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ABSTRACT: Intra-articular injection of oil solutions of lipophilic prodrugs that rapidly degrade to their parent compound in synovial fluid may constitute a feasible approach to increase the joint residence time of non-steroidal anti-inflammatory drugs. In this in vivo study, oil solutions of the N,N-diethyl glycolamide ester prodrug of naproxen (16mg/ml) were injected into the rat knee joint by dosing 6μL formulation per 100g body weight. The sustained release properties were compared to those of intra-articularly injected aqueous and oil solutions of naproxen by monitoring the naproxen serum concentrations over time. Two oils, medium-chain triglycerides and castor oil, differing with respect to viscosity were tested. After intra-articular administration of oil prodrug solutions, a significant increase in the time to maximum naproxen serum concentration from around 40 to 245min, an increase in the MRTj from around 0.11 to 3.3h and a 30% reduction in the maximum serum concentration were observed compared to that of the parent naproxen. The similar serum profiles obtained using the two oils indicate that the release was not affected by the oil viscosity. A prolonged naproxen joint residence time in rats was shown by intra-articular injection of an oil prodrug solution.
International journal of pharmaceutics 04/2013; · 2.96 Impact Factor
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ABSTRACT: An in vitro method for simultaneous assessment of platinum release and liposome stability of liposomal formulations in human plasma is demonstrated. The development and assessment of the method was performed on a PEGylated liposomal formulation containing cisplatin. Complete separation of free cisplatin, encapsulated cisplatin and cisplatin bound to plasma components was achieved by capillary electrophoresis (CE) separation and simultaneous monitoring of phosphorous (phospholipid) and platinum (cisplatin) by inductively coupled plasma mass spectrometry (ICP-MS). The method allows assessment of the encapsulation efficiency of the formulation, the physical stability of liposomes as well as cisplatin leakage in human plasma. The method was applied for studying the disintegration of liposomes and the interactions of leaked cisplatin with plasma components. Triggered release of the drug into plasma by sonication was also demonstrated. Analysis of liposomal formulations with alternative phospholipid compositions containing oxaliplatin showed similar results. Thus, the present in vitro method is suitable for mimicking the in vivo drug release profile in human plasma after administration of liposomal platinum formulations to patients. This approach may be of use in early drug development as well as in quality control.
International journal of pharmaceutics 04/2013; · 2.96 Impact Factor
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ABSTRACT: PURPOSE: Most dissolution testing systems rely on analyzing samples taken remotely from the dissolving sample surface at different time points with poor time resolution and therefore provide relatively unresolved temporally and spatially information on the dissolution process. In this study, a flexible numerical model was combined with a novel UV imaging system, allowing monitoring of the dissolution process with sub second time resolution. METHODS: The dissolution process was monitored by both effluent collection and UV imaging of compacts of paracetamol. A finite element model (FEM) was used to characterize the UV imaging system. RESULTS: A finite element model of the UV imaging system was successfully built. The dissolution of paracetamol was studied by UV imaging and by analysis of the effluent. The dissolution rates obtained from the collected effluent were in good agreement with the numerical model. The numerical model allowed an assessment of the ability of the UV imager to measure dissolution-time profiles. The simulation was able to extend the experimental results to conditions not easily obtained experimentally. CONCLUSIONS: Combining FEM,experimental dissolution data and UV imaging provided experimental validation of the FEM model as well as a detailed description of the dissolution process.
Pharmaceutical Research 01/2013; · 4.09 Impact Factor
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ABSTRACT: A capillary electrophoresis inductively coupled plasma mass spectrometry method for separation of free cisplatin from liposome-encapsulated cisplatin and protein-bound cisplatin was developed. A liposomal formulation of cisplatin based on PEGylated liposomes was used as model drug formulation. The effect of human plasma matrix on the analysis of liposome-encapsulated cisplatin and intact cisplatin was studied. The presence of 1 % of dextran and 4 mM of sodium dodecyl sulfate in HEPES buffer was demonstrated to be effective in improving the separation of liposomes and cisplatin bound to proteins in plasma. A detection limit of 41 ng/mL of platinum and a precision of 2.1 % (for 10 μg/mL of cisplatin standard) were obtained. Simultaneous measurements of phosphorous and platinum allows the simultaneous monitoring of the liposomes, liposome-encapsulated cisplatin, free cisplatin and cisplatin bound to plasma constituents in plasma samples. It was demonstrated that this approach is suitable for studies of the stability of liposome formulations as leakage of active drug from the liposomes and subsequent binding to biomolecules in plasma can be monitored. This methodology has not been reported before and will improve characterization of liposomal drugs during drug development and in studies on kinetics.
