International Journal of Pharmaceutics (v.433, #1-2)
Editorial Board (iii).
Sucrose esters as natural surfactants in drug delivery systems—A mini-review by Angéla Szűts; Piroska Szabó-Révész (1-9).
Sucrose esters (SEs) are widely used in the food and cosmetic industries and there has recently been great interest in their applicability in different pharmaceutical fields. They are natural and biodegradable excipients with well-known emulsifying and solubilizing behavior. Currently the most common pharmaceutical applications of SEs are for the enhancement of drug dissolution and drug absorption/permeation, and in controlled-release systems. Although the number of articles on SEs is continuously increasing, they have not yet been widely used in the pharmaceutical industry. The aim of this review is to discuss and summarize some of the findings and applications of SEs in different areas of drug delivery. The article highlights the main properties of SEs and focuses on their use in pharmaceutical technology and on their regulatory and toxicological status.
Keywords: Sucrose ester; Natural surfactant; Emulsifier; Stabilizer; Dissolution modifier; Absorption enhancer;
Distribution of esterase activity in porcine ear skin, and the effects of freezing and heat separation by Wing Man Lau; Keng Wooi Ng; Kristina Sakenyte; Charles M. Heard (10-15).
Porcine ear skin is widely used to study skin permeation and absorption of ester compounds, whose permeation and absorption profiles may be directly influenced by in situ skin esterase activity. Importantly, esterase distribution and activity in porcine ear skin following common protocols of skin handling and storage have not been characterised. Thus, we have compared the distribution and hydrolytic activity of esterases in freshly excised, frozen, heated and explanted porcine ear skin. Using an esterase staining kit, esterase activity was found to be localised in the stratum corneum and viable epidermis. Under frozen storage and a common heating protocol of epidermal sheet separation, esterase staining in the skin visibly diminished. This was confirmed by a quantitative assay using HPLC to monitor the hydrolysis of aspirin, in freshly excised, frozen or heated porcine ear skin. Compared to vehicle-only control, the rate of aspirin hydrolysis was approximately three-fold higher in the presence of freshly excised skin, but no different in the presence of frozen or heated skin. Therefore, frozen and heat-separated porcine ear skin should not be used to study the permeation of ester-containing permeants, in particular co-drugs and pro-drugs, whose hydrolysis or degradation can be modulated by skin esterases.
Keywords: Porcine ear skin; Esterase; Hydrolysis; Pro-drug; Co-drug;
PHEA-graft-polybutylmethacrylate copolymer microparticles for delivery of hydrophobic drugs by Mariano Licciardi; Mauro Di Stefano; Emanuela Fabiola Craparo; Giovanni Amato; Giacomo Fontana; Gennara Cavallaro; Gaetano Giammona (16-24).
Polymeric microparticles encapsulating two model hydrophobic drugs, beclomethasone dipropionate (BDP) and flutamide (FLU) were prepared by using the high pressure homogenization-solvent evaporation method starting from a oil-in-water emulsion.For the preparation of polymeric microparticles a α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) graft copolymer with comb like structure was properly synthesized via grafting from atom transfer radical polymerization (ATRP) technique, by using two subsequent synthetic steps. In the first step a polymeric multifunctional macroinitiator was obtained by the conjugation of a proper number of 2-bromoisobutyryl bromide (BIB) residues to the PHEA side chains, obtaining the PHEA-BIB copolymer. PHEA-BIB copolymer was then used as macroinitiator for the polymerization via ATRP of the hydrophobic monomer such as butyl methacrylate (BMA) to obtain the α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide-co-(N-2-ethylen-isobutyrate)-graft-poly(butyl methacrylate) copolymer (PHEA-IB-p(BMA)). Spherical microparticles with 1–3 microns diameter were prepared. Microparticles loaded with BDP or FLU were also prepared. In vitro mucoadhesion and enzymatic degradation studies evidenced bioadhesive properties and biodegradability of prepared microparticles, while release studies showed a different release profiles for the two loaded drugs: BDP was totally released from nanoparticles until 24 h in pulmonary mimicking conditions; differently a slower FLU release rate was observed in gastro-intestinal mimicking conditions. The in vitro cytotoxicity activity was assessed using 16HBE and Caco-2 cell lines. Results showed that exposure of both cell lines to BDP-loaded microparticles do not inhibited the cell growth; on the contrary FLU-loaded microparticles inhibited the cell growth, in particular of the Caco-2 cancer cell line, in a concentration- and time-dependent manner. Finally, uptake studies demonstrated that BDP-loaded microparticles and FLU-loaded microparticles effectively increased uptake of loaded drugs in a time-dependent manner, respectively on 16HBE and Caco-2 cell lines.
