45 research outputs found
Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2
The Src homology 2 (SH2) domain recognizes phosphotyrosine (pY) post translational modifications in partner proteins to trigger downstream signaling. Drug discovery efforts targeting the SH2 domains have long been stymied by the poor drug-like properties of phosphate and its mimetics. Here, we use structure-based design to target the SH2 domain of the E3 ligase suppressor of cytokine signaling 2 (SOCS2). Starting from the highly ligand-efficient pY amino acid, a fragment growing approach reveals covalent modification of Cys111 in a co-crystal structure, which we leverage to rationally design a cysteine-directed electrophilic covalent inhibitor MN551. We report the prodrug MN714 containing a pivaloyloxymethyl (POM) protecting group and evidence its cell permeability and capping group unmasking using cellular target engagement and in-cell 19F NMR spectroscopy. Covalent engagement at Cys111 competitively blocks recruitment of cellular SOCS2 protein to its native substrate. The qualified inhibitors of SOCS2 could find attractive applications as chemical probes to understand the biology of SOCS2 and its CRL5 complex, and as E3 ligase handles in proteolysis targeting chimera (PROTACs) to induce targeted protein degradation.</p
Discovery of XL01126:A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood-Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2
[Image: see text] Leucine-rich repeat kinase 2 (LRRK2) is one of the most promising targets for Parkinsonβs disease. LRRK2-targeting strategies have primarily focused on type 1 kinase inhibitors, which, however, have limitations as the inhibited protein can interfere with natural mechanisms, which could lead to undesirable side effects. Herein, we report the development of LRRK2 proteolysis targeting chimeras (PROTACs), culminating in the discovery of degrader XL01126, as an alternative LRRK2-targeting strategy. Initial designs and screens of PROTACs based on ligands for E3 ligases von HippelβLindau (VHL), Cereblon (CRBN), and cellular inhibitor of apoptosis (cIAP) identified the best degraders containing thioether-conjugated VHL ligand VH101. A second round of medicinal chemistry exploration led to qualifying XL01126 as a fast and potent degrader of LRRK2 in multiple cell lines, with DC(50) values within 15β72 nM, D(max) values ranging from 82 to 90%, and degradation half-lives spanning from 0.6 to 2.4 h. XL01126 exhibits high cell permeability and forms a positively cooperative ternary complex with VHL and LRRK2 (Ξ± = 5.7), which compensates for a substantial loss of binary binding affinities to VHL and LRRK2, underscoring its strong degradation performance in cells. Remarkably, XL01126 is orally bioavailable (F = 15%) and can penetrate the bloodβbrain barrier after either oral or parenteral dosing in mice. Taken together, these experiments qualify XL01126 as a suitable degrader probe to study the noncatalytic and scaffolding functions of LRRK2 in vitro and in vivo and offer an attractive starting point for future drug development
