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. II. W/O/W multiple emulsion technique for water-soluble drugs

Abstract

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.     

Solid lipid microparticles containing loratadine prepared using a Micromixer

Solid lipid microparticles were investigated as a taste-masking approach for a lipophilic weak base in a suspension. The idea was that the drug concentration in the aqueous phase of a suspension might be reduced by its partitioning into the solid lipid particles. Loratadine, as a model drug, was used to prepare Precirol ATO 5 microparticles by a Micromixer. The effects of three process variables: drug loading, PVA concentration and water/lipid ratio on the microparticle size, encapsulation efficiency, surface appearance, in-vitro release and drug partitioning in a suspension were studied. Loratadine release was slow in simulated saliva and very fast at the pH of stomach. In suspension of loratadine lipid microparticles, drug was released into the aqueous phase to the same concentration as in a drug suspension. Therefore, the usefulness of these microparticles for taste-masking in liquids is limited. However, they might be useful for taste-masking in solid dosage forms.     

Release and diffusional modeling of metronidazole lipid matrices.

In this study, the first aim was to investigate the swelling and relaxation properties of lipid matrix on diffusional exponent (n). The second aim was to determine the desired release profile of metronidazole lipid matrix tablets. We prepared metronidazole lipid matrix granules using Carnauba wax, Beeswax, Stearic acid, Cutina HR, Precirol ATO 5, and Compritol ATO 888 by hot fusion method and pressed the tablets of these granules. In vitro release test was performed using a standard USP dissolution apparatus I (basket method) with a stirring rate of 100 rpm at 37 degrees C in 900 ml of 0.1 N hydrochloric acid, adjusted to pH 1.2, as medium for the formulations' screening. Hardness, diameter-height ratio, friability, and swelling ratio were determined. Target release profile of metronidazole was also drawn. Stearic acid showed the highest and Carnauba wax showed the lowest release rates in all formulations used. Swelling ratios were calculated after the dissolution of tablets as 9.24%, 6.03%, 1.74%, and 1.07% for Cutina HR, Beeswax, Precirol ATO 5, and Compritol ATO 888, respectively. There was erosion in Stearic acid, but neither erosion nor swelling in Carnauba wax, was detected. According to the power law analysis, the diffusion mechanism was expressed as pure Fickian for Stearic acid and Carnauba wax and the coupling of Fickian and relaxation contributions for other Cutina HR, Beeswax, Compritol ATO 888, and Precirol ATO 5 tablets. It was found that Beeswax (kd=2.13) has a very close drug release rate with the target profile (kt=1.95). Our results suggested that swelling and relaxation properties of lipid matrices should be examined together for a correct evaluation on drug diffusion mechanism of insoluble matrices.     

Controlled Release of a Contraceptive Steroid from Biodegradable and Injectable Gel Formulations: In Vitro Evaluation

Purpose. The purpose of this study was to investigate the effects of formulation factors including varying wax concentration, drug loading and drug particle size, on drug release characteristics from both pure oil and gel formulations prepared with a combination of derivatized vegetable oil (Labrafil 1944 CS) and glyceryl palmitostearate (Precirol ATO 5), using levonorgestrel as a model drug. Methods. The effects of varying drug loadings, different drug particle sizes, and wax (Precirol) concentrations on in-vitro drug release rates were evaluated, and the mechanisms of drug release from the gels were determined. Results. Zero-order drug release rates from the 10% Precirol gel formulations containing 0.25, 0.50 and 2.00% w/v drug loadings were lower than those observed for oil formulations containing identical drug loadings. Higher zero-order release rates were observed from formulations containing smaller drug particles suspended in both oil and gel formulations. The mechanism of drug release from gels containing less than 0.25% w/w drug was diffusion-controlled. Increasing the wax concentrations in the gels from 5% w/w to 20% w/w significantly decreased the diffusivity of the drug through the gel formulations and markedly increased the force required to inject the gels from two different sizes of needles. Conclusions. This study shows how modification of the physicochemical properties of the gel formulations by changing the drug particle size, wax concentration and drug loading, affects drug release characteristics from the system.     