Keywords: Microparticles; PHEA-graft-copolymer; ATRP; Beclomethasone dipropionate; Flutamide;
Investigation of surfactant/cosurfactant synergism impact on ibuprofen solubilization capacity and drug release characteristics of nonionic microemulsions by Ljiljana Djekic; Marija Primorac; Slavica Filipic; Danica Agbaba (25-33).
The synergism in multicomponent mixtures of nonionic tensides observed in Labrasol®-based microemulsions affects the mechanism and in vitro release profile of ibuprofen solubilized at the oil/water interface.The current study investigates the performances of the multicomponent mixtures of nonionic surfactants regarding the microemulsion stabilisation, drug solubilization and in vitro drug release kinetic. The primary surfactant was PEG-8 caprylic/capric glycerides (Labrasol®). The cosurfactants were commercially available mixtures of octoxynol-12 and polysorbate 20 without or with the addition of PEG-40 hydrogenated castor oil (Solubilisant gamma® 2421 and Solubilisant gamma® 2429, respectively). The oil phase of microemulsions was isopropyl myristate. Phase behaviour study of the pseudo-ternary systems Labrasol®/cosurfactant/oil/water at surfactant-to-cosurfactant weight ratios (K m) 40:60, 50:50 and 60:40, revealed a strong synergism in the investigated tensides mixtures for stabilisation of microemulsions containing up to 80% (w/w) of water phase at surfactant +cosurfactant-to-oil weight ratio (SCoS/O) 90:10. Solubilization of a model drug ibuprofen in concentration common for topical application (5%, w/w) was achieved at the water contents below 50% (w/w). Drug free and ibuprofen-loaded microemulsions M1–M6, containing 45% (w/w) of water phase, were prepared and characterized by polarized light microscopy, conductivity, pH, rheological and droplet size measurements. In vitro ibuprofen release kinetics from the microemulsions was investigated using paddle-over-enhancer cell method and compared with the commercial 5% (w/w) ibuprofen hydrogel product (Deep Relief®, Mentholatum Company Ltd., USA). The investigated microemulsions were isotropic, low viscous Bingham-type liquids with the pH value (4.70–6.61) suitable for topical application. The different efficiency of the tensides mixtures for microemulsion stabilisation was observed, depending on the cosurfactant type and K m value. Solubilisant gamma® 2429 as well as higher K m (i.e., lower relative content of the cosurfactant) provided higher surfactant/cosurfactant synergism. The drug molecules were predominantly solubilized within the interface film. The amount of drug released from the formulations M3 (10.75%, w/w) and M6 (13.45%, w/w) (K m 60:40) was limited in comparison with the reference (22.22%, w/w) and follows the Higuchi model. Microemulsions M2 and M5 (K m 50:50) gave zero order drug release pattern and ∼15% (w/w) ibuprofen released. The release profiles from microemulsions M1 and M4 (K m 40:60) did not fit well with the models used for analysis, although the amounts of ibuprofen released (24.47%, w/w) and 17.99% (w/w), respectively) were comparable to that of the reference hydrogel. The drug release mechanism was related with the surfactant/cosurfactant synergism, thus the lower efficiency of the tensides corresponded to the faster drug release.
Keywords: Microemulsions; Surfactant/cosurfactant synergism; Drug solubilization capacity; In vitro release testing (IVRT); Ibuprofen;
Development of a micro dosing system for fine powder using a vibrating capillary. Part 1: The investigation of factors influencing on the dosing performance by Xiaolong Chen; Karlheinz Seyfang; Hartwig Steckel (34-41).
Precise filling of powder in pharmaceutical development and production is still a challenge, especially when handling small quantities of high potency actives. For this purpose, a micro dosing system for fine powder using a vibrating capillary was developed and investigated. The main objective in this work focused on flow rate and its variability in relation to parameters such as capillary diameter, frequency, and amplitude. The impact of powder properties such as density, particle size, size distribution and shape was also studied with five different kinds of lactose powder. It was found that both the frequency and the amplitude affect the flow rate and variability but with different impact. The range of flow rate can vary from 1 mg to 10 mg per second and a relative standard deviation of better than 3% can be achieved.
