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1.
Gayathri Kollamaram Alexandra Faucher Denise M. Croker Gavin M. Walker 《Pharmaceutical research》2018,35(9):181
Purpose
To use valvejet technology for printing a fixed dose combination of ramipril and glimepiride, and to investigate the stability profile of ramipril, which is susceptible to a range of processing and storage conditions.Methods
Inks of ramipril and glimepiride were formulated and printed on to HPMC film and the films were evaluated for the chemical and solid-state integrity of the APIs using HPLC and XRPD. The stability of the APIs in the inks and in the printed samples was investigated using Raman and NMR techniques.Results
The printed samples demonstrated excellent precision and accuracy in the doses of APIs deposited. Both drugs were chemically intact in the freshly printed samples and ramipril was found to be in its amorphous form. Ramipril in the printed samples has transformed into ramipril diketopiperazine when stored at 40°C with 75% RH, but remained stable when stored in a desiccator. Results from the stability study of ramipril ink show that the API has undergone degradation when stored both at room temperature and at 40°C but remained stable when stored in a refrigerator.Conclusion
An FDC of ramipril and glimepiride was successfully printed using valvejet technology. The significance of inkjet printing in producing amorphous dosage forms from solution based inks and personalised dosage forms of drugs susceptible to processing conditions was demonstrated using ramipril. This study illustrates the significance of examining the stability of the APIs in the inks and the importance of appropriate storing of both the inks and printed samples.2.
Purpose
Three- dimensional (3D) printing has received significant attention as a manufacturing process for pharmaceutical dosage forms. In this study, we used Fusion Deposition Modelling (FDM) in order to print “candy – like” formulations by imitating Starmix® sweets to prepare paediatric medicines with enhanced palatability.Methods
Hot melt extrusion processing (HME) was coupled with FDM to prepare extruded filaments of indomethacin (IND), hypromellose acetate succinate (HPMCAS) and polyethylene glycol (PEG) formulations and subsequently feed them in the 3D printer. The shapes of the Starmix® objects were printed in the form of a heart, ring, bottle, ring, bear and lion. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier Transform Infra-red Spectroscopy (FT-IR) and confocal Raman analysis were used to assess the drug – excipient interactions and the content uniformity.Results
Physicochemical analysis showed the presence of molecularly dispersed IND in the printed tablets. In vivo taste masking evaluation demonstrated excellent masking of the drug bitterness. The printed forms were evaluated for drug dissolution and showed immediate IND release independently of the printed shape, within 60 min.Conclusions
3D printing was used successfully to process drug loaded filaments for the development of paediatric printed tablets in the form of Starmix® designs.3.
Daniel Markl J. Axel Zeitler Cecilie Rasch Maria Høtoft Michaelsen Anette Müllertz Jukka Rantanen Thomas Rades Johan Bøtker 《Pharmaceutical research》2017,34(5):1037-1052
Purpose
A 3D printer was used to realise compartmental dosage forms containing multiple active pharmaceutical ingredient (API) formulations. This work demonstrates the microstructural characterisation of 3D printed solid dosage forms using X-ray computed microtomography (XμCT) and terahertz pulsed imaging (TPI).Methods
Printing was performed with either polyvinyl alcohol (PVA) or polylactic acid (PLA). The structures were examined by XμCT and TPI. Liquid self-nanoemulsifying drug delivery system (SNEDDS) formulations containing saquinavir and halofantrine were incorporated into the 3D printed compartmentalised structures and in vitro drug release determined.Results
A clear difference in terms of pore structure between PVA and PLA prints was observed by extracting the porosity (5.5% for PVA and 0.2% for PLA prints), pore length and pore volume from the XμCT data. The print resolution and accuracy was characterised by XμCT and TPI on the basis of the computer-aided design (CAD) models of the dosage form (compartmentalised PVA structures were 7.5?±?0.75% larger than designed; n?=?3).Conclusions
The 3D printer can reproduce specific structures very accurately, whereas the 3D prints can deviate from the designed model. The microstructural information extracted by XμCT and TPI will assist to gain a better understanding about the performance of 3D printed dosage forms.4.
