Preparation and characterization of a submicron lipid emulsion of docetaxel: submicron lipid emulsion of docetaxel

Docetaxel, a widely used anticancer agent, has sparingly low aqueous solubility, thus Tween 80 and ethanol need to be added into its formulation, probably resulting in the toxic effects. In this study, we aimed to utilize submicron lipid emulsions as a carrier of docetaxel to avoid these potential toxic vehicles. Preformulation study was performed for rational emulsions formulation design, including drug solubility, distribution between oil and water, and degradation kinetics. Supersaturated submicron lipid emulsion of docetaxel was prepared by temperature elevation method. Soya oil and Miglyol 812 can incorporate docetaxel up to 1.0% (drug to lipid ratio) and were used as the oil phase of emulsions. The optimal formulation of docetaxel is composed of 10% oil phase, 1.2% soybean lecithin, 0.3% Pluoronic F68, and 0.4 or 0.8 mg/mL docetaxel, with particle size in the nanometer range, entrapment efficiency more than 90%, and is physicochemically stable at 4 and 25 degrees C for 6 months. Animal studies showed that docetaxel emulsion has significantly higher area under the curve (AUC) and C(max) in rats compared to its micellar solution. The results suggested that the submicron lipid emulsion is a promising intravenous carrier for docetaxel in place of its present commercially available docetaxel micellar solution with potential toxic effects.     

Preparation and Characterization of a Submicron Lipid Emulsion of Docetaxel: Submicron Lipid Emulsion of Docetaxel

Docetaxel, a widely used anticancer agent, has sparingly low aqueous solubility, thus Tween 80 and ethanol need to be added into its formulation, probably resulting in the toxic effects. In this study, we aimed to utilize submicron lipid emulsions as a carrier of docetaxel to avoid these potential toxic vehicles. Preformulation study was performed for rational emulsions formulation design, including drug solubility, distribution between oil and water, and degradation kinetics. Supersaturated submicron lipid emulsion of docetaxel was prepared by temperature elevation method. Soya oil and Miglyol 812 can incorporate docetaxel up to 1.0% (drug to lipid ratio) and were used as the oil phase of emulsions. The optimal formulation of docetaxel is composed of 10% oil phase, 1.2% soybean lecithin, 0.3% Pluoronic F68, and 0.4 or 0.8 mg/mL docetaxel, with particle size in the nanometer range, entrapment efficiency more than 90%, and is physicochemically stable at 4 and 25°C for 6 months. Animal studies showed that docetaxel emulsion has significantly higher area under the curve (AUC) and C_max in rats compared to its micellar solution. The results suggested that the submicron lipid emulsion is a promising intravenous carrier for docetaxel in place of its present commercially available docetaxel micellar solution with potential toxic effects.     

Consideration on the formulation of benzoyl peroxide at ambient temperature: choice of non-polar solvent and preparation of submicron emulsion gels

The aim of this study performed at ambient temperature was first to determine the solubility of benzoyl peroxide in various solvents with a large range of polarity. All these solvents can be used in the dermatological field. Then, using the most suitable solvent, a new drug vehicle submicron oil-in-water emulsion was formulated. Correlation between dielectric constant (ε) and drug solubility in various solvents and different binary mixtures was verified. An original ternary diagram with surfactant-co-surfactant/oil/water was performed at low temperature to determine the regions of submicron emulsions. A dramatic change in the magnitude of benzoyl peroxide solubility occurred above a dielectric constant value of about 20. The solubility of this drug can be enhanced by the replacement of polar solvent by a vehicle of lower dielectric constant. A stable submicron emulsion gel was made with cremophor EL, glycerol, caprilic-capric triglycerides, and water in the proportion of 20-20/35/25, respectively; 1.5% benzoyl peroxide was also added. This submicron emulsion vehicle consisted of oil droplets, with a mean diameter of approximately 100-150 nm, dispersed in a continuous water phase. These studies confirm the potential of benzoyl peroxide incorporation into submicron emulsion gel and the stability of this formulation.     