Keywords: Powder; Micro-dosing; Flow rate; Vibration; Frequency; Amplitude; Capillary;
Development of a micro-dosing system for fine powder using a vibrating capillary. Part 2. The implementation of a process analytical technology tool in a closed-loop dosing system by Xiaolong Chen; Karlheinz Seyfang; Hartwig Steckel (42-50).
In an earlier study, a micro-dosing system for fine powder using a vibrating capillary which can precisely dose various lactose powders, was introduced. In scaling up to a multi-track dosing system, it was suggested that additional track cut-offs can improve the dosing performance by reducing the overruns. A non-contact in-line control unit within a closed-loop system is required to achieve this goal. Due to its very fast response time (a few milliseconds) a capacitive sensor was integrated together with multi track cut-offs into a closed-loop dosing system. With this improvement a standard dosing deviation as low as 0.1 mg was achieved. The results suggest its application in precise filling of fine pharmaceutical powders.
Keywords: Micro-dosing; Fine powder; Capacitive sensor; Track cut-off; Closed-loop;
Conception, preparation and properties of functional carrier particles for pulmonary drug delivery by Marcin Odziomek; Tomasz R. Sosnowski; Leon Gradoń (51-59).
The effectiveness of aerosol therapy is significantly reduced by the mucus layer covering the airways of the tracheobronchial tree. According to the present concept, drug particles are delivered to the lung together with the functional carrier particle that facilitates both the drug transport into the lungs and the penetration of deposited particles through the mucus. The approach of manufacturing multi-component powders with mucoactive compounds and anti-asthmatic medicines (DSCG) bound together in a single particle is additionally considered.Powders were produced with the spray-drying technique from aqueous precursor solutions containing pure low molecular weight dextran, pure mannitol and dextran/mannitol–N-acetyl cysteine (NAC) mixtures (4:1 and 1:1). NAC has been selected for this purpose as a compound, which is known to be mucolytic. Dextran and mannitol are potentially applicable in the field of inhalation drug delivery. They have been used as stabilizers of functional carrier particles. Powders were characterized for their yield and physicochemical properties including: morphology (SEM), moisture content and thermal properties (DSC). Aerosol performance was determined with NGI impactor after standardized aerosolization of the produced powders in a commercial DPI.Particle size distributions of dextran–NAC powders were characterized by high fine particle fraction (45–62%), which assures good particle deposition in the lower airways. The thermodynamic properties of the powders based on the temperature of the glass transition T g (50–63 °C) suggest the required stability during storage at moderate humidity.Preliminary examination of the required properties of these particles confirms their potential as functional carriers for pulmonary drug delivery.
Keywords: Spray drying; Functional carriers; Mucus; Mucociliary clearance; Powder properties;
A novel image analysis methodology for online monitoring of nucleation and crystal growth during solid state phase transformations by Jian X. Wu; Dengning Xia; Frans van den Berg; José Manuel Amigo; Thomas Rades; Mingshi Yang; Jukka Rantanen (60-70).
This study focuses on the development of an automated image analysis method to extract information on nucleation and crystal growth from polarized light micrographs. Using the developed image analysis method, four parameters related to nucleation and crystal growth could be extracted from the images. These parameters were crystalline count (applied as a measure of nucleation), percentage area coverage, average equivalent diameter and average crystalline area (three last parameters applied as a measure for crystal growth). The developed image analysis method was used to investigate two pharmaceutically relevant case studies: first, nitrendipine antisolvent crystallization, and second, recrystallization of amorphous piroxicam solid dispersion in an aqueous environment. In both case studies, an amorphous-to-crystalline phase transformation were observed, which were successfully monitored using real-time Raman spectroscopy. For the both case studies, the parameters related to crystallization kinetics estimated by image analysis were in close agreement with the parameters estimated by Raman spectroscopy. The developed image analysis method proved to be a valuable tool for quantitative monitoring of nucleation and crystal growth with an obvious potential for high throughput screening.
Keywords: Polarized light microscopy; Image analysis; Nucleation; Crystal growth; Solid dispersion; Antisolvent crystallization;
Miscibility analysis of particulate solid dispersions prepared by electrospray deposition by Kohsaku Kawakami (71-78).
