Process and formulation variables in the preparation of wax microparticles by a melt dispersion technique. II. W/O/W multiple emulsion technique for water-soluble drugs.

Pseudoephedrine HCl-carnauba wax microparticles were prepared by a multiple emulsion-melt dispersion technique. A heated aqueous drug solution was emulsified into the wax melt (W/O emulsion), followed by emulsification of this primary emulsion into a heated external aqueous phase (W/O/W emulsion). The drug-containing microparticles were formed after cooling and congealing of the wax phase. The encapsulation efficiencies were above 80 per cent and actual drug loadings close to 50 per cent were achieved. The surface of the microparticles had submicron pores and drug crystals were visible on cross-sections. The drug loading depended on the rate of cooling and the volume of the internal aqueous phase but was insensitive to the volume of the continuous phase. The drug release was much faster when compared to the release from polymeric microspheres.     

Process and formulation variables in the preparation of wax microparticles by a melt dispersion technique. I. Oil-in-water technique for water-insoluble drugs.

Ibuprofen-wax (carnauba, paraffin, beeswax, and the semisynthetic glyceryl esters--Gelucire 64/02 and Precirol ATO5) microparticles were prepared without organic solvents as an alternative to polymeric microparticles. In the melt dispersion technique, the drug-wax melt was emulsified into a heated aqueous phase followed by cooling to form the microparticles. The microparticles were characterized with respect to their drug loading, and morphological and release properties. They were spherical and non-agglomerated and drug loading close to 60 per cent were achieved. The more hydrophilic waxes (Gelucire 64/02 or Precirol ATO5) could be prepared without the use of surfactants. With the other waxes, increasing amounts of sodium lauryl sulphate in the external aqueous phase decreased the drug loading because of drug solubilization when compared to the polymeric stabilizer, poly(vinyl alcohol). The type of wax, the rate of cooling, and the temperature of the aqueous phase had no significant effect on the drug loading because of the low solubility of the drug in the external aqueous phase. The drug release was controlled by the hydrophobicity of the wax. Besides ibuprofen, other water-soluble drugs (ketoprofen, indomethacin, hydrocortisone) were also encapsulated by this method. The wax microparticles could be formulated into an aqueous sustained-release oral suspension dosage form.     

Poly (epsilon-caprolactone) microparticles containing Levobunolol HCl prepared by a multiple emulsion (W/O/W) solvent evaporation technique: effects of some formulation parameters on microparticle characteristics

The aim of this study was to prepare poly (epsilon-caprolactone) (PCL) microparticles of Levobunolol HC1 (L-HC1) for use as an anti-glaucomatous drug to the eye. The double emulsion (W/O/W) solvent evaporation technique was used for encapsulating L-HC1 as a hydrophilic drug. The study examined the impact of different factors including the pH and volume of the external aqueous phase, the concentration of polyvinylalcohol (PVA) and Pluronic F68 (PF68) used as stabilizers and drug/polymer ratios on the characteristics of the microparticles. Scanning electron microscopy (SEM) and differential scanning calorimetry (DSC) were used to identify the physical state of the drug and polymer. The zeta potential of the particles was also identified. Entrapment efficiency was found to be highest with a 0.5% PVA concentration and 100 mL volume of external aqueous phase at pH 12. The high efficiency was due to a reduction in the degree of drug ionization. The microparticles were spherical and appropriately sized for ophthalmic application. Drug release from the microparticles appears to consist of two components, with an initial rapid release followed by a slower stage. Drug release was slower when the microparticle was incorporated into the thermally reversible gel (Pluronic F127) in comparison to drug release from the free drug incorporated into the gel and drug release from the free microparticle.     

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.     

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...     

