共查询到20条相似文献,搜索用时 31 毫秒
1.
Monika Mueller Maybelle Q. T. Loh Rupert Tscheliessnig Doris H. Y. Tee Eddy Tan Muriel Bardor Alois Jungbauer 《Pharmaceutical research》2013,30(3):735-750
Purpose
To develop a liquid formulation for IgMs to survive physical stress and storage.Methods
Stabilizing formulations for 8 monoclonal immunoglobulin (IgMs) were found using differential scanning calorimetry (DSC). In these formulations, the IgMs were subjected to stress and storage and analyzed by size exclusion chromatography and fluorescence activated cell sorting. Structure was analyzed using small-angle X-ray scattering (SAXS).Results
The highest conformational stability was found near the isoelectric point and further enhanced by addition of sorbitol, sucrose and glycine. For 2 IgMs, the pH optimum for conformational and storage stability did not correspond. Lowering the pH led to the desired storage stability. Optimized formulations prevented aggregation and fragmentation from shear stress, freeze-thaw cycles, accelerated storage and real time storage at 4°C and ?20°C for 12 months. Optimized formulations also preserved immunoreactivity for 12 months. SAXS indicated that IgM in stabilizing conditions was closer to the structural IgM model (2RCJ) and less susceptible for aggregation.Conclusions
A long-term stabilizing formulation for 8 IgMs was found comprising 20% sorbitol and 1 M glycine at pH 5.0–5.5 which may have broad utility for other IgMs. Formulation development using DSC and accelerated storage was evaluated in this study and may be used for other proteins. 相似文献2.
Purpose
Characterization of the monoclonal antibody aggregation process and identification of stability factors that could be used as indicators of aggregation propensity with an emphasis on a large number of samples and low protein material consumption.Methods
Differential scanning calorimetry, dynamic light scattering and size exclusion chromatography were used as the main methodological approaches. Conformational stability, colloidal stability and aggregation kinetics were assessed for two different IgG monoclonal antibody (mAbs) subclasses. Aggregation was induced by exposing the mAbs to 55°C for 3 weeks. mAb samples were prepared in different formulations and concentrations from 1 mg/mL to 50 mg/mL.Results
High temperature stress of mAb samples revealed that monoclonal antibodies followed first order aggregation kinetics, which suggests that the rate-limiting step of monomer loss was unimolecular. Conformational stability of mAbs was estimated with denaturation temperature measurements. Colloidal stability was assessed with dynamic interaction parameter k D . The correlation between aggregation kinetics and colloidal and conformational stability factors was evaluated and the dynamic interaction parameter was found to be a promising predictor of aggregation propensity of monoclonal antibodies. The meaning of using an intermolecular interaction parameter for prediction of what is essentially a unimolecular process is also discussed.Conclusions
This work estimates the significance of different predictors of aggregation propensity at high concentrations as a part of a high throughput, low resource screening method and is a contribution towards determining protein aggregation phenomena in actual systems used for the development and production of biopharmaceuticals.3.
Christopher T. John Wei Xu Lisa K. Lupton Paul A. Harmon 《Pharmaceutical research》2013,30(6):1628-1641
Purpose
Nine common excipients were examined to determine their ability to cause disproportionation of the HCl salt of a a weakly basic compound. The goal was to determine which excipients were problematic and correlate the results to known properties such as surface pH, slurry pH, or molecular structure. Such a correlation enables a general, simple excipient selection process.Methods
Binary compacts and “pseudo formulations” are studied after stressing at 40°C/75%RH and 40°C/35% RH for up to 28 days. Near-Infrared (NIR) and X-Ray powder diffraction (XRPD) measurements monitored the conversion of the HCl salt to the free base.Results
The excipients which induced measureable disproportionation were magnesium stearate, sodium croscarmellose, and sodium stearyl fumarate. Magnesium stearate induced the most extensive and rapid disproportionation at 40°C/75%RH and 40°C/35%RH. Samples containing magnesium stearate showed a unique and significant water uptake above 31%RH.Conclusions
The problematic excipients are best explained by the proton accepting capacity of excipient carboxylate groups which have pKa’s higher than the pHmax of the drug salt. Alternative lubricants and disintegrants are suggested and a simple excipient screening process is proposed. Magnesium stearate was the most deleterious excipient for HCl salts due to the formation of the deliquescent salt magnesium chloride. 相似文献4.