Analytical and Bioanalytical Chemistry 09/2012; · 3.78 Impact Factor
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ABSTRACT: Intra-articular injection of two drugs in a sustained drug delivery system combining the use of lipophilic solution with the prodrug approach may provide efficient and prolonged postoperative pain treatment after arthroscopic procedures. In the present study, the concomitant release of N,N-diethyl glycolamide ester of naproxen and ropivacaine from an oil vehicle consisting of medium-chain triglycerides were investigated in vitro. The release into both phosphate buffer and 80% (v/v) synovial fluid at pH 7.4 was examined in two dialysis membrane-based release models. The ester prodrug exhibited high solubility in medium-chain triglyceride, a high partition coefficient and was rapidly converted to naproxen in synovial fluid. Compared to naproxen, the release of the prodrug from the oil was sustained. In synovial fluid, the reconversion to naproxen resulted in faster release compared to that observed using buffer. In both release models, the use of ropivacaine-prodrug combination provided concomitant release from the oil into synovial fluid with ropivacaine being released faster than naproxen. The use of lipophilic prodrugs that are converted fast to the parent drug in synovial fluid seems to be a feasible approach to obtain prolonged joint residence time.
International journal of pharmaceutics 09/2012; · 2.96 Impact Factor
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ABSTRACT: Sulfobutyl ether-β-cyclodextrin (SBEβCD) is utilized in preformulation and drug formulation as an excipient for solubilization of drugs with poor aqueous solubility. Approximately seven negative charges of SBEβCD play a role with respect to solubilization and complexation, but also have an influence on the ionic strength of the background electrolyte when the cyclodextrin is used in capillary electrophoresis. Mobility-shift affinity capillary methods for investigation of the complexation of taurocholate and taurochenodeoxycholate with the negatively charged cyclodextrin derivative applying constant power and ionic strength conditions as well as constant voltage and varying ionic strength were investigated. A new approach for the correction of background electrolyte ionic strength was developed. Mobility-shift affinity capillary electrophoresis experiments obtained at constant voltage and constant power settings were compared and found to provide binding parameters that were in good agreement upon correction. The complexation of taurochenodeoxycholate with SBEβCD was significantly stronger than the corresponding interaction involving taurocholate. The obtained stability constants for the bile salts were in the same range as those previously reported for the interaction with neutral β-cyclodextrins derivatives, i.e. the positions of the negative charges on SBEβCD and the bile salts within the complex did not lead to significant electrostatic repulsion.
Journal of Separation Science 09/2012; 35(20):2764-72. · 2.73 Impact Factor
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ABSTRACT: Upon subcutaneous administration, the distribution of drug between the delivery vehicle and the biological tissue critically affects the absorption of drug substances. Utilization of physical models resembling the native tissues appears promising for obtaining a detailed understanding of the performance of drug delivery systems based on in vitro experiments. The objective of this study was to evaluate a UV imaging-based method for real-time characterization of the release and transport of piroxicam in hydrogel-based subcutaneous tissue mimics/surrogates. Piroxicam partitioning from medium chain triglyceride (MCT) into 0.5% (w/v) agarose or 25% (w/v) F127-based hydrogels was investigated by monitoring the concentration profiles of the drug in the gels. The effect of pH on piroxicam distribution and diffusion coefficients was studied. For both hydrogel systems, the diffusion of piroxicam in the gels was not affected significantly by the pH change from 4.0 to 7.4 but a considerable change in the oil-gel distribution coefficients was found (24 and 34 times less at pH 7.4 as compared those observed at pH 4.0 for F127 and agarose gels, respectively). In addition, the release and transport processes of piroxicam upon the injection of aqueous or MCT solutions into an agarose-based hydrogel were investigated by UV imaging. The spatial distribution of piroxicam around the injection site in the gel matrix was monitored in real-time. The disappearance profiles of piroxicam from the injected aqueous solution were obtained. This study shows that the UV imaging methodology has considerable potential for characterizing transport properties in hydrogels, including monitoring the real-time spatial concentration distribution in vitro after administration by injection.
