Preparation of microcapsules and control of their morphology

For the preparation of microcapsules using the W/O/W (water in oil in water) emulsion system, it is essential to control various factors such as the dispersed state of the organic phase in the W/O/W emulsion, the difference in the solute concentration between the inner and outer aqueous phases and the volume fraction of the dispersed phase. In this study, cross-linked microcapsules were prepared by the in-situ polymerization of styrene and divinylbenzene and biodegradable microcapsules were prepared by the solvent evaporation method. The effects of the preparation conditions on the capsule morphology and entrapment efficiency of water-soluble materials were investigated. The average diameter of the surface pores and internal hollows were controlled on a sub-micron order by changing the preparation conditions such as diluent concentration, volume fraction of the dispersed droplets in the W/O (water in oil) emulsion, surfactant concentration monomer ratio and salt concentration in the outer aqueous phase. Furthermore, the water-soluble materials were completely entrapped in the biodegradable microcapsule by changing the preparation conditions such as volume fraction of the dispersed droplets in the W/O emulsion, salt concentration in the inner and outer aqueous phases, polymer concentration and supersonic irradiation of the W/O droplets.     

Rheology and stability of water-in-oil-in-water multiple emulsions containing Span 83 and Tween 80

Multiple emulsions are often stabilized using a combination of hydrophilic and hydrophobic surfactants. The ratio of these surfactants is important in achieving stable multiple emulsions. The objective of this study was to evaluate the long-term stability of water-in-oil-in-water (W/O/W) multiple emulsions with respect to the concentrations of Span 83 and Tween 80. In addition, the effect of surfactant and electrolyte concentration on emulsion bulk rheological properties was investigated. Light microscopy, creaming volume, and rheological properties were used to assess emulsion stability. It was observed that the optimal surfactant concentrations for W/O/W emulsion long-term stability were 20% wt/vol Span 83 in the oil phase and 0.1% wt/vol Tween 80 in the continuous phase. Higher concentrations of Tween 80 had a destructive effect on W/O/W emulsion stability, which correlated with the observation that interfacial film strength at the oil/water interface decreased as the Tween 80 concentration increased. High Span 83 concentrations increased the storage modulus G′ (solidlike) values and hence enhanced multiple emulsion stability. However, when 30% wt/vol Span 83 was incorporated, the viscosity of the primary W/O emulsion increased considerably and the emulsion droplets lost their shape. Salt added to the inner aqueous phase exerted an osmotic pressure that caused diffusion of water into the inner aqueous phase and increased W/O/W emulsion viscosity through an increase in the volume fraction of the primary W/O emulsion. This type of viscosity increase imposed a destabilizing effect because of the likelihood of rupture of the inner and multiple droplets.     

W/O/W型甘草酸单铵盐口服复乳的药物释放研究

Ｗ／Ｏ／Ｗ型甘草酸单铵盐口服复乳的药物释放研究高晓黎，孙殿甲，邱洪卓（新疆医学院药学系，乌鲁木齐８３００５４；天山制药工业有限公司，乌鲁木齐８３００００）甘草酸及其盐有广泛的药理作用，并在临床上用于病毒性肝炎的治疗。甘草酸单铵盐易溶于热水，冷后成凝胶...     

Microencapsulation of acetaminophen into poly(L-lactide) by three different emulsion solvent-evaporation methods