Physical characteristics of solid dispersions were investigated using carbamazepine (CBZ) and prednisolone (PDN) as model drugs, and poly(vinyl pyrrolidone) and Eudragit as polymeric excipients. Electrospray method provided particulate formulations, of which the particle size was typically in the order of micrometers, when the polymer concentration of the solution used for the preparation was below 2% (w/v). Decrease of the solution concentration and flow rate resulted in a decrease in the particle diameter, as theoretically expected. Also, the particle size could be reduced to 400 nm by increasing the conductivity of the solution by the addition of salts. When poly(vinyl pyrrolidone) K90 was used as an excipient, CBZ was homogeneously loaded up to ca. 40%, and if a greater amount was added, the excess CBZ was separated as a pure crystalline phase. PDN was homogeneously loaded up to ca. 60%. However, in contrast to CBZ, excess PDN maintained the amorphous state, even when a greater amount was added. The separated excess PDN phase was crystallized in the heating process during thermal analysis. In addition to the thermodynamic factor, there seems to be a dynamic factor to separate drug phase from the excipient phase, depending on their molecular weight and miscibility during the electrospray deposition process. The mechanism for particle formation by electrospray deposition is discussed with emphasis on the miscibility between drug and excipient.
Keywords: Electrospray deposition; Solid dispersion; Amorphous; Miscibility; Thermal analysis;
Encapsulation of azithromycin into polymeric microspheres by reduced pressure-solvent evaporation method by Xiujuan Li; Si Chang; Guangsheng Du; Yi Li; Junbo Gong; Mingshi Yang; Zhenping Wei (79-88).
F1 presented a zero-order release profile, and other formulations followed first-order kinetics except F2 which was fit well by Ritger–Peppas equation.Azithromycin loaded microspheres with blends of poly-l-lactide and ploy-d,l-lactide-co-glycolide as matrices were prepared by the atmosphere-solvent evaporation (ASE) and reduced pressure-solvent evaporation (RSE) method. Both the X-ray diffraction spectra and DSC thermographs demonstrated that poly-l-lactide existed in a crystalline form in the ASE microspheres, while an amorphous form was present in the RSE formulations. Besides, solvent removal at atmosphere gave microspheres of porous and rough surfaces, but smooth surfaces appeared in the RSE microspheres. The incorporation efficiency as well as the burst release (cumulative release in the first 24 h) in the ASE formulations was 39.94 ± 1.18% and 23.96 ± 2.01% respectively, yet the encapsulation efficiency of the microspheres fabricated under 385 mmHg was high up to 57.19 ± 3.81% and the burst release was 4.12 ± 0.15%. The in vitro drug release studies indicated that the ASE microspheres presented a zero-order profile; while the RSE formulations followed first-order kinetics. Other factors including solidification time, temperature, drug to polymer ratio and pH value of the continuous phase could also influence the physicochemical characteristics and release profiles of microspheres. In conclusion, the overall improvement of microspheres in appearance, encapsulation efficiency and controlled drug release through the RSE method could be easily fulfilled under optimal preparation conditions.
Keywords: Azithromycin; Reduced-pressure solvent evaporation; Burst release; Crystallinity; Antoine equation;
Effect of ketocholate derivatives on methotrexate uptake in Caco-2 cell monolayers by Gong Chen; Lin Yang; Hu Zhang; Ian G. Tucker; J. Paul Fawcett (89-93).
The bile salts (BS) cholate (C) and 12-monoketocholate (12-MKC) have been shown to inhibit the transcellular permeation of methotrexate (MTX) across Caco-2 cell monolayers. The aim of this study was to investigate the mechanism of this inhibition by comparing the effects of C, 7-MKC, 12-MKC, 3,7-diketocholate (DKC) and triketocholate (TKC) on MTX uptake by Caco-2 cells.Critical micelle concentrations (CMCs) and cytotoxicities of BS and their effects on membrane fluidity Caco-2 cells were determined by standard methods. MTX uptake by Caco-2 cell monolayers was determined using LC–MS/MS.Replacing hydroxyl groups in C with keto groups and changing from 7-MKC to 12-MKC resulted in BS with lower cytotoxicity, higher CMC and decreased ability to inhibit the uptake of MTX. 7- and 12-MKC increased membrane fluidity of hydrophilic regions of Caco-2 cell membranes, DKC and TKC increased membrane fluidity of hydrophobic regions and C had little effect on membrane fluidity of either region.Replacing hydroxyl groups in C with keto groups produces BS with different physicochemical properties and biological effects. Since ketocholates (but not C) decrease MTX uptake in parallel with increasing membrane fluidity, it is suggested that ketocholates inhibit MTX influx transporters indirectly through disturbing their lipid environment.