Journal of pharmaceutical and biomedical analysis 07/2012; 71:27-34. · 2.45 Impact Factor
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ABSTRACT: The present study was designed to evaluate the effect of the negatively charged food-grade emulsifier citrem on the internal nanostructures of oil-free and oil-loaded aqueous dispersions of phytantriol (PHYT) and glyceryl monooleate (GMO). To our knowledge, this is the first report in the literature on the utilization of this charged stabilizing agent in the formation of aqueous dispersions consisting of well-ordered interiors (either inverted-type hexagonal (H(2)) phases or inverted-type microemulsion systems). Synchrotron small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM) were used to characterize the dispersed and the corresponding nondispersed phases of inverted-type nonlamellar liquid-crystalline phases and microemulsions. The results suggest a transition between different internal nanostructures of the aqueous dispersions after the addition of the stabilizer. In addition to the main function of citrem as a stabilizer that adheres to the surface of the dispersed particles, it has a significant impact on the internal nanostructures, which is governed by the following factors: (1) its penetration between the hydrophobic tails of the lipid molecules and (2) its degree of incorporation into the lipid-water interfacial area. In the presence of citrem, the formation of aqueous dispersions with functionalized hydrophilic domains by the enlargement of the hydrophilic nanochannels of the internal H(2) phase in hexosomes and the hydrophilic core of the L(2) phase in emulsified microemulsions (EMEs) could be particularly attractive for solubilizing and controlling the release of positively charged drugs.
Langmuir 07/2012; 28(32):11755-66. · 4.19 Impact Factor
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ABSTRACT: Liposomes are self-assembled phospholipid vesicles and have numerous research and therapeutic applications. In the pharmaceutical and biomedical sciences liposomes find use as models of biological membranes, partitioning medium and as drug carriers. The present review addresses the use of capillary electrophoresis and liposome electrokinetic chromatography for the characterization of liposomes in a pharmaceutical context. Capillary electrophoretic techniques have been used for the measurement of electrophoretic mobility, which provides information on liposome surface charge, size and membrane permeability of liposomes. The use of liposome electrokinetic chromatography and capillary electrophoresis for determination of liposome/water partitioning and characterization of drug-liposome interactions is reviewed. A number of studies indicate that capillary electrophoresis may have a role in the characterization of liposome drug delivery systems, e.g., for the investigation of encapsulation efficiency and drug leakage. The well-known characteristics of capillary electrophoresis, i.e., low sample volume requirement, high separation efficiency in aqueous media without a stationary phase, minimal sample preparation, and a high degree of automation, makes it an attractive approach in liposome research.
Journal of chromatography. A 07/2012; · 4.19 Impact Factor
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ABSTRACT: The aim of the study was to visualize the behaviour of the hydroxypropyl methylcellulose (HPMC) in a buffer solution using UV imaging. The obtained results were related to rheological measurements in order to gain insight into critical polymer properties affecting drug release. Two viscosity grades of HPMC, 15cP and 50 cP, were used. The behaviour of the polymer at the surface of the compact was observed by UV-imaging at 214 nm for 90 min in a stagnant buffer solution and in presence of flow. Steady shear and oscillatory shear measurements were conducted to determine the rheological characteristics. Three distinctive phases could be detected by real-time UV-imaging of the HPMC; gel formation due to water penetration, further expansion of the gel into solution and finally steady conditions, where a critical polymer concentration that can withstand the shear forces without eroding was observed. The critical concentration corresponded to the rheologically determined gel point, which is the lowest concentration where a 3D-network is obtained. Higher viscosity grade HPMC swelled more rapidly and lead to a thicker gel layer, which was more resistant towards the shear forces due to the applied flow. The results showed that UV imaging is suitable for obtaining both qualitative and quantitative information on polymer behaviour.
International journal of pharmaceutics 03/2012; 427(2):345-53. · 2.96 Impact Factor
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ABSTRACT: Metal ions, especially Zn(2+) and Cu(2+), are implemented in the neuropathogenesis of Alzheimer's disease (AD) by modulating the aggregation of amyloid-β peptides (Aβ). Also, Cu(2+) may promote AD neurotoxicity through production of reactive oxygen species (ROS). Impaired metal ion homeostasis is most likely the underlying cause of aberrant metal-Aβ interaction. Thus, focusing on the body's natural protective mechanisms is an attractive therapeutic strategy for AD. The metalloprotein metallothionein-3 (MT-3) prevents Cu-Aβ-mediated cytotoxicity by a Zn-Cu exchange that terminates ROS production. Key questions about the metal exchange mechanisms remain unanswered, e.g., whether an Aβ-metal-MT-3 complex is formed. We studied the exchange of metal between Aβ and Zn(7)-MT-3 by a combination of spectroscopy (absorption, fluorescence, thioflavin T assay, and nuclear magnetic resonance) and transmission electron microscopy. We found that the metal exchange occurs via free Cu(2+) and that an Aβ-metal-MT-3 complex is not formed. This means that the metal exchange does not require specific recognition between Aβ and Zn(7)-MT-3. Also, we found that the metal exchange caused amyloid-related structural and morphological changes in the resulting Zn-Aβ aggregates. A detailed model of the metal exchange mechanism is presented. This model could potentially be important in developing therapeutics with metal-protein attenuating properties in AD.