Poly(L-lactide) (PLLA) microcapsules containing acetaminophen (APAP) were prepared by three emulsion solvent-evaporation methods including an O/W-emulsion method, an O/W-emulsion co-solvent method and a W/O/W-multiple-emulsion method. The average size and morphology of the microcapsules varied substantially among these three preparation methods. Various alcohol and alkane co-solvents were found to exert significant impact on the O/W-emulsion co-solvent method and a more lipophilic co-solvent such as heptane appeared to enhance drug encapsulation with an efficiency nearly double of the O/W-emulsion method. When a small amount of water was added as the internal aqueous phase in the W/O/W-multiple-emulsion method, the encapsulation efficiency was found nearly triple of that for the O/W-emulsion method. While having a higher encapsulation efficiency, the microcapsules prepared by the W/O/W-multiple-emulsion method had as good controlled release behaviour as those prepared by the O/W-emulsion method. The release kinetics of microcapsules prepared by the O/W-emulsion method and the O/W-emulsion co-solvent (alcohol) method fitted the Higuchi model well in corroboration with the uniform distribution of APAP in PLLA matrix, i.e. the monolithic type microcapsules. However, the release kinetics of microcapsules prepared by the O/W-emulsion co-solvent (alkane) method and the W/O/W-multiple-emulsion method fitted the first-order model better, indicating the reservoir type microcapsules.     

Preparation of soft microcapsules containing multiple core materials with interfacial dehydration reaction using the (W/O)/W emulsion

The soft microcapsules containing eucalyptus oil, ubiquinone and the fine water droplets could be prepared with interfacial dehydration reaction between hydroxy methyl cellulose and tannic acid using the water-in-oil-in-water type multiple (W/O)/W emulsion. The diameters of the microcapsules and the content and the microencapsulation efficiency of the core materials were significantly affected by the revolution velocity (Nr₁) to form the (W/O) emulsion and the revolution velocity (Nr₂) to form the (W/O)/W emulsion and the lecithin concentration. The mean diameters of the inner water droplets and those of the microcapsules were proportional to Nr₁^?1.25 and Nr₁^?0.11 for the revolution velocity (Nr₁), respectively. With increasing the revolution velocity (Nr₁), the content and the microencapsulation efficiency of the inner water droplets increased, while those of the oil phase decreased. The mean diameters of the microcapsules were proportional to Nr₂^?1.1. The content and the microencapsulation efficiency of the inner water droplets and those of the oil phase decreased with the revolution velocity (Nr₁) and increased with the lecithin concentration.     

Preparation of stable W/O/W type multiple emulsion containing water-soluble drugs and in vitro evaluation of its drug-releasing properties]

The stable water-in-oil-in-water (W/O/W) multiple emulsion was prepared by a two-step procedure for emulsification using glyceryl tricaprylate (Panasate-800) as the oil phase. The water-soluble drugs such as cefadroxil, cephradine, 4-aminoantipyrine, and antipyrine were selected and entrapped separately in the inner aqueous phase of W/O/W multiple emulsion. In consideration of parenteral administration, pH 7.4 phosphate buffered saline was used in both inner and outer aqueous phases. Moreover, these multiple emulsions could be significantly stable for a month at room temperature by the addition of hydrophilic polymer like gelatin and of amino acid like lysine to the inner aqueous phase.     

New drug salt formation in biodegradable microspheres

PURPOSE: To investigate the effects of inorganic salts in the external phase of an oil-in-water (O/W) emulsion method during microsphere preparation. METHODS: An O/W emulsion method was used to prepare poly(D,L-lactic acid) microspheres containing quinidine sulfate. Different inorganic salts were used in the external phase during microsphere preparation. Microsphere drug loading was determined by UV and the drug salt anions inside the microspheres were determined by ion chromatography. RESULTS: New drug salts were formed during encapsulation in the microspheres when salts with non-common anions to the drug salt were used. Drug loading increased when NaClO4 or NaSCN were used. The fraction of drug as the new salt in microspheres increased non-linearly with the salt concentration in the external phase, however, the fraction of drug as the new encapsulated salt was linearly related to drug loading. Drug loading decreased and new salt fraction increased with increasing organic solvent volume or with decreasing cosolvent polarity. CONCLUSIONS: Introducing salts containing non-common anions to the drug salt employed in the external phase of O/W emulsion microsphere method leads to new salt formation. The extent of new drug salt formation is affected by salt levels added, cosolvent type and polymer concentration.     

