WO2024253550A1 - Procédé de préparation de la formulation médicinale de clotrimazole avec un copolymère amphiphile et son application en thérapie anticancéreuse et en thérapie anticancéreuse combinée avec du nifuratel. - Google Patents

Procédé de préparation de la formulation médicinale de clotrimazole avec un copolymère amphiphile et son application en thérapie anticancéreuse et en thérapie anticancéreuse combinée avec du nifuratel. Download PDF

Info

Publication number
WO2024253550A1
WO2024253550A1 PCT/PL2024/050039 PL2024050039W WO2024253550A1 WO 2024253550 A1 WO2024253550 A1 WO 2024253550A1 PL 2024050039 W PL2024050039 W PL 2024050039W WO 2024253550 A1 WO2024253550 A1 WO 2024253550A1
Authority
WO
WIPO (PCT)
Prior art keywords
clotrimazole
copolymer
nifuratel
poly
cells
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/PL2024/050039
Other languages
English (en)
Inventor
Monika Gosecka
Mateusz Gosecki
Małgorzata Urbaniak
Barbara Klajnert-Maculewicz
Anna Janaszewska
Monika Marcinkowska
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.)
Uniwersytet Lodzki
Centrum Badan Molekularnych i Makromolekularnych PAN
Original Assignee
Uniwersytet Lodzki
Centrum Badan Molekularnych i Makromolekularnych PAN
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 Uniwersytet Lodzki, Centrum Badan Molekularnych i Makromolekularnych PAN filed Critical Uniwersytet Lodzki
Publication of WO2024253550A1 publication Critical patent/WO2024253550A1/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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the object of the invention is the method of producing the medicinal formulation of clotrimazole with amphiphilic copolymer and its application in the anti-cancer therapy and combined anticancer therapy with nifuratel on the example of cervical cancer.
  • Cervical cancer is a malignant epithelial cancer that arises in the cervix [1], It is one of the most common causes of death among women worldwide [2], Chemotherapy is one of the main treatments for cervical cancer. However, the use of a single therapeutic agent is not effective in the treatment of this cancer, so it is often necessary to use combination therapy [3], Various combinations of cisplatin, paclitaxel, bevacizumab, carboplatin, topotecan and gemcitabine are recommended as first line therapies [4,5], These drugs have been approved by the Food and Drug Administration (FDA) for the treatment of cervical cancer [6],
  • FDA Food and Drug Administration
  • MDR multidrug resistance
  • Clotrimazole is a hydrophobic drug used in antifungal therapies, the action of which is based on the disorder of the calcium pump, the transport of Ca 2+ in the cell and the inhibition of the synthesis of ergosterol, which leads to damage to the cell membrane of the fungus [17].
  • Clotrimazole is routinely used to treat skin infections caused by dermatophytes, yeasts, moulds and other fungal strains [18], including vulvovaginitis. Due to the poor water solubility of clotrimazole (0.49 mg/L) [19], clotrimazole has both low bioavailability and therapeutic efficacy and is therefore classified as class II drugs under the Biopharmaceutical Classification System (BCS).
  • BCS Biopharmaceutical Classification System
  • Patent US4775678A describes how to make an oil-in-water emulsion in the form of a cream or lotion containing various amounts of clotrimazole, petrolatum, cetearyl alcohol, propylene glycol, and ceteth-20, with or without other additional ingredients.
  • Patent EP000759B1 describes the formulation of clotrimazole in the form of a cream, gel based on poly(acrylic acid).
  • Clotrimazole in addition to its antifungal activity, also exhibits anticancer properties [21,24], These studies have confirmed the strong effect of the drug on the viability of mammalian cancer cells by affecting cytoskeleton-related glycolysis and inhibition of cellular glycolysis and ATP production [21,22], and that clotrimazole may be an antagonist of calmodulin (Cam) [23], Marinho-Carvalho et al.
  • Clotrimazole acts directly on glycolytic enzymes and thus fits into the Warburg effect [28], which was shown by the results of tests on cancer cells and its small effect on normal cells.
