[go: up one dir, main page]

WO2012098557A1 - Dérivé pegylé de gemcitabine et son procédé de préparation - Google Patents

Dérivé pegylé de gemcitabine et son procédé de préparation Download PDF

Info

Publication number
WO2012098557A1
WO2012098557A1 PCT/IN2011/000214 IN2011000214W WO2012098557A1 WO 2012098557 A1 WO2012098557 A1 WO 2012098557A1 IN 2011000214 W IN2011000214 W IN 2011000214W WO 2012098557 A1 WO2012098557 A1 WO 2012098557A1
Authority
WO
WIPO (PCT)
Prior art keywords
gemcitabine
peg
pegylated
formulation
drug
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2011/000214
Other languages
English (en)
Inventor
Sanjeeb Kumar Sahoo
Mallaredy VANDANA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
INSTITUTE OF LIFE SCIENCES
Original Assignee
INSTITUTE OF LIFE SCIENCES
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by INSTITUTE OF LIFE SCIENCES filed Critical INSTITUTE OF LIFE SCIENCES
Publication of WO2012098557A1 publication Critical patent/WO2012098557A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates a water soluble polymeric drug formulation and to a process for preparing the same.
  • Gemcitabine (2', 2'— diflouro deoxycytidine), is currently a valuable cytotoxic drug for several solid tumors, e.g. pancreatic, lung and breast cancer. It is currently the first line drug available in the market, for locally advanced and metastatic pancreatic cancer. In addition, it is also effective in combination chemotherapy for the treatment of non-small cell lung cancer, bladder cancer and breast cancer. Gemcitabine's unique mechanism of action renders it an ideal candidate for chemotherapy.
  • gemcitabine is first transported by human equilibrative nucleoside transporter -1 (h ENT1) via sodium-independent (equilibrative) mechanism and phosphorylated to monophosphate derivative (dFdCMP) by deoxycycitidine kinase (d CK), which is then converted to di- and triphospate derivatives (d FdCDP) and (dFdCTP, respectively).
  • h ENT1 human equilibrative nucleoside transporter -1
  • d CK deoxycycitidine kinase
  • d FdCDP di- and triphospate derivatives
  • d FdCTP di- and triphospate derivatives
  • dFdCDP inhibits ribonucleotide reductase (RR) liable for catalyzing the reaction that generates- the deoxyribonucleotides required for synthesis and repair of DNA.
  • dFdCTP incorporates into DNA as a false nucleoside, inhibiting DNA polymerase and thereby preventing the detection and repair of DNA repairing enzymes (masked chain termination).
  • gemcitabine has very short plasma circulation time or bioavailability of 30-90 mins. It gets rapidly cleared from the body through renal excretion due to the enzymatic conversion in liver and kidney to the inactive and more soluble metabolite 2', 2'- difluorodeoxyuridine (d). Thus, a frequent administration scheduled at high doses is required, in turn leading to myelosuppression, high levels of hepatoxicity & renal toxicity along with toxicity towards other tissues or organs. The austerity of such treatment causes the patient to greatly weaken and the cancer, which may have seemed gone, often comes back with a vengeance. Therefore, new therapeutic strategies are needed aiming towards improved pharmacokinetics.
  • PEG poly (ethylene glycol)
  • PEG poly (ethylene glycol)
  • FDA approved FDA approved, it is frequently used in numerous biomedical applications.
  • PEG is commercially available in a variety of molecular weights with different functional groups and has been extensively used as ready-for-use forms by chemical activation for covalent attachment to proteins. These activated PEGs are now being used for conjugation with small organic molecules acting as anticancer agents.