Atul Saluja Vikram Sadineni Amol Mungikar Vishal Nashine Andrew Kroetsch Charles Dahlheim Venkatramana M. Rao 《Pharmaceutical research》2014,31(6):1575-1587
Purpose
To enable aggregation rate prediction over a broad temperature range for complex multi-domain proteins at high concentrations.Methods
Thermal unfolding, non-isothermal kinetics and storage stability studies were conducted on a model multi-domain protein (MDP) at moderate to high concentrations (25–125 mg/mL) over a broad temperature range (4–40°C).Results
Storage stability studies indicated the aggregation of MDP in solution to be a second order process. Application of Arrhenius kinetics to accelerated stability data resulted in underestimation of the aggregation rate under refrigerated conditions. Additional studies undertaken to understand the mechanism of the aggregation process highlighted the association of the monomer (or the aggregation competent species) to be the rate-limiting step for aggregation over the temperature range studied. Thermal unfolding studies in the presence of urea were used to calculate the heat capacity change upon unfolding (Δcp,un). The resulting value of Δcp,un when used in the extended Lumry-Eyring model resulted in a more accurate and a conservative estimate of the aggregation rate under refrigerated condition. Some complicating factors for the aggregation rate prediction for multi-domain proteins at high concentration are discussed.Conclusions
The work highlights (i) the significance of incorporating unfolding thermodynamics in protein aggregation rate prediction, (ii) the advantages and challenges associated with the use of the extended Lumry-Eyring (ELE) model for rate prediction and (iii) the utility of using the Arrhenius and the ELE models in tandem during product development. 相似文献5.
Jian Hua Gu Alice Beekman Tian Wu Deirdre Murphy Piedmonte Priti Baker Michael Eschenberg Michael Hale Merrill Goldenberg 《Pharmaceutical research》2013,30(2):387-401
Purpose
A novel application of oscillatory shear rheology was used to directly monitor global phase behavior of protein formulations in the frozen state and study its correlation with physical instability of frozen protein formulations.Methods
Oscillatory rheology was used to measure changes in rheological parameters and to identify mechanical softening temperature (Ts*) and related properties of an IgG2 mAb formulation. Rheological measurements were compared to DSC/MDSC. Physical stability of IgG2 formulations was monitored by SE-HPLC.Results
Rheological parameters and Ts* of an IgG2 formulation were sensitive to physical/morphological phase changes during freezing and thawing. Ts* of the frozen formulation was a function of concentration of protein and excipient. Complex modulus, G*, and phase angle, δ, for IgG2 at 70 mg/mL in a sucrose-containing formulation showed the system was not completely frozen at ?10°C, which correlated to stability data consistent with ice-induced protein aggregation.Conclusions
We report the first application of oscillatory shear rheology to study phase behavior of IgG2 in a sucrose-containing formulation and its correspondence with physical stability not explained by glass transition (Tg’). We provide a mechanism and data suggesting that protein instability occurs at the ice/water interface. 相似文献6.
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7.
Purpose
To evaluate the effect of tablet compression on the physical stability of amorphous indomethacin.Methods
The amorphous indomethacin generated by melt cooling, rapid (5°C/min) or slow (0.2°C/min) cooling, was evaluated by PXRD, mDSC and FTIR analysis. Non-isothermal crystallisation behaviour was assessed using mDSC and any structural changes with compression were monitored by FTIR. Amorphous indomethacin was compressed in a DSC pan using a custom made die cavity-punch setup and further analysed in the primary container to minimize stress due to sample transfer and preparation.Results
Compression of amorphous indomethacin induced and increased the extent of crystallisation upon heating. DSC results revealed that amorphous indomethacin generated by rapid cooling is more prone to compression induced crystallisation than the slowly cooled one. Onset temperature for crystallisation (T c ) of uncompressed slowly and rapidly cooled samples are 121.4 and 124°C and after compression T c decreased to ca 109 and ca 113°C, respectively. Compression of non-aged samples led to higher extent of crystallisation predominantly into ??-form. Aging followed by compression led to crystallisation of mainly the ??-form.Conclusions
Compression affects the physical stability of amorphous indomethacin. Structural changes originated from tablet compression should be duly investigated for the stable amorphous formulation development. 相似文献8.
