Preparation and in vitro evaluation of ethyl cellulose microspheres containing stavudine by the double emulsion method

The aim of this study was to formulate and evaluate microspheres of stavudine by water-in-oil-in-oil (w/o/o) double emulsion solvent diffusion method using ethyl cellulose and ethyl cellulose in combination with polyvinyl pyrrolidone. A mixed solvent system consisting of acetonitrile and dichloromethane in an 1: 1 ratio and light liquid paraffin was chosen as primary and secondary oil phase, respectively. Span 80 was used as surfactant for stabilizing the secondary oil phase. The influence of formulation factors like stirring speed, surfactant concentration on particle size and polymer:drug ratio and combination of polymers on drug release characteristics of the microspheres was investigated. The prepared microspheres characterized by micrometric properties, drug loading, Fourier transform infrared spectroscopy, X-ray powder difractometry and scanning electron microscopy. The prepared microspheres were white, free flowing and spherical in shape, stable in nature, with 41-65% of drug entrapment efficiency. The best-fit release kinetics was achieved with Higuchi plot followed by first order and zero order. The release of stavudine was influenced by the drug to polymer ratio, particle size and polymer combination.     

Micromeritics and release behaviours of cellulose acetate butyrate microspheres containing theophylline prepared by emulsion solvent evaporation and emulsion non-solvent addition method

The present research work compares the effect of microsphere preparation technique on micromeritics and release behaviors of theophylline microspheres. Microspheres were prepared by oil-in oil (O₁/O₂) emulsion solvent evaporation method (ESE) using different ratios of anhydrous theophylline to cellulose acetate butyrate (CAB). Cyclohexane was used as non-solvent to modify the ESE technique (MESE method) and the effect of non-solvent volume on properties of microspheres was investigated. The obtained microspheres were analyzed in terms of drug content, particle size and encapsulation efficiency. The morphology of microsphere was studied using scanning electron microscope. The solid state of microspheres, theophylline and CAB were investigated using X-ray, FT-IR and DSC. The drug content of microspheres prepared by MESE method was significantly lower (15.54% ± 0.46) than microspheres prepared by ESE method (41.08 ± 0.40%). The results showed that as the amount of cyclohexane was increased from 2 mL to 6 mL the drug content of microspheres was increased from 15.54% to 28.71%. Higher encapsulation efficiencies were obtained for microspheres prepared by ESE method (95.87%) in comparison with MESE method (64.71%). Mean particle size of microsphere prepared by ESE method was not remarkably affected by drug to polymer ratio, whereas in MSES method when the volume of cyclohexane was increased the mean particle size of microsphere was significantly decreased. The ratio of drug to polymer significantly changed the rate of drug release from microspheres and the highest drug release was obtained for the microsphere with high drug to polymer ratio. The amount of cyclohexane did not significantly change the drug release. Although, x-ray showed a small change in crystallinity of theophylline in microspheres, DSC results proved that theophylline in microspheres is in amorphous state. No major chemical interaction between the drug and polymer was reported during the encapsulation process.     

Factorial design based optimization of the formulation of albumin microspheres containing adriamycin

The use of factorial design in the formulation of adriamycin-associated albumin microspheres, using the heat-stabilization technique, is illustrated. The effect of stabilization temperature, protein concentration and stabilization time on the entrapment and recovery of adriamycin in microspheres have been investigated using a 2 x 4 x 4 factorial design. The associated drug content in unwashed and four times washed microspheres was determined using HPLC. Maximum drug association and drug recovery were obtained from microspheres synthesised using 25 per cent w/v albumin solution and stabilized at 120 degrees C for 2.5 min. Under these conditions, the entrapped and total associated drug content of the microspheres was about 4 per cent and 12 per cent w/w respectively, and the drug recovery was about 75 per cent. The in vitro dissolution study carried out using dynamic dialysis revealed that the release of adriamycin from these particles follows a bi-phasic pattern. The results demonstrate that use of short stabilization time, low protein concentration and low stabilization temperature are required for the formulation of microspheres with high adriamycin content.     