Improvement of encapsulation efficiency of water-in-oil-inwater emulsion with hypertonic inner aqueous phase

Water-in-oil-in-water (w/o/w) emulsions encapsulating tryptophan or theophylline were prepared where these compounds are regarded as model drugs. The effects of sodium chloride on the drug entrapment into the w/o/w emulsions and on the separation of aqueous phases were studied. The degree of encapsulation of tryptophan in the w/o/w emulsion increased with the concentration of sodium chloride added in the inner aqueous phase, while it decreased with that in the outer aqueous phase. As for theophylline, although the degree increased with a concentration of sodium chloride in the inner phase, the effect was smaller than that on tryptophan. The difference in the effects between on tryptophan and on theophylline was attributed to their partition coefficients. Theophylline was easily leaked out from the inner phase to the outer aqueous phase after its dissolution and diffusion in the oil phase due to a higher partition coefficient. More than 55%of the aqueous phase was separated from the w/o/w emulsion within 24h, when sodium chloride was not added in the inner aqueous phase. However, the separation was not observed when more than 0.2M sodium chloride was added. To the contrary, sodium chloride added in the outer aqueous phase accelerated the separation. It was, therefore, concluded that sodium chloride in the inner aqueous phase plays an important role in suppression of the separation and in encapsulation of the drug which does not penetrate into the oil membrane.     

Preparation of double-encapsulated microcapsules for mitigating drug loss and extending release

The double-encapsulated microcapsules were prepared by the non-solvent addition, phase-separation method to form core material and, encapsulated with the O/W emulsion non-solvent addition method to increase drug loading and regulate drug release rate. The drug used was theophylline, which is watersoluble. Dichloromethane and n-hexane were used as the solvent and non-solvent, respectively. This study investigated how various core material and microcapsule EC/TH ratios affect the drug loss, particle size, surface morphology and release rate. The drug loss of the double-encapsulated microcapsules was 12.8% less than that of microcapsules prepared by the O/W emulsion non-solvent addition method alone. The particle size of these double-encapsulated microcapsules decreased as the concentration of EC polymer was increased in the second encapsulation process. The roughness of their surface was also in proportion to the concentration of polymer solution used in the second encapsulation process. The dissolution study showed that the T 20 of the double-encapsulated microcapsules ranged from 2-35.4 h, while that of the O/W emulsion non-solvent addition method microcapsules was from 2.7-7.7 h. The greater the level of EC in the polymer solution, the slower the release rate of the drug from the microcapsules when the EC was not over the critical amount.     

A new method of preparing monocored water-loaded microcapsules using interfacial polymer deposition process

A new method was proposed to prepare monocored water-loaded microcapsules with diameters of 50 microns or larger by making use of the process of interfacial polymer deposition. A solution of ethylcellulose or polystyrene in dichloromethane was added dropwise to an O/W emulsion in which n-hexane was dispersed as fine droplets in aqueous gelatin solution. Successive evaporation of dichloromethane at 40 degrees C and n-hexane at 80 degrees C gave monocored water-loaded ethylcellulose or polystyrene microcapsules. Monocored water-loaded ethylcellulose/polystyrene composite microcapsules were similarly prepared using mixed solutions of the two polymers in dichloromethane instead of ethylcellulose or polystyrene solution. When those mixed solutions which exhibit phase separation were used, the composite microcapsules obtained had a patchwork-like structure in which polystyrene-rich islands are dispersed in the ethylcellulose-rich sea.     

Releasing properties of water soluble drug in internal water phase of W/O/W multiple emulsions]