Comparative Assessment of Quality Requirements for Medicinal Products Containing Diosmin
Currently, there is an increase in preand post-approval testing of medicinal products containing diosmin and hence a need to unify approaches to standardisation of this group of pharmaceuticals. Moreover, the State Pharmacopoeia of the Russian Federation lacks a monograph for these products.The aim of the study was to determine an approach to standardisation of medicinal products containing diosmin.Materials and methods: the study analysed scientific publications, as well as monographs of leading foreign pharmacopoeias. Experimental work was carried out using samples of diosmin-containing pharmaceuticals in the form of 500 and 1000 mg film-coated tablets produced by Russian and foreign manufacturers. The study involved high performance liquid chromatography with UV detection using an Agilent 1260 Infinity II liquid chromatography system with a diode array detector. The following reference standards were used: a diosmin RS, USP grade; a hesperidin CRS, Ph. Eur. Grade; and a diosmin CRS for testing chromatography system suitability for identification of impurities A, B, C, D, E, and F, Ph. Eur. grade.Results: the authors reviewed quality requirements for pharmaceutical products containing diosmin and analysed experimental data obtained during preand post-approval testing of Russian and foreign medicines. The comparison of regulatory documents for registered diosmin-containing medicinal products showed a difference in approaches to assessing the contents of related substances and active pharmaceutical ingredients. Having analysed the literature, experimental data and regulatory requirements for standardisation of diosmin-containing pharmaceuticals, the authors recommended an approach to standardisation. According to the approach, concomitant flavonoids (hesperidin, isorchoifolin, linarin, and diosmetin) contributing to the pharmacological activity of a medicinal product are specified as part of Assay, and process-related by-products (impurities A and D) are specified and evaluated as part of Related substances tests.Conclusion: the authors propose to evaluate the contents of concomitant flavonoids (hesperidin, isorchoifolin, linarin, diosmetin) under Assay and to specify impurities A and D, as well as single unidentified impurities and total amount of impurities under Related substances