用正交设计法优选湿疹乳剂的基质组成及工艺

目的：优选湿疹乳剂的基质组成及工艺。方法：针对影响乳剂稳定性的因素,用正交设计法,以油相、乳化剂和乳化温度为可变因素,选用Ｌ９（３４）表进行实验。结果：最优的基质组成及工艺是：硬脂酸７．０ｇ,液体石蜡４．０ｍｌ,凡士林０．６ｇ,单硬脂酸甘油酯３．４ｇ,三乙醇胺０．６５ｍｌ,吐温８０２．０ｇ,乳化温度９０℃。结论：按此法制备出的软膏符合中国药典１９９５年版的规定     

Production and characterization of polymer microspheres containing trace explosives using precision particle fabrication technology

Well characterized test materials are essential for validating the performance of current trace explosive detection systems. These test materials must replicate trace explosive contamination in the form of small particles with characteristic diameters in the micrometer range. In this work, Precision Particle Fabrication was used to fabricate monodisperse polymer microspheres that contain high explosives. Three high explosives were successfully incorporated into the microspheres. Ion mobility spectrometry confirmed that the encapsulation efficiency was typically greater than 50%, with some suspected loss to the aqueous phase during production. This study demonstrates that, with this technique, polymer microspheres containing explosives can be produced with sufficient encapsulation, along with tightly controlled particle size distributions at high production rates. These microspheres have proven to be a valuable test material for trace explosive detectors because of their highly precise size, shape and explosive composition.     

Preparation of roxithromycin-polymeric microspheres by the emulsion solvent diffusion method for taste masking

Microspheres of roxithromycin with Eudragit S100 and silica were prepared by the emulsion solvent diffusion method to mask the bitter taste of the antibiotic. The effect of different polymers and drug-polymer ratios on the taste masking and the characteristics of the microspheres were investigated. It was found that Eudragit S100 was the best for masking the unpleasant taste of roxithromycin among the six kinds of polymers investigated. The results of DSC, X-ray diffraction and IR showed that there were several combinations of roxithromycin and Eudragit S100. The influence of other formulation factors, i.e. dichloromethane-acetone ratios and silica-polymer ratios on the properties of the microspheres were also examined. In conclusion, the results of the present study will be helpful for the preparation of oral forms of roxithromycin with an acceptable taste.     

Conformation of some oligopeptides containing Lys,Ala, and Tyr

We have studied by X-ray diffraction and infrared spectroscopy the structure of the following peptides: N-acetyl-Lys-Ala-Tyr-Ala-Lys-ethylamide; N-acetyl-Lys-d (Ala)-Tyr-Ala-Lys-ethylamide; N-acetyl-Lys-Ala-Lys-Ala-Lys-ethylamide; N-acetyl-Lys-Ala-Lys-ethylamide and N-acetyl-Tyr-Ala-Lys-ethyalmide. All of them show a cross-β structure, most likely with an antiparallel organization of the peptide chains. The d -Ala residue present in one of the peptides apparently does not interfere with the formation of the pleated-sheet structure. Due to the sequence of the peptides we have used, most of them are organized in double layers: one hydrophobic, containing the methyl groups of alanine, and the other one hydrophilic, containing the lysine side chains. Tyrosine is also found in the latter layer.     

蛋白质多肽长效微球注射剂的体内药动学及分析方法研究进展*

长效微球注射剂作为一类处于热点研究中的新型释药系统，在蛋白质、多肽的递送中受到了日益广泛的重视和应用。但是，微球的释药机制复杂，蛋白质、多肽的体内药物分析又存在着诸多困难，因而蛋白质、多肽长效微球注射剂的体内药物释放及评价是此类药物制剂研发的瓶颈之一。现介绍近年来蛋白质、多肽长效微球注射剂的体内释药机制及药动学研究进展，并着重对蛋白质、多肽长效微球注射剂的体内药物分析方法进行综述。     

Chitosan microspheres containing the natural urucum pigment

An increasing trend in the food and pharmaceutical industries is toward replacing synthetic additives with natural products. However, in this regard, difficulties may be encountered due to the instability of such compounds. Encapsulation has become an important process to protect natural pigments. This paper reports on the encapsulation of the natural urucum pigment with chitosan using different techniques and its release under different pH conditions. The material loaded with pigment was evaluated by infrared spectroscopy, scanning electron microscopy and thermal analysis. Chitosan was found to be an effective encapsulating agent for urucum pigment. No investigations have previously been reported on the relation of chitosan to the stability of encapsulated natural pigments.     

Chitosan microspheres containing the natural urucum pigment

An increasing trend in the food and pharmaceutical industries is toward replacing synthetic additives with natural products. However, in this regard, difficulties may be encountered due to the instability of such compounds. Encapsulation has become an important process to protect natural pigments. This paper reports on the encapsulation of the natural urucum pigment with chitosan using different techniques and its release under different pH conditions. The material loaded with pigment was evaluated by infrared spectroscopy, scanning electron microscopy and thermal analysis. Chitosan was found to be an effective encapsulating agent for urucum pigment. No investigations have previously been reported on the relation of chitosan to the stability of encapsulated natural pigments.     