A stable water/liquid paraffin system water-in-oil-in-water (W/O/W) multiple emulsion was prepared by the two-step procedure of emulsification using a variety of nonionic emulsifying agents, such as Span 80 and Tween 20. After comparison of the releasing properties of such water soluble drugs as cefadroxil, cephradine, 4-aminoantipyrine and antipyrine which were entrapped separately in the inner aqueous phase of the W/O/W multiple emulsion, a large difference was observed. It was ascertained that the difference in these releasing properties was due to no physical rupture by the microscopic observation and the results of the release test of W/O/W multiple emulsion with two kinds of drugs entrapped simultaneously in an inner aqueous phase. This reason was presumed to be dependent on permeation in the oily phase of the drug itself. It was proved that the differences of releasing properties tended to depend on the molecular weight and were closely related to the drug concentration of outer aqueous phase of W/O/W multiple emulsion containing the drug in both aqueous phases prepared as an experimental model. Therefore, two possible mechanisms for the releasing of drugs in W/O/W multiple emulsion may be interpreted as follows: the first is that the mixed and inversed micelles formed by Span 80 and Tween 20 agents in the oily phase act as a carrier of drugs, and the second is that drug molecules diffuse through small pore existing in very thin lamella of the emulsifying agents partially formed in the oil layer owing to the fluctuation of the thickness.     

Microencapsulation with carrageenan-locust bean gum mixture in a multiphase emulsification technique for sustained drug release

Abstract

A multiphase emulsification technique was modified in this process of microencapsulating gentamicin sulphate, thus avoiding the necessity for a surfactant in preparing the secondary emulsion for a W/O/W emulsion. Various proportions of iota-carrageenan (i-C) and locust bean gum (LBG) were investigated for the W/O/W emulsion after forming the primary W/O emulsion with sorbitan trioleate, Span 85. Upon removal of the oil phase (chloroform) from the W/O/W emulsion by heating (60-65°C), microcapsules or ‘W/W particles containing drug dissolved in sodium hyaluronate were spontaneously formed. These were dispersed in a solution of a mixture of 5-10 per cent w/v polyvinyl alcohol, PVA (average MW 50000-106000; 98 per cent hydrolysed) and 3 per cent v/v polyethylene glycol 200 (PEG 200), and dried to form the hydrogel film casts. Our in vitro experiments in isotonic phosphate buffer solution (pH 7-4) at 37°C., showed that the release of gentamicin sulphate was dependent on concentration of LBG, and concentration or molecular weight of PVA. With the exception of PVA hydrogel matrix preparations containing 20 per cent w/v LBG, all other formulations showed a significant initial ‘burst' release of drug within 6h. The drug-containing microcapsules in the PVA hydrogel film with 20 per cent w/v LBG, exhibited an almost zero-order release of drug up to 140h. It is postulated that an effective barrier or high-density membrane enveloping the microcapsules was formed between i-C and LBG because of their unique molecular configurations. This phenomenon, together with the possible adsorption of i-C molecules at the transient oil and outer aqueous phase interface, presumably eliminated the need for a permanent oil phase and/or an O/W surfactant normally required for preparing W/O/W emulsions.     

Biodegradable submicron carriers for peptide drugs: Preparation of dl-lactide/glycolide copolymer (PLGA) nanospheres with nafarelin acetate by a novel emulsion-phase separation method in an oil system

PLGA nanospheres, biodegradable polymeric carriers for peptide drugs, were prepared by a novel emulsion-phase separation method. The preparation was carried out in an oil phase system in order to improve the entrapment efficiency of water-soluble peptide. An LH-RH analogue (nafarelin acetate (NA)) was employed as a model peptide drug to investigate the encapsulation efficiency. An aqueous solution of the drug was emulsified by addition with stirring to a dichloromethane-acetone mixture containing dissolved PLGA. The gradual addition of Triester oil (caprylate and caprate triglyceride) into the resultant w/o emulsion induced phase separation of PLGA at the interface of aqueous droplets. It was found that the aqueous droplets effectively worked as a coacervation-inducing agent of the polymer. PLGA coacervates precipitated around the aqueous emulsion droplets containing the peptide which were hardened by evaporation of the solvent, producing spherical drug carriers. The presence of surfactant significantly reduced the size of the aqueous droplets, resulting in submicron-sized PLGA spheres (mean diameter, 500–800 nm). The recovery of drug entrapped in the nanospheres was markedly increased compared with our previous preparation technique in a water system. Further, optimum conditions in the present method for preparing nanospheres were established to enhance the recovery of nanospheres and the efficiency of drug entrapment.     