  • clotrimazole has not proven itself in chemotherapy due to its low solubility in hydrophilic media [29]. Cancer treatments require new chemotherapy strategies. For example, cervical cancer, one of the most aggressive forms of cancer in women and the fourth most common cancer in the world, is resistant to conventional chemotherapy [30], Effective therapy, especially in the early stages of the disease, can determine the effectiveness of treatment. Due to the beneficial effect of Warburg observed for clotrimazole, increasing its solubility in the aquatic environment may be of key importance for increasing the potential of the drug in anticancer therapies.
  • Medical formulation or ‘formulation’ refers to a preparation which is in such form that the biological activity of the active ingredient contained therein is effective and which does not contain additional components that are unacceptably toxic to the individual to whom the formulation will be administered.
  • the term “therapy” or “treatment” refers to the use of a drug containing new compounds according to the invention of formula (I), to treat a disease or medical condition and includes the prevention of an illness or condition, the elimination of a disease or condition, and/or the alleviation of one or more symptoms of a disease or condition.
  • PBGE-PGGE refers to a copolymer with a hydrophobic poly(benzyl-glycidyl ether) core and a hydrophilic coating of poly(glyceryl -glyceryl ether)
  • NIF stands for nifuratel
  • CLOT is clotrimazole
  • clotrimazole dissolves in methanol, the solutions are mixed together, and left at 50°C to evaporate methanol, after which the mixture is suspended in deionized water, filtered and freeze-dried.
  • aqueous solutions of a polyether-based copolymer are mixed together with a hydrophobic core made of poly(benzyl-glycidyl ether) or polyepoxybutane and a hydrophilic coating with poly(glyceryl -glyceryl ether) diols or hyperbranched polyglycidol with encapsulated clotrimazole and boric acid-enriched acrylamide copolymer.
  • boric acid 2-acrylamidophenylboric acid is preferably used.
  • the application consists in the use of this formulation in anticancer therapy and combined anticancer therapy with nifuratel in the form of an aqueous solution or in the form of a hydrogel on the example of cervical cancer.
  • the formulation produced by the method of invention may be in the form of powder, granules, concentrate for the preparation of an aqueous suspension intended for intravenous injection or for use on diseased tissue or for administration in hydrogel form.
  • the invention provides:
  • the creators of this invention conducted comprehensive research aimed at determining the structure of copolymers providing not only increased solubility of clotrimazole in the polymer structure, and thus increased bioavailability of the drug, but also found that the two- component drug formulation consisting of copolymer and clotrimazole is characterized by excellent performance in this respect.
  • the creators of the described invention conducted research aimed at determining the exhaustive characterization of copolymers using ID and 2D nuclear magnetic resonance spectroscopy and copolymer-drug formulation using ID nuclear magnetic resonance spectroscopy. It was found that in the obtained formulation the drug is bound to the copolymer on the principle of non-specific effects.
  • copolymer-drug formulation against cancer cells was found on the example of cervical cancer cells HeLa (CRM-CCL-2 - ATCC). Therefore, the formulation of a nonlinear amphiphilic copolymer with clotrimazole is expected to be an excellent drug for the treatment of cancer on the example of cervical cancer.
  • the hydrogel platform produced on the basis of copolymer-drug also has a selective anti-cancer effect on cancer cells, as shown on the example of cervical cancer cells HeLa (CRM-CCL-2 - ATCC).
