对去甲斑蝥素白蛋白微球的制备工艺及质量进行研究。方法:以白蛋白为载体,采用乳化交联法制备去甲斑蝥素白蛋白微球。在单因素考察的基础上,利用正交设计优化去甲斑蝥素白蛋白微球制备工艺,并对微球的粒径、形态、体外释放特性及稳定性进行研究。结果:制得的微球形态圆整,平均粒径为(0.54±0.13)μm,平均载药量为(51.36±2.45)%,平均包封率为(62.28±3.27)%,体外释放符合Higuchi方程,Q=10.1854t1/2-1.0858(r=0.998 1)。结论:本实验获得了较理想的去甲斑蝥素白蛋白微球,其体外释放特性符合长效制剂特征。     

Electron microscopic studies on tissue distribution of lipid microspheres used as drug delivery carriers

The tissue distribution of lipid microspheres (LMs), drug carriers for targeting therapy of anti-inflammatory drugs, was morphologically studied by electron microscope. In areas of inflammation in rats and mice, LMs were taken up by macrophages and accumulated around endothelial cells of blood vessels, and were observed to penetrate to the outer layer of blood vessels. LMs were also observed in reticuloendothelial cells such as Kupffer cells and splenic macrophages. Furthermore, the uptake of LMs by polymorphonucleocytes (PMNs) in areas of inflammation was enhanced 2-3 fold when LMs were coated with homogeneous IgG. These findings are in agreement with the tissue distribution results previously reported by the authors in studies using radioisotope-labelled LMs. The present and previous reports indicate that LMs could be used as a novel drug carrier, similarly to liposomes, in a drug delivery system specific for areas of inflammation and reticuloendothelial systems.     

Excipient quantitation and drug distribution during formulation optimization

An oral granules formulation experienced high drug content and increased variability when the process was scaled up from lab scale to clinical manufacturing scale. It was suspected that mannitol, due to its smaller particle size and lower density, was preferentially lost during the top spray granulation process, thereby causing active enrichment in the remaining granules. In order to troubleshoot the problem, rapidly evaluate solutions, and further optimize the formulation, a simple and rapid analytical technique was required. Since mannitol does not have a UV chromophore, conventional HPLC/UV analysis could not be used. Three alternative analytical techniques were evaluated in terms of ease of use, reproducibility, linear dynamic range and rapidity. The HPLC/RID (refractive index detector) and HPLC/ELSD (evaporative light scattering detector) provided rapid, reproducible alternate techniques to HPLC/UV, whereas LC/MS showed poor reproducibility. Analysis of the sieve samples of the granulations by HPLC/RID and HPLC/ELSD confirmed that poor active drug distribution was due to mannitol losses in the filter bag, as well as increased low size granules low in active drug content. The resultant formulation process was modified and a reduction in the initial air flow at start-up reduced losses of mannitol in the granulator filters.     

Extended release lipophilic indomethacin microspheres: formulation factors and mathematical equations fitted drug release rates.

Extended release liphophilic microspheres of indomethacin were prepared using cetostearyl alcohol (CsA), stearyl alcohol (SA) and cetyl alcohol (CA) in the various drug-lipid ratios. The release of indometacin was studied on the basis of USP criteria and the effects of drug-lipid ratio, the size of microspheres and carboxymethylcellulose sodium (CMC-Na) added as a hydrophilic polymer on the drug release were investigated. In vitro dissolution studies were performed using USP XXIII apparatus I at pH 6.2. Release profiles were evaluated according to first order, Higuchi square root of time and Hixson-Crowell cube root models. The best fit was found with the square root of time model (r2=0.991) for the microspheres (125-250 microm) prepared in 1:4:1 drug-lipid-copolymer ratio using stearyl alcohol. With a further regression analysis, an excellent equation (Release%=-10.721+42.549*square root of (t)-4.027*t) was developed for empirical drug estimation (r2=0.998).     

