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1.
Purpose
Freeze-thaw cycling is an important processing step in the preparation of liposomes that leads to the encapsulation of drug molecules. There is considerable variability in the number of freeze-thaw cycles reported in the literature. This work is designed to aid in liposomal formulation design by gaining an insight into the drug encapsulation process and an understanding of liposome stabilization during various thawing conditions.Methods
The effects of different thawing temperatures, as well as “annealing” at subzero temperatures on a liposome formulation, are reported here.Results
Two freeze-anneal-thaw (FANNT) cycles (freezing to ?196°C, annealing at ?1.4°C for ~30 min, thawing at 65°C) resulted in the maximum predicted encapsulation efficiency without causing any significant change in particle size or zeta potential. Annealing at ?22°C was shown to be destabilizing due to limited hydration of the liposomes in the frozen state.Conclusions
It was shown that two important processes are occurring during the FANNT cycling that affect liposome encapsulation efficiency. The first is drug diffusion in the frozen state and the second is fusion/destabilization of the liposomes. This is the first report on the annealing of liposomes and understanding the mechanism of drug encapsulation using the freeze-thaw cycling method. 相似文献2.
S Prasad V Cody JK Saucier-Sawyer TR Fadel RL Edelson MA Birchall DJ Hanlon 《Pharmaceutical research》2012,29(9):2565-2577
Purpose
In order to investigate Poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NP) as potential vehicles for efficient tumor antigen (TA) delivery to dendritic cells (DC), this study aimed to optimize encapsulation/release kinetics before determining immunogenicity of antigen-containing NP.Methods
Various techniques were used to liberate TA from cell lines. Single (gp100) and multiple (B16-tumor lysate containing gp100) antigens were encapsulated within differing molecular weight PLGA co-polymers. Differences in morphology, encapsulation/release and biologic potency were studied. Findings were adopted to encapsulate fresh tumor lysate from patients with advanced tumors and compare stimulation of tumor infiltrating lymphocytes (TIL) against that achieved by soluble lysate.Results
Four cycles of freeze-thaw + 15 s sonication resulted in antigen-rich lysates without the need for toxic detergents or protease inhibitors. The 80KDa polymer resulted in maximal release of payload and favorable production of immunostimulatory IL-2 and IFN-γ. NP-mediated antigen delivery led to increased IFN-γ and decreased immunoinhibitory IL-10 synthesis when compared to soluble lysate.Conclusions
Four cycles of freeze-thaw followed by 15 s sonication is the ideal technique to obtain complex TA for encapsulation. The 80KDa polymer has the most promising combination of release kinetics and biologic potency. Encapsulated antigens are immunogenic and evoke favorable TIL-mediated anti-tumor responses. 相似文献3.
Mette Hamborg Lene Jorgensen Anders Riber Bojsen Dennis Christensen Camilla Foged 《Pharmaceutical research》2013,30(1):140-155
Purpose
Understanding the nature of adjuvant-antigen interactions is important for the future design of efficient and safe subunit vaccines, but remains an analytical challenge. We studied the interactions between three model protein antigens and the clinically tested cationic liposomal adjuvant composed of dimethyldioctadecylammonium (DDA) and trehalose 6,6??-dibehenate (TDB).Methods
The effect of surface adsorption to DDA/TDB liposomes on colloidal stability and protein physical stability/secondary structure was investigated by dynamic light scattering, circular dichroism, Fourier transform infrared spectroscopy and differential scanning calorimetry.Results
Bovine serum albumin and ovalbumin showed strong liposome adsorption, whereas lysozyme did not adsorb. Upon adsorption, bovine serum albumin and ovalbumin reduced the phase transition temperature and narrowed the gel-to-liquid phase transition of the liposomes implying interactions with the lipid bilayer. The protein-to-lipid ratio influenced the liposome colloidal stability to a great extent, resulting in liposome aggregation at intermediate ratios. However, no structural alterations of the model proteins were detected.Conclusions
The antigen-to-lipid ratio is highly decisive for the aggregation behavior of DDA/TDB liposomes and should be taken into account, since it may have an impact on general vaccine stability and influence the choice of analytical approach for studying this system, also/especially at clinically relevant protein-to-lipid ratios.A graphical overview of the influence of the protein-to-lipid-mass ratios on the vaccine system. Different physical states observed for the vaccine system: A) Lysozyme and DDA/TDB liposomes: No measurable positive interaction. B) At low concentrations of BSA/ovalbumin and DDA/TDB liposomes: No detectable aggregation (all the protein is adsorbed). C) Intermediate concentrations of BSA/ovalbumin and DDA/TDB liposomes; Aggregation and partial adsorption of the protein. D) High concentrations of BSA: The liposomes are stabilized by a protein corona and protein is present in bulk 相似文献
4.