Dong-Min Seon Yuri Park Gwan-Tae Yu Myoung-Hwan Park Jongwan Choi 《Toxicology and Environmental Health Sciences》2018,10(1):72-78
Objective
Use of transparent organosilane hybrid films to protect substrates such as glasses and plastics is of great importance for electronic applications. In this study, graphene oxides (GOs) were chemically conjugated with organosilane oligomers to improve the dispersibility and hardness of organosilane coatings.Methods
The GO-conjugation with organosilane oligomers (GO-oSi) was prepared through a two-step route featuring amine-carboxyl coupling reaction and oligomerization with silica precursors. The structural properties of GO-oSi were characterized using Fourier transform infrared spectroscopy, Raman spectroscopy, and X-ray photoelectron spectroscopy.Results
The stability of the GO-organosilane coating dispersion was confirmed after storage in ethanol for 10 days via Tyndall effect analysis. After photopolymerization with organosilane coating agent, the transparencies of the GO-organosilane films were 94% or more, the enhanced hardness was characterized from 3H to 5H through pencil hardness testing.Conclusion
The simple strategy of pre-conjugation of GOs with organosilane oligomers has the potential to enhance dispersion and hardness of a wide variety of coating materials.5.
Anran Hu Chen Chen Michael D. Mantle Bettina Wolf Lynn F. Gladden Ali Rajabi-Siahboomi Shahrzad Missaghi Laura Mason Colin D. Melia 《Pharmaceutical research》2017,34(5):941-956
Purpose
Investigate the extended release behaviour of compacts containing mixtures of hydrophilic HPMC and PEO in hydrating media of differing ionic strengths.Methods
The extended release behaviour of various HPMC:PEO compacts was investigated using dissolution testing, confocal microscopy and magnetic resonance imaging, with respect to polymer ratio and ionic strength of the hydrating media.Results
Increasing HPMC content gave longer extended release times, but a greater sensitivity to high ionic dissolution environments. Increasing PEO content reduced this sensitivity. The addition of PEO to a predominantly HPMC matrix reduced release rate sensitivity to high ionic environments. Confocal microscopy of early gel layer development showed the two polymers appeared to contribute independently to gel layer structure whilst together forming a coherent and effective diffusion barrier. There was some evidence that poorly swollen HPMC particles added a tortuosity barrier to the gel layer in high ionic strength environments, resulting in prolonged extended release. MRI provides unique, non-invasive spatially resolved information from within the HPMC:PEO compacts that furthers our understanding of USP 1 and USP 4 dissolution data.Conclusions
Confocal microscopy and MRI data show that combinations of HPMC and PEO have advantageous extended release properties, in comparison with matrices containing a single polymer.6.
M. Elisa Melian A. Beatriz Munguía Ricardo Faccio Santiago Palma Laura Domínguez 《Journal of pharmaceutical innovation》2018,13(1):58-68
Purpose
Solid dispersions (SDs) of a poorly water-soluble drug were prepared, and their physicochemical properties were compared to those of control physical mixtures (PMs). Among the multiple techniques used to characterize the solid state of preparations, confocal micro Raman spectroscopy (CMRS) was used as a non-destructive tool to qualitatively probe content uniformity and distribution of drug and carrier.Methods
SDs and PMs of drug (fenbendazole, FBZ) were prepared containing two different carriers (poloxamer P188 or P407) with different drug polymer ratios. The preparations were characterized by powder X-ray diffractometry, Fourier transform infrared spectroscopy, thermal analysis, scanning electron microscopy, and in vitro dissolution assay. In addition, CMRS technique and principal component analysis (PCA) were used in order to statistically define the content uniformity and distribution of the drug within the polymeric matrix.Results
In vitro dissolution results exhibited a marked improvement when the drug was formulated as SD compared to control PM and to pure drug. The solid state of these preparations characterized by X-ray powder diffraction and Fourier transform infrared spectroscopy showed no changes in the crystalline state of the drug and no chemical interactions between the components. Raman studies showed a better content uniformity of the drug within the polymeric matrix when subjected to SD process, correlating with the improved dissolution profile.Conclusion
This study provides evidence of the potential of the confocal Raman imaging technique, providing a fast and powerful method to characterize solid dispersions which could be incorporated towards the use of quality by design (QbD) approaches in pharmaceutical development.7.