Hideo Miyanishi Takayuki Nemoto Masayasu Mizuno Hisashi Mimura Satoshi Kitamura Yasunori Iwao Shuji Noguchi Shigeru Itai 《Pharmaceutical research》2013,30(2):502-511
Purpose
To investigate crystallization behavior on the surface of amorphous solid dispersion powder using inverse gas chromatography (IGC) and to predict the physical stability at temperatures below the glass transition temperature (T g).Methods
Amorphous solid dispersion powder was prepared by melt-quenching of a mixture of crystalline nifedipine and polyvinylpyrrolidon (PVP) K-30. IGC was conducted by injecting undecane (probe gas) and methane (reference gas) repeatedly to the solid dispersion at temperatures below T g. Surface crystallization was evaluated by the retention volume change of undecane based on the observation that the surface of the solid dispersion with crystallized nifedipine gives an increased retention volume.Results
On applying the retention volume change to the Hancock-Sharp equation, surface crystallization was found to follow a two-dimensional growth of nuclei mechanism. Estimation of the crystallization rates at temperatures far below T g using the Avrami-Erofeev equation and Arrhenius equation showed that, to maintain its quality for at least three years, the solid dispersion should be stored at ?20°C (T g???65°C).Conclusions
IGC can be used to evaluate crystallization behavior on the surface of a solid dispersion powder, and, unlike traditional techniques, can also predict the stability of the solid dispersion based on the surface crystallization behavior. 相似文献9.
10.
Mo Dan Daniel F. Scott Peter A. Hardy Robert J. Wydra J. Zach Hilt Robert A. Yokel Younsoo Bae 《Pharmaceutical research》2013,30(2):552-561
Purpose
To develop cross-linked nanoassemblies (CNAs) as carriers for superparamagnetic iron oxide nanoparticles (IONPs).Methods
Ferric and ferrous ions were co-precipitated inside core-shell type nanoparticles prepared by cross-linking poly(ethylene glycol)-poly(aspartate) block copolymers to prepare CNAs entrapping Fe3O4 IONPs (CNA-IONPs). Particle stability and biocompatibility of CNA-IONPs were characterized in comparison to citrate-coated Fe3O4 IONPs (Citrate-IONPs).Results
CNA-IONPs, approximately 30 nm in diameter, showed no precipitation in water, PBS, or a cell culture medium after 3 or 30 h, at 22, 37, and 43°C, and 1, 2.5, and 5 mg/mL, whereas Citrate-IONPs agglomerated rapidly (> 400 nm) in all aqueous media tested. No cytotoxicity was observed in a mouse brain endothelial-derived cell line (bEnd.3) exposed to CNA-IONPs up to 10 mg/mL for 30 h. Citrate-IONPs (> 0.05 mg/mL) reduced cell viability after 3 h. CNA-IONPs retained the superparamagnetic properties of entrapped IONPs, enhancing T2-weighted magnetic resonance images (MRI) at 0.02 mg/mL, and generating heat at a mild hyperthermic level (40?~?42°C) with an alternating magnetic field (AMF).Conclusion
Compared to citric acid coating, CNAs with a cross-linked anionic core improved particle stability and biocompatibility of IONPs, which would be beneficial for future MRI and AMF-induced remote hyperthermia applications. 相似文献11.
Phillip M. Lovalenti Jeff Anderl Luisa Yee Van Nguyen Behnaz Ghavami Satoshi Ohtake Atul Saxena Thomas Voss Vu Truong-Le 《Pharmaceutical research》2016,33(5):1144-1160
Purpose
The goal of this research is to develop stable formulations for live attenuated influenza vaccines (LAIV) by employing the drying methods freeze drying, spray drying, and foam drying.Methods
Formulated live attenuated Type-A H1N1 and B-strain influenza vaccines with a variety of excipient combinations were dried using one of the three drying methods. Process and storage stability at 4, 25 and 37°C of the LAIV in these formulations was monitored using a TCID50 potency assay. Their immunogenicity was also evaluated in a ferret model.Results
The thermal stability of H1N1 vaccine was significantly enhanced through application of unique formulation combinations and drying processes. Foam dried formulations were as much as an order of magnitude more stable than either spray dried or freeze dried formulations, while exhibiting low process loss and full retention of immunogenicity. Based on long-term stability data, foam dried formulations exhibited a shelf life at 4, 25 and 37°C of >2, 1.5 years and 4.5 months, respectively. Foam dried LAIV Type-B manufactured using the same formulation and process parameters as H1N1 were imparted with a similar level of stability.Conclusion
Foam drying processing methods with appropriate selection of formulation components can produce an order of magnitude improvement in LAIV stability over other drying methods.12.