Poly (ε-caprolactone) microparticles containing Levobunolol HCl prepared by a multiple emulsion (W/O/W) solvent evaporation technique: Effects of some formulation parameters on microparticle characteristics

Abstract

The aim of this study was to prepare poly (ε-caprolactone) (PCL) microparticles of Levobunolol HC1 (L-HC1) for use as an anti-glaucomatous drug to the eye. The double emulsion (W/O/W) solvent evaporation technique was used for encapsulating L-HC1 as a hydrophilic drug. The study examined the impact of different factors including the pH and volume of the external aqueous phase, the concentration of polyvinylalcohol (PVA) and pluronic® F68 (PF68) used as stabilizers and drug/polymer ratios on the characteristics of the microparticles. Scanning electron microscopy (SEM) and differential scanning calorimetry (DSC) were used to identify the physical state of the drug and polymer. The zeta potential of the particles was also identified. Entrapment efficiency was found to be highest with a 0.5% PVA concentration and 100 mL volume of external aqueous phase at pH 12. The high efficiency was due to a reduction in the degree of drug ionization. The microparticles were spherical and appropriately sized for ophthalmic application. Drug release from the microparticles appears to consist of two components, with an initial rapid release followed by a slower stage. Drug release was slower when the microparticle was incorporated into the thermally reversible gel (Pluronic® F127) in comparison to drug release from the free drug incorporated into the gel and drug release from the free microparticle.     

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.     

Preparation of multi-phase microspheres of poly(D,L-lactic acid) and poly(D,L-lactic-co-glycolic acid) containing a W/O emulsion by a multiple emulsion solvent evaporation technique.

Multi-phase microspheres of poly(D,L-lactic acid) (PLA) or poly(D,L-lactic-co-glycolic acid) (PLGA) containing a water-in-oil (W/O) emulsion were prepared by a multiple emulsion solvent evaporation technique. Acetonitrile was used as the solvent for the polymers and light mineral oil as the dispersion medium for the encapsulation procedure. Process and formulation parameters to optimize the microencapsulation of a W/O emulsion containing water-soluble drugs were investigated. Drug loading efficiencies of 80-100 per cent were obtained under specific preparative conditions. The drug loading efficiency in the microspheres was dependent upon the ratio of the W/O emulsion to polymer and the concentration of surfactant in the mineral oil. Compared to conventional microspheres, in which fine drug particles are homogeneously dispersed in the polymer beads, the multi-phase microspheres permit the higher encapsulation efficiency of water-soluble drugs and eliminate partitioning into the polymer-acetonitrile phase which results in low encapsulation efficiency with conventional solvent evaporation techniques.     

Slow release of chloroquine phosphate from multiple taste-masked W/O/W multiple emulsions

Abstract

The efficacy and safety of chloroquine as an antimalarial has contributed to the survival of millions in the past 50 years. Chloroquine is widely available, cheap, well tolerated and orally well absorbed. Therefore, it remains an important antimalarial drug. However, on oral administration, particularly to children, the unpleasant taste is a problem. This could be avoided by ‘taste-masked and controlled release’ formulations such as multiple emulsions. Although Plasmod-ium falciparum has developed resistance to many antimalarial drugs, including chloroquine, resistance may be attributed, among other factors, to subclinical dosage of chloroquine from administered pharmaceutical forms. This could also be relevant in the treatment of rheumatoid arthritis. Multiple W/O/W emulsions of chloroquine phosphate were prepared. Assessment of emulsion stability showed no significant change in the system. Prolonged storage (four months) of the emulsion resulted in negligible loss of chloroquine phosphate. The results suggest, therefore, that chloroquine phosphate releases due to diffusion of the drug from the internal globules and not as a consequence of instability of the W/O/W emulsion. These characteristics are in accordance with the requirements for controlled release Pharmaceuticals. Stability of multiple emulsions could have resulted from interfacial polymerization or complexion between molecules. Release assessments showed faster rates for W/O/W emulsions which had smaller internal aqueous globules and, therefore, an increased interfacial area. Furthermore, transport of high-diffusion coefficient micelles could have given a greater solute flux in these systems.     

Microencapsulation of peptides and proteins

Microcapsules were prepared by using a double-emulsion technique. A new production method called 'induced phase separation method' was applied to encapsulate peptides and proteins. To find the optimal adjuvants a matrix was set up combining the appropriate organic solvents and the suitable surfactants. The polymer was chosen with regard to the required release period. The aqueous drug solution was intensively mixed with the organic polymer solution. An aqueous surfactant solution was slowly added to the O/W emulsion. The obtained W/O/W emulsion is stirred under partial vacuum conditions until the organic solvent was removed. After removing the solvent from the W/O/W emulsion the microcapsules were washed and lyophilized. The morphology of the microparticles (spheres, sponges, capsules, surplus polymer) was checked by microscopy, particle size distributions were measured by laser diffraction.     