Tochukwu C. Okwuosa Dominika Stefaniak Basel Arafat Abdullah Isreb Ka-Wai Wan Mohamed A. Alhnan 《Pharmaceutical research》2016,33(11):2704-2712
Purpose
The fabrication of ready-to-use immediate release tablets via 3D printing provides a powerful tool to on-demand individualization of dosage form. This work aims to adapt a widely used pharmaceutical grade polymer, polyvinylpyrrolidone (PVP), for instant on-demand production of immediate release tablets via FDM 3D printing.Methods
Dipyridamole or theophylline loaded filaments were produced via processing a physical mixture of API (10%) and PVP in the presence of plasticizer through hot-melt extrusion (HME). Computer software was utilized to design a caplet-shaped tablet. The surface morphology of the printed tablet was assessed using scanning electron microscopy (SEM). The physical form of the drugs and its integrity following an FDM 3D printing were assessed using x-ray powder diffractometry (XRPD), thermal analysis and HPLC. In vitro drug release studies for all 3D printed tablets were conducted in a USP II dissolution apparatus.Results
Bridging 3D printing process with HME in the presence of a thermostable filler, talc, enabled the fabrication of immediate release tablets at temperatures as low as 110°C. The integrity of two model drugs was maintained following HME and FDM 3D printing. XRPD indicated that a portion of the loaded theophylline remained crystalline in the tablet. The fabricated tablets demonstrated excellent mechanical properties, acceptable in-batch variability and an immediate in vitro release pattern.Conclusions
Combining the advantages of PVP as an impeding polymer with FDM 3D printing at low temperatures, this approach holds a potential in expanding the spectrum of drugs that could be used in FDM 3D printing for on demand manufacturing of individualised dosage forms.8.
Purpose
The goal of this research was to study the molecular interactions in situ between actives and surfactants in self-emulsifying delivery systems (SEDDS) in order to illuminate the factor(s) and how they influence the drug performance in these systems.Method
We have developed an approach to evaluate the mechanism of performance of SEDDS formulations using an in situ Raman technique. Self-emulsifying delivery systems for seven actives with different physicochemical properties were formulated. One gram of the SEDDS was dispersed in 100 mL of media, and the precipitation behavior of the actives was noted. Using an immersion probe, these dispersions were tested continuously and spectra were obtained to determine the drug-excipient interactions.Results
The changes in the molecular vibrational peaks confirmed that the drug-TPGS hydrogen bonding was responsible for maintaining the drug in solution. The interaction between Labrasol and the actives was weak and broke upon dispersion leading to precipitation of the drug. Also, the hydrogen bond donor strength of the functional group gave a good indication of the bond strength between TPGS and the drugs which determined the performance of the actives in the system.Conclusion
It could be suggested that the hydrogen bond strength correlates well to the precipitation behavior from the SEDDS dispersions. Thus, studying the structures and physicochemical properties of the drug candidates and the excipients could significantly minimize the steps involved in developing successful lipid-based delivery systems.9.
Anna-Kaisa Koskinen Sara J. Fraser-Miller Johan P. Bøtker Ville P. Heljo Jonathan E. Barnsley Keith C. Gordon Clare J. Strachan Anne M. Juppo 《Pharmaceutical research》2016,33(7):1752-1768
Purpose
Isomalt is a sugar alcohol used as an excipient in commercially available solid oral dosage forms. The potential of isomalt as a novel freeze-drying excipient was studied in order to increase knowledge of the behavior of isomalt when it is freeze-dried.Methods
Isomalt was freeze-dried in four different diastereomer compositions and its physical stability was investigated with differential scanning calorimetry, Fourier-transform infrared and Raman spectroscopy, X-ray powder diffraction, Karl-Fischer titration and thermogravimetric analysis in order to verify the solid state form of isomalt after freeze-drying and observe any changes occurring during storage in three different relative humidity conditions.Results
Isomalt was successfully transformed into the amorphous form with freeze-drying and three diastereomer combinations remained stable as amorphous during storage; one of the diastereomer compositions showed signs of physical instability when stored in the highest relative humidity condition. The four different crystalline diastereomer mixtures showed specific identifiable solid state properties.Conclusions
Isomalt was shown to be a suitable excipient for freeze-drying. Preferably a mixture of the diastereomers should be used, as the mixture containing only one of the isomers showed physical instability. A mixture containing a 1:1 ratio of the two diastereomers showed the best physical stability in the amorphous form.10.