Purpose
The impact of freeze-thaw (F/T) on structure integrity of protein therapeutics is poorly understood, partially due to lack of methods to detect protein structural perturbations during F/T processing in the frozen state.Methods
A new approach of hydrogen/deuterium exchange was developed to separate and distinguish the specific impact of single freezing and F/T cycling on protein structure, using lactate dehydrogenase (LDH) as model system.Results
In the freezing process, a fraction of LDH molecules that was inversely dependent on protein concentration was observed to partially denature its structure. Local structural perturbations were localized by peptide level HX analysis to the surface residues in segments 91–132, 170–237 and 288–331. In contrast, F/T cycling led to irreversible LDH aggregation with global structural unfolding. Residual solvent-protected structure was only detected in the aggregates for three segments, 13–31, 109–117 and 133–143, that were coincident with the consensus aggregation hotspots predicted by four different algorithms.Conclusions
Results indicate freezing preferentially disturbs local structure at the surface residues, consistent with ice-solution interface-mediated denaturation mechanism. F/T-induced aggregation begins as partial denaturation during freezing, but is accompanied by more comprehensive structural rearrangement during F/T cycling. 相似文献5.
Purpose
Preparation, optimization and in vitro evaluation of core-shell nanoparticles comprising of a hydrophilic core of BSA surrounded by a hydrophobic shell of PLGA for loading water-soluble drugs.Methods
A double emulsion method was optimized for preparation of BSA-PLGA based core-shell nanoparticles. Proof of concept for core-shell type structure was established by visual techniques like confocal microscopy and TEM. Characterization was done for particle size, encapsulation efficiency, drug loading and in vitro drug release. Cellular uptake was assessed using confocal microscopy, bio-TEM and HPLC assay, and cytotoxic activity was tested by MTT assay in MG-63 osteosarcoma cells.Results
The optimized core-shell nanoparticles showed a particle size of 243 nm (PDI-0.13) and encapsulation efficiency of 40.5% with a drug loading of 8.5% w/w. In vitro drug release studies showed a sustained release for 12 h. Cellular uptake studies indicated a rapid and efficient uptake within 2 h. TEM studies indicated that the core-shell nanoparticles were localized in cytoplasm region of the cells. Gemcitabine loaded core-shell nanoparticles showed enhanced cytotoxicity against MG-63 cells as compared to marketed formulation of gemcitabine (GEMCITE®).Conclusion
These results indicate that core-shell nanoparticles can be a good carrier system for delivering hydrophilic drugs like gemcitabine successfully to the cells with enhanced efficacy.Core-Shell Nanoparticles with a hydrophilic BSA core and hydrophobic PLGA shell for carrier system of hydrophilic drugs 相似文献
6.
Natassa Pippa Faidra Psarommati Stergios Pispas Costas Demetzos 《Pharmaceutical research》2013,30(9):2385-2395
Purpose
Fractal analysis was used as a tool in order to study the morphological characteristics of PEGylated liposomes. We report on the morphological characteristics of stealth liposomes composed of DPPC and DPPE-PEG 3000 in two dispersion media using fractal analysis.Methods
Light scattering techniques were used in order to elucidate the size, the morphology and the surface charge of PEGylated liposomes as a function of PEGylated lipid concentration and temperature. Fluorescence spectroscopy studies revealed a microenvironment of low polarity inside the liposomal membranes.Results
All formulations were found to retain their physicochemical characteristics for at least 3 weeks. The hydrodynamic radii (Rh) of stealth liposomes were stable in the process of heating up to 50°C; while the fractal dimension values (df) which correspond to their morphology, have been changed during heating. Hence, these results are a first indication of the presence of a heterogeneous microdomain structure of the stealth liposomal system. The amphiphilic drug indomethacin (IND) was successfully encapsulated within the liposomes and led to an increased size of stealth liposomes, while the morphology of liposomal vectors changed significantly at the highest molar ratio of PEGylated lipid.Conclusions
We can state that this approach can promote a new analytical concept based on the morphological characteristics and quantify the shape of drug carriers complementary to that of the conventional analytical techniques. 相似文献7.