Stabilization of protein encapsulated in poly(lactide-co-glycolide) microspheres by novel viscous S/W/O/W method

In stabilizing proteins during microsphere fabrication, the viscous solid-in-water-in-oil-in-water (S/W/O/W) method was compared to the conventional multi-emulsion W/O/W and S/O/W method. Solid proteins lyophilized with cyclodextrin derivatives and polyethylene glycol (PEG) pass through an organic solvent phase and are then embedded in aqueous microdroplets of first emulsion. Proteins were stabilized at the water/organic solvent interface by an internal aqueous phase containing viscous polysaccharides, and then can be safely encapsulated without degradation. In addition, these microspheres showed a long-term protein release followed by nearly zero-order kinetics with minimal initial burst. This means that the viscous S/W/O/W method provides a safe strategy for microsphere fabrication and has promising properties, involving the preservation of protein bioactivity, the inhibition of protein denaturation or agglomeration, and long-term protein release.     

Microencapsulation of acetaminophen into poly(L-lactide) by three different emulsion solvent-evaporation methods

Poly(L-lactide) (PLLA) microcapsules containing acetaminophen (APAP) were prepared by three emulsion solvent-evaporation methods including an O/W-emulsion method, an O/W-emulsion co-solvent method and a W/O/W-multiple-emulsion method. The average size and morphology of the microcapsules varied substantially among these three preparation methods. Various alcohol and alkane co-solvents were found to exert significant impact on the O/W-emulsion co-solvent method and a more lipophilic co-solvent such as heptane appeared to enhance drug encapsulation with an efficiency nearly double of the O/W-emulsion method. When a small amount of water was added as the internal aqueous phase in the W/O/W-multiple-emulsion method, the encapsulation efficiency was found nearly triple of that for the O/W-emulsion method. While having a higher encapsulation efficiency, the microcapsules prepared by the W/O/W-multiple-emulsion method had as good controlled release behaviour as those prepared by the O/W-emulsion method. The release kinetics of microcapsules prepared by the O/W-emulsion method and the O/W-emulsion co-solvent (alcohol) method fitted the Higuchi model well in corroboration with the uniform distribution of APAP in PLLA matrix, i.e. the monolithic type microcapsules. However, the release kinetics of microcapsules prepared by the O/W-emulsion co-solvent (alkane) method and the W/O/W-multiple-emulsion method fitted the first-order model better, indicating the reservoir type microcapsules.     

Study of a microencapsulation process of a virucide agent by a solvent evaporation technique

Abstract

A highly water-soluble virucide agent was microencapsulated by a water/oil/water emulsification-solvent evaporation method. An aqueous drug solution was emulsified into a solution of polymer in methylene chloride, followed by emulsification of the primary emulsion in an external aqueous phase. Microcapsules were formed after solvent evaporation, the solidification of the microcapsule walls was followed by an optical method. The influence of stirring speed was analysed to find the optimal hydrodynamic conditions with respect to the process yield, corresponding to the weight of obtained microcapsules per litre of water/oil/water emulsion, the initial virucide agent content and the drug release kinetics. The optimal conditions were obtained for the complete suspension speed. The improvement of the microencapsulation process was attempted by increasing the concentration of the primary emulsion and by the reuse of the external aqueous phase after removal of the microcapsules.     