Keywords: Ketocholate derivatives; Methotrexate; Membrane fluidity; Cytotoxicity; Caco-2 cells;
Development of a precipitation-resistant solution formulation to increase in vivo exposure of a poorly water-soluble compound by Lori Burton; William Ying; Rajesh Gandhi; Ronald West; Christine Huang; Simon Zhou; Keyur Shah; Jinling Chen; Xiaohang Shen (94-101).
In vitro and in vivo investigations were conducted to develop a suitable formulation for early toxicology and clinical studies of ((R)-7-(3,4-dichlorophenyl)-5-methyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(4-fluorophenyl)pyrrolidin-1-yl)methanone (Compound A), a nonionizable and poorly water-soluble compound that selectively inhibits the ultrarapid potassium current (IKur) and is intended for the treatment of arrhythmia. Various nonaqueous solution formulations were evaluated, in vitro, for ability to prevent or delay precipitation of Compound A from solution following dilution with water. The plasma exposures of precipitation-resistant solutions, non precipitation-resistant solutions, and aqueous suspensions were then compared in rats, dogs, and/or humans. The data indicated that a solubilized, precipitation-resistant formulation achieved the highest plasma concentrations in all species and also improved dose proportionality, particularly in rats. Development of such formulations may be highly valuable for achieving in vivo blood levels often required for successful toxicological and early clinical evaluation of poorly soluble compounds.
Keywords: Poorly soluble; Nonionizable; Precipitation-resistant; Nonaqueous; Oral bioavailability;
Huperzine A–phospholipid complex-loaded biodegradable thermosensitive polymer gel for controlled drug release by Xiaoqing Cai; Yuxia Luan; Yue Jiang; Aixin Song; Wei Shao; Zhonghao Li; Zhongxi Zhao (102-111).
The huperzine A–phospholipid complex loaded biodegradable thermosensitive PLGA–PEG–PLGA polymer gel was studied as injectable implant system for controlled release of huperzine-A (HA). First, HA molecules were successfully incorporated into the soybean phosphatidylcholine (SP) molecules to form the huperzine-A–soybean phosphatidylcholine complexes (HA–SPC), which was proved by FT-IR, DSC, XRD, solubility study, TEM, etc. The results indicated that hydrogen bonds and electrostatic interaction between HA and SP molecules play an important role in the formation of HA–SPC. Secondly, the HA–SPC was loaded into biodegradable PLGA–PEG–PLGA thermosensitive gel as injectable implant material to control the release of HA. The in vitro and in vivo drug release behaviors of the prepared products were studied. The in vitro release studies demonstrated that the HA–SPC-loaded gel significantly reduced the initial burst of drug release and extended the release period to about 2 weeks. The in vivo pharmacokinetics study of HA–SPC-loaded gel in rabbits showed that plasma concentration of HA (2.54–0.15 ng/mL) was detected for nearly 2 weeks from delivery systems upon single subcutaneous injection. What's more, the in vitro release pattern correlated well with the in vivo pharmacokinetics profile. The present study indicates that HA–SPC loaded PLGA–PEG–PLGA thermal gel may be an attractive candidate vehicle for controlled HA release.
Keywords: Huperzine-A; Phospholipid complex; PLGA–PEG–PLGA thermogel; Drug release;
Smart design of intratumoral thermosensitive β-lapachone hydrogels by Artificial Neural Networks by P. Díaz-Rodríguez; M. Landin (112-118).
This study presents Artificial Neural Networks (ANN) as a tool for designing injectable intratumoral formulations of the anticancer drug β-lapachone. This methodology permits insight into the interactions between variables and determines the design space of the formulation without the restrictions of an experimental design. An ANN model for two critical parameters of the formulations; the amount of solubilized drug and gel temperature was developed and validated. The model allowed an understanding of interactions between ingredients in the formulation and the fundamental phenomena as the formation of polypseudorotaxanes to be detected and quantified.