Kashappa-Goud H. Desai Samer Kadous Steven P. Schwendeman 《Pharmaceutical research》2013,30(7):1768-1778
Purpose
To investigate the effect of γ-irradiation of poly(lactic-co-glycolic acid) (PLGA)/Al(OH)3/0 or 5 wt% diethyl phthalate (DEP) microspheres for active self-healing encapsulation of vaccine antigens.Methods
Microspheres were irradiated with 60Co at 2.5 and 1.8 MRad and 0.37 and 0.20 MRad/h. Encapsulation of tetanus toxoid (TT) was achieved by mixing Al(OH)3-PLGA microspheres with TT solution at 10–38°C. Electron paramagnetic resonance (EPR) spectroscopy was used to examine free radical formation. Glass transition temperature (Tg) and molecular weight of PLGA was measured by differential scanning calorimetry and gel permeation chromatography, respectively. Loading and release of TT were examined by modified Bradford, amino acid analysis, and ELISA assays.Results
EPR spectroscopy results indicated absence of free radicals in PLGA microspheres after γ-irradiation. Antigen-sorbing capacity, encapsulation efficiency, and Tg of the polymer were also not adversely affected. When DEP-loaded microspheres were irradiated at 0.2 MRad/h, some PLGA pores healed during irradiation and PLGA healing during encapsulation was suppressed. The molecular weight of PLGA was slightly reduced when DEP-loaded microspheres were irradiated at the same dose rate. At the 0.37 MRad/h dose rate, these trends were not observed and the full immunoreactivity of TT was preserved during encapsulation and 1-month release. Gamma irradiation slightly increased TT initial burst release. The small increase in total irradiation dose from 1.8 to 2.5 MRad had insignificant effect on the polymer and microspheres properties analyzed.Conclusions
Gamma irradiation is a plausible approach to provide a terminally sterilized, self-healing encapsulation PLGA excipient for vaccine delivery. 相似文献8.
Aviral Jain Manish K. Chourasia Vandana Soni Nitin K. Jain Piush Khare Yashwant Gupta Dr Sanjay K. Jain 《American Journal of Drug Delivery》2006,4(1):43-49
Background
The blood-brain barrier (BBB) is an obstacle for pharmacologists wishing to find treatments for patients with brain disorders. The BBB restricts the uptake of many valuable hydrophilic drugs and limits their efficacy because of the presence of tight junctions, a high metabolic capacity, low pinocytic vesicular traffic, and efficient efflux mechanisms.Aim
The present study aimed to characterize lactyl stearate-coupled liposomes and their potential for the brain targeting of rifampin (rifampicin).Method
A liposomal delivery system was prepared for achieving the brain-targeted delivery of rifampin in 21 albino rats utilizing the monocarboxylic acid transport system. Liposomes were prepared by the cast-film method using phosphatidylcholine and cholesterol. Similarly, lactyl stearate-coupled liposomal systems were prepared by casting lactyl stearate film with lipids. These liposomal formulations were characterized for entrapment efficiency, vesicle size, in vitro drug release (using dialysis membrane), and in vivo drug accumulation in various tissues.Results
Coupling of lactyl stearate to liposomes had a profound influence on entrapment efficiency. Entrapment efficiency was reduced from 41.28 ± 2.02% in uncoupled liposomes to 34.23 ± 1.60% in coupled liposomes. The vesicle size was increased after coupling with lactyl stearate. The in vitro drug release for the uncoupled formulation LIPO-3 was 62.9 ± 3.01% after 24 hours, whereas that of the coupled formulation LIPO-3-Ls-III was 44.5 ± 2.09%. The percentage of rifampin dose recovered from the brain following administration of lactyl stearate-coupled liposomes to albino rats at different time intervals was about 6–8 times higher than with uncoupled liposomes and about 10–12 times higher than with the plain drug solution.Conclusion
Lactyl stearate-coupled liposomes were better localized within the brain compared to uncoupled liposomes. Lactyl stearate-coupled liposomes could be an excellent carrier system for brain targeting of the hydrophilic drug rifampin. 相似文献9.