Opioid peptides. Pharmacological activity and lipophilic character of dermorphin oligopeptides. IV

The preliminary pharmacological activity pattern in guinea pig ileum and mouse vas deferens bioassays of five dermorphin related tetrapeptides is reported. The biological activities of the compounds under examination appear to be correlated in a statistically significant way to the lipophilic character of the C-terminal substituents.     

Review and current status of emulsion/dispersion technology using an internal gelation process for the design of alginate particles

Emulsification/internal gelation has been suggested as an alternative to extrusion/external gelation in the encapsulation of several compounds including sensitive biologicals such as protein drugs. Protein-loaded microparticles offer an inert environment within the matrix and encapsulation is conducted at room temperature in a media free of organic solvents. Recently, the concept of internal gelation has been applied to formulating nanoparticles as drug delivery systems. Emulsification/internal gelation technologies available for microparticles preparation, particularly that involving alginate polymer, are described as well as recent advances towards applications in nanotechnology. Those methods show great promise as a tool for the development of encapsulation processes, especially for the new field of nanotechnology using natural polymers.     

Formulation and evaluation of ethyl cellulose microspheres prepared by the multiple emulsion technique

The aim of this study was to formulate and evaluate microencapsulated controlled release preparations of metformin hydrochloride using ethyl cellulose as the retardant material with high entrapment efficiency and extended release. Microspheres were prepared by the double emulsion solvent diffusion method. A mixed solvent system consisting of acetonitrile and dichloromethane in 1:1 ratio and light liquid paraffin were chosen as the primary and secondary oil phases, respectively. Span 80 was used as the surfactant for stabilizing the secondary oil phase. The prepared microspheres were characterized by drug loading, optical microscopy and scanning electron microscopy (SEM). The in vitro release studies were performed in a series of buffer solutions with variable pH. The drug loaded microspheres showed 55-85% of entrapment and the release was extended for up to 12 h. SEM studies revealed that the microspheres were spherical and porous in nature. Data obtained from in vitro release studies were fitted to various kinetic models and high correlation was obtained with the Higuchi model. The drug release was found to be diffusion controlled. Oral administration of the microspheres to the albino mice provided decreased plasma glucose for more than 10 h.     

Manufacturing techniques and excipients used during the design of biodegradable polymer-based microspheres containing therapeutic peptide/protein for parenteral controlled drug delivery

In the last couple of decades, use of biodegradable polymer-based microspheres has been recognized as an interesting and promising approach for parenteral controlled delivery of therapeutic peptide/protein, including antigens. The main objectives of this review are (i) to update the current state of art of manufacturing of peptide/protein-loaded microspheres through both conventional and newer microencapsulation techniques, and (ii) to bring into focus the various possible instability problems, and the investigated mechanistic ways to obviate the instability problems of peptide/protein drug during microspheres preparation as well as its release from the microspheres. The solubilization, stabilization, and preservation enhancing excipients that are used in peptide/protein-loaded microspheres are briefly overviewed.     

PLGA microspheres containing bee venom proteins for preventive immunotherapy

Bee venom (BV) allergy is potentially dangerous for allergic individuals because a single bee sting may induce an anaphylactic reaction, eventually leading to death. Currently, venom immunotherapy (VIT) is the only treatment with long-lasting effect for this kind of allergy and its efficiency has been recognized worldwide. This therapy consists of subcutaneous injections of gradually increasing doses of the allergen. This causes patient lack of compliance due to a long time of treatment with a total of 30-80 injections administered over years. In this article we deal with the characterization of different MS-PLGA formulations containing BV proteins for VIT. The PLGA microspheres containing BV represent a strategy to replace the multiple injections, because they can control the solute release. Physical and biochemical methods were used to analyze and characterize their preparation. Microspheres with encapsulation efficiencies of 49-75% were obtained with a BV triphasic release profile. Among them, the MS-PLGA 34 kDa-COOH showed to be best for VIT because they presented a low initial burst (20%) and a slow BV release during lag phase. Furthermore, few conformational changes were observed in the released BV. Above all, the BV remained immunologically recognizable, which means that they could continuously stimulate the immune system. Those microspheres containing BV could replace sequential injections of traditional VIT with the remarkable advantage of reduced number of injections.     