  • both the aqueous suspension of the copolymer with the drug as well as the hydrogel exert the expected effect when administered to cervical cancer cells. From the obtained values of IC 50 it is clear that the drug encapsulated in the structure of a copolymer works more effectively compared to a free drug, while, importantly, despite the encapsulation, the drug retains its selectivity toward cancer cells with a simultaneous reduced toxicity toward normal cells (i.e. non-cancerous HMEC-1 - CRL-3243 - ATCC).
  • amphiphilic copolymer with clotrimazole and with another active substance on the example of nifuratel is shown in example ZE 1 and example 2, respectively.
  • the aqueous solution was lyophilized and the amount of encapsulated drug in the copolymer structure of u was determined by 1 H NMR spectroscopy in DMSO using an internal standard (dimethylformamide).
  • the encapsulation capacity of the drug in the structure of non-linear amphiphilic copolymers is given in Table 2.
  • Example 2 Dissolution of nifuratel in the structure of a non-linear amphiphilic copolymer.
  • a 0.40 mg/ml methanol stock solution of nifuratel has been prepared. 200 mg of polyether- based amphiphilic copolymer was dissolved in 10 ml of methanol. A 26 ml nifuratel solution was added to the copolymer solution. The copolymer solution with the drug was mixed for 30 minutes. The methanol was then allowed to evaporate completely at 50°C. The polymer-drug mixture was suspended in two portions of 15 ml deionized water and filtered through a 0.45 pm PTFE (PureLand) hydrophobic syringe filter.
  • PureLand 0.45 pm PTFE
  • the aqueous solution was lyophilized and the amount of encapsulated drug in the structure of the copolymer was determined by NMR spectroscopy in DMSO using an internal standard (dimethylformamide).
  • the encapsulation capacity of the drug in the structure of a nonlinear amphiphilic copolymer is given in Table 2.
  • Example 3 Formation of a hydrogel based on the copolymer-drug formulation with a total polymer weight fraction equal to 17.25 t% and a concentration of clotrimazole 2.64 10' 5 mol/g hydrogel.
  • the formulation of clotrimazole with the copolymer PBGE-PGGE l (0.0161 g) with a loading capacity of 33.97 mg CLOT/g gel was dissolved in 181 pl of deionized water with pure PBGE-PGGE l (0.0125 g).
  • the concentration of clotrimazole gel was 2.64 10' 5 mol/g hydrogel.
  • Example 4 Formation of a hydrogel based on the copolymer-drug formulation with a total polymer weight fraction equal to 17.25 wt% and a concentration of nifuratel 1.44 10' 5 moles of the drug/g hydrogel.
  • nifuratel with the copolymer PBGE-PGGE l (0.0141 g) with a loading capacity of 35.04 mg NIF/g gel was dissolved in 181 pl of deionized water with pure PBGE- PGGE l (0.0125 g).
  • Example 5 Formation of hydrogel based on the formulation of the copolymer PBGE- PGGE l-LEK with a total polymer weight fraction equal to 17.25 tt% and a concentration of clotrimazole 2.88 10' 5 mol/g hydrogel and a concentration of nifuratel 1.54 10' 5 mol/g hydrogel.
  • Example 6 Action of an aqueous solution of the medicinal formulation of clotrimazole and a nonlinear amphiphilic copolymer with a distinguished poly(benzyl-glycidyl ether) core and a poly(glyceryl-glyceryl ether) coating (Example 1) on the example of a three-arm copolymer, consisting in a selective increase in cervical cancer cell mortality compared to clotrimazole itself.
  • Cervical cancer cells HeLa (CRM-CCL-2 - ATCC) were grown and screened in culture bottles (NunclonTM Delta Surface for Thermo Scientific Nunc adhesive cell culture) in DMEM medium (11966025 by Gibco Thermo Scientific) supplemented with 10% fetal bovine serum (F9665 FBS Sigma-Aldrich).
  • HMEC-1 non-cancer cells (CRL-3243 - ATCC) were bred and sieved in culture bottles (NunclonTM Delta Surface for Thermo Scientific Nunc adhesive cell culture) in MCDB 131 medium (10372019 by Gibco Thermo Scientific) supplemented with 10% fetal bovine serum (F9665 FBS Sigma-Aldrich), hydrocortisone (1 pg.
  • Ml-1 L-glutamine (10 mm) and epithelial growth factor (10 ng. ml-1).
  • the cells were seeded into 96-hole transparent plates with a density of 3 x 10 4 cells per hole. After 24 hours of incubation in a suitable medium, clotrimazole and corresponding formulations of this drug were added to the cells in copolymers, prepared in a PBS buffer solution, in the concentration range from 1pm to 500pm. The cells were then incubated in 24 hours and 48 hours, respectively.