Consideration on the Formulation of Benzoyl Peroxide at Ambient Temperature: Choice of Non-Polar Solvent and Preparation of Submicron Emulsion Gels

ABSTRACT

The aim of this study performed at ambient temperature was first to determine the solubility of benzoyl peroxide in various solvents with a large range of polarity. All these solvents can be used in the dermatological field. Then, using the most suitable solvent, a new drug vehicle submicron oil-in-water emulsion was formulated. Correlation between dielectric constant (ε) and drug solubility in various solvents and different binary mixtures was verified. An original ternary diagram with surfactant–co-surfactant/oil/water was performed at low temperature to determine the regions of submicron emulsions. A dramatic change in the magnitude of benzoyl peroxide solubility occurred above a dielectric constant value of about 20. The solubility of this drug can be enhanced by the replacement of polar solvent by a vehicle of lower dielectric constant. A stable submicron emulsion gel was made with cremophor EL, glycerol, caprilic–capric triglycerides, and water in the proportion of 20–20/35/25, respectively; 1.5% benzoyl peroxide was also added. This submicron emulsion vehicle consisted of oil droplets, with a mean diameter of approximately 100–150 nm, dispersed in a continuous water phase. These studies confirm the potential of benzoyl peroxide incorporation into submicron emulsion gel and the stability of this formulation.     

Chemical stability of teniposide in aqueous and parenteral lipid emulsions

The purpose of this study was to investigate the degradation kinetics of teniposide in lipid emulsion and aqueous solution. The chemical stability of teniposide in lipid emulsion and aqueous solution at various pH values and temperatures was monitored by high-performance liquid chromatography. In addition, the viscosities of emulsion at different temperatures were investigated. The degradation of teniposide both in emulsion and in aqueous solution was shown to follow pseudo-first-order degradation kinetics. The t (1/2) values of teniposide lipid emulsion (TLE) and the aqueous solution were 80 and 2.6 days at 10 degrees C, respectively. Under the most stable pH range of 6.0-6.5, stability of teniposide in the emulsion increased more than 30-fold compared with that in aqueous solution. Furthermore, there was a difference between the shelf life of TLE actually measured (29 days) at 10 degrees C and the one deduced (15 days) from the degradation data of high temperatures by Arrhenius equation. It could be hypothesized that the difference was due to a slower diffusion of teniposide from oil phase to aqueous phase at the lower temperatures, which would be a speed-limited process in the degradation of TLE. The results of viscosity test confirmed the presumption.     

Chemical Stability of Teniposide in Aqueous and Parenteral Lipid Emulsions

The purpose of this study was to investigate the degradation kinetics of teniposide in lipid emulsion and aqueous solution. The chemical stability of teniposide in lipid emulsion and aqueous solution at various pH values and temperatures was monitored by high-performance liquid chromatography. In addition, the viscosities of emulsion at different temperatures were investigated. The degradation of teniposide both in emulsion and in aqueous solution was shown to follow pseudo-first-order degradation kinetics. The t_1/2 values of teniposide lipid emulsion (TLE) and the aqueous solution were 80 and 2.6 days at 10°C, respectively. Under the most stable pH range of 6.0–6.5, stability of teniposide in the emulsion increased more than 30-fold compared with that in aqueous solution. Furthermore, there was a difference between the shelf life of TLE actually measured (29 days) at 10°C and the one deduced (15 days) from the degradation data of high temperatures by Arrhenius equation. It could be hypothesized that the difference was due to a slower diffusion of teniposide from oil phase to aqueous phase at the lower temperatures, which would be a speed-limited process in the degradation of TLE. The results of viscosity test confirmed the presumption.     