  • PEGylated drugs offer the advantages of low-dose along with long circulation displaying passive tumor targeting due to leakiness of angiogenic tumor blood vessels by Enhanced Permeability and Retention (EPR) effect; thereby facilitating superior therapeutic approach over the current chemotherapy regime for active or more aggressive cancer .
  • EPR Enhanced Permeability and Retention
  • use of a water soluble polymer like PEG act as a platform for drug targeting in non-immunogenic and non-toxic manner by increasing hydrodynamic volume after PEGylation and limiting its cellular uptake to the endocytic route leading to slower renal clearance and longer blood circulation time. Consequently,the pharmacokinetics of the drugs gets enhanced after conjugating with PEG.
  • An object of this invention is to propose a water soluble polymeric drug formulation. Another object of this invention is to propose as process for the preparation of water soluble polymeric drug formulation.
  • Further object of this invention is to propose a water soluble polymeric drug formulation which can be use as anticancer drug.
  • Still another object of this invention is to propose a polymeric drug formulation with improved pharmacokinetics.
  • Still further object of this invention is to propose a polymeric drug formulation with improved body distribution length with prolonged blood circulation.
  • Yet another object of this invention is to propose as polymeric drug formulation with high solubility and excellent biocompatibility.
  • a water soluble polymeric drug formulation comprising the amphiphilic polymer conjugated to the amino group of gemcitabine.
  • FIGURE 1 UV spectra of PEGylated gemcitabine in comparison to gemcitabine in aqueous solution.
  • FIGURE 2 FT-IR spectra of (A) HOOC - PEG-COOH (B) PEGylated gemcitabine and (C) Gemcitabine.
  • FIGURE 3 1H NMR spectra of (A) HOOC-PEG-COOH (B) Gemcitabine and (C) PEGylated gemcitabine.
  • the PEGylated gemcitabine was synthesized by conjugating gemcitabine to HOOC- PEG-COOH in dimethylsulfoxide (DMSO), in the presence of triemylarnine (TEA). Briefly, HOOC-PEG-COOH (O.lmM) was dissolved in 2.5 ml of DMSO to which TEA (0.05 ml) was added. Further, NHS (lOOmM) and EDC (400 mM) were added to the above solution and the reaction mixture was stirred for 30 mins. Later, the PEG-(NHS) 2 was coupled to gemcitabine.
  • DMSO dimethylsulfoxide
  • TEA triemylarnine
  • the reaction mixture was then kept on constant magnetic stirring for overnight at room temperature.
  • the characterization of the PEGylated gemcitabine was done by UV spectroscopy, FT-IR and 1H-MNR spectroscopy and reverse-phase chromatography in HPLC.
  • the UV analysis for the PEGylated gemcitabine was determined spectrophotometrically. Briefly, 1 mg of PEGylated gemcitabine conjugates were dissolved in 1 ml of deionized water, and UV special scan was recorded with a wavelength ranging from 200 run to 400nm using the ELISA plate Reader (SynergyTM HT, Bio Tek Instruments Inc., USA).
  • the FTIR spectra for native gemcitabine, HOOC-PEG-COOH and PEGylated gemcitabine were obtained from SPECTRUM RX 1 (Perkin Elmer, FTIR spectrometer, USA) for characterizing the chemical integrity of the PEGylated gemcitabine. Briefly, the samples were pressed into a potassium bromide pellet before obtaining their IP absorption spectra. The spectra were detected in KBr disks over a range of 4400-400 cm "
  • the native gemcitabine, HOOC -PEG -COOH and PEGylated gemcitabine were dissolved in DMSO -d 6 (99.9 atom % deuterium-enriched, Sigma -Aldrich Inc., USA) with 0.1 % TMS serving as an internal reference.
  • the NMR experiments were performed using a Bruker BioSpin (Fallanden, Switzerland) Avance -III 400 MHz FT -NMR spectrometer (9.4 T, 54 nm vertical -bore magnet) equipped with a 5 mm BBFO - Plus multinuclear probehead with Z - Gradient, operating at a proton frequency of 400.13 MHz.