  • MTT [3-(4.5-dimethylthiazol-2-yl)-2.5-diphenyltetrazolium bromide] was added to the treated cells and incubated for 3 hours. The procedure was followed by the so-called ‘MTT method’, which uses colorimetry based on the reduction reaction of yellow MTT to blue formazate, resulting in a cell viability level.
  • Clotrimazole dissolved in the structure of non-linear amphiphilic copolymers is soluble in water, it acts more effectively on cervical cancer cells HeLa than a free drug and at the same time shows reduced toxicity to non-cancerous cells HMEC-1 - selective action on cancer cells.
  • Example 7 The effect of an aqueous solution of the medicinal formulation of clotrimazolecopolymer P(BGE-GGE)_1 in combination anticancer therapy with nifuratel (examples 2 and 3) in which cervical cancer cell mortality was selectively increased compared to clotrimazole alone and encapsulated with nifuratel alone.
  • Cervical cancer cells HeLa (CRM-CCL-2 - ATCC) were grown and screened in culture bottles (NunclonTM Delta Surface for Thermo Scientific Nunc adhesive cell culture) in DMEM medium (11966025 by Gibco Thermo Scientific) supplemented with 10% fetal bovine serum (F9665 FBS Sigma-Aldrich).
  • HMEC-1 non-cancer cells (CRL-3243 - ATCC) were bred and sieved in culture bottles (NunclonTM Delta Surface for Thermo Scientific Nunc adhesive cell culture) in MCDB 131 medium (10372019 by Gibco Thermo Scientific) supplemented with 10% fetal bovine serum (F9665 FBS Sigma-Aldrich), hydrocortisone (1 pg.
  • Ml-1 L-glutamine (10 mm) and epithelial growth factor (10 ng. ml-1).
  • the cells were seeded into 96-hole transparent plates with a density of 3 x 10 4 cells per hole. After 24 hours of incubation in a suitable medium, clotrimazole and the corresponding formulation of this drug in a copolymer, in and without the presence of another biologically active substance nifuratel, prepared in PBS buffer solution, in the concentration range from 1pm to 500pm, were added to the cells. The cells were then incubated in 24 hours and 48 hours, respectively.
  • MTT [3-(4.5-dimethylthiazol-2-yl)-2.5-diphenyltetrazolium bromide] was added to the treated cells and incubated for 3 hours. The procedure was followed by the so-called “MTT method”, which uses colorimetry based on the reduction reaction of yellow MTT to blue formazate, resulting in a cell viability level [21],
  • the interaction coefficient of CDI compounds was determined, co-efficient drug interaction) defined as the quotient of the absorbance ratio of cells treated with a combination of two compounds for control and the absorbance ratio of cells treated with a single compound for control.
  • a CDI value ⁇ 0.7 indicates significant synergy [22],
  • PBGE-PGGE 1 CLOT C >500 286.89 ⁇ 3.27 389.22 ⁇ 4.75 166.07 ⁇ 2.28
  • Example 8 Action of hydrogel based on the formulation of clotrimazole and amphiphilic star copolymer with a distinguished poly(benzyl-glycidyl ether) core and a poly(glyceryl-glyceryl ether) coating (Example 4) on the example of a three-spoke copolymer, consisting in a selective increase in the mortality of cervical cancer cells.
  • Cervical cancer cells HeLa CCM-CCL-2 - ATCC
  • DMEM medium 11966025 by Gibco Thermo Scientific
  • 10% fetal bovine serum F9665 FBS Sigma-Aldrich
  • HMEC-1 non-cancer cells (CRL-3243 - ATCC) were bred and sieved in culture bottles (NunclonTM Delta Surface for Thermo Scientific Nunc adhesive cell culture) in MCDB 131 medium (10372019 by Gibco Thermo Scientific) supplemented with 10% fetal bovine serum (F9665 FBS Sigma-Aldrich), hydrocortisone (1 pg. Ml-1), L-glutamine (10 mm) and epithelial growth factor (10 ng. ml-1). The cells were seeded into 12-hole transparent plates, with an ibidi separator (Cat.No:81176) placed, in a density of 3 x 10 5 cells per well.
  • ibidi separator Cat.No:81176
  • Hmecl control t 24 h 73163.00 ⁇ 7.53 84680.00 ⁇ 7.26 86.40 ⁇ 0.01
  • HeLa gel with clotrimazole t 0 h 35453.00 ⁇ 23.81 86534.00 ⁇ 17.48 40.97 ⁇ 0.03