Christen J. Boyer David H. Ballard Jungmi W. Yun Adam Y. Xiao Jeffery A. Weisman Mansoureh Barzegar Jonathan Steven Alexander 《Pharmaceutical research》2018,35(8):155
Purpose
Cell migration/invasion assays are widely used in commercial drug discovery screening. 3D printing enables the creation of diverse geometric restrictive barrier designs for use in cell motility studies, permitting on-demand assays. Here, the utility of 3D printed cell exclusion spacers (CES) was validated as a cell motility assay.Methods
A novel CES fit was fabricated using 3D printing and customized to the size and contour of 12 cell culture plates including 6 well plates of basal human brain vascular endothelial (D3) cell migration cells compared with 6 well plates with D3 cells challenged with 1uM cytochalasin D (Cyto-D), an F-actin anti-motility drug. Control and Cyto-D treated cells were monitored over 3 days under optical microscopy.Results
Day 3 cell migration distance for untreated D3 cells was 1515.943μm?±?10.346μm compared to 356.909μm?±?38.562μm for the Cyt-D treated D3 cells (p?<?0.0001). By day 3, untreated D3 cells reached confluency and completely filled the original voided spacer regions, while the Cyt-D treated D3 cells remained significantly less motile.Conclusions
Cell migration distances were significantly reduced by Cyto-D, supporting the use of 3D printing for cell exclusion assays. 3D printed CES have great potential for studying cell motility, migration/invasion, and complex multi-cell interactions.11.
Hyeong-Seok?Lim Su?Jin?Kim Yook-Hwan?Noh Byung?Chul?Lee Seok-Joon?Jin Hyun?Soo?Park Soohyeon?Kim In-Jin?Jang Sang?Eun?Kim
Purpose
To evaluate the potential usage of D2 receptor occupancy (D2RO) measured by positron emission tomography (PET) in antipsychotic development.Methods
In this randomized, parallel group study, eight healthy male volunteers received oral doses of 0.5 (n?=?3), 1 (n?=?2), or 3 mg (n?=?3) of haloperidol once daily for 7 days. PET’s were scanned before haloperidol, and on days 8, 12, with serial pharmacokinetic sampling on day 7. Pharmacokinetics and binding potential to D2 receptor in putamen and caudate nucleus over time were analyzed using NONMEM, and simulations for the profiles of D2RO over time on various regimens of haloperidol were conducted to find the optimal dosing regimens.Results
One compartment model with a saturable binding compartment, and inhibitory Emax model in the effect compartment best described the data. Plasma haloperidol concentrations at half-maximal inhibition were 0.791 and 0.650 ng/ml, in putamen and caudate nucleus. Simulation suggested haloperidol 2 mg every 12 h is near the optimal dose.Conclusion
This study showed that sparse D2RO measurements in steady state pharmacodynamic design after multiple dosing could reveal the possibility of treatment effect of D2 antagonist, and could identify the potential optimal doses for later clinical studies by modeling and simulation.12.
Wiebke Kempin Vanessa Domsta Georg Grathoff Iris Brecht Beatrice Semmling Susan Tillmann Werner Weitschies Anne Seidlitz 《Pharmaceutical research》2018,35(6):124
Purpose
Dissolution speeds of tablets printed via Fused Deposition Modeling (FDM) so far are significantly lower compared to powder or granule pressed immediate release tablets. The aim of this work was to print an actual immediate release tablet by choosing suitable polymers and printing designs, also taking into account lower processing temperatures (below 100°C) owing to the used model drug pantoprazole sodium.Methods
Five different pharmaceutical grade polymers polyvinylpyrrolidone (PVP K12), polyethylene glycol 6000 (PEG 6000), Kollidon® VA64, polyethylene glycol 20,000 (PEG 20,000) and poloxamer 407 were successfully hot-melt-extruded to drug loaded filaments and printed to tablets at the required low temperatures.Results
Tablets with the polymers PEG 6000 and PVP K12 and with a proportion of 10% pantoprazole sodium (w/w) demonstrated a fast drug release that was completed within 29 min or 10 min, respectively. By reducing the infill rate of PVP tablets to 50% and thereby increase the tablet porosity it was even possible to reduce the mean time for total drug release to only 3 min.Conclusions
The knowledge acquired through this work might be very beneficial for future FDM applications in the field of immediate release tablets especially with respect to thermo-sensitive drugs.13.