  • the spectroscopic task was controlled by a HP xw- 4600 workstation, and the spectral plotting was obtained using Bruker' s TOPSPIN 2.1 ' RP - HPLC method for quantification of total gemcitabine
  • the amount of gemcitabine in the conjugate was measured with RP-HPCL system of WaterTM 600 (waters Co., Milford MA, USA) using a C 18 column (Nova-Pak ® C- 18, 3.9 MM X300MM. Water Associates) operated at 40° C with Waters 2489 UV/Visible Detector at a wavelength of 268 nm.
  • eluents eluent A was 2.5 mM phosphate buffer, pH 7.0 and eluent B was composed by 50 % of A and 50 % of acetonitrile 95:5 v/v was used , at a flow rate of 1 ml/min .
  • the total amount of gemcitabine in PEGylated gemcitabine was determined from the peak area correlated with the standard curve.
  • the standard curve of gemcitabine was prepared under identical conditions. All analysis was preformed in triplicates.
  • the cytotoxic effect of native gemcitabine and PEGylated gemcitabine was assayed colorimetrically by the MTT staining method.
  • the adherent cells (A 549 and MIA PaCa 2 ) were plated at a density of 2000 cells per wall and the suspension cells (K562 and Y79) were plated at a density of 3000 cells per wall separately in 96-well plates (Corning, YSA). The plated cells were then kept overnight in appropriate growth medium with 10 % FBS and 10,000 units/ml penicillin and streptomycin at 37 ° C.
  • the crystals of produced formazon were dissolved with 1 . 00 ⁇ of DMSO and optical density was measured at 540 nm using the ELISA plate Reader (Synergy TM ⁇ BioTek Instruments Inc., USA).
  • the drug concentration which caused a 50 % inhibition of the control growth rate (IC50) was calculated by nonlinear regression analysis using the equation for a sigmoid plot.
  • the conjugation chemistry for low molecular weight drugs is less complex in comparison to the proteins because of the reduced number of functional groups present on a low molecular weight drug molecule, the absence of conformational constrains, and easier purification and characterization steps for the polymer drug conjugates.
  • the macromolecular prodrug was synthesized by covalent linkage of gemcitabine hydrochloride (299 .68 gm/mol) to the HOOC-PEG-COOH (5 kDa) backbone.
  • the selection of the functional group of polymer used for conjugation of amino drug is important.
  • PEGylated gemcitabine was synthesized by the covalent of linkage of the carboxyl group of PEG (NHS) 2 with the amino group of gemcitabine at room temperature.
  • the conjugation was preformed in two steps. Initially, the HOOC-PEG-COOH was activated to PEG - (NHS) 2 by using EDC as the catalyst. Further, the conjugation of gemcitabine was done by reacting with activated PEG-(NHS) 2 in presence of TEA as a catalyst.
  • the TEA helps in deprotonation of the gemcitabine primary ammonium salt, inducing its solubilization in organic solvent, here DMSO.
  • the organic gemcitabine solution is then made to react with the NHS moiety of PEG.
  • the NHS ester of PEG reacts with the gemcitabine in presence of TEA dissolved in DMSO to yield the corresponding amide conjugate.
  • the product was purified by dialysis of the reaction mixture against distilled water.
  • UV spectra of conjugates showed disappearance of the typical UV peak of gemcitabine (268 nm) and formation of the new peaks of the PEGylated gemcitabine (246 and 298 nm), which are due to acylation of gemcitabine at N4 amino group due to amide bond formation with PEG ( Figure 1).
  • the spectra of the conjugates have shown the similar trends as those obtained from PEG-Ara-C.
  • FT E analysis was used to investigate the conjugation efficiency of gemcitabine with the polymer.
  • the HOOC-PEG-CCOH exhibited the characteristic peaks on IR spectrum at 2900.22 cm “1 . 1743.89 cm 1094.85 cm “1 and 3460.50 cm _1 , as shown in figure 2 A.