  • Example 9 Action of a hydrogel based on the formulation of a PBGE-PGGE-drug copolymer with different polymer weight fraction and concentration of clotrimazole and nifuratel (example 5) on the example of a PBGE-PGGE copolymer, consisting in a selective increase in cervical cancer cell mortality.
  • Cervical cancer cells HeLa (CRM-CCL-2 - ATCC) were grown and screened in culture bottles (NunclonTM Delta Surface for Thermo Scientific Nunc adhesive cell culture) in DMEM medium (11966025 by Gibco Thermo Scientific) supplemented with 10% fetal bovine serum (F9665 FBS Sigma-Aldrich).
  • HMEC-1 non-cancer cells (CRL-3243 - ATCC) were bred and sieved in culture bottles (NunclonTM Delta Surface for Thermo Scientific Nunc adhesive cell culture) in MCDB 131 medium (10372019 by Gibco Thermo Scientific) supplemented with 10% fetal bovine serum (F9665 FBS Sigma-Aldrich), hydrocortisone (1 pg.
  • Ml-1 L-glutamine (10 mm) and epithelial growth factor (10 ng. ml-1).
  • the cells were seeded into 12-hole transparent plates, with an ibidi separator (Cat.No:81176) placed, in a density of 3 x 10 5 cells per well. After 24 hours of incubation in a suitable medium, a suitable formulation of clotrimazole and nifuratel in the copolymer, prepared in PBS buffer solution, was added to the separator chambers. The cells were then incubated within 24 hours. The effects of the formulation were monitored under the Nikon Eclipse E200 microscope (fig. 2).
  • ImageJ 33 evaluated the area of cells and determined the cell growth or loss caused by clotrimazole, nifuratel, and both. Comparing the results from Table 6, after 24 hours of culture (1), an increase in the number of control cells, untreated, in the HeLa tumour cell line by 26.70 %, in the HMEC1 non-tumour cell line by 64.37 %, (2) a 50.29 % decrease in the number of cells treated with PBGE-PGGE l hydrogel-enriched HeLa clotrimazole, in HMEC1 line by 3.31 %, (3) a decrease in the number of cells treated with PBGE-PGGE l Nifuratel-enriched HeLa by 52.10 %, a 73.30 % increase in HMEC1, (2) a decrease in the number of cells treated with PBGE-PGGE l hydrogel enriched with both HeLa drugs by 99.43 %, an increase in HMEC1 by 9.36 %, indicating (i) a selective effect of the gel formulation enriched with
  • Hmecl control t 0 h 44893.00 ⁇ 18.78 85408.00 ⁇ 14.20 52.56 ⁇ 0.02
  • Hmecl control t 24 h 73163.00 ⁇ 7.53 84680.00 ⁇ 7.26 86.40 ⁇ 0.01
  • HeLa gel with clotrimazole t 0 h 35453.00 ⁇ 23.81 86534.00 ⁇ 17.48 40.97 ⁇ 0.03
  • HeLa gel with nifuratel t 24 h 21748.00 ⁇ 31.15 86013.00 ⁇ 27.36 25.28 ⁇ 0.04
  • HeLa gel with clotrimazole and 244.00 ⁇ 20.83 85904.00 ⁇ 34.96 0.28 ⁇ 0.02 nifuratel t 24 h
  • 6- h tip // ww .can cer , gov/ab out-can cer/tr eatment/d rugs/cervi cal #2.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Gynecology & Obstetrics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Urology & Nephrology (AREA)
  • Reproductive Health (AREA)
  • Engineering & Computer Science (AREA)
  • Dispersion Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention résout le problème du procédé de fabrication d'une formulation médicamenteuse d'un copolymère amphiphile non linéaire à base de polyéthers à noyau hydrophobe enrichi en groupements alkyles ou aromatiques et à revêtement hydrophile contenant des groupements diols, avec du clotrimazole difficilement soluble dans l'eau, et l'utilisation de cette formulation en thérapie anticancéreuse et en thérapie anticancéreuse combinée avec du nifuratel sous la forme d'une solution aqueuse ou sous la forme d'un hydrogel, de préférence en thérapie du cancer du col de l'utérus.
PCT/PL2024/050039 2023-06-07 2024-06-07 Procédé de préparation de la formulation médicinale de clotrimazole avec un copolymère amphiphile et son application en thérapie anticancéreuse et en thérapie anticancéreuse combinée avec du nifuratel. Ceased WO2024253550A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PL445173A PL248983B1 (pl) 2023-06-07 2023-06-07 Sposób wytwarzania formulacji leczniczej klotrimazolu z amfifilowym kopolimerem i jej zastosowanie w terapii przeciwnowotworowej i skojarzonej terapii przeciwnowotworowej z nifuratelem
PLP.445173 2023-06-07