Lipid emulsions as a potential delivery system for ocular use of azithromycin

Objective: To obtain stable positively charged Azithromycin (AZI) emulsions with a mean droplet size of 120 nm for the treatment of eye diseases. Methods: The emulsions were obtained by using a suitable homogenization process. The physical stability was monitored by measuring the particle size, zeta potential, and visible appearance. The drug entrapment efficiency was measured by both ultracentrifugation and ultrafiltration methods. Compared with a phosphate solution of AZI, the stability profiles of AZI in lipid emulsions at various pH values were monitored by high-performance liquid chromatography. A pharmacokinetic study was performed to determine the drug levels in rabbit tear fluid using Ultra-performance liquid Chromatography–mass spectrometry. Results: Almost all the AZI in the lipid emulsion was distributed in the oil phase and small unilamellar liposomes without contact with water, thereby avoiding hydrolysis. The elimination of the AZI lipid emulsions in tear fluid was consistent with the basic linear pharmacokinetic characteristics. The AUC_0-t of the AZI lipid emulsion (1%, w/v) and aqueous solution drops (1%, w/v) was 1873.58 ± 156.87 and 1082.46 ± 179.06 μgh/ml respectively. Conclusions: This study clearly describes a new formulation of AZI lipid emulsion for ocular administration, and lipid emulsions are promising vehicles for ophthalmic drug delivery.     

High drug loading self-microemulsifying/micelle formulation: design by high-throughput formulation screening system and in vivo evaluation

Purpose: To design a high drug loading formulation of self-microemulsifying/micelle system. Methods: A poorly-soluble model drug (CH5137291), 8 hydrophilic surfactants (HS), 10 lipophilic surfactants (LS), 5 oils, and PEG400 were used. A high loading formulation was designed by a following stepwise approach using a high-throughput formulation screening (HTFS) system: (1) an oil/solvent was selected by solubility of the drug; (2) a suitable HS for highly loading was selected by the screenings of emulsion/micelle size and phase stability in binary systems (HS, oil/solvent) with increasing loading levels; (3) a LS that formed a broad SMEDDS/micelle area on a phase diagram containing the HS and oil/solvent was selected by the same screenings; (4) an optimized formulation was selected by evaluating the loading capacity of the crystalline drug. Aqueous solubility behavior and oral absorption (Beagle dog) of the optimized formulation were compared with conventional formulations (jet-milled, PEG400). Results: As an optimized formulation, d-α-tocopheryl polyoxyethylene 1000 succinic ester: PEG400?=?8:2 was selected, and achieved the target loading level (200?mg/mL). The formulation formed fine emulsion/micelle (49.1?nm), and generated and maintained a supersaturated state at a higher level compared with the conventional formulations. In the oral absorption test, the area under the plasma concentration-time curve of the optimized formulation was 16.5-fold higher than that of the jet-milled formulation. Conclusions: The high loading formulation designed by the stepwise approach using the HTFS system improved the oral absorption of the poorly-soluble model drug.     

Optimization of self-microemulsifying drug delivery systems (SMEDDS) using a D-optimal design and the desirability function

D-optimal design and the desirability function were applied to optimize a self-microemulsifying drug delivery system (SMEDDS). The optimized key parameters were the following: 1) particle size of the dispersed emulsion, 2) solubility of the drug in the vehicle, and 3) the vehicle compatibility with the hard gelatin capsule. Three formulation variables, PEG200, a surfactant mixture, and an oil mixture, were included in the experimental design. The results of the mathematical analysis of the data demonstrated significant interactions among the formulation variables, and the desirability function was demonstrated to be a powerful tool to predict the optimal formulation for the explored system.     

抗低温地下混装乳化炸药工艺配方研究

针对低温对地下混装乳化炸药技术的影响,通过混装乳化炸药组分分析,进行系列化实验研究,确定抗低温地下现场混装乳化炸药工艺配方。即在常规地下混装乳化炸药工艺配方的基础上,往水相中加入析晶点调节剂A,油相中加入富含亲水基团且具立体结构组分B,敏化组分中加入冰点调节剂C。由实验验证和工业化应用表明,设计的工艺配方能够有效解决由低温引起的基质储存稳定性差、远距离输送压力高、敏化低效以及装药返药等问题,且具有良好的装药爆破效果。     

High drug loading self-microemulsifying/micelle formulation: design by high-throughput formulation screening system and in vivo evaluation

Purpose: To design a high drug loading formulation of self-microemulsifying/micelle system.