The influence of various amphiphilic excipients on the physicochemical properties of carbamazepine-loaded microparticles

The objective of the present study was to prepare multiple-unit formulations of carbamazepine (CBZ) using an emulsion congealing technique. CBZ-hydrogenated castor oil (HCO) (Cutina? HR) wax microparticles were prepared without organic solvents as an alternative to polymeric microparticles. The process involved emulsification and solidification of CBZ-HCO melt at a significantly low temperature (5°C). Five amphiphilic excipients (Pluronic F-68 (PL), Labrasol (LB), Gelucire 44/14 (GL 44/14), D-α-tocopheryl PEG 1000 succinate (TPGS) and Docusate sodium (DOSS) were added with the wax melt. The microparticles were characterized with respect to their particle size distribution, drug loading, morphological character, drug-excipient interaction, differential scanning calorimetry, Fourier-transform infra-red (FT-IR) and release properties. An average value for production yield was 83.45%. Evaluation of the release data indicates that the release mechanism from the prepared Cutina? HR microparticles follows both the Higuchi model of diffusion and anomalous release mechanism. Microparticles containing 5% Labrasol, TPGS and GL 44/14 had the highest extent of dissolution.     

Studies on the in vitro release characteristics of ibuprofenloaded polystyrene microparticles

Ibuprofen-loaded polystyrene microparticles were prepared by the emulsionsolvent evaporation process from an aqueous system. The effects of different parameters on the drug content and on the release of the drug from the microparticles were investigated. The drug content, in all the formulations, was less than the theoretical drug loading. The lower drug content was due to drug partitioning to the external aqueous phase during formulation. Statistical analysis revealed that the variation in the concentrations of the emulsion stabilizer and the organic disperse phase volume did not significantly alter the release of the drug. Although an increase in drug loading increased drug release from the microparticles, a biphasic linear relationship was observed between the time required for 50% drug release and the drug loading. The effect of size of the microparticles on drug release was more important for the low drug-loaded microparticles than that for the high drug-loaded microparticles. Such release behaviour from the microparticles was explained on the basis of the morphological structure of the microparticles.     

Studies on the in vitro release characteristics of ibuprofen-loaded polystyrene microparticles

Ibuprofen-loaded polystyrene microparticles were prepared by the emulsion-solvent evaporation process from an aqueous system. The effects of different parameters on the drug content and on the release of the drug from the microparticles were investigated. The drug content, in all the formulations, was less than the theoretical drug loading. The lower drug content was due to drug partitioning to the external aqueous phase during formulation. Statistical analysis revealed that the variation in the concentrations of the emulsion stabilizer and the organic disperse phase volume did not significantly alter the release of the drug. Although an increase in drug loading increased drug release from the microparticles, a biphasic linear relationship was observed between the time required for 50% drug release and the drug loading. The effect of size of the microparticles on drug release was more important for the low drug-loaded microparticles than that for the high drug-loaded microparticles. Such release behaviour from the microparticles was explained on the basis of the morphological structure of the microparticles.     

Preparation of preformed porous PLGA microparticles and antisense oligonucleotides loading

The objective of this study was to load preformed highly porous microparticles with drug. The microparticles were prepared by a modified multiple emulsion (w/o/w) solvent evaporation method with the addition of pore formers (NaCl into the internal aqueous phase or of glycerol monooleate to the poly(lactide-co-glycolide) (PLGA) polymer phase). The drug-free solidified microparticles were then washed with either water (for NaCl) or hexane (for glycerol monooleate) to extract the pore formers. The drug was then loaded into the preformed porous microparticles by incubation in aqueous drug solutions followed by air- or freeze-drying. The drug was strongly bound to the polymeric surface with air-dried microparticles. A biphasic drug release with an initial rapid release phase (burst effect) was followed by a slower release up to several weeks. The initial burst was dependent on the drug loading and could be significantly reduced by wet (non-aqueous) temperature curing.     

Properties of lipophilic matrix tablets containing phenylpropanolamine hydrochloride prepared by hot-melt extrusion.