Biochemistry 02/2012; 51(8):1697-706. · 3.42 Impact Factor
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ABSTRACT: This report details the structural characterization and the in vitro drug-release properties of different local anesthetic bupivacaine (BUP)-loaded inverted-type liquid crystalline phases and microemulsions. The effects of variations in the lipid composition and/or BUP concentration on the self-assembled nanostructures were investigated in the presence of the commercial distilled glycerol monooleate Myverol 18-99K (GMO) and medium-chain triglycerides (MCT). Synchrotron small-angle X-ray scattering (SAXS) and rotating dialysis cell model were used to characterize the BUP formulations and to investigate the in vitro BUP release profiles, respectively. The evaluation of SAXS data for the BUP-loaded GMO/MCT formulations indicates the structural transition of inverted-type bicontinuous cubic phase of the symmetry Pn3m → inverted-type hexagonal (H(2)) phase → inverted-type microemulsion (L(2)) with increasing MCT content (0-40 wt %). In the absence of MCT, the solubilization of BUP induces the transition of Pn3m → H(2) at pH 7.4; whereas a transition of Pn3m → (Pn3m + H(2)) is detected as the hydration is achieved at pH 6.0. To mimic the drug release and transport from in situ formed self-assembled systems after subcutaneous administration, the release experiments were performed by injecting low viscous stimulus-responsive precursors to a buffer in the dialysis cell leaving the surface area between the self-assembled system and the release medium variable. Our results suggest that the pH-dependent variations in the lipidic partition coefficient, K(l/w), between the liquid crystalline nanostructures and the surrounding buffer solution are significantly affecting BUP release rates. Thus, a first step toward understanding of the drug-release mechanism of this drug-delivery class has been undertaken tackling the influence of drug ionization as well as the type of the self-assembled nanostructure and its release kinetics under pharmaceutically relevant conditions.
Langmuir 02/2012; 28(5):2881-9. · 4.19 Impact Factor
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ABSTRACT: A capillary electrophoresis-inductively coupled plasma mass spectrometry (CE-ICP-MS) method was developed for separation of the free oxaliplatin drug substance from liposome-entrapped oxaliplatin. Simultaneous determination of phosphorous and platinum opened the possibility to simultaneously monitor the liposomes (phospholipids) and platinum-based drug. In order to suppress the interferences, argon gas was used as a collision gas in ICP-MS. A detection limit of 29 ng/mL of platinum and a precision of 2.9% (for 10 μg/mL of oxaliplatin standard) were obtained. Measurement of the total concentration of free and encapsulated oxaliplatin by CE-ICP-MS was compared with total determination by ICP-MS after microwave digestion and showed a good agreement. A liposomal formulation of oxaliplatin based on PEGylated liposomes was used as a model drug formulation. Studies of accelerated drug release induced by sonication and phospholipase A(2) catalyzed hydrolysis were performed. It was demonstrated that the CE-ICP-MS was an efficient in vitro characterization method in the development and quality assurance purposes of lipsome-based formulation of metallodrugs.
Analytical and Bioanalytical Chemistry 02/2012; 402(6):2131-9. · 3.78 Impact Factor
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ABSTRACT: Protein charge is an important parameter in the understanding of protein interactions and function. Proteins are subject to dynamic charge regulation, that is, the influence of the local environment (such as charged interfaces and biopolymers) on protein charge. Charge regulation is governed by differences in the dielectric and electrostatic environment between adsorbed protein and the free protein in bulk solution. In this work protein charge regulation is addressed experimentally by employing electrochemistry at interfaces between two immiscible electrolyte solutions (ITIES) as well as theoretically by developing a new protein adsorption model at ITIES. Electrochemistry at ITIES is shown to be particularly well suited to study protein charge regulation as the adsorbed protein experiences a different dielectric environment compared to the bulk phase and the external control of the water/oil potential difference allows systematic studies on how potential induced ion gradients affect protein charge. The theoretical model incorporates all the features of the experimental system and specifically takes into account protein charge regulation at ITIES as well as the impact of the formation of dielectric layers on the experimentally observed impedance. The model parameters include the protein charge-pH profile, bulk pH, and the overall potential difference. It is shown that the formation of a dielectric layer and the associated charge regulation are the main factors dictating the observed experimental behavior. Finally, the theoretical model is used to interpret literature results, and the consistency between the model and the relatively large data set suggests that the model may be used more generally for understanding and predicting protein adsorption.