Methods: A poorly-soluble model drug (CH5137291), 8 hydrophilic surfactants (HS), 10 lipophilic surfactants (LS), 5 oils, and PEG400 were used. A high loading formulation was designed by a following stepwise approach using a high-throughput formulation screening (HTFS) system: (1) an oil/solvent was selected by solubility of the drug; (2) a suitable HS for highly loading was selected by the screenings of emulsion/micelle size and phase stability in binary systems (HS, oil/solvent) with increasing loading levels; (3) a LS that formed a broad SMEDDS/micelle area on a phase diagram containing the HS and oil/solvent was selected by the same screenings; (4) an optimized formulation was selected by evaluating the loading capacity of the crystalline drug. Aqueous solubility behavior and oral absorption (Beagle dog) of the optimized formulation were compared with conventional formulations (jet-milled, PEG400).

Results: As an optimized formulation, d-α-tocopheryl polyoxyethylene 1000 succinic ester: PEG400?=?8:2 was selected, and achieved the target loading level (200?mg/mL). The formulation formed fine emulsion/micelle (49.1?nm), and generated and maintained a supersaturated state at a higher level compared with the conventional formulations. In the oral absorption test, the area under the plasma concentration-time curve of the optimized formulation was 16.5-fold higher than that of the jet-milled formulation.

Conclusions: The high loading formulation designed by the stepwise approach using the HTFS system improved the oral absorption of the poorly-soluble model drug.     

Preformulation characterization of topical Ibuprofen Piconol

Development of a topical pharmaceutical is facilitated by generation of a different type of preformulation profile than needed prior to tablet or parenteral product development. Ibuprofen piconol is a non-steroidal, anti-inflammatory (NSAID) drug marketed in Japan for the topical relief of primary thermal burns and sunburns. A complete preformation characterization was completed for this compound and is reported here to serve as a template for development of future topical drug products. The physical properties compiled include melting properties, specific gravity, viscosity, hygroscopicity, moisture content, acid-base properties, surface tension, solubility and partitioning. Chemical stability results are given for the bulk drug, the drug in solution, and the drug after formulation in both a cream and an ointment. These studies indicate that ibuprofen piconol is a chemically stable, slightly hygroscopic liquid that strongly partitions into the oil phase and shows no indication of surface activity. This drug has very limited solubility in water (16.5 ppm), modest solubility in glycerol (16.4 mg/ml), and is miscible with less polar organics except for silicone fluids.     

Optimization of Self-Microemulsifying Drug Delivery Systems (SMEDDS) Using a D-Optimal Design and the Desirability Function

ABSTRACT

D-optimal design and the desirability function were applied to optimize a self-microemulsifying drug delivery system (SMEDDS). The optimized key parameters were the following: 1) particle size of the dispersed emulsion, 2) solubility of the drug in the vehicle, and 3) the vehicle compatibility with the hard gelatin capsule. Three formulation variables, PEG200, a surfactant mixture, and an oil mixture, were included in the experimental design. The results of the mathematical analysis of the data demonstrated significant interactions among the formulation variables, and the desirability function was demonstrated to be a powerful tool to predict the optimal formulation for the explored system.     

