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Vírusellenes terápiás lehetőségek COVID–19 fertőzés kezelésére
Antiviral therapies for COVID-19 infections
Összefoglaló. A COVID–19-járvány egyre növekvő számú fertőzött betegének ellátása érdekében rövid időn belül szükség mutatkozott vírusellenes terápiás lehetőségekre. A gyors reagálás szempontját figyelembe véve erre a célra elsősorban más vírusok ellen már kifejlesztett vírusellenes szerek jöhetnek szóba. A magyar betegek ellátásbiztonsága szempontjából különösen fontos a hatóanyagok és gyógyszerkészítmények hazai gyártása. Ezt a cél tűzte ki a favipiravir, egy széles spektrumú antivirális hatóanyag hazai fejlesztése, amely sikeresen befejeződött, a gyógyszerkészítmény klinikai vizsgálata folyamatban van.
Summary. Increasing impact of COVID-19 on the healthcare system prompted the identification of potential antiviral therapies. Due to the immediate demand, known drugs were subjected to repositioning attempts. These drugs include agents inhibiting the viral entry into the host cells, drugs potentially blocking the release of the viral RNA from the endosomes, antivirals inhibiting the replication of the viral RNA and finally compounds that might prevent the assembly of the new virion. Since there is less experience with camostat and nafamostat, the entry inhibitors tested in Japan, and due to the ambiguous data collected with the endosome blocking chloroquine and hydroxyl-chloroquine, we focused on the actual antiviral treatment options for COVID-19 infections. In addition to favipiravir and remdesivir that were used early, at the onset of the pandemic, we discuss novel candidates including molnupiravir, a promising antiviral actually investigated in clinical trials. Considering the needs of Hungarian COVID patients and the security of supply as first priority, we selected favipiravir and developed a convenient process for the industry-scale production of the active pharmaceutical ingredient (API). At the end of this review we summarize the development and clinical investigation of favipiravir, a wide spectrum antiviral drug used for the treatment of mild and moderate COVID patients in Hungary in both ambulant and clinical settings. The Hungarian COVID Task Force set up two consortia, one for the development and the other for the clinical investigations of favipiravir. The objective of the favipiravir development consortium was to develop processes for the production of Favipiravir API and dosage forms. The consortium completed the pilot plant scale industrial production of the API and produced clinical samples for the upcoming trials. The selection and laboratory scale optimization of the synthesis route was performed at the Medicinal Chemistry Research Group of the Research Center for Natural Sciences. The laboratory scale synthesis was scaled up for pilot plant production at EVI plc and Gedeon Richter plc. GMP production was realized at the facilities of Gedeon Richter plc. Finished dosage forms were developed at Meditop Ltd who produced the clinical samples under GMP conditions. The clinical consortium is headed by the Hungarian section of the European Clinical Research Infrastructure Network (ECRIN) and organized two trials. One of these trials investigates favipiravir produced in Hungary while the other trial is performed with favipiravir produced in Japan. Both studies were approved by the Hungarian regulatory agency (OGYÉI) and are ongoing.
concentrated PWW's, mother liquors of chemical, pharmaceutical production contain high amount and all kinds of organic and inorganic materials. These waters are rather complex mixtures containing several solvents, salts and all the organic molecules which were
be used for the determination of the residual impurities during the cleaning validation of the equipment of pharmaceutical production plants. The accuracy and the recovery rate of this method are comparable with those of the classical analysis method
Az ionkromatográfia alkalmazhatóságának lehetőségei a gyógyszeranalitikában
Potential applications of ion chromatography in drug analysis
Összefoglalás.
Gyógyszermolekulák kémiai szintézissel történő előállítása során előfordulhat, hogy a szintézisút toxikus vegyületeket tartalmaz, vagy szintézis során képződik toxikus melléktermék. Ezeket az anyagokat alacsony koncentrációszinten kell kizárni a gyártott végtermékben, hogy az adott hatóanyag törzskönyvezése sikeres legyen. Így a genotoxikus (megváltoztatja a DNS által tárolt genetikai információt), rákkeltő szennyezők analitikai kontrollja folyamatos kihívás elé állítja az analitikusokat. Erre a vizsgálatra a legelterjedtebb módszer a nagyhatékonyságú folyadékkromatográfia. Ennek egyik speciális változata, a nagyhatékonyságú ionkromatográfia alkalmas a kis méretű ionos vagy ionizálható molekulák, pl. szervetlen anionok és kationok, szerves savak, aminok, valamint hidrolizálható vegyületek vizsgálatára. A kéziratban bemutatásra kerül a nagyhatékonyságú ionkromatográfiás technika, valamint annak gyógyszeranalitikai alkalmazása.
Summary.
In the production of drug molecules, the synthesis pathway may contain toxic compounds, or a toxic by-product may be formed during synthesis. These substances must be excluded at low concentration levels in the final manufactured product in order for the registration of the active substance to be successful. The drug analytics task to quantify these contaminations. This part of the pharmaceutical industry involves a wide spectrum of analytical techniques, which together complement each other to give a complete picture of the product being manufactured. Measurement techniques range from titration to large instrumentation (mass spectrometry, nuclear magnetic resonance spectrometry). Chromatography is one of the most widely used techniques. Lots of pollutant which must have quantified, have polar properties and its may present a risk for patients. The analytical control of genotoxic (altering the genetic information stored in DNA), carcinogenic contaminants is a constant challenge for analysts. Organic acids, amines, acid chlorides which are easily ionizable, hydrolysable are difficult to analyze at low concentration limits by the means of gas chromatography or high performance liquid chromatography. For the analysis of such contaminants, the high performance ion exchange chromatography method is a possible solution. In drug analytics, the ion chromatography techniques (ion exchange, ion exclusion, ion pair, ligand exchange) are not as widely used as the other liquid chromatography methods. In addition to inorganic anions and cations, ion chromatography is a suitable chromatographic method for the analysis of organic acids, amines, and hydrolysable compounds. In case of amines, this technique has better peak symmetry and theoretical plate height than gas chromatography. However, additional acidic API may cause the disappearance of these peaks. With this instrument, not only impurities can be tested, but also the counter ions of basic drug substances can be easily measured to verify the molecular composition of the active pharmaceutical ingredient. The manuscript describes the applications of ion exchange chromatography through some examples from pharmaceutical industry. In some cases, the methods have been validated according to international guidelines to demonstrate the applicability of high-performance ion exchange chromatography for the analysis of ionizable organic/inorganic compounds in pharmaceutical production.
. They have been isolated from the environment or on human skin and mucous membranes. Therefore, the study of presence of the species of these genera needs more attention in microbial identification methods in pharmaceutical production. Therefore, the
. Conclusions Even though the BNZ recrystallisation conditions were varied, only one polymorphic form of BNZ was detected. This result validates the stability of BNZ as a monoclinic unit cell, which is desirable for pharmaceutical production and product
imported chemical products were used for pharmaceutical production. Establishment of RIKEN Dr. Jokichi Takamine initiated the movement of establishing a national research institute in June 1913. 9 He was a