Π Π°Π·ΡΠ°Π±ΠΎΡΠΊΠ° ΡΠ½ΠΈΡΠΈΡΠΈΡΠΎΠ²Π°Π½Π½ΠΎΠΉ ΠΠΠΠ₯-ΠΌΠ΅ΡΠΎΠ΄ΠΈΠΊΠΈ ΠΎΠΏΡΠ΅Π΄Π΅Π»Π΅Π½ΠΈΡ ΡΠΎΠ΄ΡΡΠ²Π΅Π½Π½ΡΡ ΠΏΡΠΈΠΌΠ΅ΡΠ΅ΠΉ ΠΈ ΠΊΠΎΠ»ΠΈΡΠ΅ΡΡΠ²Π΅Π½Π½ΠΎΠΉ ΠΎΡΠ΅Π½ΠΊΠΈ Π΄Π΅ΠΉΡΡΠ²ΡΡΡΠ΅Π³ΠΎ Π²Π΅ΡΠ΅ΡΡΠ²Π° ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ² ΠΏΠ°ΠΏΠ°Π²Π΅ΡΠΈΠ½Π° Π³ΠΈΠ΄ΡΠΎΡ Π»ΠΎΡΠΈΠ΄Π°
Abstract. Papaverine hydrochloride products are used as anticonvulsants in routine medical practice. Most of the approved product specification files include thin-layer chromatography for assessment of product-related impurities and UV spectrophotometry for determination of active pharmaceutical ingredients. An HPLC assay is not used for determination of papaverine hydrochloride in drug dosage forms.The aim of the study was to develop an HPLC test method for determination of product-related impurities and for quantification of papaverine hydrochloride in solutions for injection, tablets, and rectal suppositories.Materials and methods: samples of the following Russian-made papaverine products were used in the study: Papaverine, solution for injection, 20Β mg/mL; Papaverine, rectal suppositories, 20Β mg; Papaverine, tablets, 40Β mg. The Agilent 1260 Infinity II DAD System was used for the HPLC assay, and the Agilent 8453Π UV-Vis System was used for recording UV spectra. The determination of product-related impurities and the assay of active ingredients were performed simultaneously by HPLC using a reversed-phase column Kromasil 100-5-C18, 250Γ4.6Β mm, 5 ΞΌm, the gradient elution mode, and detection atΒ Β Β Β 238 nm. Papaverine Hydrochloride USP RS, 99% purity, and Noscapine EP CRS were used as reference standards.Results: the study demonstrated that determination of product-related impurities and assay of active ingredients in papaverine products can be performed simultaneously using HPLC.Conclusions: the authors proposed an HPLC test method for determination of active ingredients in papaverine products, which is aligned with the βconsistent standardisationβ principle and can be recommended for inclusion into draft monographs for papaverine products.Π Π΅Π·ΡΠΌΠ΅. ΠΡΠ΅ΠΏΠ°ΡΠ°ΡΡ ΠΏΠ°ΠΏΠ°Π²Π΅ΡΠΈΠ½Π° Π³ΠΈΠ΄ΡΠΎΡ
Π»ΠΎΡΠΈΠ΄Π° ΠΏΡΠΈΠΌΠ΅Π½ΡΡΡΡΡ Π² ΠΌΠ΅Π΄ΠΈΡΠΈΠ½ΡΠΊΠΎΠΉ ΠΏΡΠ°ΠΊΡΠΈΠΊΠ΅ Π² ΠΊΠ°ΡΠ΅ΡΡΠ²Π΅ ΡΠΏΠ°Π·ΠΌΠΎΠ»ΠΈΡΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ ΡΡΠ΅Π΄ΡΡΠ²Π°. Π Π±ΠΎΠ»ΡΡΠΈΠ½ΡΡΠ²ΠΎ Π·Π°ΡΠ΅Π³ΠΈΡΡΡΠΈΡΠΎΠ²Π°Π½Π½ΡΡ
Π½ΠΎΡΠΌΠ°ΡΠΈΠ²Π½ΡΡ
Π΄ΠΎΠΊΡΠΌΠ΅Π½ΡΠΎΠ² Π½Π° ΡΡΠΈ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΡ Π²ΠΊΠ»ΡΡΠ΅Π½Π° ΠΌΠ΅ΡΠΎΠ΄ΠΈΠΊΠ° ΠΎΡΠ΅Π½ΠΊΠΈ ΡΠΎΠ΄ΡΡΠ²Π΅Π½Π½ΡΡ
ΠΏΡΠΈΠΌΠ΅ΡΠ΅ΠΉ ΠΌΠ΅ΡΠΎΠ΄ΠΎΠΌ ΡΠΎΠ½ΠΊΠΎΡΠ»ΠΎΠΉΠ½ΠΎΠΉ Ρ
ΡΠΎΠΌΠ°ΡΠΎΠ³ΡΠ°ΡΠΈΠΈ, Π΄Π»Ρ ΠΎΠΏΡΠ΅Π΄Π΅Π»Π΅Π½ΠΈΡ Π΄Π΅ΠΉΡΡΠ²ΡΡΡΠ΅Π³ΠΎ Π²Π΅ΡΠ΅ΡΡΠ²Π° ΠΈΡΠΏΠΎΠ»ΡΠ·ΡΠ΅ΡΡΡ Π£Π€-ΡΠΏΠ΅ΠΊΡΡΠΎΡΠΎΡΠΎΠΌΠ΅ΡΡΠΈΡ. ΠΠΎΠ»ΠΈΡΠ΅ΡΡΠ²Π΅Π½Π½ΠΎΠ΅ ΠΎΠΏΡΠ΅Π΄Π΅Π»Π΅Π½ΠΈΠ΅ ΠΏΠ°ΠΏΠ°Π²Π΅ΡΠΈΠ½Π° Π³ΠΈΠ΄ΡΠΎΡ
Π»ΠΎΡΠΈΠ΄Π° Π² Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΡ
ΡΠΎΡΠΌΠ°Ρ
ΠΌΠ΅ΡΠΎΠ΄ΠΎΠΌ Π²ΡΡΠΎΠΊΠΎΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΠΉ ΠΆΠΈΠ΄ΠΊΠΎΡΡΠ½ΠΎΠΉ Ρ