Near-Infrared Image-Guided Delivery and Controlled Release Using Optimized Thermosensitive Liposomes
Purpose
To engineer optimized near-infrared (NIR) active thermosensitive liposomes to potentially achieve image-guided delivery of chemotherapeutic agents.Methods
Thermosensitive liposomes were surface-coated with either polyethylene glycol or dextran. Differential scanning calorimetry and calcein release studies were conducted to optimize liposomal release, and flow cytometry was employed to determine the in vitro macrophage uptake of liposomes. Indocyanine green (ICG) was encapsulated as the NIR dye to evaluate the in vivo biodistribution in tumor-bearing mice.Results
The optimized thermosensitive liposome formulation consists of DPPC, SoyPC, and cholesterol in the 100:50:30 molar ratio. Liposomes with dextran and polyethylene glycol demonstrated similar thermal release properties; however in vitro macrophage uptake was greater with dextran. Non-invasive in vivo NIR imaging showed tumor accumulation of liposomes with both coatings, and ex vivo NIR imaging correlated well with actual ICG concentrations in various organs of healthy mice.Conclusions
The optimized thermosensitive liposome formulation demonstrated stability at 37?°C and efficient burst release at 40 and 42?°C. Dextran exhibited potential for application as a surface coating in thermosensitive liposome formulations. In vivo studies suggest that liposomal encapsulation of ICG permits reliable, real-time monitoring of liposome biodistribution through non-invasive NIR imaging. 相似文献10.
Purpose
To test targeted liposomes in an effort to improve drug transport across cellular barriers into the brain.Methods
Therefore we prepared Mitoxantrone (MTO) entrapping, rigid and fluid liposomes, equipped with a 19-mer angiopeptide as ligand for LDL lipoprotein receptor related protein (LRP) targeting.Results
Fluid, ligand bearing liposomes showed in vitro the highest cellular uptake and transcytosis and were significantly better than the corresponding ligand-free liposomes and rigid, ligand-bearing vesicles. Treatment of mice, transplanted with human breast cancer cells subcutaneously and into the brain, with fluid membrane liposomes resulted in a significant reduction in the tumor volume by more than 80% and in a clear reduction in drug toxicity. The improvement was mainly depended on liposome fluidity while the targeting contributed only to a minor degree. Pharmacokinetic parameters were also improved for liposomal MTO formulations in comparison to the free drug. So the area under the curve was increased and t1/2 was extended for liposomes.Conclusion
Our data show that it is possible to significantly improve the therapy of brain metastases if MTO-encapsulating, fluid membrane liposomes are used instead of free MTO. This effect could be further enhanced by fluid, ligand bearing liposomes. 相似文献11.
Gayong Shim Sangbin Lee Junhyeok Choi Soondong Lee Chan-Wha Kim Yu-Kyoung Oh 《Pharmaceutical research》2014,31(8):2178-2185
Purpose
Anticancer chemotherapy usually involves the administration of several anticancer drugs that differ in their action mechanisms. Here, we aimed to test whether the combination of omacetaxine mepesuccinate (OMT) and doxorubicin (DOX) could show synergism, and whether the liposomal co-delivery of these two drugs could enhance their antitumor effects in cervical carcinoma model.Method
OMT-loaded liposomes (OL) were prepared by loading the drug in the lipid bilayers. OL were then electrostatically complexed with DOX, yielding double-loaded liposomes (DOL). DOX-loaded liposomes (DL) were formulated by electrostatic interaction with negatively charged empty liposomes (EL). The combination index (CI) values were calculated to evaluate the synergism of two drugs. In vitro antitumor effects against HeLa cells were measured using CCK-8, calcein staining, and crystal violet staining. In vivo antitumor effects of various liposomes were tested using HeLa cell-bearing mice.Results
Combination of DOX and OMT had ratio-dependent synergistic activities, with very strong synergism observed at a molar ratio of 4:1 (DOX:OMT). The sizes of EL, DL, OL, and DOL did not significantly differ, but the zeta potentials of DL and DOL were slightly higher than those of OL and EL. In vitro, DOL showed higher antitumor activity than OL, DL or EL in cervical carcinoma HeLa cells. In vivo, unlike other liposomes, DOL reduced the tumor growths by 98.6% and 97.3% relative to the untreated control on day 15 and 25 after the cessation of treatment, respectively.Conclusions
These results suggest that liposomal co-delivery of DOX and OMT could synergistically potentiate antitumor effects. 相似文献12.