  • the absorption band at 1743.89 cm “1 is attributed to the carboxylic (-COOH) group, 1094. 85 cm “1 is attributed to C-O-C stretching vibration of repeated -0-CH 2 - CH 2 of polyethylene glycol (PEG) backbone.
  • the broad-band at 3460.50 cm _1 is due to the stretching vibration of -OH group corresponding to enhanced hydrogen bonding and 2900.22 cm “1 is due to -CH stretching vibrations due to symmetric and anti-symmetric modes of methylene groups.
  • Figure 2 C shows the FT IP spectra of native gemcitabine with characteristic peaks of amide bands at 1681.51 cm “1 and 1724.64 cm “1 with 3256 cm “1 at 1681.51 cm “1 for stretching vibration of (-NH 2 ). After conjugation, the PEGylated gemcitabine, as shown in Figure 2 B, displays the characteristics peaks at 2887 cm “1 , 1717 cm “1 , 1651 cm “1 , and 1578 cm “1 .
  • the synthesized PEGylated gemcitabine conjugate was also corroborated by ⁇ NMR spectra using DMSO solvent as shown in Figure 3.
  • the typical H -NMR spectrum of liner HOOC-PEG-COOH is shown in figure 3A gives signal at the range of ⁇ -3.3-3.6 ppm for the protons of -O- CH2 CH2-(PEG chain ) 2 .
  • the PEGylated gemcitabine was further assessed by RP-HPLC for the evaluation of the amount of gemcitabine conjugated to PEG.
  • the quantification of gemcitabine in the conjugate was determined by RP-HPCL analysis of the hydrolyzed product of the PEGylated gemcitabine.
  • the hydrolysis was performed by the incubation of 1 ml of 1 N NaOH, which released gemcitabine from conjugate.
  • the amount o f gemcitabine conjugated to PEG in 1 mg of PEGylated gemcitabine was found to be 70.0 ⁇ g.
  • Invitro cytotoxicity of PEGylated gemcitabine is analyzed by RP-HPLC for the evaluation of the amount of gemcitabine conjugated to PEG.
  • the quantification of gemcitabine in the conjugate was determined by RP-HPCL analysis of the hydrolyzed product of the PEGylated gemcitabine.
  • the hydrolysis was performed by the incubation of 1 ml of 1 N NaOH, which released gemcita
  • PEGylated gemcitabine was evaluated for in vitro antitumor activity by using the MTT assay based for 3 days and 5 days on four different cancer cell lines: MIA Pa Ca 2, A 549, K562 and Y79 as shown in Figure 4.
  • the incubation in the presence of PEGylated gemcitabine induced an increase in cytotoxicity in all cancer lines when compared to the native drug.
  • the findings showed that the PEGylated gemcitabine exhibited significantly higher cytotoxicity at low drug concentration and comparable cytotoxicity at high drug concentration in comparison with the native gemcitabine from both 3 days and 5 days treatment. This demonstrates that the enhanced cytotoxicity of the PEGylated gemcitabine comes form the conjugation strategy of prolonged release.
  • the IC 50 value i.e., the drug concentration at which 50% cells have been killed at a given period, is listed is Table l.It can be concluded from Table 1 that the PEGylated gemcitabine achieved much lower IC50 values than the native gemcitabine in all the cases for the Mia Pa Ca 2 and Y79 cells. It is thus evidenced in vitro, that the PEGylation gemcitabine greatly enhanced that the therapeutic effects of gemcitabine for a longer period of time. The improved cytotoxicity of PEGylated gemcitabine exhibited in MTT assay can be attributed to its enhanced permeation and prolonged localization.
  • a 549 and MIA Pa Ca 2 cells were cultured in DMEM(DMEM, PAN-Biotech GmbH, Aidenbach, Germany) and K562 and Y79 cells were cultured in RPMI (RPMI 1640, PAN- Biotech, GmbH, Aidenbach, Germany) with 1% L- Glutamine, 10% fetal bovine serum (GIBCO, USA) , 10,000 units/ml penicillin and streptomycin and maintained at 3f C in an incubator (Hera Cell, Thermo Scientific, Waltham, MA) in an atmosphere of 5 % carbon dioxide (C0 2 ).
  • A549 human lung carcinoma
  • MIA PaCa 2 human pancreatic carcinoma
  • Y79 human retinoblastoma
  • 562 human chronic myeloid leukemia