ΡΠΎΠΌΠ°ΡΠΎΠ³ΡΠ°ΡΠΈΠΈ (ΠΠΠΠ₯) Π½Π΅ ΠΏΡΠΎΠ²ΠΎΠ΄ΠΈΡΡΡ.Π¦Π΅Π»Ρ ΡΠ°Π±ΠΎΡΡ: ΡΠ°Π·ΡΠ°Π±ΠΎΡΠΊΠ° ΠΌΠ΅ΡΠΎΠ΄ΠΈΠΊΠΈ ΠΎΠΏΡΠ΅Π΄Π΅Π»Π΅Π½ΠΈΡ ΡΠΎΠ΄ΡΡΠ²Π΅Π½Π½ΡΡ
ΠΏΡΠΈΠΌΠ΅ΡΠ΅ΠΉ ΠΈ ΠΊΠΎΠ»ΠΈΡΠ΅ΡΡΠ²Π΅Π½Π½ΠΎΠ³ΠΎ ΠΎΠΏΡΠ΅Π΄Π΅Π»Π΅Π½ΠΈΡ ΠΏΠ°ΠΏΠ°Π²Π΅ΡΠΈΠ½Π° Π³ΠΈΠ΄ΡΠΎΡ
Π»ΠΎΡΠΈΠ΄Π° Π² ΡΠ°ΡΡΠ²ΠΎΡΠ΅ Π΄Π»Ρ ΠΈΠ½ΡΠ΅ΠΊΡΠΈΠΉ, ΡΠ°Π±Π»Π΅ΡΠΊΠ°Ρ
ΠΈ ΡΡΠΏΠΏΠΎΠ·ΠΈΡΠΎΡΠΈΡΡ
ΡΠ΅ΠΊΡΠ°Π»ΡΠ½ΡΡ
ΠΌΠ΅ΡΠΎΠ΄ΠΎΠΌ ΠΠΠΠ₯.ΠΠ°ΡΠ΅ΡΠΈΠ°Π»Ρ ΠΈ ΠΌΠ΅ΡΠΎΠ΄Ρ: ΠΎΠ±ΡΠ΅ΠΊΡΠ°ΠΌΠΈ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ ΡΠ²Π»ΡΠ»ΠΈΡΡ ΠΎΠ±ΡΠ°Π·ΡΡ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ² ΠΏΠ°ΠΏΠ°Π²Π΅ΡΠΈΠ½Π° ΠΎΡΠ΅ΡΠ΅ΡΡΠ²Π΅Π½Π½ΡΡ
ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄ΠΈΡΠ΅Π»Π΅ΠΉ: Β«ΠΠ°ΠΏΠ°Π²Π΅ΡΠΈΠ½, ΡΠ°ΡΡΠ²ΠΎΡ Π΄Π»Ρ ΠΈΠ½ΡΠ΅ΠΊΡΠΈΠΉ 20Β ΠΌΠ³/ΠΌΠ»Β», Β«ΠΠ°ΠΏΠ°Π²Π΅ΡΠΈΠ½, ΡΡΠΏΠΏΠΎΠ·ΠΈΡΠΎΡΠΈΠΈ ΡΠ΅ΠΊΡΠ°Π»ΡΠ½ΡΠ΅, 20Β ΠΌΠ³Β», Β«ΠΠ°ΠΏΠ°Π²Π΅ΡΠΈΠ½, ΡΠ°Π±Π»Π΅ΡΠΊΠΈ 40Β ΠΌΠ³Β». ΠΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠ΅ ΠΏΡΠΎΠ²ΠΎΠ΄ΠΈΠ»ΠΈ ΠΌΠ΅ΡΠΎΠ΄ΠΎΠΌ ΠΠΠΠ₯ Π½Π° ΠΆΠΈΠ΄ΠΊΠΎΡΡΠ½ΠΎΠΌ Ρ
ΡΠΎΠΌΠ°ΡΠΎΠ³ΡΠ°ΡΠ΅ Agilent 1260 Infinity II DAD System , ΡΠ΅Π³ΠΈΡΡΡΠ°ΡΠΈΡ Π£Π€-ΡΠΏΠ΅ΠΊΡΡΠΎΠ² β Π½Π° ΡΠΏΠ΅ΠΊΡΡΠΎΡΠΎΡΠΎΠΌΠ΅ΡΡΠ΅ Agilent 8453Π UV-Vis System. ΠΡΠ΅Π½ΠΊΡ ΡΠΎΠ΄Π΅ΡΠΆΠ°Π½ΠΈΡ ΡΠΎΠ΄ΡΡΠ²Π΅Π½Π½ΡΡ
ΠΏΡΠΈΠΌΠ΅ΡΠ΅ΠΉ ΠΈ ΠΊΠΎΠ»ΠΈΡΠ΅ΡΡΠ²Π΅Π½Π½ΠΎΠ΅ ΠΎΠΏΡΠ΅Π΄Π΅Π»Π΅Π½ΠΈΠ΅ Π΄Π΅ΠΉΡΡΠ²ΡΡΡΠΈΡ
Π²Π΅ΡΠ΅ΡΡΠ² ΠΏΡΠΎΠ²ΠΎΠ΄ΠΈΠ»ΠΈ ΠΎΠ΄Π½ΠΎΠ²ΡΠ΅ΠΌΠ΅Π½Π½ΠΎ ΠΌΠ΅ΡΠΎΠ΄ΠΎΠΌ ΠΠΠΠ₯ Π½Π° ΠΎΠ±ΡΠ°ΡΠ΅Π½Π½ΠΎ-ΡΠ°Π·ΠΎΠ²ΠΎΠΉ ΠΊΠΎΠ»ΠΎΠ½ΠΊΠ΅ Kromasil 100-5-C18, ΡΠ°Π·ΠΌΠ΅Ρ ΠΊΠΎΠ»ΠΎΠ½ΠΊΠΈ 250Γ4,6Β ΠΌΠΌ, ΡΠ°Π·ΠΌΠ΅Ρ ΡΠ°ΡΡΠΈΡ 5Β ΠΌΠΊΠΌ, Π² ΡΡΠ»ΠΎΠ²ΠΈΡΡ
Π³ΡΠ°Π΄ΠΈΠ΅Π½ΡΠ½ΠΎΠ³ΠΎ ΡΠ»ΡΠΈΡΠΎΠ²Π°Π½ΠΈΡ Ρ Π΄Π΅ΡΠ΅ΠΊΡΠΈΡΠΎΠ²Π°Π½ΠΈΠ΅ΠΌ ΠΏΡΠΈ 238Β Π½ΠΌ. Π ΠΊΠ°ΡΠ΅ΡΡΠ²Π΅ ΡΡΠ°Π½Π΄Π°ΡΡΠ½ΡΡ
ΠΎΠ±ΡΠ°Π·ΡΠΎΠ² ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π»ΠΈ ΠΏΠ°ΠΏΠ°Π²Π΅ΡΠΈΠ½Π° Π³ΠΈΠ΄ΡΠΎΡ
Π»ΠΎΡΠΈΠ΄ ΠΊΠ²Π°Π»ΠΈΡΠΈΠΊΠ°ΡΠΈΠΈ USP RS Ρ ΡΠΎΠ΄Π΅ΡΠΆΠ°Π½ΠΈΠ΅ΠΌ Π΄Π΅ΠΉΡΡΠ²ΡΡΡΠ΅Π³ΠΎ Π²Π΅ΡΠ΅ΡΡΠ²Π° 99,9% ΠΈ Π½ΠΎΡΠΊΠ°ΠΏΠΈΠ½ ΠΊΠ²Π°Π»ΠΈΡΠΈΠΊΠ°ΡΠΈΠΈ EP CRS.Π Π΅Π·ΡΠ»ΡΡΠ°ΡΡ: ΠΏΠΎΠΊΠ°Π·Π°Π½Π° Π²ΠΎΠ·ΠΌΠΎΠΆΠ½ΠΎΡΡΡ ΠΎΠ΄Π½ΠΎΠ²ΡΠ΅ΠΌΠ΅Π½Π½ΠΎΠ³ΠΎ ΠΎΠΏΡΠ΅Π΄Π΅Π»Π΅Π½ΠΈΡ ΡΠΎΠ΄ΡΡΠ²Π΅Π½Π½ΡΡ
ΠΏΡΠΈΠΌΠ΅ΡΠ΅ΠΉ ΠΈ ΠΊΠΎΠ»ΠΈΡΠ΅ΡΡΠ²Π΅Π½Π½ΠΎΠ³ΠΎ ΠΎΠΏΡΠ΅Π΄Π΅Π»Π΅Π½ΠΈΡ Π΄Π΅ΠΉΡΡΠ²ΡΡΡΠΈΡ
Π²Π΅ΡΠ΅ΡΡΠ² Π² ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠ°Ρ
ΠΏΠ°ΠΏΠ°Π²Π΅ΡΠΈΠ½Π° ΠΌΠ΅ΡΠΎΠ΄ΠΎΠΌ ΠΠΠΠ₯.ΠΡΠ²ΠΎΠ΄Ρ: ΠΏΡΠ΅Π΄Π»ΠΎΠΆΠ΅Π½Π° ΠΌΠ΅ΡΠΎΠ΄ΠΈΠΊΠ° ΠΎΠΏΡΠ΅Π΄Π΅Π»Π΅Π½ΠΈΡ Π΄Π΅ΠΉΡΡΠ²ΡΡΡΠΈΡ
Π²Π΅ΡΠ΅ΡΡΠ² Π² ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠ°Ρ
ΠΏΠ°ΠΏΠ°Π²Π΅ΡΠΈΠ½Π° ΠΌΠ΅ΡΠΎΠ΄ΠΎΠΌ ΠΠΠΠ₯, ΡΠ΄ΠΎΠ²Π»Π΅ΡΠ²ΠΎΡΡΡΡΠ°Ρ ΠΏΡΠΈΠ½ΡΠΈΠΏΡ ΡΠΊΠ²ΠΎΠ·Π½ΠΎΠΉ ΡΡΠ°Π½Π΄Π°ΡΡΠΈΠ·Π°ΡΠΈΠΈ, ΠΊΠΎΡΠΎΡΠ°Ρ ΠΌΠΎΠΆΠ΅Ρ Π±ΡΡΡ ΡΠ΅ΠΊΠΎΠΌΠ΅Π½Π΄ΠΎΠ²Π°Π½Π° Π΄Π»Ρ Π²ΠΊΠ»ΡΡΠ΅Π½ΠΈΡ Π² ΠΏΡΠΎΠ΅ΠΊΡ ΡΠ°ΡΠΌΠ°ΠΊΠΎΠΏΠ΅ΠΉΠ½ΡΡ
ΡΡΠ°ΡΠ΅ΠΉ Π½Π° ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΡ ΠΏΠ°ΠΏΠ°Π²Π΅ΡΠΈΠ½Π°
Π‘ΡΠ°Π²Π½ΠΈΡΠ΅Π»ΡΠ½Π°Ρ ΠΎΡΠ΅Π½ΠΊΠ° ΡΡΠ΅Π±ΠΎΠ²Π°Π½ΠΈΠΉ ΠΊ ΠΊΠ°ΡΠ΅ΡΡΠ²Ρ Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΡ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ², ΡΠΎΠ΄Π΅ΡΠΆΠ°ΡΠΈΡ Π΄ΠΈΠΎΡΠΌΠΈΠ½