Keywords: β-Lapachone; Pluronic, Artificial Neural Networks; Cyclodextrins; Modeling;
Development and validation of a paediatric oral formulation of clonidine hydrochloride by A.L. de Goede; R.R. Boedhram; M. Eckhardt; L.M. Hanff; B.C.P. Koch; C.H. Vermaat; A. Vermes (119-120).
Many drugs are unavailable in suitable paediatric dosage forms. We describe the development and validation of a stable paediatric oral formulation of clonidine hydrochloride 50 μg/ml, allowing individualised paediatric dosing and easy administration. Stability of the extemporaneously compounded formulation of clonidine hydrochloride was assessed using a validated HPLC method. Clonidine hydrochloride was stable in the buffered aqueous solution at room temperature for up to 9 months. The described formulation is chemically stable for at least 9 months when stored in brown 100 ml PET bottles at room temperature, enabling adequate oral treatment in paediatric patients.
Keywords: Clonidine hydrochloride; Formulation; Compounding; Stability; Paediatric dosage form; High Performance Liquid Chromatography (HPLC);
Paclitaxel-incorporated nanoparticles of hydrophobized polysaccharide and their antitumor activity by Sang Joon Lee; Gun-Young Hong; Young-Il Jeong; Mi-Sun Kang; Jong-Suk Oh; Chae-Eun Song; Hyun Chul Lee (121-128).
The aim of this study was to characterize paclitaxel-incorporated polysaccharide nanoparticles and evaluate their antitumor activity in vitro and in vivo. Pullulan was hydrophobically modified using acetic anhydride to make the paclitaxel-incorporated nanoparticles. Pullulan acetate (PA) was used to encapsulate paclitaxel using the nanoprecipitation method. The particles had spherical shapes under electron microscopy with sizes <100 nm. The sizes of paclitaxel-incorporated nanoparticles increased to >100 nm, and higher drug feeding induced higher particle size and drug content. Initial drug burst release was observed until 2 days and then the drug was continuously released over 1 week. Intrinsic cytotoxicity of empty PA nanoparticles was tested with RAW264.7 macrophage cells for biocompatibilty. The viability of RAW264.7 cells was >93% at all concentrations of empty PA nanoparticles, indicating that the PA nanoparticles are not acutely cytotoxic to normal human cells. The nanoparticles showed lower antitumor activity in vitro against HCT116 human colon carcinoma cells than that of paclitaxel itself, indicating the sustained release properties of nanoparticles. An in vivo study using HCT116 human colon carcinoma-bearing mice showed that paclitaxel-incorporated PA nanoparticles reduced tumor growth more than that of paclitaxel itself. These results indicate that PA paclitaxel-incorporated nanoparticles are a promising candidate for antitumor drug delivery.
Keywords: Nanoparticles; Paclitaxel; Pullulan; Polysaccharide; HCT116;
The effect of poly(ethylene glycol) coating on colloidal stability of superparamagnetic iron oxide nanoparticles as potential MRI contrast agent by Afshin Masoudi; Hamid Reza Madaah Hosseini; Mohammad Ali Shokrgozar; Reza Ahmadi; Mohammad Ali Oghabian (129-141).
Superparamganetic iron oxide-based contrast agents in magnetic resonance imaging (MRI) have offered new possibility for early detection of lymph nodes and their metastases. According to important role of nanoparticle size in biodistribution, magnetite nanoparticles coated with different polyethylene glycol (PEG) concentrations up to 10/1 PEG/iron oxide weight ratio in an ex situ manner. To predict the PEG-coated nanoparticle behavior in biological media, such as blood stream or tissue, colloidal stability evaluation was performed to estimate the coating endurance in different conditions. Accordingly, optical absorbance measurements were conducted in solutions with different values of pH and NaCl concentrations. The results indicated that at neutral pH condition, nanoparticles treated by 3/1 ratio possessed better stability parameters. Investigating at high pH of 10 resulted in superior stability for bare magnetite nanoparticles due to its higher electrophoretic mobility. Coating material was attacked at acidic solutions which cause samples with higher PEG weight ratio to be settled slower. In various ionic strengths of 10−5 to 0.1 M, 3/1 ratio samples offered greater resistivity to sedimentation. The nanoparticles were further investigated by exposure to L929 cell and following up the iron uptake within cells. Finally, detection sensitivities in lymph nodes were evaluated. Particle uptake and the most signal reduction for in vivo MRI studies were also obtained by nanoparticles acquiring lower PEG contents that showed better colloidal stability.