Solid lipid microparticles: formulation, preparation, characterisation, drug release and applications

This review details the properties of solid lipid microparticles (SLMs): a promising drug carrier system that has been until now rather unexploited. First, the advantages of SLMs compared with other drug carrier systems are listed. Then an overview of SLM manufacturing compounds and techniques is presented. A detailed discussion of the characteristics of SLMs follows, and includes the determination of particle size distribution, the determination of SLM morphology, the solid-state analysis, the determination of SLM drug loading and the factors influencing it. The in vitro drug release studies that have been carried out so far and the parameters affecting them are also described. Some preliminary in vivo aspects (in vivo drug release studies, biocompatibility studies and in vivo fate) are also considered.     

Solid lipid microparticles: formulation,preparation, characterisation,drug release and applications

This review details the properties of solid lipid microparticles (SLMs): a promising drug carrier system that has been until now rather unexploited. First, the advantages of SLMs compared with other drug carrier systems are listed. Then an overview of SLM manufacturing compounds and techniques is presented. A detailed discussion of the characteristics of SLMs follows, and includes the determination of particle size distribution, the determination of SLM morphology, the solid-state analysis, the determination of SLM drug loading and the factors influencing it. The invitro drug release studies that have been carried out so far and the parameters affecting them are also described. Some preliminary invivo aspects (invivo drug release studies, b-iocompatibility studies and invivo fate) are also considered.     

Use of lipid microspheres as a drug carrier for antitumour drugs

9-Oxo-15-hydroxy-delta 7,10,13-prostatrienoic acid methyl ester (delta 7-PGA1), an antitumour drug was incorporated into lipid microspheres of 0.2 micron diameter (lipo-delta 7-PGA1). In in-vivo experiments, lipo-delta 7-PGA1 had a significantly greater antitumour activity than free delta 7-PGA1 against P388 leukaemia. Lipo-delta 7-PGA1 slightly, but significantly, prolonged the survival time of mice inoculated with L1210 leukaemia, whereas free delta 7-PGA1 did not. Against MM46 ascites tumour, the survival time after treatment with 10 mg kg-1 of lipo-delta 7-PGA1 was significantly greater than that after the same dose of free delta 7-PGA1. The results suggest that lipid microspheres can be used as drug delivery carriers for lipid soluble antitumour agents.     

激光共聚焦显微镜分析载蛋白微球的结构及药物分布

目的:采用激光共聚焦显微镜(CLSM)表征微球,获得微球内部药物分布及结构信息。方法:分别以异硫氰酸荧光素牛血清白蛋白(FITC-BSA)和牛血清白蛋白(BSA)为蛋白模型药物,采用复乳化法制备聚酯类聚合物微球。运用CLSM对载FITC-BSA的微球扫描成像,进行图像分析和三维重建;并通过CLSM考察载BSA微球对异硫氰酸荧光素(FITC)的摄取,研究微球突释。结果:CLSM实现微球内部药物分布的可视化及其三维重构,并检测药物分布均匀性。摄取实验表明,在释放初期,包载药物很可能通过与微球表面相连接的孔洞扩散释放,造成突释。结论:CLSM可观察微球内部药物分布及结构。     

A freeze-dried formulation of bacteriophage encapsulated in biodegradable microspheres

With the emergence of widespread antibiotic resistance, there has been renewed interest in the use of bacteriophages. While their potency, safety and specificity have underpinned their clinical potential, to date, little work has been focussed on their formulation with respect to controlled release and/or passive targeting. Here, we show that bacteriophages selective for Staphylococcus aureus or Pseudomonas aeruginosa can be encapsulated into biodegradable polyester microspheres via a modified w/o/w double emulsion-solvent extraction protocol with only a partial loss of lytic activity. Loss of lytic activity could be attributed to the exposure of the bacteriophages to the water-dichloromethane interface, with the lyophilization process itself having little effect. The microspheres were engineered to have an appropriate size and density to facilitate inhalation via a dry-powder inhaler and fluorescently labeled bacteriophages were distributed entirely within the internal porous matrix. The release profile showed a burst release phase (55-63% release within 30 min), followed by a sustained release till around 6 h, as appropriate for pulmonary delivery. Despite the poor shelf-life of the formulation, the work is proof-of-concept for the formulation and controlled delivery of bacteriophages, as suitable for the treatment of bacterial lung infections.     