Publications (1)

Publication Number Publication Date
WO2024253550A1 true WO2024253550A1 (fr) 2024-12-12

Family

ID=92295479

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/PL2024/050039 Ceased WO2024253550A1 (fr) 2023-06-07 2024-06-07 Procédé de préparation de la formulation médicinale de clotrimazole avec un copolymère amphiphile et son application en thérapie anticancéreuse et en thérapie anticancéreuse combinée avec du nifuratel.

Country Status (2)

Country Link
PL (1) PL248983B1 (fr)
WO (1) WO2024253550A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110060036A1 (en) * 2008-03-29 2011-03-10 Emory University Branched Multifunctional Nanoparticle Conjugates And Their Use

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110060036A1 (en) * 2008-03-29 2011-03-10 Emory University Branched Multifunctional Nanoparticle Conjugates And Their Use

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
GOSECKA MONIKA ET AL: "Selective Anticervical Cancer Injectable and Self-Healable Hydrogel Platforms Constructed of Drug-Loaded Cross-Linkable Unimolecular Micelles in a Single and Combination Therapy", vol. 16, no. 12, 15 March 2024 (2024-03-15), pages 14605 - 14625, XP009557631, ISSN: 1944-8244, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/acsami.4c01524> [retrieved on 20241014], DOI: 10.1021/ACSAMI.4C01524 *
GOSECKA MONIKA ET AL: "Self-Healable, Injectable Hydrogel with Enhanced Clotrimazole Solubilization as a Potential Therapeutic Platform for Gynecology", vol. 23, no. 10, 8 September 2022 (2022-09-08), pages 4203 - 4219, XP009557630, ISSN: 1525-7797, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/acs.biomac.2c00691> [retrieved on 20241014], DOI: 10.1021/ACS.BIOMAC.2C00691 *
GOSECKI MATEUSZ ET AL.: "Cross-linkable star-hyperbranched unimolecular micelles for the enhancement of the anticancer activity of clotrimazole", vol. 11, no. 24, 1 February 2023 (2023-02-01), pages 5552 - 5564, XP009557628, ISSN: 2050-750X, Retrieved from the Internet <URL:https://xlink.rsc.org/?DOI=D2TB02629E> [retrieved on 20241011], DOI: 10.1039/D2TB02629E *
MATEUSZ GOSECKI ET AL: "Polyglycidol, Its Derivatives, and Polyglycidol-Containing Copolymers-Synthesis and Medical Applications", POLYMERS, vol. 8, no. 6, 9 June 2016 (2016-06-09), CH, pages 227, XP055500646, ISSN: 2073-4360, DOI: 10.3390/polym8060227 *
MONIKA GOSECKA ET AL: "Hydrophobized Hydrogels: Construction Strategies, Properties, and Biomedical Applications", ADVANCED FUNCTIONAL MATERIALS, WILEY - V C H VERLAG GMBH & CO. KGAA, DE, vol. 33, no. 25, 3 April 2023 (2023-04-03), pages n/a, XP072519664, ISSN: 1616-301X, DOI: 10.1002/ADFM.202212302 *
ZIEMCZONEK PIOTR ET AL: "Star-Shaped Poly(furfuryl glycidyl ether)-Block-Poly(glyceryl glycerol ether) as an Efficient Agent for the Enhancement of Nifuratel Solubility and for the Formation of Injectable and Self-Healable Hydrogel Platforms for the Gynaecological Therapies", vol. 22, no. 16, 4 August 2021 (2021-08-04), pages 8386, XP009557629, ISSN: 1422-0067, Retrieved from the Internet <URL:https://www.mdpi.com/1422-0067/22/16/8386> [retrieved on 20241011], DOI: 10.3390/IJMS22168386 *

Also Published As

Publication number Publication date
PL445173A1 (pl) 2024-12-09
PL248983B1 (pl) 2026-02-16

