Browsing by Subject "INDOMETHACIN"

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  • Poller, Bettina; Strachan, Clare; Broadbent, Roland; Walker, Greg F. (2017)
    The purpose of this study was to evaluate electrospun drug loaded nanofibers as a new matrix for mini tablets. Prednisone, a poorly water-soluble drug, was loaded into povidone (polyvinylpyrrolidone, PVP) nanofibers using the process of electrospinning. The drug-loaded nanofiber mat was compressed into minitablets with a 2 mm diameter and a height of 2.63 0.04 mm. SEM analysis of the minitablet identified a nano-web structure with a nanofiber diameter in the range of 400-500 nm. The minitablets met the requirements of the US Pharmacopeia with respect to content uniformity and friability. DSC and XRPD analysis of the minitablet indicated that the drug-polymer mixture was a one-phase amorphous system. XRPD analysis of the drug loaded nanofiber mat after 10-months of storage at ambient temperature showed no evidence of recrystallization of the drug. Solubility and dissolution properties of the drug formulated into a nanofiber mat and minitablet were evaluated. These results show that electrospun nanofibers may provide a useful matrix for the further development of minitablets. (C) 2017 Elsevier B.V. All rights reserved.
  • Boldt, Robert; Mäkelä, Pauliina M.; Immeli, Lotta; Sund, Reijo; Leskinen, Markus; Luukkainen, Päivi; Andersson, Sture (2021)
    Very low birthweight (VLBW) infants are at risk of intraventricular haemorrhage (IVH) and delayed closure of ductus arteriosus. We investigated mean arterially recorded blood pressure (MAP) changes during the first day of life in VLBW infants as potential risk factors for a patent ductus arteriosus (PDA) and IVH. This retrospective cohort study exploring MAP changes during adaption and risk factors for a PDA and IVH comprised 844 VLBW infants admitted to the Helsinki University Children's Hospital during 2005-2013. For each infant, we investigated 600 time-points of MAP recorded 4-24 hours after birth. Based on blood pressure patterns revealed by a data-driven method, we divided the infants into two groups. Group 1 (n = 327, mean birthweight = 1019 g, mean gestational age = 28 + (1/7) weeks) consisted of infants whose mean MAP was lower at 18-24 hours than at 4-10 hours after birth. Group 2 (n = 517, mean birthweight = 1070 g, mean gestational age = 28 + (5/7) weeks) included infants with a higher mean MAP at 18-24 hours than at 4-10 hours after birth. We used the group assignments, MAP, gestational age at birth, relative size for gestational age, surfactant administration, inotrope usage, invasive ventilation, presence of respiratory distress syndrome or sepsis, fluid intake, and administration of antenatal steroids to predict the occurrence of IVH and use of pharmacological or surgical therapy for a PDA before 42 weeks of gestational age. Infants whose mean MAP is lower at 18-24 hours than at 4-10 hours after birth are more likely to undergo surgical ligation of a PDA (odds ratio = 2.1; CI 1.14-3.89; p = 0.018) and to suffer from IVH (odds ratio = 1.83; CI 1.23-2.72; p = 0.003).
  • Palomäki, Emmi A. K.; Yliruusi, Jouko K.; Ehlers, Henrik (2019)
    In this paper, the effect of the gaseous environment on recrystallization of amorphous paracetamol was investigated. The experiments were conducted with a headspace gas consisting of dry air, dry carbon dioxide, dry nitrogen and humid air in four temperatures ranging from 5 degrees C below onset of T-g to 5 degrees C above onset of T-g. The recrystallization was monitored using Raman spectroscopy and subsequent multivariate analysis. In temperatures below onset of T-g, the presence of oxygen delayed the onset of recrystallization, with an increasing delay with lower temperature. When comparing samples exposed to dry headspace gases, the crystallization was fastest below onset of Tg when exposed to nitrogen. Being an inert gas, nitrogen did not seem to interfere with the molecules allowing them to freely find their inherent arrangement, whereas the presence of oxygen delayed the formation of stabile nuclei. Above onset of T-g, no differences in onset of crystallization was detected between dry gas atmospheres. Amorphous paracetamol crystallized to form II in all measurements and the samples did not reach full crystallinity within the duration of the experiments. The results show that the headspace gas has an effect on nucleation in the amorphous sample.