Wenjin Cao Yong Xie Sampathkumar Krishnan Hong Lin Margaret Ricci 《Pharmaceutical research》2013,30(1):131-139
Purpose
To study the impact of different process conditions and formulation compositions on metastable mannitol forms in protein formulations during lyophilization.Methods
Mannitol was studied with and without other formulation components. A cryostage was used to mimic the different processing steps during lyophilization. The different mannitol forms were monitored and quantified with an in situ Raman spectroscopic method. In addition, a Raman imaging method was developed to characterize the spatial distribution of mannitol forms in final lyophilization samples from the freeze-drying stage.Results
Amorphous mannitol was observed during fast cooling (10°C/min) and with the addition of other formulation component. Amorphous mannitol crystallized into mainly ?? and hemihydrate forms during annealing at ?20°C. Under vacuum without moisture, dried amorphous mannitol could transform to mainly ?? form at 45°C and greater. The transformation mechanism of the hemihydrate mannitol was similar to that of amorphous form.Conclusion
Mannitol tends to crystallize into stable crystalline forms by itself, but the addition of lyoprotectant (e.g. sucrose) and protein helps stabilize the metastable forms (hemihydrate and amorphous). The metastable forms are capable of transforming into mixtures of different forms, with heat and moisture being the critical processing factors. 相似文献13.
Varnäs K Nyberg S Karlsson P Pierson ME Kågedal M Cselényi Z McCarthy D Xiao A Zhang M Halldin C Farde L 《Psychopharmacology》2011,213(2-3):533-545
Rationale
The serotonin 5-HT1B receptor is a potential target for the pharmacologic treatment of depression. Positron emission tomography (PET) determination of 5-HT1B receptor occupancy with drug candidates targeting this receptor in non-human primate and human subjects may facilitate translation of research from animal models and guide dose selection for clinical studies. AZD3783 is a recently developed, orally bioavailable 5-HT1B receptor antagonist with potential antidepressant properties.Objectives
To determine the relationship between plasma concentration of AZD3783 and occupancy at primate brain 5-HT1B receptors using PET and the radioligand [11C]AZ10419369.Methods
PET studies with [11C]AZ10419369 were performed in three non-human primates at baseline and after intravenous injection of AZD3783. Subsequently, PET measurements were undertaken in six human subjects at baseline and after administration of different single oral doses of AZD3783 (1?C40?mg).Results
After administration in non-human primates and human subjects, AZD3783 reduced regional [11C]AZ10419369 binding in a dose-dependent and saturable manner. The AZD3783 plasma concentration required for 50% receptor occupancy (K i,plasma) for monkeys was 25 and 27?nmol/L in occipital cortex and striatum, respectively. Corresponding estimates for human occipital cortex and ventral striatum were 24 and 18?nmol/L, respectively.Conclusions
The potential antidepressant AZD3783 binds in a saturable manner to brain 5-HT1B receptors with a similar in vivo affinity for human and monkey receptors. [11C]AZ10419369 can be successfully used to determine occupancy at brain 5-HT1B receptors in vivo and constitutes a useful tool for dose selection in clinical studies with 5-HT1B receptor compounds. 相似文献14.