Similar Documents

Publication Publication Date Title
Li et al. Exosome-liposome hybrid nanoparticle codelivery of TP and miR497 conspicuously overcomes chemoresistant ovarian cancer
Hong et al. Improving the anticancer effect of afatinib and microRNA by using lipid polymeric nanoparticles conjugated with dual pH-responsive and targeting peptides
Wu et al. Synergistic therapeutic effects of Schiff's base cross-linked injectable hydrogels for local co-delivery of metformin and 5-fluorouracil in a mouse colon carcinoma model
Upadhyay et al. Transferrin-decorated thymoquinone-loaded PEG-PLGA nanoparticles exhibit anticarcinogenic effect in non-small cell lung carcinoma via the modulation of miR-34a and miR-16
Chen et al. Synergistic cytotoxicity and co-autophagy inhibition in pancreatic tumor cells and cancer-associated fibroblasts by dual functional peptide-modified liposomes
Wen et al. Micellar delivery of miR-34a modulator rubone and paclitaxel in resistant prostate cancer
Lee et al. KSP siRNA/paclitaxel-loaded PEGylated cationic liposomes for overcoming resistance to KSP inhibitors: Synergistic antitumor effects in drug-resistant ovarian cancer
Vartak et al. Susceptibility of lung carcinoma cells to nanostructured lipid carrier of ARV-825, a BRD4 degrading proteolysis targeting chimera
Jia et al. Self-assembled fluorescent hybrid nanoparticles-mediated collaborative lncRNA CCAT1 silencing and curcumin delivery for synchronous colorectal cancer theranostics
David-Naim et al. Polymeric nanoparticles of siRNA prepared by a double-emulsion solvent-diffusion technique: Physicochemical properties, toxicity, biodistribution and efficacy in a mammary carcinoma mice model
Song et al. Enzyme‐responsive branched glycopolymer‐based nanoassembly for Co‐delivery of paclitaxel and akt inhibitor toward synergistic therapy of gastric cancer
CN105338973A (zh) 使用辅酶q10联合疗法治疗癌症
Chong et al. Synergistic antitumor effect of 3-bromopyruvate and 5-fluorouracil against human colorectal cancer through cell cycle arrest and induction of apoptosis
Yang et al. Enhancing the therapeutic effect via elimination of hepatocellular carcinoma stem cells using Bmi1 siRNA delivered by cationic cisplatin nanocapsules
CN113456824B (zh) 一种抗肿瘤载药纳米复合材料
Cai et al. Glutamine metabolism targeting liposomes for synergistic chemosensitization and starvation therapy in ovarian cancer
Lv et al. A polymeric nanocarrier that eradicates breast cancer stem cells and delivers chemotherapeutic drugs
Li et al. Combinatorial miRNA-34a replenishment and irinotecan delivery via auto-fluorescent polymeric hybrid micelles for synchronous colorectal cancer theranostics
Hu et al. Polymer micelle-based combination therapy of paclitaxel and resveratrol with enhanced and selective antitumor activity
Gosecka et al. Selective anticervical cancer injectable and self-healable hydrogel platforms constructed of drug-loaded cross-linkable unimolecular micelles in a single and combination therapy
Vahedi et al. Synergistic anticancer effects of co-delivery of linc-RoR siRNA and curcumin using polyamidoamine dendrimers against breast cancer
Fang et al. ZEB1 knockdown mediated using polypeptide cationic micelles inhibits metastasis and effects sensitization to a chemotherapeutic drug for cancer therapy
US9415011B1 (en) Method for treatment of liver cancer and inhibition of metastasis with CXC-chemokine-receptor 4-targeted nanoparticle
Wang et al. “Layer peeling” co-delivery system for enhanced RNA interference-based tumor associated macrophages-specific chemoimmunotherapy
KR102407261B1 (ko) 나노 항암제형 및 그 제조 방법

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: 24754431

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2024754431

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2024754431

Country of ref document: EP

Effective date: 20260107

ENP Entry into the national phase

Ref document number: 2024754431

Country of ref document: EP

Effective date: 20260107

ENP Entry into the national phase

Ref document number: 2024754431

Country of ref document: EP

Effective date: 20260107