The objective of the present study was to investigate the influence of formulation factors on the physical properties of hot-melt extruded granules and compressed tablets containing wax as a thermal binder/retarding agent, and to compare the properties of granules and tablets with those prepared by a high-shear melt granulation (MG) method. Powder blends containing phenylpropanolamine hydrochloride, Precirol and various excipients were extruded in a single-screw extruder at open-end discharge conditions. The extrudates were then passed through a 14-mesh screen to form granules. The extrusion conditions and the optimum amount of wax to function as the thermal binder were dependent on the properties of the filler excipients. At the same wax level, drug release from tablets decreased in the order of using microcrystalline cellulose (MCC), lactose and Emcompress as the filler excipient. The observed differences in the dissolution properties of the tablets were due to the differences in the solubility, swellability and density of the filler excipients. Replacing Precirol with Sterotex K, a higher melting point wax, resulted in slightly increased dissolution rates, when the extrusion was performed at the same temperature conditions. Hot-melt extruded granules were observed to be less spherical than high-shear melt granules and showed lower values of bulk/tap densities. However, tablets containing MCC or lactose granules prepared by hot-melt extrusion (HME) exhibited higher hardness values. Slower drug release rates were found for tablets containing MCC by HME compared with MG. Analysis of the hot-melt extruded granules showed better drug content uniformity among granules of different size ranges compared with high-shear melt granules, resulting in a more reproducible drug release from the corresponding tablets.     

A burst drug release caused by imperfection of polymeric film-coated microparticles prepared by a fluidized bed coater

The aim of this study was to investigate the drug release from microparticles coated with various polymeric films. Ibuprofen-loaded microparticles with diameter of 250 and 300 microm were prepared by a fluidized bed granulator. Five polymers were used as coating materials, i.e., ethylene vinyl acetate, ethyl cellulose, ethyl cellulose aqueous dispersion, polyethacrylate or Eudragit NE 30D, and carnauba wax. The coating was performed with a fluidized bed coater. Afterwards the coated microparticles were characterized in terms of particle size, morphology, and drug content. The drug dissolution was also investigated in pH 7.4 phosphate buffer. In our attempts for production of extended release ibuprofen microparticles coated with polymeric films, it was shown that the coating process had a significant effect on drug release. The undesired burst release of ibuprofen was observed in all film-coated microparticulate formulations, resulting from the imperfection of coating films.     

Solid lipid microparticles containing loratadine prepared using a Micromixer

Solid lipid microparticles were investigated as a taste-masking approach for a lipophilic weak base in a suspension. The idea was that the drug concentration in the aqueous phase of a suspension might be reduced by its partitioning into the solid lipid particles. Loratadine, as a model drug, was used to prepare Precirol® ATO 5 microparticles by a Micromixer. The effects of three process variables: drug loading, PVA concentration and water/lipid ratio on the microparticle size, encapsulation efficiency, surface appearance, in-vitro release and drug partitioning in a suspension were studied. Loratadine release was slow in simulated saliva and very fast at the pH of stomach. In suspension of loratadine lipid microparticles, drug was released into the aqueous phase to the same concentration as in a drug suspension. Therefore, the usefulness of these microparticles for taste-masking in liquids is limited. However, they might be useful for taste-masking in solid dosage forms.     

Oil-in-oil microencapsulation technique with an external perfluorohexane phase

Commonly, the microencapsulation of a lipophilic drug in a polymeric matrix via an ordinary oil/oil emulsification allows entrapping limited drug amounts due to its loss into the external phase. In this present paper, a new microencapsultion method describes the use of perfluorohexane as an external oil phase in order to produce microparticles of polyvinylpyrrolidon/vinylacetate (copovidone) and Eudragit RS. Due to its highly non-solvent properties to most compounds, very limited miscibility with organic solvents, and very low toxicity, perfluorohexane (PFH) represents an excellent liquid for an external phase of the emulsion. Copovidone and Eudragit RS microparticles were prepared by an oil/PFH method trapping ibuprofen as a lipophilic model drug and compared to results from conventional methods (oil/water and oil/oil). Morphological analyses of the obtained particles underlined the general matrix structure. The particle size varied between 75microm (oil/oil) and 400microm (oil/PFH) largely influenced by the stirring speed. Although drug release kinetics were principally similar for all preparation methods, it was generally found that encapsulation rates of oil/water and oil/PFH systems (oil/water: 74+/-9%; oil/PFH: 86+/-10%) were superior to ordinary oil/oil emulsification (3+/-1%). The use of PFH was found to be a new promising tool for the preparation of microparticles. This modified emulsification method allowed the entrapment of lipophilic drugs into hydrophilic or lipophilic polymers in the absence of an aqueous phase.     