A novel formulation design about water-insoluble oily drug: preparation of zedoary turmeric oil microspheres with self-emulsifying ability and evaluation in rabbits

To enhance in vivo absorption of zedoary turmeric oil (ZTO) and develop new formulations of a water-insoluble oily drug, novel ZTO microspheres with self-emulsifying ability, called self-emulsifying microspheres here, were prepared in a liquid system by the quasi-emulsion solvent diffusion method. The microspheres containing hydroxypropyl methylcellulose acetate succinate (HPMCAS-LG), Talc and Aerosil 200 formed the stable surfactant-free emulsion when exposed to the pH 6.8 phosphate buffer, and were significantly different from the conventional self-emulsifying systems (SES), defined as isotropic mixtures of oil, surfactant and drug. Micromeritic properties, the efficiency of emulsification and the drug-release rate of the resultant microspheres were investigated. The bioavailability of the microspheres to the conventional self-emulsifying formulation for oral administration was evaluated in 12 healthy rabbits. A HPLC method was employed to determine the plasma concentration of Germacrone, an indexical component found in ZTO. The release rates of ZTO and Germacrone from the microspheres were enhanced significantly with increasing amounts of dispersing agents, and the efficiency of self-emulsification greatly depended on the HPMCAS-LG/Aerosil 200 ratio. The emulsion droplets released from the microspheres were much smaller than that of the conventional SES. The microsphere bioavailability (F) to the conventional SES for oral administration was 157.7%. Our method greatly improved the bioavailability of the water-insoluble oily drug from the self-emulsifying microspheres over the conventional SES and it is useful for the oily drug to form solid preparations.     

Carboplatin-loaded PLGA microspheres for intracerebral injection: formulation and characterization

The purpose of this study is to prepare and characterize injectable carboplatinloaded poly(D,L-lactic-co-glycolic) acid copolymer (PLGA) microspheres for the intracerebral treatment of malignant glioma. The microspheres were prepared by an acetone/mineral oil emulsion and solvent evaporation method. Preparation variables were optimized and the following processing conditions resulted in the highest drug loading and best yields of the microspheres compared with those prepared with the other variables: the PLGA concentration was 8%(w/w) in the internal phase; the emulsifier (Span 80) concentration was 8%(w/w) in the external phase; the ratio of the internal phase: the external phase was 1:8; the stirring speed was 1500 rpm; the emulsion time was 15 min; the solvent evaporation time was 3.75 hr. Microspheres so prepared were analysed for size distribution, drug loading, in vitro release and morphological characteristics. The drug release in phosphate buffer solution started with a 10- day slow release period, followed by a fast near zero order release period from 12 to 22 days. The carboplatin release in brain homogenate was slower than in phosphate buffer solution. The morphological changes of the microspheres during the in vitro degradation correlated with the drug relase profile. In conclusion, the carboplatin-loaded PLGA microspheres were specifically prepared to meet the specification as an injectable and biodegradable brain implant.     

Oral lipid based drug delivery system (LBDDS): formulation, characterization and application: a review

The major problem in oral drug formulations is low and erratic bioavailability, which mainly results from poor aqueous solubility. This may lead to high inter- and intra subject variability, lack of dose proportionality and therapeutic failure. The improvement of bio-availability of drugs with such properties presents one of the greatest challenges in drug formulations. Oral lipid based formulations are attracting considerable attention due to their capacity to increase the solubility, facilitating gastrointestinal absorption and reduce or eliminate the effect of food on the absorption of poorly water soluble, lipophilic drug and thus increasing the bioavailability. The present review outlines the recent findings on self-emulsifying drug delivery system (SEDDS), self-micro/nanoemulsifying drug delivery system (SMEDDS/SNEDDS) and evaluation of these formulations published over the past decade. The application of lipid based formulations as a promising system for the oral delivery of many therapeutic agents including traditional medicine (TM) has also been examined in the current review.     