Inclusion complexation of lorazepam with different cyclodextrins suitable for parenteral use

The development of a parenteral lorazepam formulation, using cyclodextrins (CDs) as inclusion complexation agents, was investigated. CDs suitable for parenteral injection, i.e., hydroxypropyl-β-cyclodextrin (HP-β-CD), hydroxypropyl-γ-cyclodextrin (HP-γ-CD), sulfobutylether-7-β-cyclodextrin (SBE-7-β-CD), and maltosyl-β-cyclodextrin (malt-β-CD) were studied for the possibility to increase the solubility of lorazepam. Lorazepam interacted with all tested CD derivatives and 1:1 complexes are formed. HP-β-CD exerts the highest solubility improvement, reaching about 6 mg/ml lorazepam in 30% (w/v) CD solution. When using SBE-7-β-CD or malt-β-CD only half of that concentration can be dissolved. HP-γ-CD interacts much less with lorazepam. Parenteral solutions with 4 mg/ml in 30% (w/v) HP-β-CD solution, with 2 mg/ml in 30% (w/v) SBE-7-β-CD, and with 2 mg/ml lorazepam in 15% (w/v) HP-β-CD, were prepared. Sterile filtration of the formulation needs to be applied because of massive degradation of lorazepam during autoclaving. No precipitation is observed after dilution of the different formulations with (physiological) water or with 5% dextrose in water, which proves their suitability for administration with perfusions. The stability of the preparations was investigated in aqueous medium. During the first month, in all solutions more than 90% of lorazepam remained; after 3 months, less than 60% of lorazepam remained in the solutions with 15% (w/v) HP-β-CD and around 65-70% in the solutions with 30% (w/v) of CDs. Because of this short stability time, the preparations need to be lyophilized.     

Preformulation characterization of topical Ibuprofen Piconol

Abstract

Development of a topical pharmaceutical is facilitated by generation of a different type of preformulation profile than needed prior to tablet or parenteral product development. Ibuprofen piconol is a non-steroidal, anti-inflammatory (NSAID) drug marketed in Japan for the topical relief of primary thermal burns and sunburns. A complete preformation characterization was completed for this compound and is reported here to serve as a template for development of future topical drug products. The physical properties compiled include melting properties, specific gravity, viscosity, hygroscopicity, moisture content, acid-base properties, surface tension, solubility and partitioning. Chemical stability results are given for the bulk drug, the drug in solution, and the drug after formulation in both a cream and an ointment. These studies indicate that ibuprofen piconol is a chemically stable, slightly hygroscopic liquid that strongly partitions into the oil phase and shows no indication of surface activity. This drug has very limited solubility in water (16.5 ppm), modest solubility in glycerol (16.4 mg/ml), and is miscible with less polar organics except for silicone fluids.     

Preparation and Evaluation of 2-(Allylthio)Pyrazine-Loaded Lipid Emulsion with Enhanced Stability and Liver Targeting

To develop 2-(allylthio)pyrazine (2-AP)-loaded lipid emulsion for parenteral administration, various lipid emulsions were prepared with soybean oil, lecithin, and other carriers using homogenization method, and their physical stabilities were investigated by measuring their droplet sizes. The pharmacokinetics and tissue distribution of 2-AP in lipid emulsion after intravenous administration to rats were evaluated compared with 2-AP in solution. 2-AP was lipophilic, sparingly water-soluble, and unstable in aqueous medium. The 2-AP-loaded lipid emulsion composed of 1% of 2-AP, 4% of soybean oil, 4% of lecithin, and 91% of water was physically and chemically stable for at least 8 weeks. It gave significantly faster clearance of 2-AP and higher affinity to the organs, especially the liver, compared with the 2-AP in solution, suggesting that it could selectively deliver 2-AP to the liver. Thus, the lipid emulsion with soybean oil and lecithin could be used as a potential dosage form with the liver-targeting property and enhanced stability of sparingly water-soluble 2-AP.     

Influences of combustion improver content and motionless time on the stability of two-phase emulsions

The heavy molecular bonds of liquid fuels can be broken with the assistance of a nitromethane fuel additive by virtue of its explosive and flammable properties to obtain greater heat release. Because of the immiscibility between nitromethane and petro-diesel, two-phase emulsions of nitromethane dispersed in the oil phase of a mixture of diesel and biodiesel were prepared. The experimental results show that microwave irradiation produced an emulsion with a larger number of dispersed nitromethane droplets in the continuous oil mixture, a smaller mean droplet size, and lower turbidity than magnetic stirring, and thus was a better method for preparation of the two-phase emulsion. The increase in the nitromethane weight fraction increased the number of dispersed nitromethane droplets and the emulsion turbidity. In addition, allowing the emulsion preparation to remain motionless for a longer period of time after either method resulted in an obvious reduction in the emulsification stability (ES).     