Trehalose-hydroxyethylcellulose microspheres containing vancomycin for topical drug delivery.

A new formulation, in which vancomycin is entrapped into trehalose and hydroxyethylcellulose (Natrosol) spherical matrices, is described. Microspheres were produced by the solvent evaporation method. The entrapped drug was fully recovered following microspheres dissolution. Differential scanning calorimetry analyses proved that Natrosol maintains trehalose in its amorphous form. The stabilizing effects of trehalose on vancomycin were evaluated even after long storage and heating of microspheres. Calorimetric data indicated no decomposition of the entrapped drug. In vitro drug release, already performed by using a general two-compartment linear time-invariant open model, suggests that the new delivery system is suitable for topical application on extensive and purulent or burn wounds, when the skin is heavily damaged and the barrier disrupted. The system activation is determined by osmotic phenomena. The prepared new delivery system seems to have characteristics suitable for topical applications on extensive and purulent wounds. The system is able to take away serous exudates from wounds, thus letting the matrix to swell and form a viscous gel-like dispersion that, in turn, enables drug diffusion.     

Multiple indications for anti-inflammatory apolipoprotein mimetic peptides

Apolipoprotein mimetic peptides dramatically reduce atherosclerosis in animal models, and may be an excellent mode of therapy to treat a variety of vascular inflammatory conditions, including atherosclerosis. Studies of apolipoprotein mimetic peptides in models of inflammatory disorders other than atherosclerosis, including viral influenza, asthma, chronic rejection after heart transplantation, sickle cell disease, scleroderma, diabetes, cognitive dysfunction and renal inflammation, suggest that apolipoprotein mimetic peptides may have efficacy in a wide range of inflammatory conditions.     

An improvement of double emulsion technique for preparing bovine serum albumin-loaded PLGA microspheres

A modified double emulsion technique was adopted to prepare bovine serum albumin (BSA) loaded poly (D,l-lactic-co-glycolic acid) (PLGA) microspheres. In the formulations, polysorbates (Tween) such as Tween20®, Tween40® or Tween80®, instead of frequently used poly (vinyl alcohol) (PVA), was used as the emulsifier. Microspheres with porous surface, large particle size, low microsphere yield (～65.4%) and BSA entrapment efficiency (～25.2%) were obtained when Tween80® aqueous solution alone was used as the outer aqueous phase. However, microspheres with smooth surface, high yield and BSA entrapment efficiency could be produced successfully by introducing sodium chloride or glucose into the outer aqueous phase. Adding 5.0%(w/v) sodium chloride into the continuous phase led to increase in microsphere yield and BSA entrapment efficiency from 65.4% and 25.2% to ～100% and 76.6%, respectively. Microsphere yield and BSA entrapment efficiency increased from 64.5% and 25.2% to 97.2% and 89.3%, respectively, when 15.0%(w/v) glucose was added into the continuous phase. In constrast to the microspheres prepared in the presence of additive, a more marked burst release was observed for microspheres prepared without additive in the continuous phase, which may be attributed to the porous morphology of the latter.     

An improvement of double emulsion technique for preparing bovine serum albumin-loaded PLGA microspheres

A modified double emulsion technique was adopted to prepare bovine serum albumin (BSA) loaded poly (D,L-lactic-co-glycolic acid) (PLGA) microspheres. In the formulations, polysorbates (Tween) such as Tween20, Tween40 or Tween80, instead of frequently used poly (vinyl alcohol) (PVA), was used as the emulsifier. Microspheres with porous surface, large particle size, low microsphere yield (approximately 65.4%) and BSA entrapment efficiency (approximately 25.2%) were obtained when Tween80 aqueous solution alone was used as the outer aqueous phase. However, microspheres with smooth surface, high yield and BSA entrapment efficiency could be produced successfully by introducing sodium chloride or glucose into the outer aqueous phase. Adding 5.0%(w/v) sodium chloride into the continuous phase led to increase in microsphere yield and BSA entrapment efficiency from 65.4% and 25.2% to approximately 100% and 76.6%, respectively. Microsphere yield and BSA entrapment efficiency increased from 64.5% and 25.2% to 97.2% and 89.3%, respectively, when 15.0%,(w/v) glucose was added into the continuous phase. In constrast to the microspheres prepared in the presence of additive, a more marked burst release was observed for microspheres prepared without additive in the continuous phase, which may be attributed to the porous morphology of the latter.