Currently, there is an increase in pre- and post-approval testing of medicinal products containing diosmin and hence a need to unify approaches to standardisation of this group of pharmaceuticals. Moreover, the State Pharmacopoeia of the Russian Federation lacks a monograph for these products.The aim of the study was to determine an approach to standardisation of medicinal products containing diosmin.Materials and methods: the study analysed scientific publications, as well as monographs of leading foreign pharmacopoeias. Experimental work was carried out using samples of diosmin-containing pharmaceuticals in the form of 500 and 1000 mg film-coated tablets produced by Russian and foreign manufacturers. The study involved high performance liquid chromatography with UV detection using an Agilent 1260 Infinity II liquid chromatography system with a diode array detector. The following reference standards were used: a diosmin RS, USP grade; a hesperidin CRS, Ph. Eur. Grade; and a diosmin CRS for testing chromatography system suitability for identification of impurities A, B, C, D, E, and F, Ph. Eur. grade.Results: the authors reviewed quality requirements for pharmaceutical products containing diosmin and analysed experimental data obtained during pre- and post-approval testing of Russian and foreign medicines. The comparison of regulatory documents for registered diosmin-containing medicinal products showed a difference in approaches to assessing the contents of related substances and active pharmaceutical ingredients. Having analysed the literature, experimental data and regulatory requirements for standardisation of diosmin-containing pharmaceuticals, the authors recommended an approach to standardisation. According to the approach, concomitant flavonoids (hesperidin, isorchoifolin, linarin, and diosmetin) contributing to the pharmacological activity of a medicinal product are specified as part of Assay, and process-related by-products (impurities A and D) are specified and evaluated as part of Related substances tests.Conclusion: the authors propose to evaluate the contents of concomitant flavonoids (hesperidin, isorchoifolin, linarin, diosmetin) under Assay and to specify impurities A and D, as well as single unidentified impurities and total amount of impurities under Related substances.Π Π½Π°ΡΡΠΎΡΡΠ΅Π΅ Π²ΡΠ΅ΠΌΡ ΡΡΡΠ΅ΡΡΠ²ΡΠ΅Ρ ΠΏΠΎΡΡΠ΅Π±Π½ΠΎΡΡΡ Π² ΡΠ½ΠΈΡΠΈΠΊΠ°ΡΠΈΠΈ ΠΏΠΎΠ΄Ρ
ΠΎΠ΄ΠΎΠ² ΠΊ ΡΡΠ°Π½Π΄Π°ΡΡΠΈΠ·Π°ΡΠΈΠΈ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ² Π΄ΠΈΠΎΡΠΌΠΈΠ½Π° Π² ΡΠ²ΡΠ·ΠΈ Ρ ΡΠ²Π΅Π»ΠΈΡΠ΅Π½ΠΈΠ΅ΠΌ ΠΎΠ±ΡΠ΅ΠΌΠ° ΠΏΡΠΎΠ²Π΅Π΄Π΅Π½ΠΈΡ ΡΠ΅Π³ΠΈΡΡΡΠ°ΡΠΈΠΎΠ½Π½ΠΎΠΉ ΠΈ ΠΏΠΎΡΡΡΠ΅Π³ΠΈΡΡΡΠ°ΡΠΈΠΎΠ½Π½ΠΎΠΉ ΡΠΊΡΠΏΠ΅ΡΡΠΈΠ·Ρ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ² ΡΡΠΎΠΉ Π³ΡΡΠΏΠΏΡ, Π° ΡΠ°ΠΊΠΆΠ΅ Ρ Π½Π΅ΠΎΠ±Ρ