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.     

Effects of salt addition on the microencapsulation of proteins using W/O/W double emulsion technique

The influence of co-encapsulation of stabilizing additives together with BSA on microsphere characteristics using the modified water-in-oil-in-water emulsion solvent evaporation (W/O/W) method was investigated. For this purpose, poly(L-lactide) microspheres containing bovine serum albumin (BSA) were prepared. The morphology, porosity, specific surface area, particle size, encapsulation efficiency and kinetics of drug release of protein loaded microspheres were analysed in relation to the influence of co-encapsulated stabilizing additives such as electrolytes. High salt concentrations in the internal (W1) aqueous phase, often necessary to stabilize protein or antigen solutions, led to an increase in particle size, particle size distribution, porosity and specific surface area. Bulk density and encapsulation efficiency decreased. The release profile was characterized by a high initial burst due to the highly porous structure. Addition of salt to the external or continuous water phase (W2), however, stabilized the encapsulation process and, therefore, resulted in improved microsphere characteristics as a dense morphology, a reduced initial burst release, a drastically increased bulk density and encapsulation efficiency. Analysis of the specific surface area (BET) showed that the addition of salt to W2, regardless of the salt concentration in the W1 phase, decreased the surface area of the microspheres approximately 23-fold. Microsphere properties were influenced by salts additions through the osmotic pressure gradients between the two aqueous phases and the water flux during microsphere formation. Release profiles and encapsulation efficiencies correlated well with the porosity and the surface area of microspheres. Furthermore, the influence of a low molecular weight drug and different time-points of salt addition to W2 on microsphere characteristics were studied by encapsulation of acid orange 63 (AO63), confirming the results obtained with BSA. This study suggests that modification of the external water phase by adding salts is a simple and efficient method to encapsulate stabilized protein solution, with high encapsulation efficiency and good microsphere characteristics.     

Topical delivery of urea encapsulated in biodegradable PLGA microparticles: O/W and W/O creams

This study describes the formulation and characterization of O/W and W/O creams containing urea-loaded microparticles prepared with poly (D, L-lactic-co-glycolic acid) (PLGA) in order to encapsulate and stabilize urea. The solvent evaporation method was used for preparing PLGA microparticles containing urea. The microparticles size was evaluated by laser light diffractometry. The resulting microparticles were then incorporated in O/W and W/O creams and stability and the release pattern from the creams was evaluated by UV-spectrophotometry. The particle size of PLGA microparticles was in the range of 1–5 µm and most microparticles had a particle size smaller than 3 µm. The encapsulation efficiency was calculated as 40.5%?±?3.4. This study also examined release pattern of urea which varied among different formulations. The results showed that the release from O/W creams followed Higuchi kinetics while the release from W/O creams showed the zero order kinetics and the creams containing microparticulated urea had slower release than free urea creams.     

内水相添加氯化钠对W/O/W型复乳性质的影响

目的探讨在内水相中添加氯化钠(NaCl)对W/O/W型复乳性质的影响。方法在前期试验优选出较佳W/O/W复乳处方的基础上,以1 g/L NaCl水溶液代替处方中的纯化水作为内水相,采用二步乳化法制备复乳,从显微结构、粒径分布、稳定性等方面比较复乳性质的变化。结果在内水相中添加NaCl(1 g/L)时,复乳主要为B型结构,外观较圆整,液滴大小较均匀,且乳滴不易聚集成一团,大部分粒子粒径在20～40μm之间,稳定性良好。结论在内水相中添加NaCl(1 g/L),有助于优化W/O/W型复乳物理化学性质,提高其稳定性。     

Tabletted polylactide microspheres prepared by a w/o emulsion-spray drying method

An emulsification-spray drying technique is used to prepare poly(D, L-lactic acid) (PDLLA) microparticles loaded with a water soluble, non-steroidal antiinflammatory drug (NSAID), sodium naproxen (NaNPX). The method involves the preparation of a w/o emulsion in which the water soluble drug is dissolved in the aqueous dispersed phase, while the polymer is dissolved in the organic continuous phase. As a comparison, microparticles were prepared by spraying a suspension of the drug into an organic solution of the polymer. The spray-dried particles were characterized using SEM, DSC, XRD and in vitro release tests. The spray-dried product was then compressed (direct compression) to obtain controlled release matrix tablets. All microparticles release NaNPX within 30min. The matrix tablets release the drug in 8-10h; the matrix tablets characterized by the presence of surfactant (due to the emulsion used to obtain the microparticles) have the highest release rate.     