James W. Murrough Shannan Henry Jian Hu Jean-Dominique Gallezot Beata Planeta-Wilson John F. Neumaier Alexander Neumeister 《Psychopharmacology》2011,213(2-3):547-553
Rationale
Although serotonin (5-HT) dysregulation is implicated in the pathophysiology of major depressive disorder (MDD), the role of specific receptor subtypes remains to be elucidated. Emerging preclinical research suggests an important role for the 5-HT1B receptor in behavioral regulation and depressive phenotypes. In particular, 5-HT1B heteroreceptors located within the striatum have been shown to play an essential role in antidepressant action.Objectives
The objective of this study was to determine 5-HT1B receptor binding potential (BP ND) in the region of the ventral striatum/ventral pallidum (VS/VP) in individuals with MDD and healthy control participants.Methods
Ten participants with MDD (30.8?±?9.5?years, five men/five women) in a current major depressive episode (MDE) and ten healthy control participants (30.7?±?10.5?years, five men/five women) underwent positron emission tomography (PET) scanning with the selective 5-HT1B receptor radioligand [11C]P943.Results
Within the VS/VP region of interest, [11C]P943 BP ND was significantly reduced in the MDD group compared with the healthy control group (1.37?±?0.13 and 1.68?±?0.16, respectively; 18.7% between-group difference; p?<?0.001).Conclusions
Consistent with preclinical and postmortem data, our findings suggest abnormally reduced function of VS/VP 5-HT1B receptors in humans with MDD. Abnormal 5-HT1B heteroreceptor function may contribute to dysfunctional reward signaling within the striatum, including the nucleus accumbens, via interaction with dopamine, ??-amino-butyric acid, or glutamate systems. Our findings suggest reduced 5-HT1B receptor signaling in the VS/VP in MDD and contribute to the therapeutic rationale for testing 5-HT1B agonists as a novel class of antidepressants. 相似文献15.
Purpose
To provide the physicochemical properties of vitrified trehalose for predicting its recrystallization.Methods
Thin films of vitrified trehalose solutions were prepared at room temperature and exposed to various humid and temperature atmospheres. The in-situ amount of retained water in the vacuum-dried trehalose thin film during exposure was determined using its FTIR spectrum by quantifying the extremely infinitesimal amount of retained water in the trehalose solution. Recrystallization of the sample was also assessed by the FTIR spectrum of trehalose dihydrate.Results
The effective water absorption coefficient, h meff , exponentially increased to the water activity of the trehalose sample, A w , at 25°C and 40°C at which the increasing rates are comparable. The surface energy of trehalose dihydrate, γ, was found to be lower than the value calculated from the reported equation, neglecting the effects of the activity of the solute and solvent water.Conclusions
The retained water in trehalose considerably increases its affinity for water vapor, and the change in this affinity with regard to the water activity is nearly independent of temperature. The dihydrate nucleation rate of trehalose-water system is maximal when trehalose weight ratio is ~0.8 at 25°C and is slightly higher (~0.85) at 40°C.16.
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
17.
Rationale
Serotonergic (5-hydroxytryptamine, 5-HT) and opioidergic mechanisms are intimately involved in appetite regulation.Objectives
In view of recent evidence of positive anorectic interactions between opioid and various non-opioid substrates, our aim was to assess the behavioural specificity of anorectic responses to the opioid receptor antagonist naltrexone, the 5-HT2C/1B receptor agonist mCPP and their combination.Methods
Behavioural profiling techniques, including the behavioural satiety sequence (BSS), were used to examine acute drug effects in non-deprived male rats tested with palatable mash. Experiment 1 characterised the dose–response profile of mCPP (0.1–3.0 mg/kg), while experiment 2 assessed the effects of combined treatment with a sub-anorectic dose of mCPP (0.1 mg/kg) and one of two low doses of naltrexone (0.1 and 1.0 mg/kg).Results
Experiment 1 confirmed the dose-dependent anorectic efficacy of mCPP, with robust effects on intake and feeding-related measures observed at 3.0 mg/kg. However, that dose was also associated with other behavioural alterations including increased grooming, reductions in locomotion and sniffing, and disruption of the BSS. In experiment 2, naltrexone dose-dependently reduced food intake and time spent feeding, effects accompanied by a behaviourally selective acceleration in the BSS. However, the addition of 0.1 mg/kg mCPP did not significantly alter the behavioural changes observed in response to either dose of naltrexone given alone.Conclusions
In contrast to recently reported positive anorectic interactions involving low-dose combinations of opioid receptor antagonists or mCPP with cannabinoid CB1 receptor antagonists, present results would not appear to provide any support for potentially clinically relevant anorectic interactions between opioid and 5-HT2C/1B receptor mechanisms. 相似文献18.