Langmuir 12/2011; 28(3):1804-15. · 4.19 Impact Factor
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ABSTRACT: The understanding of protein adsorption at charged surfaces is important for a wide range of scientific disciplines including surface engineering, separation sciences and pharmaceutical sciences. Compared to chemical entities having a permanent charge, the adsorption of small ampholytes and proteins is more complicated as the pH near a charged surface can be significantly different from the value in bulk solution. In this work, we have developed a phenomenological adsorption model which takes into account the combined role of interfacial ion distribution, interfacial charge regulation of amino acids in the proximity of the surface, electroneutrality, and mass balance. The model is straightforward to apply to a given set of experimental conditions as most model parameters are obtained from bulk properties and therefore easy to estimate or are directly measurable. The model provides a detailed understanding of the importance of surface charge on adsorption and in particular of how changes in surface charge, concentration, and surface area may affect adsorption behavior. The model is successfully used to explain the experimental adsorption behavior of the two model proteins lysozyme and α-lactalbumin. It is demonstrated that it is possible to predict the pH and surface charge dependent adsorption behavior from experimental or theoretical estimates of a preferred orientation of a protein at a solid charged interface.
Langmuir 02/2011; · 4.19 Impact Factor
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ABSTRACT: A capillary electrophoresis-based method to characterize a PEGylated liposomal drug formulation of the anti-cancer agent oxaliplatin was developed. Pharmaceutical characterization in terms of determination of the free and total oxaliplatin concentrations in the liposomal formulation was successfully performed allowing calculation of the percentage of encapsulated drug and encapsulation efficiency. The trapping efficiency was likewise calculated. The capillary electrophoresis method allowed liposome characterization in the intended formulation media (sucrose solution with low electrolyte concentration), and the attained results were consistent with inductively coupled plasma mass spectrometry measurements. Accelerated drug leakage studies were initiated by the sonication of the PEGylated formulation, using an ultrasound probe, subsequently the drug leakage was determined by capillary electrophoresis. The results obtained with the PEGylated liposomes demonstrate that capillary electrophoresis may be a useful tool for the characterization of liposomal drug formulations.
Journal of pharmaceutical and biomedical analysis 01/2011; 55(1):16-22. · 2.45 Impact Factor
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ABSTRACT: RESULTS: Basic physicochemical properties including their apparent solubility in aqueous buffer and vegetable oils of a series of 11 peptidomimetics varying with respect to chain length and degree of N-methylation were estimated. It was observed that the compounds in contact with water transformed into sticky, slowly dissolving semisolid materials. Based on these observations, the in vitro release behavior of selected peptide derivatives from oil solutions and in situ formed precipitates was investigated using a validated in vitro release model. CONCLUSION: The results of this investigation suggest that both types of oil-based drug delivery systems might constitute alternative sustained release formulation principles of such amorphous peptide derivatives for the intra-articular route of administration.
Drug Development and Industrial Pharmacy 01/2011; 37(1):62-71. · 1.49 Impact Factor
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Journal of Analytical Atomic Spectrometry 01/2011; 26:1466-1473. · 3.22 Impact Factor
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ABSTRACT: Development of suitable in vitro release models for formulation development as well as quality control purposes has to be initiated in the early design phase of injectable depots. Optimally, construction of an in vitro release model may lead to the establishment of in vitro in vivo correlations. By using a model compound (sodium diatrizoate, DTZ), the purpose of this study was to investigate the possibility of establishing in vitro in vivo relations between the DTZ disappearance profile obtained from the donor compartment of the rotating dialysis cell model and the joint disappearance profile following intra-articular administration. In vitro experiments were conducted by applying solutions of DTZ to the donor compartment. In the in vivo experiments, five horses were subjected to both intravenous and intra-articular administration of an aqueous solution of 3.9 mg DTZ/kg. A strong relation (R(2)=0.99) was obtained between the disappearance data from the donor compartment of the in vitro model and the disappearance data from the synovial fluid after intra-articular administration of DTZ. Furthermore, a relation (R(2)=0.91) between the appearance data obtained from the acceptor compartment and the deconvolved appearance serum data upon intra-articular administration of DTZ was obtained. The correlations obtained in this study hold promise that the rotating dialysis cell model has a role in the prediction of the intra-articular fate of drugs injected as solutions.
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 09/2010; 41(1):10-5. · 2.61 Impact Factor