ΠΎΠ΄ΠΈΠΌΠΎΡΡΡΡ ΡΠ°Π·ΡΠ°Π±ΠΎΡΠΊΠΈ ΡΠ°ΡΠΌΠ°ΠΊΠΎΠΏΠ΅ΠΉΠ½ΠΎΠΉ ΡΡΠ°ΡΡΠΈ Π½Π° ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΡ Π΄ΠΈΠΎΡΠΌΠΈΠ½Π° Π΄Π»Ρ ΠΠΎΡΡΠ΄Π°ΡΡΡΠ²Π΅Π½Π½ΠΎΠΉ ΡΠ°ΡΠΌΠ°ΠΊΠΎΠΏΠ΅ΠΈ Π ΠΎΡΡΠΈΠΉΡΠΊΠΎΠΉ Π€Π΅Π΄Π΅ΡΠ°ΡΠΈΠΈ.Π¦Π΅Π»Ρ ΡΠ°Π±ΠΎΡΡ: ΠΎΠΏΡΠ΅Π΄Π΅Π»Π΅Π½ΠΈΠ΅ ΠΏΠΎΠ΄Ρ
ΠΎΠ΄Π° ΠΊ ΡΡΠ°Π½Π΄Π°ΡΡΠΈΠ·Π°ΡΠΈΠΈ Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΡ
ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ², ΡΠΎΠ΄Π΅ΡΠΆΠ°ΡΠΈΡ
Π΄ΠΈΠΎΡΠΌΠΈΠ½.ΠΠ°ΡΠ΅ΡΠΈΠ°Π»Ρ ΠΈ ΠΌΠ΅ΡΠΎΠ΄Ρ: ΠΎΠ±ΡΠ΅ΠΊΡΠ°ΠΌΠΈ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ ΡΠ»ΡΠΆΠΈΠ»ΠΈ Π΄Π°Π½Π½ΡΠ΅ Π½Π°ΡΡΠ½ΡΡ
ΠΏΡΠ±Π»ΠΈΠΊΠ°ΡΠΈΠΉ, Π° ΡΠ°ΠΊΠΆΠ΅ ΡΠ°ΡΡΠ½ΡΠ΅ ΠΌΠΎΠ½ΠΎΠ³ΡΠ°ΡΠΈΠΈ Π²Π΅Π΄ΡΡΠΈΡ
Π·Π°ΡΡΠ±Π΅ΠΆΠ½ΡΡ
ΡΠ°ΡΠΌΠ°ΠΊΠΎΠΏΠ΅ΠΉ. ΠΠΊΡΠΏΠ΅ΡΠΈΠΌΠ΅Π½ΡΠ°Π»ΡΠ½Π°Ρ ΡΠ°Π±ΠΎΡΠ° ΠΏΡΠΎΠ²ΠΎΠ΄ΠΈΠ»Π°ΡΡ Π½Π° ΠΎΠ±ΡΠ°Π·ΡΠ°Ρ
ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ² Π΄ΠΈΠΎΡΠΌΠΈΠ½Π° Π² ΡΠΎΡΠΌΠ΅ ΡΠ°Π±Π»Π΅ΡΠΎΠΊ, ΠΏΠΎΠΊΡΡΡΡΡ
ΠΏΠ»Π΅Π½ΠΎΡΠ½ΠΎΠΉ ΠΎΠ±ΠΎΠ»ΠΎΡΠΊΠΎΠΉ, Π² Π΄ΠΎΠ·ΠΈΡΠΎΠ²ΠΊΠ΅ 500 ΠΈ 1000 ΠΌΠ³, ΠΎΡΠ΅ΡΠ΅ΡΡΠ²Π΅Π½Π½ΡΡ
ΠΈ Π·Π°ΡΡΠ±Π΅ΠΆΠ½ΡΡ
ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄ΠΈΡΠ΅Π»Π΅ΠΉ. ΠΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠ΅ ΠΎΡΡΡΠ΅ΡΡΠ²Π»ΡΠ»ΠΈ ΠΌΠ΅ΡΠΎΠ΄ΠΎΠΌ Π²ΡΡΠΎΠΊΠΎΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΠΉ ΠΆΠΈΠ΄ΠΊΠΎΡΡΠ½ΠΎΠΉ Ρ
ΡΠΎΠΌΠ°ΡΠΎΠ³ΡΠ°ΡΠΈΠΈ Ρ Π£Π€-Π΄Π΅ΡΠ΅ΠΊΡΠΈΡΠΎΠ²Π°Π½ΠΈΠ΅ΠΌ Π½Π° ΠΆΠΈΠ΄ΠΊΠΎΡΡΠ½ΠΎΠΌ Ρ
ΡΠΎΠΌΠ°ΡΠΎΠ³ΡΠ°ΡΠ΅ Agilent 1260 Infinity II DAD System. Π ΠΊΠ°ΡΠ΅ΡΡΠ²Π΅ ΡΡΠ°Π½Π΄Π°ΡΡΠ½ΡΡ
ΠΎΠ±ΡΠ°Π·ΡΠΎΠ² ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π»ΠΈ Π΄ΠΈΠΎΡΠΌΠΈΠ½ ΠΊΠ²Π°Π»ΠΈΡΠΈΠΊΠ°ΡΠΈΠΈ USP RS, Π³Π΅ΡΠΏΠ΅ΡΠΈΠ΄ΠΈΠ½ ΠΊΠ²Π°Π»ΠΈΡΠΈΠΊΠ°ΡΠΈΠΈ EP CRS ΠΈ Π΄ΠΈΠΎΡΠΌΠΈΠ½ Π΄Π»Ρ ΠΏΡΠΎΠ²Π΅ΡΠΊΠΈ ΠΏΡΠΈΠ³ΠΎΠ΄Π½ΠΎΡΡΠΈ Ρ
ΡΠΎΠΌΠ°ΡΠΎΠ³ΡΠ°ΡΠΈΡΠ΅ΡΠΊΠΎΠΉ ΡΠΈΡΡΠ΅ΠΌΡ ΠΊΠ²Π°Π»ΠΈΡΠΈΠΊΠ°ΡΠΈΠΈ EP CRS Π΄Π»Ρ ΠΈΠ΄Π΅Π½ΡΠΈΡΠΈΠΊΠ°ΡΠΈΠΈ ΠΏΡΠΈΠΌΠ΅ΡΠ΅ΠΉ A, B, C, D, E ΠΈ F.Π Π΅Π·ΡΠ»ΡΡΠ°ΡΡ: ΠΏΡΠΎΠ²Π΅Π΄Π΅Π½ Π°Π½Π°Π»ΠΈΡΠΈΡΠ΅ΡΠΊΠΈΠΉ ΠΎΠ±Π·ΠΎΡ ΡΡΠ΅Π±ΠΎΠ²Π°Π½ΠΈΠΉ ΠΊ ΠΊΠ°ΡΠ΅ΡΡΠ²Ρ Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΡ
ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ², ΡΠΎΠ΄Π΅ΡΠΆΠ°ΡΠΈΡ
Π΄ΠΈΠΎΡΠΌΠΈΠ½, Ρ Π°Π½Π°Π»ΠΈΠ·ΠΎΠΌ ΡΠΊΡΠΏΠ΅ΡΠΈΠΌΠ΅Π½ΡΠ°Π»ΡΠ½ΡΡ
Π΄Π°Π½Π½ΡΡ
, ΠΏΠΎΠ»ΡΡΠ΅Π½Π½ΡΡ
Π² Ρ
ΠΎΠ΄Π΅ ΡΠ΅Π³ΠΈΡΡΡΠ°ΡΠΈΠΎΠ½Π½ΠΎΠΉ ΠΈ ΠΏΠΎΡΡΡΠ΅Π³ΠΈΡΡΡΠ°ΡΠΈΠΎΠ½Π½ΠΎΠΉ ΡΠΊΡΠΏΠ΅ΡΡΠΈΠ·Ρ ΡΠΎΡΡΠΈΠΉΡΠΊΠΈΡ
ΠΈ Π·Π°ΡΡΠ±Π΅ΠΆΠ½ΡΡ
Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΡ
ΡΡΠ΅Π΄ΡΡΠ². Π‘ΡΠ°Π²Π½ΠΈΡΠ΅Π»ΡΠ½ΡΠΉ Π°Π½Π°Π»ΠΈΠ· Π½ΠΎΡΠΌΠ°ΡΠΈΠ²Π½ΠΎΠΉ Π΄ΠΎΠΊΡΠΌΠ΅Π½ΡΠ°ΡΠΈΠΈ Π·Π°ΡΠ΅Π³ΠΈΡΡΡΠΈΡΠΎΠ²Π°Π½Π½ΡΡ
Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΡ
ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ², ΡΠΎΠ΄Π΅ΡΠΆΠ°ΡΠΈΡ
Π΄ΠΈΠΎΡΠΌΠΈΠ½, ΠΏΠΎΠΊΠ°Π·Π°Π» ΡΠ°Π·Π»ΠΈΡΠΈΠ΅ Π² ΠΏΠΎΠ΄Ρ
ΠΎΠ΄Π°Ρ
ΠΊ ΠΎΡΠ΅Π½ΠΊΠ΅ ΡΠΎΠ΄Π΅ΡΠΆΠ°Π½ΠΈΡ ΡΠΎΠ΄ΡΡΠ²Π΅Π½Π½ΡΡ
ΠΏΡΠΈΠΌΠ΅ΡΠ΅ΠΉ ΠΈ Π΄Π΅ΠΉΡΡΠ²ΡΡΡΠΈΡ
Π²Π΅ΡΠ΅ΡΡΠ². ΠΠ½Π°Π»ΠΈΠ· Π΄Π°Π½Π½ΡΡ
Π»ΠΈΡΠ΅ΡΠ°ΡΡΡΡ, ΡΠΊΡΠΏΠ΅ΡΠΈΠΌΠ΅Π½ΡΠ°Π»ΡΠ½ΡΡ
Π΄Π°Π½Π½ΡΡ