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une formulation de médicament polymère hydrosoluble comprenant le polymère amphiphile conjugué au groupe amino de la gemcitabine. L'invention concerne également un procédé de préparation d'une formulation de médicament polymère hydrosoluble comprenant les étapes de : (a) apport d'un ester N-hydroxysuccinidique de PEG par la réaction du groupe carboxyle de PEG avec le N-hydroxysuccinimide (NHS) en présence d'EDC en tant que catalyseur ; (b) conjugaison dudit polymère avec le groupe amino de la gemcitabine.
PCT/IN2011/000214 2011-01-20 2011-03-29 Dérivé pegylé de gemcitabine et son procédé de préparation Ceased WO2012098557A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN77KO2011 2011-01-20
IN77/KOL/2011 2011-01-20

Publications (1)

Publication Number Publication Date
WO2012098557A1 true WO2012098557A1 (fr) 2012-07-26

Family

ID=44501828

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2011/000214 Ceased WO2012098557A1 (fr) 2011-01-20 2011-03-29 Dérivé pegylé de gemcitabine et son procédé de préparation

Country Status (1)

Country Link
WO (1) WO2012098557A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8956613B2 (en) 2012-11-13 2015-02-17 BoYen Therapeutics, Inc. Gemcitabine prodrugs and uses thereof
EP3228650A4 (fr) * 2014-12-04 2018-10-17 Delta-Fly Pharma, Inc. Nouveau dérivé peg
WO2020023793A1 (fr) * 2018-07-27 2020-01-30 Concentric Analgesics, Inc. Promédicaments pegylés d'agonistes du trpv1 phénolique
US10717712B2 (en) 2018-07-27 2020-07-21 Concentric Analgesics, Inc. Pegylated prodrugs of phenolic TRPV1 agonists
US10821105B2 (en) 2016-05-25 2020-11-03 Concentric Analgesics, Inc. Prodrugs of phenolic TRPV1 agonists in combination with local anesthetics and vasoconstrictors for improved local anesthesia
US11634384B2 (en) 2014-11-25 2023-04-25 Concentric Analgesics, Inc. Prodrugs of phenolic TRPV1 agonists

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021135A2 (fr) * 1999-09-23 2001-03-29 Enzon, Inc. Conjugues polymeres d'ara-c et de derives d'ara-c
US20040053976A1 (en) * 1998-04-17 2004-03-18 Martinez Anthony J. Terminally-branched polymeric linkers and polymeric conjugates containing the same
US20090012252A1 (en) * 2005-05-11 2009-01-08 Akira Masuda Polymeric Derivative of Cytidine Metabolic Antagonist

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040053976A1 (en) * 1998-04-17 2004-03-18 Martinez Anthony J. Terminally-branched polymeric linkers and polymeric conjugates containing the same
WO2001021135A2 (fr) * 1999-09-23 2001-03-29 Enzon, Inc. Conjugues polymeres d'ara-c et de derives d'ara-c
US20090012252A1 (en) * 2005-05-11 2009-01-08 Akira Masuda Polymeric Derivative of Cytidine Metabolic Antagonist

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PASUT G ET AL: "Antitumoral activity of PEG-gemcitabine prodrugs targeted by folic acid", JOURNAL OF CONTROLLED RELEASE, ELSEVIER, AMSTERDAM, NL, vol. 127, no. 3, 8 May 2008 (2008-05-08), pages 239 - 248, XP022617739, ISSN: 0168-3659, [retrieved on 20080215], DOI: 10.1016/J.JCONREL.2008.02.002 *
VANDANA M ET AL: "Long circulation and cytotoxicity of PEGylated gemcitabine and its potential for the treatment of pancreatic cancer", BIOMATERIALS 2010 ELSEVIER LTD GBR LNKD- DOI:10.1016/J.BIOMATERIALS.2010.08.010, vol. 31, no. 35, December 2010 (2010-12-01), pages 9340 - 9356, XP002658104, ISSN: 0142-9612 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8956613B2 (en) 2012-11-13 2015-02-17 BoYen Therapeutics, Inc. Gemcitabine prodrugs and uses thereof
US9540410B2 (en) 2012-11-13 2017-01-10 BoYen Therapeutics, Inc. Gemcitabine prodrugs and uses thereof
US9890189B2 (en) 2012-11-13 2018-02-13 BoYen Therapeutics, Inc. Gemcitabine prodrugs and uses thereof
US11634384B2 (en) 2014-11-25 2023-04-25 Concentric Analgesics, Inc. Prodrugs of phenolic TRPV1 agonists
EP3228650A4 (fr) * 2014-12-04 2018-10-17 Delta-Fly Pharma, Inc. Nouveau dérivé peg
US10111955B2 (en) 2014-12-04 2018-10-30 Delta-Fly Pharma, Inc. PEG derivative
US10821105B2 (en) 2016-05-25 2020-11-03 Concentric Analgesics, Inc. Prodrugs of phenolic TRPV1 agonists in combination with local anesthetics and vasoconstrictors for improved local anesthesia
US11464767B2 (en) 2016-05-25 2022-10-11 Concentric Analgesics, Inc. Prodrugs of phenolic TRPV1 agonists in combination with local anesthetics and vasoconstrictors for improved local anesthesia
WO2020023793A1 (fr) * 2018-07-27 2020-01-30 Concentric Analgesics, Inc. Promédicaments pegylés d'agonistes du trpv1 phénolique
US10717712B2 (en) 2018-07-27 2020-07-21 Concentric Analgesics, Inc. Pegylated prodrugs of phenolic TRPV1 agonists
US11242325B2 (en) 2018-07-27 2022-02-08 Concentric Analgesics, Inc. Pegylated prodrugs of phenolic TRPV1 agonists