Purpose
Despite the fact that r-hGH was first approved for use by FDA in 1995 and the conventional dosage form in the market has a limitation of daily subcutaneous injections, there remains a lack of sustained delivery system in the market. Nutropin depot, a long-acting dosage form of r-hGH was approved for marketing by FDA in 1999, however, it was discontinued in 2004. Since then, unabating efforts have been made to develop biodegradable polymer based formulations for r-hGH delivery. However, grey area is the comprehension of structural stability of r-hGH at an interface with the polymer and it is of utmost important to attain safe and efficacious sustained delivery system. The purpose of this study was to evaluate the changes in structure of r-hGH upon adsorption at biodegradable PLGA nanoparticles of different hydrophobicity as a function of pH.Methods
DLS, fluorescence spectroscopy, and CD were collectively employed to evaluate structural changes in r-hGH.Results
The studies revealed that r-hGH is most stable with low to high hydrophobicity PLGA grades under pH 7.2 followed by 5.3.Conclusion
Overall, the nature and magnitude of structural changes observed has a strong dependence on the pH and differences and degree of hydrophobicity of PLGA.14.
Adrian Schmidt Hans de Waard Peter Kleinebudde Markus Krumme 《Pharmaceutical research》2018,35(8):167
Purpose
It was investigated if continuous wet granulation and drying could be combined in a twin-screw granulator with the aim to provide (pre-)dried granules in a single-step process, i.e. in-barrel-drying.Methods
To have a consistent and robust material propulsion mechanism, a twin-screw granulator was divided into two compartments. One compartment was operated at lower temperature to granulate and to pre-heat the material, while another compartment was operated at very high temperature to evaporate the granulation liquid as rapidly as possible. Design of experiments was used to investigate the in-barrel-drying process in detail. The process was further investigated for twin-screw wet granulation with API suspension feed, and compared against traditional fluidised-bed drying. Granule and compact properties were evaluated to study the process impact on the product quality.Results
In-barrel-drying was demonstrated as feasible and yielded completely dried and granulated material at specific settings. The evaporation zone temperature and the processed mass of water were identified as key parameters to balance the evaporation capacity of the process and the material throughput. Granules and compacts showed an acceptable product quality.Conclusions
In-barrel-drying can be used to condense the wet granulation and drying process steps into one piece of equipment, thereby limiting or even omitting downstream drying process steps.15.
Objective
Although the organic compounds, 2-propylaniline and 4-propylaniline are frequently used in many industrial sectors, and have little information about the potential genetic toxicity, and it is covered by the Occupational Safety & Health Act (OSHAct) in Korea.Methods
The mutation test of 2-propylaniline and 4-propylaniline was evaluated in five different doses for each chemical through a well-known Ames bacterial mutation test. This test was performed regardless of metabolic activation.Results
In this assay, we obtained positive results under all tested conditions, indicating that these two chemicals have mutagenic and potentially carcinogenic properties.Conclusion
Both 2-propylaniline and 4-propylaniline were mutagenic under the conditions of these tests. This result means that all of these chemicals exhibit mutations and potential carcinogenicity.16.