ΠΈ ΡΡΠ΅Π±ΠΎΠ²Π°Π½ΠΈΠΉ Π½ΠΎΡΠΌΠ°ΡΠΈΠ²Π½ΡΡ
Π΄ΠΎΠΊΡΠΌΠ΅Π½ΡΠΎΠ² Π² ΠΎΠ±Π»Π°ΡΡΠΈ ΡΡΠ°Π½Π΄Π°ΡΡΠΈΠ·Π°ΡΠΈΠΈ, ΠΏΡΠ΅Π΄ΡΡΠ²Π»ΡΠ΅ΠΌΡΡ
ΠΊ ΡΡΠ°Π½Π΄Π°ΡΡΠΈΠ·Π°ΡΠΈΠΈ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ², ΡΠΎΠ΄Π΅ΡΠΆΠ°ΡΠΈΡ
Π΄ΠΈΠΎΡΠΌΠΈΠ½, ΠΏΠΎΠ·Π²ΠΎΠ»ΡΠ΅Ρ ΡΠ΅ΠΊΠΎΠΌΠ΅Π½Π΄ΠΎΠ²Π°ΡΡ ΠΏΠΎΠ΄Ρ
ΠΎΠ΄, ΡΠΎΠ³Π»Π°ΡΠ½ΠΎ ΠΊΠΎΡΠΎΡΠΎΠΌΡ ΡΠΎΠΏΡΡΡΡΠ²ΡΡΡΠΈΠ΅ ΡΠ»Π°Π²ΠΎΠ½ΠΎΠΈΠ΄Ρ (Π³Π΅ΡΠΏΠ΅ΡΠΈΠ΄ΠΈΠ½, ΠΈΠ·ΠΎΡΡ
ΠΎΠΉΡΠΎΠ»ΠΈΠ½, Π»ΠΈΠ½Π°ΡΠΈΠ½, Π΄ΠΈΠΎΡΠΌΠ΅ΡΠΈΠ½), ΠΎΠ±Π΅ΡΠΏΠ΅ΡΠΈΠ²Π°ΡΡΠΈΠ΅ Π²ΠΊΠ»Π°Π΄ Π² ΡΠ°ΡΠΌΠ°ΠΊΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΎΠ΅ Π΄Π΅ΠΉΡΡΠ²ΠΈΠ΅ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠ°, Π½ΠΎΡΠΌΠΈΡΡΡΡΡΡ Π² ΡΠΎΡΡΠ°Π²Π΅ ΠΏΠΎΠΊΠ°Π·Π°ΡΠ΅Π»Ρ Β«ΠΠΎΠ»ΠΈΡΠ΅ΡΡΠ²Π΅Π½Π½ΠΎΠ΅ ΠΎΠΏΡΠ΅Π΄Π΅Π»Π΅Π½ΠΈΠ΅Β». ΠΡΠΈΠΌΠ΅ΡΠΈ, ΠΎΡΠ½ΠΎΡΡΡΠΈΠ΅ΡΡ ΠΊ ΠΏΠΎΠ±ΠΎΡΠ½ΡΠΌ ΠΏΡΠΎΠ΄ΡΠΊΡΠ°ΠΌ ΠΏΡΠΈ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄ΡΡΠ²Π΅ Π΄ΠΈΠΎΡΠΌΠΈΠ½Π° (ΠΏΡΠΈΠΌΠ΅ΡΠΈ Π ΠΈ D), Π½ΠΎΡΠΌΠΈΡΡΡΡΡΡ ΠΈ ΠΎΡΠ΅Π½ΠΈΠ²Π°ΡΡΡΡ ΠΏΡΠΈ ΠΈΡΠΏΡΡΠ°Π½ΠΈΡΡ
ΠΏΠΎ ΠΏΠΎΠΊΠ°Π·Π°ΡΠ΅Π»Ρ Β«Π ΠΎΠ΄ΡΡΠ²Π΅Π½Π½ΡΠ΅ ΠΏΡΠΈΠΌΠ΅ΡΠΈΒ».ΠΡΠ²ΠΎΠ΄Ρ: ΠΏΡΠ΅Π΄Π»ΠΎΠΆΠ΅Π½ΠΎ ΠΏΡΠΎΠ²ΠΎΠ΄ΠΈΡΡ ΠΎΡΠ΅Π½ΠΊΡ ΡΠΎΠ΄Π΅ΡΠΆΠ°Π½ΠΈΡ ΡΠΎΠΏΡΡΡΡΠ²ΡΡΡΠΈΡ
ΡΠ»Π°Π²ΠΎΠ½ΠΎΠΈΠ΄ΠΎΠ² (Π³Π΅ΡΠΏΠ΅ΡΠΈΠ΄ΠΈΠ½Π°, ΠΈΠ·ΠΎΡΡ
ΠΎΠΉΡΠΎΠ»ΠΈΠ½Π°, Π»ΠΈΠ½Π°ΡΠΈΠ½Π°, Π΄ΠΈΠΎΡΠΌΠ΅ΡΠΈΠ½Π°) Π² ΡΠΎΡΡΠ°Π²Π΅ ΠΏΠΎΠΊΠ°Π·Π°ΡΠ΅Π»Ρ Β«ΠΠΎΠ»ΠΈΡΠ΅ΡΡΠ²Π΅Π½Π½ΠΎΠ΅ ΠΎΠΏΡΠ΅Π΄Π΅Π»Π΅Π½ΠΈΠ΅Β», ΠΏΡΠΈΠΌΠ΅ΡΠΈ Π ΠΈ D, Π° ΡΠ°ΠΊΠΆΠ΅ Π΅Π΄ΠΈΠ½ΠΈΡΠ½ΡΠ΅ Π½Π΅ΠΈΠ΄Π΅Π½ΡΠΈΡΠΈΡΠΈΡΠΎΠ²Π°Π½Π½ΡΠ΅ ΠΏΡΠΈΠΌΠ΅ΡΠΈ ΠΈ ΡΡΠΌΠΌΡ ΠΏΡΠΈΠΌΠ΅ΡΠ΅ΠΉ Π½ΠΎΡΠΌΠΈΡΠΎΠ²Π°ΡΡ Π² ΠΏΠΎΠΊΠ°Π·Π°ΡΠ΅Π»Π΅ Β«Π ΠΎΠ΄ΡΡΠ²Π΅Π½Π½ΡΠ΅ ΠΏΡΠΈΠΌΠ΅ΡΠΈΒ»
Towards a Biologically Plausible Computational Model of Developmental Learning with Robotic Applications
Building robots that are able to efficiently operate in the real world is a formidable challenge. Functioning in the real world is extremely difficult, because it requires a vast amount of knowledge about the world, specific tasks, and the robotβs own body, as well as the ability to handle unexpected situations. Despite the undoubtable power of modern machine learning approaches and great success in the solving of task-specific problems (especially in controlled environments), such algorithms as supervised and reinforcement learning have significant limitations in real world environments, because they require from the designer either a prepared set of labelled examples of desired behaviours or an adequate reward function. Even having these pre-requisites, the algorithm faces the problem of the greater size of the environment comparing to the agentβs learning abilities. In contrast, humans or animals efficiently gather knowledge of the world during the developmental stage. Children and young animals are intrinsically motivated to use exploration and play to select and learn information about the world that is useful in the future, but also fits into their existing mental schemas and satisfies the