Nanostructured lipid carriers (NLCs) as drug delivery platform: Advances in formulation and delivery strategies

NLCs have provoked the incessant impulsion for the development of safe and valuable drug delivery systems owing to their exceptional physicochemical and then biocompatible characteristics. Throughout the earlier period, a lot of studies recounting NLCs based formulations have been noticeably increased. They are binary system which contains both solid and liquid lipids aiming to produce less ordered lipidic core. Their constituents particularly influence the physicochemical properties and effectiveness of the final product. NLCs can be fabricated by different techniques which are classified according to consumed energy. More utilization NLCs is essential due to overcome barriers surrounded by the technological procedure of lipid-based nanocarriers’ formulation and increased information of the core mechanisms of their transport via various routes of administration. They can be used in different applications and by different routes such as oral, cutaneous, ocular and pulmonary. This review article seeks to present an overview on the existing situation of the art of NLCs for future clinics through exposition of their applications which shall foster their lucid use. The reported records evidently demonstrate the promise of NLCs for innovate therapeutic applications in the future.     

Carboplatin-loaded PLGA microspheres for intracerebral injection: formulation and characterization.

The purpose of this study is to prepare and characterize injectable carboplatin-loaded poly(D,L,-lactic-co-glycolic) acid copolymer (PLGA) microspheres for the intracerebral treatment of malignant glioma. The microspheres were prepared by an acetone/mineral oil emulsion and solvent evaporation method. Preparation variables were optimized and the following processing conditions resulted in the highest drug loading and best yields of the microspheres compared with those prepared with the other variables: the PLGA concentration was 8% (w/w) in the internal phase; the emulsifier (Span 80) concentration was 8% (w/w) in the external phase; the ratio of the internal phase: the external phase was 1:8; the stirring speed was 1500 rpm; the emulsion time was 15 min; the solvent evaporation time was 3.75 hr. Microspheres so prepared were analysed for size distribution, drug loading, in vitro release and morphological characteristics. The drug release in phosphate buffer solution started with a 10-day slow release period, followed by a fast near zero order release period from 12 to 22 days. The carboplatin release in brain homogenate was slower than in phosphate buffer solution. The morphological changes of the microspheres during the in vitro degradation correlated with the drug relase profile. In conclusion, the carboplatin-loaded PLGA microspheres were specifically prepared to meet the specification as an injectable and biodegradable brain implant.     

Design and formulation of mucoadhesive microspheres of sitagliptin

Mucoadhesive microspheres of sitagliptin (SITCM), a new anti-diabetic drug was prepared with carbopol 934?P using Buchi B-90 nano spray drier and optimized to analyse the key effects and relations of three factors on formulation of SITCM were studied. The appearance of the microspheres was found to be shriveled to nearly spherical, with a narrow size of 2–8?µm. The drug loading and percentage yield was found to be 73?±?0.2% and 92?±?0.3%, respectively. In vitro release indicated Korsmeyer–Peppas pattern mucoadhesion of SITCM-8 was found to be 7.8?±?0.3?h. In vivo studies in rats suggest that the sitagliptin was retained in the gastrointestinal tract for an extended period of time (～12?h) and control group was reduced significantly (～4?h). This study concludes that the mucoadhesive microsphere could be one of the most appropriate drug delivery approaches for the successful delivery of sitagliptin.     