  • Rojalin, Tatu; Kurki, Lauri; Laaksonen, Timo; Viitala, Tapani; Kostamovaara, Juha; Gordon, Keith C.; Galvis, Leonardo; Wachsmann-Hogiu, Sebastian; Strachan, Clare J.; Yliperttula, Marjo (2016)
    In this work, we utilize a short-wavelength, 532-nm picosecond pulsed laser coupled with a time-gated complementary metal-oxide semiconductor (CMOS) single-photon avalanche diode (SPAD) detector to acquire Raman spectra of several drugs of interest. With this approach, we are able to reveal previously unseen Raman features and suppress the fluorescence background of these drugs. Compared to traditional Raman setups, the present time-resolved technique has two major improvements. First, it is possible to overcome the strong fluorescence background that usually interferes with the much weaker Raman spectra. Second, using the high photon energy excitation light source, we are able to generate a stronger Raman signal compared to traditional instruments. In addition, observations in the time domain can be performed, thus enabling new capabilities in the field of Raman and fluorescence spectroscopy. With this system, we demonstrate for the first time the possibility of recording fluorescence-suppressed Raman spectra of solid, amorphous and crystalline, and non-photoluminescent and photoluminescent drugs such as caffeine, ranitidine hydrochloride, and indomethacin (amorphous and crystalline forms). The raw data acquired by utilizing only the picosecond pulsed laser and a CMOS SPAD detector could be used for identifying the compounds directly without any data processing. Moreover, to validate the accuracy of this time-resolved technique, we present density functional theory (DFT) calculations for a widely used gastric acid inhibitor, ranitidine hydrochloride. The obtained time-resolved Raman peaks were identified based on the calculations and existing literature. Raman spectra using non-time-resolved setups with continuous-wave 785- and 532-nm excitation lasers were used as reference data. Overall, this demonstration of time-resolved Raman and fluorescence measurements with a CMOS SPAD detector shows promise in diverse areas, including fundamental chemical research, the pharmaceutical setting, process analytical technology (PAT), and the life sciences.
  • Selin, Markus; Nummelin, Sami; Deleu, Jill; Ropponen, Jarmo; Viitala, Tapani; Lahtinen, Manu; Koivisto, Jari; Hirvonen, Jouni; Peltonen, Leena; Kostiainen, Mauri A.; Bimbo, Luis M. (2018)
    Pharmaceutical nanosuspensions are formed when drug crystals are suspended in aqueous media in the presence of stabilizers. This technology offers a convenient way to enhance the dissolution of poorly water-soluble drug compounds. The stabilizers exert their action through electrostatic or steric interactions, however, the molecular requirements of stabilizing agents have not been studied extensively. Here, four structurally related amphiphilic Janus-dendrimers were synthesized and screened to determine the roles of different macromolecular domains on the stabilization of drug crystals. Physical interaction and nanomilling experiments have substantiated that Janus-dendrimers with fourth generation hydro- philic dendrons were superior to third generation analogues and Poloxamer 188 in stabilizing indomethacin suspensions. Contact angle and surface plasmon resonance measurements support the hypothesis that Janus-dendrimers bind to indomethacin surfaces via hydrophobic interactions and that the number of hydrophobic alkyl tails determines the adsorption kinetics of the Janus-dendrimers. The results showed that amphiphilic Janus-dendrimers adsorb onto drug particles and thus can be used to provide steric stabilization against aggregation and recrystallization. The modular synthetic route for new amphiphilic Janus-dendrimers offers, thus, for the first time a versatile platform for stable general-use stabilizing agents of drug suspensions.
  • Stukelj, Jernej; Agopov, Mikael; Yliruusi, Jouko; Strachan, Clare J.; Svanbäck, Sami (2020)
    Poor solubility of crystalline drugs can be overcome by amorphization - the production of high-energy disordered solid with improved solubility. However, the improved solubility comes at a cost of reduced stability; amorphous drugs are prone to recrystallization. Because of recrystallization, the initial solubility enhancement is eventually lost. Therefore, it is important to understand the recrystallization process during storage of amorphous materials and its impact on dissolution/solubility. Here, we demonstrate the use of image-based single-particle analysis (SPA) to consistently monitor the solubility of an amorphous indomethacin sample over time. The results are compared to the XRPD signal of the same sample. For the sample stored at 22 degrees C/23 % relative humidity (RH), full crystallinity as indicated by XRPD was reached around day 40, whereas a solubility corresponding to that of the. crystalline form was measured with SPA at day 25. For the sample stored at 22 degrees C/75 % RH, the XRPD signal indicated a rapid initial phase of crystallization. However, the sample failed to fully crystallize in 80 days. With SPA, solubility slightly above that of the crystalline. form was measured already on the second day. To conclude, the solubility measured with SPA directly reflects the solid-state changes occurring on the particle surface. Therefore, it can provide vital information - in a straightforward manner while requiring only minuscule sample amounts - for understanding the effect of storage conditions on the dissolution/solubility of amorphous materials, especially important in pharmaceutical science.