Jacob Bouman Peter Belton Paul Venema Erik van der Linden Renko de Vries Sheng Qi 《Pharmaceutical research》2016,33(3):673-685
Purpose
In earlier studies, the corn protein zein is found to be suitable as a sustained release agent, yet the range of drugs for which zein has been studied remains small. Here, zein is used as a sole excipient for drugs differing in hydrophobicity and isoelectric point: indomethacin, paracetamol and ranitidine.Methods
Caplets were prepared by hot-melt extrusion (HME) and injection moulding (IM). Each of the three model drugs were tested on two drug loadings in various dissolution media. The physical state of the drug, microstructure and hydration behaviour were investigated to build up understanding for the release behaviour from a zein based matrix for drug delivery.Results
Drug crystallinity of the caplets increases with drug hydrophobicity. For ranitidine and indomethacin, swelling rates, swelling capacity and release rates were pH dependent as a consequence of the presence of charged groups on the drug molecules. Both hydration rates and release rates could be approached by existing models.Conclusion
The drug state and pH dependant electrostatic interactions are hypothesised to influence release kinetics. Both factors can potentially be used to influence release kinetics release, thereby broadening the horizon for zein as a tuneable release agent.17.
Yusuke Masuo Shushi Nagamori Aoi Hasegawa Kazuki Hayashi Noriyoshi Isozumi Noritaka Nakamichi Yoshikatsu Kanai Yukio Kato 《Pharmaceutical research》2017,34(6):1233-1243
Purpose
Monoamine oxidases (MAOs) are non-CYP enzymes that contribute to systemic elimination of therapeutic agents, and localized on mitochondrial membranes. The aim of the present study was to validate quantitative estimation of metabolic clearance of MAO substrate drugs using human liver microsomes (HLMs).Methods
Three MAO substrate drugs, sumatriptan, rizatriptan and phenylephrine, as well as four CYP substrates were selected, and their disappearance during incubation with HLMs or mitochondria (HLMt) was measured. Metabolic clearance (CL) was then calculated from the disappearance curve.Results
CL obtained in HLMs for sumatriptan and a typical MAO substrate serotonin was correlated with that obtained in HLMt among ten human individual livers. Hepatic intrinsic clearance (CLint,vitro) estimated from CL in HLMs was 14–20 and 2–5 times lower than in vivo hepatic intrinsic clearance (CLint,vivo) obtained from literature for MAO and CYP substrates, respectively. Utilization of HLMs for quantitatively assessing metabolic clearance of MAO substrates was further validated by proteomics approach which has revealed that numerous proteins localized on inner and outer membranes of mitochondria were detected in both HLMs and HLMt.Conclusion
CLint,vitro values of MAO substrate drugs can be quantitatively estimated with HLMs and could be used for semi-quantitative prediction of CLint,vivo values.18.
Lim-Kyu Lee Seung-Min Yang Jaehong Park Junghwan Kim 《Toxicology and Environmental Health Sciences》2018,10(1):42-48
Objective
This study promotes health management activities in Y combined cycle power plants in Korea, focusing on occupational health activities, such as preventing cardiovascular disease and musculoskeletal disorders and managing work environment measurements.Methods
The results of the present study were collected from the company’s internal documents and reports in Y combined cycle power plant.Results
Diverse results for workplace activities are summarized. Furthermore, this study discusses attempts to reduce potential safety risks and to improve workers’ health conditions at the Y combined cycle power plants in Korea.Conclusion
The Y combined cycle plant discussed seeks to prevent accidents to improve workers’ health; thus, specific efforts related to onsite health and expected results for workers are evaluated.19.
Rizzo M Lamers CT Sauer CG Ramaekers JG Bechara A Andersen GJ 《Psychopharmacology》2005,179(3):559-566
Rationale
Illicit drug use can increase driver crash risk due to loss of control over vehicle trajectory. This study asks, does recreational use of ±3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) and tetrahydrocannabinol (THC; marijuana) impair cognitive processes that help direct our safe movement through the world?Objective
This study assesses the residual effects of combined MDMA/THC use, and of THC use alone, upon perceived trajectory of travel.Methods
Perception of self-motion, or heading, from optical flow patterns was assessed using stimuli comprising random dot ground planes presented at three different densities and eight heading angles (1, 2, 4 and 8° to the left or right). On each trial, subjects reported if direction of travel was to the left or the right.Results
Results showed impairments in both drug groups, with the MDMA/THC group performing the worst.Conclusions
The finding that these psychoactive agents adversely affect heading perception, even in recently abstinent users, raises potential concerns about MDMA use and driving ability.20.