Keywords: Iron oxide nanoparticle; Colloidal stability; Polyethylene glycol; MRI contrast agent;
Niosomes and discomes for ocular delivery of naltrexone hydrochloride: Morphological, rheological, spreading properties and photo-protective effects by Hamdy Abdelkader; Zimei Wu; Raida Al-Kassas; Raid G. Alany (142-148).
Naltrexone hydrochloride (NTX) is a promising treatment for corneal disorders linked to diabetes mellitus (diabetic keratopathy). However, NTX has a major stability problem due to autoxidation, which is likely to hinder its formulation as eye drops for treatment of diabetic keratopathy. In this study, in-house developed NTX non-ionic surfactant vesicles (niosomes and discomes) were evaluated for their spreading, rheological properties and their ability to impede the inevitable autoxidation of NTX in aqueous solutions. The measured contact angles and spreading coefficients for niosomes reflected significantly (P < 0.05) better wetting and spreading abilities than the aqueous vehicle. The prepared niosomes were significantly more viscous (P < 0.05) than the aqueous solution. The lipid content, size and composition of niosomes are the main factors affecting the viscosity of niosomal dispersions. Exposure of NTX solution to artificial daylight illumination (10,000 lux) can produce extensive degradation of NTX due to oxidation. The prepared formulations were able to significantly (P < 0.05) protect the encapsulated NTX from the photo-induced oxidation compared with free NTX solutions. The investigated niosomes lend themselves as a potential ocular delivery modality for NTX.
Keywords: Niosomes; Discomes; Naltrexone hydrochloride; Autoxidation; Contact angle; Viscosity;
Formation of ultrafine deferasirox particles via rapid expansion of supercritical solution (RESS process) using Taguchi approach by Iman Asghari; Feridun Esmaeilzadeh (149-156).
The poor water solubility of many drugs is a challenge in pharmaceutical research. Recently, there have been great interests in finding environmentally friendly methods producing fine particles of pharmaceutical products for applications in pharmaceutical engineering. A promising method to improve the bioavailability of pharmaceutical agents is the rapid expansion of supercritical solutions. Deferasirox (DFS), a tridentate chelator, requires two molecules for iron (III) coordination. The bioavailability (the percentage of the drug absorbed compared to its initial dosage) is limited by this insolubility. The effect of four different RESS parameters including, extraction temperature (308–318 K), extraction pressure (140–200 bar), effective nozzle diameter (500–1200 μm), with and without cosolvents were investigated on the size and morphology of the precipitated particles of deferasirox based on Taguchi design. The results show great reduction in the size of the precipitated particles of deferasirox (50 nm–5 μm) via RESS process compared with the original particles of deferasirox (5–500 μm).
Keywords: Nanoparticles; Iron chelator; Deferasirox; RESS process; SC-CO2; Taguchi;
Studies on the preparation, characterization and pharmacokinetics of Amoitone B nanocrystals by Leilei Hao; Xiaoyong Wang; Dianrui Zhang; Qingyan Xu; Siyang Song; Feihu Wang; Caiyun Li; Hejian Guo; Yue Liu; Dandan Zheng; Qiang Zhang (157-164).
Amoitone B, as a new derivative of cytosporone B, has been proved to be a natural agonist for Nur77. It exhibits remarkable anticancer activity in vivo and has the potential to be a therapeutic agent for cancer treatment. However, the poor solubility and dissolution rate result in low therapeutic index for injection and low bioavailability for oral administration, therefore limiting its application. In order to magnify the clinical use of Amoitone B, nanocrystal was selected as an application technology to solve the above problems. In this study, the optimized Amoitone B nanocrystals with small and uniform particle size were successfully prepared by microfluidization method and investigated by morphology, size distribution, and zeta potential. The differential scanning calorimetry (DSC) and X-ray diffraction (XRD) confirmed there was no crystalline state changed in the size reduction process. For Amoitone B nanocrystals, an accelerated dissolution velocity and increased saturation solubility were achieved in vitro and a markedly different pharmacokinetic property in vivo was exhibited with retarded clearance and magnified AUC compared with Amoitone B solution. These results implied that developing Amoitone B as nanocrystals is a promising choice for intravenous delivery and further application for cancer therapy.
Keywords: Amoitone B; Nanocrystals; Microfluidization method; In vitro dissolution; Pharmacokinetics;