  • Semjonov, Kristian; Lust, Andres; Kogermann, Karin; Laidmäe, Ivo; Maunu, Sirkka Liisa; Hirvonen, Sami-Pekka; Yliruusi, Jouko; Nurk, Gunnar; Lust, Enn; Heinamäki, Jyrki (2018)
    The present study introduces a modified melt-electrospinning (MES) method for fabricating the melt-electrospun fibers (MSFs) of a poorly water-soluble drug and carrier polymer. The MES of poorly water-soluble model drug indomethacin (IND) and hydrophilic carrier polymer, Soluplus (R) (SOL) were prepared at a 1:3 drug-polymer weight ratio. Water was used as an external plasticizer to regulate a MES processing temperature and to improve fiber formation. The fiber size, surface morphology, physical solid state, drug-polymer (carrier) interactions, thermal and chemical stability and dissolution behavior of MSFs were investigated. Solid state nuclear magnetic resonance spectroscopy (NMR) was used to measure T1(H-1), and the domain size of IND in MSFs (25-100 nm) was calculated from these results. Solid-state and thermal analysis confirmed the presence of amorphous solid dispersions of IND and SOL. IND was found to be chemically stable during an entire MES process. Only small drug content variability of different MSF batches was detected with high performace liquid chromatography (HPLC). Given findings were verified with the liquid NMR spectroscopy. The dissolution of MSFs was significantly faster than that of physical mixtures (PMs) or pure drug. The enhanced dissolution of MSFs was caused by high surface area, amorphous state of the drug and solubilizing properties of the carrier polymer (SOL).
  • Singhal, Mayank; Baumgartner, Ana; Turunen, Elina; van Veen, Bert; Hirvonen, Jouni; Peltonen, Leena (2020)
    Aqueous solubility of a drug substance is an important attribute affecting oral bioavailability. Nanonization, particle size reduction to submicron level, is an elegant approach to improve drug solubility and dissolution by increasing the surface energy, which in turn necessitates the use of stabilizers. The purpose of this study was to develop a nanosuspension of a practically water-insoluble investigational molecule by nanomilling approach using wet media milling. A variety of polymeric and surface active excipients were tested for their wettability. A combination of hydroxypropyl methylcellulose and sodium lauryl sulfate (SLS) were selected as stabilizers on the bases of compatibility studies and efficient wettability behaviour in contact angle measurements (≈80˚). A factorial design set-up was used to study the effect of milling bead diameter and stabilizer concentration on the efficiency of particle size reduction. Nanonization outcome was different when milling beads of 0.5 mm and 1 mm diameter were used at different concentrations of the stabilizers, which demonstrated the complex nature of the whole system. Storage of the nanosuspensions under different temperature conditions resulted only in minor changes of the particle size fractions.
  • Herbers, Elena; Patrikoski, Mimmi; Jokinen, Riikka; Wagner, Anita; Hassinen, Antti; Heinonen, Sini; Miettinen, Susanna; Peltoniemi, Hilkka; Pirinen, Eija; Pietiläinen, Kirsi H. (2022)
    Mitochondrial dysfunction in white adipose tissue is strongly associated with obesity and its metabolic complications, which are important health challenges worldwide. Human adipose-derived stromal/stem cells (hASCs) are a promising tool to investigate the underlying mechanisms of such mitochondrial dysfunction and to subsequently provide knowledge for the development of treatments for obesity-related pathologies. A substantial obstacle in using hASCs is that the key compounds for adipogenic differentiation in vitro increase mitochondrial uncoupling, biogenesis, and activity, which are the signature features of brown adipocytes, thus altering the white adipocyte phenotype towards brown-like cells. Additionally, commonly used protocols for hASC adipogenic differentiation exhibit high variation in their composition of media, and a systematic comparison of their effect on mitochondria is missing. Here, we compared the five widely used adipogenic differentiation protocols for their effect on metabolic and mitochondrial phenotypes to identify a protocol that enables in vitro differentiation of white adipocytes and can more faithfully recapitulate the white adipocyte phenotype observed in human adipose tissue. We developed a workflow that included functional assays and morphological analysis of mitochondria and lipid droplets. We observed that triiodothyronine- or indomethacin-containing media and commercially available adipogenic media induced browning during in vitro differentiation of white adipocytes. However, the differentiation protocol containing 1 mu M of the peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist rosiglitazone prevented the browning effect and would be proposed for adipogenic differentiation protocol for hASCs to induce a white adipocyte phenotype. Preserving the white adipocyte phenotype in vitro is a crucial step for the study of obesity and associated metabolic diseases, adipose tissue pathologies, such as lipodystrophies, possible therapeutic compounds, and basic adipose tissue physiology.