Shahriar Absar Kamrun Nahar Young Min Kwon Fakhrul Ahsan 《Pharmaceutical research》2013,30(6):1663-1676
Purpose
To test the hypothesis that thrombus-specific tissue plasminogen activator (tPA)-loaded nanocarriers enhance thrombolytic efficacy and attenuate hemorrhagic complications.Methods
A series of pegylated and non-pegylated tPA-loaded liposomes were prepared and their surfaces were decorated with the peptide sequence (CQQHHLGGAKQAGDV) of fibrinogen gamma-chain that binds with GPIIb/IIIa expressed on activated platelets. All formulations were characterized for physical properties, stability and in vitro release profile. The thrombolytic activities of tPA-loaded liposomes were tested by visual end-point detection, fibrin agar-plate and human blood clot-lysis assays. The thrombus-specificity of the peptide-modified-liposomes was evaluated by studying the binding of fluorescent peptide-liposomes with activated platelets. The pharmacokinetic profile and thrombolytic efficacy were evaluated in healthy rats and an inferior vena-cava rat model of thrombosis, respectively.Results
Both pegylated and non-pegylated peptide-modified-liposomes showed favorable physical characteristics and colloidal stability. Formulations exhibited an initial burst release (40–50% in 30 min) followed by a continuous release of tPA (80–90% in 24 h) in vitro. Encapsulated tPA retained >90% fibrinolytic activity as compared to that of native tPA. Peptide-grafted-liposomes containing tPA demonstrated an affinity to bind with activated platelets. The half-life of tPA was extended from 7 to 103 and 141 min for non-pegylated and pegylated liposomes, respectively. Compared to native tPA, liposomal-tPA caused a 35% increase in clot-lysis, but produced a 4.3-fold less depletion of circulating fibrinogen.Conclusions
tPA-loaded homing-peptide-grafted-liposomes demonstrate enhanced thrombolytic activity with reduced hemorrhagic risk. 相似文献19.
Simone Limmer Jasmin Hahn Rebecca Schmidt Kirsten Wachholz Anja Zengerle Katharina Lechner Hansjörg Eibl Rolf D. Issels Martin Hossann Lars H. Lindner 《Pharmaceutical research》2014,31(9):2276-2286
Purpose
The pyrimidine analogue gemcitabine (dFdC) is frequently used in the treatment of patients with solid tumors. However, after i.v. application dFdC is rapidly inactivated by metabolization. Here, the potential of thermosensitive liposomes based on 1,2-dipalmitoyl-sn-glycero-3-phosphodiglycerol (DPPG2-TSL) were investigated as carrier and targeting system for delivery of dFdC in combination with local hyperthermia (HT).Methods
DPPG2-TSL were prepared by the lipid film hydration and extrusion method and characterized by dynamic light scattering, thin layer chromatography, phosphate assay and HPLC. In vivo experiments were performed in Brown Norway rats with a syngeneic soft tissue sarcoma. Local HT treatment was performed by light exposure.Results
DPPG2-TSL were stable at 37°C in serum and showed a temperature dependent dFdC release >40°C. Plasma half-life of dFdC was strongly increased from 0.07 h (non-liposomal) to 0.53 h (liposomal, vesicle size 105 nm) or 2.59 h (liposomal, 129 nm). Therapy of BN175 tumors with dFdC encapsulated in DPPG2-TSL + HT showed significant improvement in tumor growth delay compared to non-liposomal dFdC without HT (p?0.05), non-liposomal dFdC with HT (p?0.01), and liposomal dFdC without HT (p?0.05), respectively.Conclusions
Gemcitabine encapsulated in DPPG2-TSL in combination with local HT is a promising tool for the treatment of solid tumors. Therefore, these encouraging results ask for further investigation and evaluation. 相似文献20.
Jessica J. Hung Barton J. Dear Aileen K. Dinin Ameya U. Borwankar Sumarth K. Mehta Thomas T. Truskett Keith P. Johnston 《Pharmaceutical research》2018,35(7):133