复乳法制备阿柔比星A的聚乳酸聚乙醇酸共聚物纳米粒影响包封率因素考察

以含阿柔比星A(Aclarubicin A，ACRB-A)的酸性溶液为内水相，采用复乳法制备ACRB-A(PLGA)纳米粒。考察了有机溶剂、油酸的量、稳定剂种类、投药量、乳化剂、Na2SO4的量和外水相的pH值几个主要因素对ACRB-APLGA纳米粒包封率的影响。结果表明，以二氯甲烷和丙酮为有机溶剂、油酸(15mg)、右旋糖酐-70、ACRB-A的浓度(Smg／ml)、以F68和Tween-80为乳化剂、2％的Na2SO4和外水相的pH等于8有利于提高ACRB-A的包封率。经实验条件优化后制备的ACRB-A PLGA包封率为85．41％，纳米粒粒径为272nm，粒径分散指数为0．213。     

Preparation of solid lipid nanoparticles from W/O/W emulsions: Preliminary studies on insulin encapsulation

Abstract

A method to produce solid lipid nanoparticles (SLN) from W/O/W multiple emulsions was developed applying the solvent-in-water emulsion-diffusion technique. Insulin was chosen as hydrophilic peptide drug to be dissolved in the acidic inner aqueous phase of multiple emulsions and to be consequently carried in SLN. Several partially water-miscible solvents with low toxicity were screened in order to optimize emulsions and SLN composition, after assessing that insulin did not undergo any chemical modification in the presence of the different solvents and under the production process conditions. SLN of spherical shape and with mean diameters in the 600–1200 nm range were obtained by simple water dilution of the W/O/W emulsion. Best results, in terms of SLN mean diameter and encapsulation efficiencies, were obtained using glyceryl monostearate as lipid matrix, butyl lactate as a solvent, and soy lecithin and Pluronic®F68 as surfactants. Encapsulation efficiencies up to 40% of the loaded amount were obtained, owing to the actual multiplicity of the system; the use of multiple emulsion-derived SLN can be considered a useful strategy to encapsulate a hydrophilic drug in a lipid matrix.     

盐酸倍他洛尔蒙脱石微球的制备及其体外释放性能的研究

目的制备可满足缓释要求的镶嵌蒙脱石的离子交换缓释微球。方法采用S/O1/O2/O3复乳-溶剂挥发法制备微球,考察处方因素包括复乳相体积比例、药物质量浓度、膜材用量和乳化剂质量分数对微球制备的影响。以微球体外释放为考察指标,优化微球处方。结果研究所得到的微球最佳处方为大豆油∶药物=6∶1,药物∶膜材=1∶5,乳化剂质量分数为0.5%²%。除乳化剂外,其他因素对微球体外释放均有较大影响。所制备微球的体外释放可以达到10h,基本无突释现象。进行形态观察发现,微球较为圆整,粒径比较均匀。结论采用优化处方以复乳-溶剂挥发法所制备盐酸倍他洛尔蒙脱石微球体外具有缓释性能。     

A Novel Method of Preparing PLGA Microcapsules Utilizing Methylethyl Ketone

Purpose. To substitute dichloromethane with a safer solvent, a solvent extraction process using methylethyl ketone (MEK) was developed to prepare poly(d,l-lactide-co-glycolide) microcapsules. Methods. The MEK dispersed phase containing PLGA and progesterone was emulsified in the MEK-saturated aqueous phase (W₁) to make a transient oil-in-water (O/W₁) emulsion. It was then transferred to a sufficient amount of water (W₂) so that MEK residing in polymeric droplets could be extracted effectively into the continuous phase. Results. This solvent extraction process provided the encapsulation efficiency for progesterone ranging from 77 to 60%. The amount of MEK predissolved in W₁ as well as the degree of progesterone payload, influenced the encapsulation efficiency. The leaching profile of MEK analyzed by GC substantiated that, upon dispersion of O/W₁ to W₂, MEK quickly diffused into the continuous phase. Such a rapid diffusion of MEK from and the ingression of water into polymeric droplets produced hollow microcapsules, as evidenced by their SEM micrographs. Conclusions. When solvent extraction/evaporation techniques are employed for preparing PLGA microcapsules, water-immiscibility of a dispersed phase is not an absolute prerequisite to the successful microencapsulation. Adjustment of an initial extraction rate of MEK and formation of a primary transient O/W₁ emulsion are found to be very crucial not only for the success of microencapsulation but also for the determination of microcapsule morphology.