Mixed lipid phase SMEDDS as an innovative approach to enhance resveratrol solubility

Context: Despite its promising therapeutic activities, clinical use of resveratrol (RSV) is compromised with unfavorable biopharmaceutical properties, namely low water solubility.

Objective: This work deals with improving RSV solubility and release rate through its incorporation in innovative mixed lipid phase self-microemulsifying drug delivery systems (SMEDDS).

Methods: (Pseudo)ternary diagrams were constructed for different oils and surfactant mixtures. Selected systems were further evaluated for RSV solubility, self-emulsification ability, accelerated stability, dynamic viscosity, compatibility with hard gelatin capsules and in vitro dissolution of RSV.

Results: Lipid phase composed of diverse lipid species, castor oil (long-chained triglyceride) and Capmul MCM (mixture of medium chain mono and diglycerides) allowed formulation of mixed lipid SMEDDS with lower surfactants content (60% Cremophor EL/RH 40/RH?60). Mixed lipid phase SMEDDS showed best self-emulsifying ability with regard to self-emulsifying time as well as droplet size and monodispersity of microemulsions obtained upon SMEDDS dilution with aqueous phase. Overall, incorporation of RSV in SMEDDS resulted in improved solubility (over 23-fold) and dissolution rate compared to crystalline RSV. All SMEDDS formulations were adequately viscous for filling into hard gelatin capsules (>150?mPa?s for empty SMEDDS; >400?mPa?s for RSV-loaded SMEDDS) and no leaking was observed during three months of storage.

Conclusion: The presented work indicates the promising potential of mixed lipid SMEDDS formulations for future development of SMEDDS with lower surfactant content and no added cosolvents for incorporation of RSV and other poorly soluble drugs.     

乳化炸药微观结构对其宏观性能的影响分析

分析乳化炸药内相粒子大小和分布、界面膜、油膜、第三相物质(敏化剂)对其爆炸性能、稳定性、流变性或黏度等宏观性能的影响,建立了微观结构与宏观性能的关联关系,对一些常见现象进行了解释。分析认为,乳化炸药内相粒子的大小与分布,主要取决于机械作用强度和乳化剂的种类和用量两个方面。在相同的配方和工艺条件下,乳化炸药的内相粒子越小,粒径分布越窄,其稳定性和爆炸性能就越好,黏度较大。内相粒子间界面膜和油膜既与内相粒子密切相关,也对乳化炸药的黏度、流动性和稳定性有重要作用。依据热点理论,当气泡或者气泡载体的尺寸在有效范围之内,且分布均匀时,则形成热点的时间接近,有利于爆炸反应的快速激发和传递,宏观上表现为乳化炸药爆轰感度、爆速和猛度等较大。     

乳化炸药微观结构对其宏观性能的影响分析

分析乳化炸药内相粒子大小和分布、界面膜、油膜、第三相物质(敏化剂)对其爆炸性能、稳定性、流变性或黏度等宏观性能的影响,建立了微观结构与宏观性能的关联关系,对一些常见现象进行了解释。分析认为,乳化炸药内相粒子的大小与分布,主要取决于机械作用强度和乳化剂的种类和用量两个方面。在相同的配方和工艺条件下,乳化炸药的内相粒子越小,粒径分布越窄,其稳定性和爆炸性能就越好,黏度较大。内相粒子间界面膜和油膜既与内相粒子密切相关,也对乳化炸药的黏度、流动性和稳定性有重要作用。依据热点理论,当气泡或者气泡载体的尺寸在有效范围之内,且分布均匀时,则形成热点的时间接近,有利于爆炸反应的快速激发和传递,宏观上表现为乳化炸药爆轰感度、爆速和猛度等较大。