Tim Serno Elisabeth H?rtl Ahmed Besheer Reinhard Miller Gerhard Winter 《Pharmaceutical research》2013,30(1):117-130
Purpose
To test the hypothesis of surface displacement as the underlying mechanism for IgG stabilization by polysorbates and HP??CD against surface-induced aggregation.Methods
Adsorption/desorption-kinetics of IgG-polysorbate 80/-HP??CD were monitored. Maximum bubble pressure method was used for processes within seconds from surface formation. Profile analysis tensiometry was applied over long periods and to assess surface rheologic properties. Additionally, the kinetics of adsorption, desorption and surface displacement was followed by a double-capillary setup of the profile analysis tensiometer, allowing drop bulk exchange.Results
Weak surface activity for HP??CD vs. much higher surface activity for polysorbate 80 was shown. Protein-displacement when exceeding a polysorbate 80 concentration close to the CMC and a lack of protein displacement for HP??CD was observed. The drop bulk exchange experiments show IgG displacement by polysorbate 80 independent of the adsorption order. In contrast, HP??CD coexists with IgG at the air-water interface when the surface layer is built from a mixed IgG-HP??CD-solution. Incorporation of HP??CD in a preformed IgG-surface-layer does not occur.Conclusions
The results confirm surface displacement as the stabilization mechanism of polysorbate 80, but refute the frequently held opinion, that HP??CD stabilizes proteins against aggregation at the air-water interface in a manner comparable to non-ionic surfactants. 相似文献13.
Structure and Function of Purified Monoclonal Antibody Dimers Induced by Different Stress Conditions
Paul R Graff-Meyer A Stahlberg H Lauer ME Rufer AC Beck H Briguet A Schnaible V Buckel T Boeckle S 《Pharmaceutical research》2012,29(8):2047-2059
Purpose
To investigate structure and function of different monoclonal antibody (MAb) dimers.Methods
MAb dimers were induced by process-related, low pH and UV light stress. Dimers were isolated and purified by chromatography and extensively characterized by biochemical, structural and functional methods.Results
Highly purified dimer forms were obtained which enabled detailed characterization. Dimers induced by process stress were associated by a single non-covalent interaction site between two Fab domains in a characteristic ??bone-like?? structure observed in Transmission Electron Microscopy (TEM). These dimers showed reduced potency and antigen binding affinity. Low pH stress generated more stable but also non-covalently associated dimers without chemical alterations in a typical ??closed?? conformation according to TEM. These dimer species were more compact and more hydrophobic as dimers induced by process stress. They showed bioactivity and antigen binding affinity similar to the native monomer. Light-induced dimers, exhibiting various different conformations, were the most stable dimers with various chemical modifications leading to a broad range in size, charge and hydrophobicity. These dimers fully lost bioactivity and antigen binding affinity.Conclusion
The use of highly purified MAb dimers and a panel of characterizations methods enabled to obtain a clear picture about molecular architecture and function of dimers. 相似文献14.
M. F. Ebbesen B. Whitehead B. Ballarin-Gonzalez P. Kingshott K. A. Howard 《Pharmaceutical research》2013,30(7):1758-1767
Purpose
This work describes a method for functionalisation of nanoparticle surfaces with hydrophilic “nano-shields” and the application of advanced surface characterisation to determine PEG amount and accumulation at the outmost 10 nm surface that is the predominant factor in determining protein and cellular interactions.Methods
Poly(lactic-co-glycolic acid) (PLGA) nanoparticles were prepared with a hydrophilic PEGylated “nano-shield” inserted at different levels by hydrophobic anchoring using either a phospholipid-PEG conjugate or the copolymer PLGA-block-PEG by an emulsification/diffusion method. Surface and bulk analysis was performed including X-ray photoelectron spectroscopy (XPS), nuclear magnetic resonance spectroscopy (NMR) and zeta potential. Cellular uptake was investigated in RAW 264.7 macrophages by flow cytometry.Results
Sub-micron nanoparticles were formed and the combination of (NMR) and XPS revealed increasing PEG levels at the particle surface at higher PLGA-b-PEG copolymer levels. Reduced cellular interaction with RAW 264.7 cells was demonstrated that correlated with greater surface presentation of PEG.Conclusion
This work demonstrates a versatile procedure for decorating nanoparticle surfaces with hydrophilic “nano-shields”. XPS in combination with NMR enabled precise determination of PEG at the outmost surface to predict and optimize the biological performance of nanoparticle-based drug delivery. 相似文献15.