Tabletted polylactide microspheres prepared by a w/o emulsion-spray drying method

An emulsification-spray drying technique is used to prepare poly(D,L-lactic acid) (PDLLA) microparticles loaded with a water soluble, non-steroidal anti-inflammatory drug (NSAID), sodium naproxen (NaNPX). The method involves the preparation of a w/o emulsion in which the water soluble drug is dissolved in the aqueous dispersed phase, while the polymer is dissolved in the organic continuous phase. As a comparison, microparticles were prepared by spraying a suspension of the drug into an organic solution of the polymer. The spray-dried particles were characterized using SEM, DSC, XRD and in vitro release tests. The spray-dried product was then compressed (direct compression) to obtain controlled release matrix tablets. All microparticles release NaNPX within 30 min. The matrix tablets release the drug in 8-10 h; the matrix tablets characterized by the presence of surfactant (due to the emulsion used to obtain the microparticles) have the highest release rate.     

Pharmacokinetics of Vancomycin after Intravenous Administration of a W/O/W Emulsion to Rats

A stable water-in-oil-in-water multiple emulsion (w/o/w emulsion) was prepared, and its potential for drug delivery was evaluated. W/o/w emulsions were prepared using a Lipiodol Ultra-Fluid(r) and isopropyl myristate oil mixture for the oily phase and vancomycin (VCM) for the entrapped drug. The surfactants, HCO-40 (5% [w/v]) and Pluronic F-88 were dissolved in the oily phase and the external aqueous phase, respectively. Resultant w/o/w emulsions were evaluated for entrapment efficiency, particle size, viscosity, drug release in vitro, and disposition kinetics of the drug and the w/o/w emulsion in vivo. The particle size of the w/o/w emulsion decreased with an increase in the concentration of F-88 in the external aqueous phase and stirring speed at the second emulsification stage (the smallest being 2.9 ± 1.5 μm). Entrapment efficiency of VCM in the w/o/w emulsion decreased with an increase in the concentration of F-88 (the maximum being 65.3 ± 5.4%). VCM release from the w/o/w emulsion was prolonged and tended to be slower with an increase in the particle size of the emulsion. After intravenous administration, significant differences in pharmacokinetic parameters, such as k₂₁, k_elβ, AUC₀-±, MRT₀-₆, and MRT₀-±, were observed between the VCM solution and the w/o/w emulsion-entrapped drug. When the w/o/w emulsion with Sudan II in the oily phase was administered intravenously, the emulsion accumulated in the lung at first (the highest value was observed just after administration) and then in the liver (the highest value was observed at 60 min). The w/o/w emulsion prepared in this study is expected to be a possible carrier for the prolonged release of water-soluble drugs after intravenous administration.     

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.     

Topical delivery of urea encapsulated in biodegradable PLGA microparticles: O/W and W/O creams

This study describes the formulation and characterization of O/W and W/O creams containing urea-loaded microparticles prepared with poly (D, L-lactic-co-glycolic acid) (PLGA) in order to encapsulate and stabilize urea. The solvent evaporation method was used for preparing PLGA microparticles containing urea. The microparticles size was evaluated by laser light diffractometry. The resulting microparticles were then incorporated in O/W and W/O creams and stability and the release pattern from the creams was evaluated by UV-spectrophotometry. The particle size of PLGA microparticles was in the range of 1-5 microm and most microparticles had a particle size smaller than 3 microm. The encapsulation efficiency was calculated as 40.5% +/- 3.4. This study also examined release pattern of urea which varied among different formulations. The results showed that the release from O/W creams followed Higuchi kinetics while the release from W/O creams showed the zero order kinetics and the creams containing microparticulated urea had slower release than free urea creams.     

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.