Similar Documents

Publication Publication Date Title
Khandare et al. Novel polymeric prodrug with multivalent components for cancer therapy
Calderón et al. Development of enzymatically cleavable prodrugs derived from dendritic polyglycerol
KR101444274B1 (ko) 약제복합체용 블록 공중합체 및 의약조성물
EP2070971B1 (fr) Mélange d'un dérivé de résorcinol avec un polymère
Cavallaro et al. Folate-mediated targeting of polymeric conjugates of gemcitabine
Jun et al. Selective tumor targeting by enhanced permeability and retention effect. Synthesis and antitumor activity of polyphosphazene–platinum (II) conjugates
EP2042195A1 (fr) Conjugué polymère d'une combrétastatine
Cheng et al. Construction and evaluation of PAMAM–DOX conjugates with superior tumor recognition and intracellular acid-triggered drug release properties
KR101743399B1 (ko) 폴리에틸렌글리콜과 트리페닐포스포늄이 컨쥬게이트된 물질 및 이를 적용한 미토콘드리아 표적 자기조립형 나노약물 전달체
US20100093935A1 (en) Method of preparing polyglutamate conjugates
WO2012098557A1 (fr) Dérivé pegylé de gemcitabine et son procédé de préparation
Feng et al. Tumor-specific delivery of doxorubicin through conjugation of pH-responsive peptide for overcoming drug resistance in cancer
US20250009895A1 (en) Drug loading monomolecular nano polymer, prodrug, micelle, drug delivery system, preparation method, and use
Tai et al. A novel rapamycin-polymer conjugate based on a new poly (ethylene glycol) multiblock copolymer
Jangid et al. Phenylboronic acid conjugated PAMAM G4 dendrimers augmented usnic acid delivery to gastric cancer cells
Zhou et al. A linear polyethylenimine (LPEI) drug conjugate with reversible charge to overcome multidrug resistance in cancer cells
WO2018038165A1 (fr) Polymère, procédé de production de polymère et conjugué de médicament
Li et al. Facile one-pot synthesis of amphiphilic acid/hypoxia co-triggered degradable diblock polyprodrug for tumor selective drug delivery
EP2737896B1 (fr) Micelles d'umirolimus pour le traitement du cancer
US20070292384A1 (en) Water soluble micelle-forming and biodegradable cyclotriphosphazene-taxol conjugate anticancer agent and preparation method thereof
CN113710323B (zh) 偶联物及癌治疗剂
EP3419668B1 (fr) Conjugués polymères et leurs utilisations
US9421276B2 (en) Clickable polyoxetane carrier for drug delivery
JP7223502B6 (ja) 医薬組成物
US11091498B2 (en) Topoisomerase poisons

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11731513

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11731513

Country of ref document: EP

Kind code of ref document: A1