Effect of formulation variables on in vitro drug release and micromeritic properties of modified release ibuprofen microspheres

Modified release microspheres of the non-steroidal anti-inflammatory drug, ibuprofen, were formulated and prepared using the emulsion solvent diffusion technique. The contribution of various dispersed phase and continuous phase formulation factors on in vitro drug release and micromeritic characteristics of microspheres was examined. The results demonstrated that the use of Eudragit RS 100 and Eudragit RL 100 as embedding polymers modified the drug release properties as a function of polymer type and concentration. Eudragit RS 100 retarded ibuprofen release from the microspheres to a greater extent than Eudragit RL 100. The drug/polymer concentration of the dispersed phase influenced the particle size and drug release properties of the formed microspheres. It was found that the presence of emulsifier was essential for microsphere formation. Increasing the concentration of emulsifier, sucrose fatty acid ester F-70, decreased the particle size which contributed to increased drug release properties. Scanning electron microscopy revealed profound distortion in both the shape and surface morphology of the microspheres with the use of magnesium stearate as added emulsifier. The application of an additional Eudragit RS 100 coat onto formed microspheres using fluid bed technology was successful and modulated the drug release properties of the coated microspheres.     

Interleukin-2 lipid microspheres. I. development and evaluation of the colloidal drug carrier

Undesirable toxic effects associated with intravenous interleukin-2 (IL2) therapy have limited its use for the treatment of cancer. Therefore, we investigated properties of a colloidal carrier system intended for the delivery of IL2. Lipid microspheres (LMS) are 10% (v/v) soybean oil emulsions stabilized with block copolymers of the poloxamer and poloxamine type. Poloxamers 238, 338, 407 or poloxamine 908 LMS were evaluated for physical stability, in vitro toxicity, and in vivo biodistribution. With the exception of 2% poloxamer 238 LMS, all preparations displayed acceptable stability when stored for 3 months at 4° or 37°C. In addition, all LMS preparations exhibited physical stability when subjected to freeze-thaw cycling and extended periods of freezing. In vitro cellular toxicity was evaluated in a murine cytotoxic T lymphocyte cell line (CTLL-2) and human peripheral blood mononuclear cells (PBMC). The calculated IC₅₀ of LMS was approximately 30 and 10 mg/liter in CTLL-2 cells and PBMC, respectively. Biodistribution studies involving ¹²⁵I-labeled LMS revealed that 2 h after intravenous administration there was significantly greater recovery of the poloxamer 338 and 407 LMS-associated radioactivity, where blood, liver, spleen, and bone marrow accounted for most of the radioactivity. Overall, the data suggest that LMS have the potential to serve as a drug delivery system.     

Interleukin-2 lipid microspheres. I. development and evaluation of the colloidal drug carrier

Abstract

Undesirable toxic effects associated with intravenous interleukin-2 (IL2) therapy have limited its use for the treatment of cancer. Therefore, we investigated properties of a colloidal carrier system intended for the delivery of IL2. Lipid microspheres (LMS) are 10% (v/v) soybean oil emulsions stabilized with block copolymers of the poloxamer and poloxamine type. Poloxamers 238, 338, 407 or poloxamine 908 LMS were evaluated for physical stability, in vitro toxicity, and in vivo biodistribution. With the exception of 2% poloxamer 238 LMS, all preparations displayed acceptable stability when stored for 3 months at 4° or 37°C. In addition, all LMS preparations exhibited physical stability when subjected to freeze-thaw cycling and extended periods of freezing. In vitro cellular toxicity was evaluated in a murine cytotoxic T lymphocyte cell line (CTLL-2) and human peripheral blood mononuclear cells (PBMC). The calculated IC₅₀ of LMS was approximately 30 and 10 mg/liter in CTLL-2 cells and PBMC, respectively. Biodistribution studies involving ¹²⁵I-labeled LMS revealed that 2 h after intravenous administration there was significantly greater recovery of the poloxamer 338 and 407 LMS-associated radioactivity, where blood, liver, spleen, and bone marrow accounted for most of the radioactivity. Overall, the data suggest that LMS have the potential to serve as a drug delivery system.