Matrix mini-tablets based on starch/microcrystalline wax mixtures

Matrix mini-tablets based on a combination of microcrystalline waxes and starch derivatives were prepared using ibuprofen as a model drug. The production of mini-tablets was preferred over the production of pellets, as up-scaling of the pelletisation process seemed problematic. Prior to tabletting, melt granulation in a hot stage screw extruder and milling were required. The in vitro drug release was varied using microcrystalline waxes with a different melting range, the slowest drug release being obtained with a formulation containing a microcrystalline wax with a melting range between 68 and 72 degrees C. Generally speaking increasing the wax concentration resulted in a slower drug release. In vitro drug release profiles were also modified using different starches and mixtures of starches. Increasing the ibuprofen concentration to 70% resulted in a faster drug release rate.     

Formulation and evaluation of verapamil hydrochloride loaded solid lipid microparticles

The present study aimed to produce verapamil hydrochloride-loaded solid lipid microparticles (SLM) by the w/o/w emulsion solvent evaporation technique, using diethyl ether as solvent phase, glyceryl monostearate as biodegradable polymer and Span 60 as surfactant. SLM of spherical shape were prepared by simple dilution of the emulsion with water. To increase the lipid load the process was conducted at 50 degrees C, and in order to reach sub-micron size, a high-shear homogenizer was used. The encapsulation efficiency of prepared SLM reached 74.29 +/- 0.76%. Particle size (98.55 +/- 1.42 microm), surface morphology (spherical) and drug loading efficiency (18.57 +/- 1.25% w/w) were investigated. And optimization of drug polymer ratio (3:1), nature and concentration of emulsion stabilizer in the external aqueous (0.1%), phase viscosity of external aqueous phase (0.5%), volume of external aqueous phase and stirring rate (1000 rpm) were detected. Analysis of microsphere content after processing showed that verapamil did not undergo any chemical modification within the micro-particles. The in-vitro release of verapamil from the microparticles was very low and an initial burst effect of 17% of the dose was observed. The slow release may help to avoid a high frequency of administration. The prepared solid lipid microparticles appear to have interesting perspectives as delivery systems for the oral administration of verapamil hydrochloride with improved half-life, improved bioavailability, and minimized local and systemic gastrointestinal disturbances of the drug.     

Controlled release tamsulosin hydrochloride from alginate beads with waxy materials

The objective of this study was to develop oral controlled release delivery systems for tamsulosin hydrochloride (TSH) using alginate beads with various waxy materials, such as Compritol 888 ATO, Precirol ATO 5 and Gelucires. The beads were prepared from sodium alginate-waxy material-TSH slurry dropped onto calcium chloride to form spherical beads. The effects of the addition of various waxy materials to alginate beads on the drug encapsulation efficiency, bead size and morphology were investigated. The drug encapsulation efficiency significantly increased with the addition of waxy materials. The TSH-loaded alginate beads with and without waxy materials were almost spherical particles with an average diameter of 1.44 and 1.22 mm, respectively. In dissolution study, the TSH-loaded alginate beads with waxy materials exhibited controlled release behaviour over a 6-h period, while beads without waxy materials showed release of 100% TSH within 2 h. These results may be attributed to the formation of a more rigid alginate matrix structure due to incorporated waxy materials. From the Dunnett's t-test and the f2 factor, the release of TSH from alginate beads, a similar dissolution pattern to that of the marketed product (Harunal capsules) could be achieved by adding Gelucire 50/13 into TSH-loaded alginate beads. From these results, oral controlled release of TSH could be achieved with loading in alginate beads with waxy materials, such as Compritol 888 ATO, Precirol ATO 5 and Gelucires.     