David Cipolla Huiying Wu Simon Eastman Tom Redelmeier Igor Gonda Hak-Kim Chan 《Pharmaceutical research》2016,33(11):2748-2762
Purpose
In order to attenuate the drug release rate, a single freeze-thaw step was previously shown to convert encapsulated drug into a single nanocrystal within each liposome vesicle. The goal of this study was to alter the nanocrystalline character, and thus the drug encapsulation state and release profile, by addition of surfactant prior to freeze-thaw.Methods
A liposomal ciprofloxacin (CFI) formulation was modified by the addition of surfactant and frozen. After thawing, these formulations were characterized in terms of drug encapsulation by centrifugation-filtration, liposome structure by cryo-TEM imaging, vesicle size by dynamic light scattering, and in vitro release (IVR) performance.Results
The addition of increasing levels of polysorbate 20 (0.05 to 0.4%) or Brij 30 (0.05 to 0.3%) to the CFI preparations followed by subsequent freeze-thaw, resulted in a greater proportion of vesicles without drug nanocrystals and reduced the extent of growth of the nanocrystals thus leading to modified release rates including an increase in the ratio of non-encapsulated to sustained release of drug.Conclusions
This study provides another lever to achieve the desired release rate profile from a liposomal formulation by addition of surfactant and subsequent freeze-thaw, and thus may provide a personalized approach to treating patients.16.
Rationale
Amygdala-related circuitry helps translate learned Pavlovian associations into appetitive and aversive motivation, especially upon subsequent encounters with cues.Objectives
We asked whether ??-opioid stimulation via microinjections of the specific agonist d-Ala2, N-MePhe4, Gly-ol)-enkephalin (DAMGO) in central nucleus of amygdala (CeA), or the adjacent basolateral amygdala (BLA) would magnify sucrose or sex ??wanting??, guided by available cues.Materials and methods
CeA or BLA DAMGO enhancement of cue-triggered ??wanting?? was assessed using Pavlovian to instrumental transfer (PIT). Unconditioned food ??wanting?? was measured via intake, and male sexual ??wanting?? for an estrous female was measured in a sexual approach test. Sucrose hedonic taste ??liking?? was measured in a taste reactivity test.Results
CeA (but not BLA) DAMGO increased the intensity of phasic peaks in instrumental sucrose seeking stimulated by Pavlovian cues over precue levels in PIT, while suppressing seeking at other moments. CeA DAMGO also enhanced food intake, as well as sexual approach and investigation of an estrous female by males. DAMGO ??wanting?? enhancements were localized to CeA, as indicated by ??Fos plume??-based anatomical maps for DAMGO causation of behavioral effects. Despite increasing ??wanting??, CeA DAMGO decreased the hedonic impact or ??liking?? for sucrose in a taste reactivity paradigm.Conclusions
CeA ??-opioid stimulation specifically enhances incentive salience, which is dynamically guided to food or sex by available cues. 相似文献17.
Rezvan Zabihollahi Elahe Motevaseli Seyed Mehdi Sadat Ali Reza Azizi-Saraji Sogol Asaadi-Dalaie Mohammad Hossein Modarressi 《Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences》2012,20(1):1-7
Background
The vaccine industry is one of the most important health-related industries. It can be affected by accession to the World Trade Organization (WTO) because of probable dramatic changes in the business environment. Iran has already initiated accession negotiations.Purpose of the study
In this paper, we investigate the position of, challenges to, and opportunities for vaccine manufacturing in Iran with regard to accession to the WTO.Methods
This is a qualitative and cross sectional study. To collect information, we designed a questionnaire and interviewed some of the vaccine industry??s key opinion leaders in Iran. Before the interviews were conducted, the questionnaires were sent to these individuals by email.Results
According to the interviewees, the country??s main challenges with regard to accession to the WTO are the lack of firm internal intellectual property (IP) rules, not being recognized as pre-qualified by the World Health Organization (WHO), the use of old equipment, and a lack of cooperation with global vaccine companies.Major conclusions
Iran??s local vaccine industry, with a long history and international reputation that could be used as an advantage, is faced with several challenges, such as problems with keeping up with Current Good Manufacturing Practice (cGMP), a lack of adequate and meaningful investment in research and development (R&D), and limitations on private sector participation in the production of vaccines. Gradual privatization of the industry, improved international relations, utilization of the R&D power of small hi-tech companies, consistent education of human resources, and modernization of infrastructures and equipment are among the suggested solutions. 相似文献18.