physical constraints. According to White, intrinsically motivated learning (also referred to as self-motivated exploratory activity) is responsible for the formation of a wide range of salient competences, from grasping and walking to language. Moreover, this ability to explore and learn for the sake of knowledge typically persists over a lifetime, progressing in complexity and allowing the adaption of the organismβs behaviour to the dynamically changing environment. The current research project aims to apply the developmental learning concept to robotics, taking an approach of building a biologically plausible model of intrinsic motivation. Page ii In particular, we have proposed a theory that explains neurological mechanisms underlying an inverted U-shaped dependence of the activity of deep cortical areas with respect to familiarity of perceived information. We have shown that our model is able to account for recent neuroimaging studies that have not been explained yet. Furthermore, we have linked the neural activity to behavioural response through the feeling of pleasure, showing that the neural activity effectively might be considered as a reinforcement signal that shapes the animal behaviour. We have conducted several computational experiments showing that such behaviour could structure exploration and is beneficial for building a world model in close-to-real world conditions. Finally, we have demonstrated in a simulation that exploration on the periphery of knowledge could lead to an emergence of competences
Dissociable forms of repetition priming: A computational model
Nondeclarative memory and novelty processing in the brain is an actively studied field of neuroscience, and reducing neural activity with repetition of a stimulus (repetition suppression) is a commonly observed phenomenon. Recent findings of an opposite trend specifically, rising activity for unfamiliar stimuliβquestion the generality of repetition suppression and stir debate over the underlying neural mechanisms. This letter introduces a theory and computational model that extend existing theories and suggests that both trends are, in principle, the rising and falling parts of an inverted U-shaped dependence of activity with respect to stimulus novelty that may naturally emerge in a neural network with Hebbian learning and lateral inhibition. We further demonstrate that the proposed model is sufficient for the simulation of dissociable forms of repetition priming using real-world stimuli. The results of our simulation also suggest that the novelty of stimuli used in neuroscientific research must be assessed in a particularly cautious way. The potential importance of the inverted-U in stimulus processing and its relationship to the acquisition of knowledge and competencies in humans is also discusse