Fabrication and evaluation of Phytomenadione as a nanostructure lipid carrier for enhancement of bioavailability

Abstract

Owing to its limited aqueous solubility, Phytomenadione (vitamin K) undergoes a low bioavailability (50%) with a large inter-individual variability after oral administration. Therefore, the aim of this work was to incorporate vitamin K into nanostructure lipid carrier systems to improve its aqueous solubility and bioavailability. Phytomenadione was used as a liquid lipid; Precirol ATO5, and Compritol ATO were used as solid lipids; Labrasol and Cremophore EL as water soluble surfactants; Capryol 90 and Lauroglycol as lipid soluble surfactants. Eight formulas were prepared and characterized for their particle sizes, zeta potential, entrapment efficiencies, and drug release. Those formulas had particle sizes ranging from 25.4 to 68.3?nm. The best formula, consisting of 15% Phytomenadione, 45% Precirol ATO5, 30% Cremophore EL, and 10% Lauroglycol 90, was selected for stability study and characterized by the techniques mentioned above and scanning electron microscopy. It had the highest drug loading and an acceptable in vitro release profile (94.54% within 30?min). This formula was also chemically and physically stable, and it recorded a relative bioavailability of 645.5% in rabbits compared to the commercial conventional tablet. This formula could be a promising carrier regarding its ease of preparation, dosage form versatility and enhanced bioavailability.     

Modification of the tri-phasic drug release pattern of leuprolide acetate-loaded poly(lactide-co-glycolide) microparticles.

Leuprolide acetate-loaded poly(lactide-co-glycolide) (PLGA RG503H) microparticles prepared by the solvent evaporation method had a tri-phasic drug release pattern over a duration of up to 2 months. An initial release was followed by a slow drug release phase and a final rapid drug release. The objective of this study was to identify parameters, which shift the release profile from the tri-phasic to a more continuous release profile. Varying formulation and processing parameters (e.g., drug loading, volume of the external aqueous phase, using low molecular weight PLGA, different microparticle drying methods) affected the initial release (burst) but did not influence the drug release thereafter. The addition of the hydrophilic polymer polyvinylpyrrolidone (PVP) led to the formation of more porous microparticles. This influenced the initial release but did not change the tri-phasic drug release pattern. The inclusion of medium chain triglycerides (MCT) successfully shifted the tri-phasic pattern to a continuous release profile. MCT accelerated the leuprolide release in the second, slow release phase and reduced it in the final rapid release phase. MCT led to the formation of microparticles with an irregular surface and a highly porous inner structure. Differential scanning calorimetry (DSC) revealed a high encapsulation efficiency of MCT (88-105%) in the microparticles and an unchanged glass transition temperature (Tg) of PLGA.     

氯霉素固体脂质纳米粒的制备及质量评价

目的:制备氯霉素固体脂质纳米粒(CAP-SLN)并考察其质量。方法:选取CAP与甘油棕榈酸硬脂酸酯(PrecirolATO5)比例(药脂比)、泊洛沙姆含量、乳化温度和初乳-分散相的体积比为考察因素,包封率和载药量为评价指标,设计正交试验并优化处方,利用乳化蒸发-低温固化法制备CAP-SLN;同时以粒径、Zeta电位、包封率、载药量、稳定性及体外释放度为指标评价其质量。结果:最佳制备处方药脂比为1∶10,泊洛沙姆含量为2%,乳化温度为70℃,初乳-分散相的体积比为1∶7。所制纳米粒平均粒径为227nm,Zeta电位为-30.5mV,平均包封率为65.9%,平均载药量为6.59%;于4℃环境中考察30d,其包封率、粒径无显著变化,25℃环境中包封率显著降低、粒径明显增大;在前4h内有明显突释现象,药物累积释放率达58.86%,48h时累积释放率达85.09%,体外释药行为符合Weibull方程。结论:该制剂处方设计和工艺方法可行,制剂质量符合要求,可达到缓释效果。     

Preparation of biodegradable poly(+/-)lactide microparticles using a spray-drying technique

Drug containing biodegradable poly(+/-)lactide microparticles were prepared by using a spray-drying technique. Formulations containing model drugs in either a dissolved (progesterone) or dispersed state (theophylline) were spray-dried. The spray-drying method was less dependent on the solubility characteristics of the drug when compared with traditional microencapsulation techniques such as phase separation or solvent evaporation techniques. Differential scanning calorimetry and scanning electron microscopy were used to characterize the microparticles. The drug release profiles were characterized by a rapid release phase (burst effect) followed by a slow release phase, the extent of each phase being dependent on the drug loading.