Robert Carlisle Leonard W. Seymour Constantin C. Coussios 《Pharmaceutical research》2013,30(2):352-361
Purpose
To improve the delivery of liposomes to tumors using P-selectin glycoprotein ligand 1 (PSGL1) mediated binding to selectin molecules, which are upregulated on tumorassociated endothelium.Methods
PSGL1 was orientated and presented on the surface of liposomes to achieve optimal selectin binding using a novel streptavidin-protein G linker molecule. Loading of PSGL1 liposomes with luciferin allowed their binding to e-selectin and activated HUVEC to be quantified in vitro and their stability, pharmacokinetics and tumor accumulation to be tested in vivo using murine models.Results
PSGL1 liposomes showed 5-fold (p?<?0.05) greater selectin binding than identically formulated control liposomes modified with ligand that did not contain the selectin binding domain. When added to HUVEC, PSGL1 liposomes showed >7-fold (p?<?0.001) greater attachment than control liposomes. In in vivo studies PSGL1 liposomes showed similar stability and circulation to control liposomes but demonstrated a >3-fold enhancement in the level of delivery to tumors (p?<?0.05).Conclusions
The technologies and strategies described here may contribute to clinical improvements in the selectivity and efficacy of liposomal drug delivery agents. 相似文献19.
The carrier ability of liposomes for a model hydrophilic compound vas investigated in the rabbit eye. Dihydrostreptomycin sulfate was encapsulated in various types of liposomes, i.e. large and small uni- and multilamellar vesicles having either positive or neutral surface charge. An aqueous solution served as control preparation. Results indicated that liposomal encapsulation reduced the ocular drug con- centration. Addition of empty liposomes to the control solution did not alter drug levels in most of the ocular tissues. Among the liposomal preparations the large multi- and unilamellar vesicles provided higher drug concentration in all ocular tissue than the small unilamellar ones. Introduction of a positive charge on liposome surface enhanced liposome-conjunctiva interactions. The results suggest that liposomal encapsulation alters drug disposition in the eye lepending on the type of liposomes and the physicochemical properties of the encapsulated drug. In the case of the dihydrostreptomycin sulfate and possibly other hydrophilic drugs the liposomal encapsulation provides no advantages as far as drug delivery is concerned. 相似文献
20.
Yi Wang Wei Kang Liang-jian Hong Wen-li Hai Xiao-yang Wang Hai-feng Tang Xiang-rong Tian 《Journal of natural medicines》2013,67(1):70-77
Three new triterpenoid saponins, tomentoside A (1), B (2) and C (3), along with four known saponins (4?C7) were isolated from the root of Anemone tomentosa. The structures of the new compounds were elucidated as 3-O-??-d-ribopyranosyl-(1??3)-??-l-rhamnopyranosyl-(1??2)-[??-d-glucopyranosyl-(1??4)]-??-l-arabinopyranosyl hederagenin 28-O-??-l-rhamnopyranosyl-(1??4)-??-d-glucopyranosyl-(1??6)-??-d-glucopyranoside (1), 3-O-??-d-ribopyranosyl-(1??3)-??-l-rhamnopyranosyl-(1??2)-[??-d-glucopyranosyl-(1??4)]-??-d-xylopyranosyl hederagenin 28-O-??-l-rhamnopyranosyl-(1??4)-??-d-glucopyranosyl-(1??6)-??-d-glucopyranoside (2) and 3-O-??-d-galactopyranosyl-(1??3)-??-l-rhamnopyranosyl-(1??2)-??-d-xylopyranosyl oleanolic acid 28-O-??-l-rhamnopyranosyl-(1??4)-??-d-glucopyranosyl-(1??6)-??-d-glucopyranoside (3) on the basis of chemical and spectral evidence. In the oligosaccharide chains of compound 3, the characteristic d-galactose residue is a rare structural feature and secondly encountered among triterpenoid saponins from Anemone. 相似文献