Classifications

• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/26—Iron; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
  • A61P33/06—Antimalarials
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present invention relates to a novel combination of antimalarial active ingredients, namely ferroquine and an artemisinin derivative, as well as to a pharmaceutical composition comprising such an association, useful for the treatment and / or prevention of malaria.
• Malaria is one of the leading infectious causes of death in the world and affects more than 500 million people annually, of whom 3 million die each year. This scourge mainly affects sub-Saharan Africa, South-East Asia and Latin America.
• Plasmodium falciparum which is widespread in Africa, is the most virulent parasite and is responsible for the deadly forms of the disease.
• artemisinin has a potent antimalarial activity.
• Derivatives with improved pharmacological properties such as artemether, arteether and artesunate are also commercially available.
• Artemisinin and its derivatives are now among the most effective active ingredients against Plasmodium falciparum. However, the use of artesimine or its derivatives as monotherapy may be a causal factor in the selection of resistant parasitic strains.
• the scientific community is now advocating the use of combinations of active principles, and in particular combinations of artemisinin or its derivatives with other antimalarial active ingredients.
• These combination therapies called ACTs (Artemisinin-based Combination Therapies), have been recommended since 2002 by the World Health Organization (WHO). They offer multiple advantages: improvement of the therapeutic efficacy on the resistant strains, protection of the two active principles against the appearance of resistance, reduction of the transmission of the disease and the propagation of resistances.
• ferroquine is a molecule active against chloroquine-resistant Plasmodium falciparum strains.
• Ferroquine also known as ferrocene-chloroquine or ferrochloroquine, is 7-chloro-4 - [( ⁇ 2 - [( ⁇ , N-dimethylamino) methyl] ferrocenyl ⁇ methyl) amino] quinoline. It is a 4-aminoquinoline derivative coupled to a ferrocene ring.
• This molecule is described in particular in patent EP 0 824 536 and in J. Med. Chem., 1997, 40, 3715-3718, Antimicrob. Agents Chemother., 1998, 42, 540-544, J. Org. Chem., 1999, 589, 59-65 and J. Organometallic Chem., 2004, 689, 4678-4682.
• the present invention therefore relates to a new association between ferroquine (molecule (I) shown below in free base form and where Fe represents a ferrocene ring) and an artemisinin derivative.
• ferroquine may be in free base form, but also in salt, hydrate or solvate form (the latter being defined as associations or combinations of ferroquine with, respectively, one or more molecules of water or solvent). Ferroquine is advantageously used in free base form.
• artemisinin derivative present in the combinations according to the invention advantageously consists of artesunate (II) or artemether (III):
• the invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising, as active ingredients, an association between ferroquine (I) and an artemisinin derivative, advantageously artesunate (II) or artemether (III).
• Such a pharmaceutical composition contains therapeutically effective doses of ferroquine, or a pharmaceutically acceptable salt, a hydrate or a solvate of ferroquine, and at least one artemisinin derivative, as well as at least one pharmaceutically acceptable excipient.
• Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
• Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
• oral administration forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
• the compounds according to the invention can be used in creams, gels, ointments or lotions.
• Preferred routes of administration are the oral, rectal and injectable routes.
• the active ingredients are mixed with one or more pharmaceutical excipients, such as gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose or the like.
• the tablets can be coated with sucrose, a cellulose derivative or other materials suitable for coating.
• the tablets can be made by various techniques, such as direct compression, dry granulation, wet granulation or hot melt.
• a capsule preparation can also be obtained by mixing the active ingredients with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
• aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol, are used.
• the daily doses in each of the two active ingredients of the combination according to the invention are as follows:
• ferroquine between 50 and 1600 mg, preferably between 200 and 1200 mg, more preferably between 400 and 800 mg per person per day;
• - Artemisinin derivative between 1 and 10 mg / kg / day, preferably between 2 and 6 mg / kg / day, more preferably about 4 mg / kg / day.
• the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.
• the combination according to the invention is intended to be administered for 3 consecutive days, in one or more daily doses of each of the two active ingredients, preferably a single dose per day.
• This treatment time limited to 3 days is particularly advantageous, in comparison with the 7 days recommended for a monotherapy with artemisinin derivatives, in that it allows a better observation of the treatment by the patients, thus avoiding the premature stops of the treatment which induce in the long term a resistance of the parasite.
• each of the two active ingredients can be carried out simultaneously, or separated or spread over time (sequential administration).
• the two active ingredients can be united in a single pharmaceutical form (fixed combination), such as in a tablet or capsule suitable for oral administration.
• the two active ingredients of the combination according to the invention can also, whether their administration is simultaneous or not, be present in different pharmaceutical forms.
• the combinations according to the invention may be in the form of a kit comprising, on the one hand, ferroquine or a salt, hydrate or solvate of ferroquine, and, on the other hand, at least one derivative of artemisinin such as artesunate or artemether, said ferroquine and said artemisinin derivative being in separate compartments and intended to be administered simultaneously, separated or spread over time (sequential administration).
• a unit dosage form of ferroquine in tablet form may comprise the following components:
• a unitary form of administration of artesunate in tablet form may comprise 50 or 100 mg of artesunate and usual excipients, for example lactose, croscarmellose, anhydrous colloidal silica, microcrystalline cellulose and magnesium stearate.
• excipients for example lactose, croscarmellose, anhydrous colloidal silica, microcrystalline cellulose and magnesium stearate.
• the present invention also relates to a method of treating and / or preventing malaria which comprises administering to a patient a therapeutically effective dose of ferroquine, or a pharmaceutically acceptable salt, a hydrate or of a ferroquine solvate, and a therapeutically effective dose at least one artemisinin derivative, said doses being administered simultaneously or sequentially to said patient, as described above.
• the combination according to the invention was the subject of biochemical tests in vivo in Plasmodium falciparum-type Plasmodium-infected mice (Plasmodium vinckei vinckei strain), making it possible to demonstrate its efficacy for the treatment of malaria.
• mice Female “Swiss” mice, eight weeks old and one day old, are inoculated with Plasmodium vinckei vinckei parasites (Rodhain, 1952). The mice are previously acclimated for two weeks. The mice are fed and drink ad libitum.
• Plasmodium vinckei vinckei strain is maintained by weekly infection in mice by 10 7 parasitized erythrocytes suspended in phosphate buffered saline (0.9%).
• Parasitaemia is expressed as a percentage of infected erythrocytes present in the sample in a sample of 1000 cells, six or seven mice are used per dose. The mice for which the smear J4 reveals no interference trace will be checked again at the 10 th, 17 ièm ⁇ , 24 th, 31 th, 38 th, 45 th, 52 th and 59 th day to detect a possible resurgence of parasites.
• Ferroquine is mixed with methylcellulose (0/5 (w / w)) and Polysorbate 80 (0/5 (w / w)). The preparation is stable for at least 7 days in the dark, cold (4 ° C) and 4 hours at room temperature. The final ferroquine suspension has a concentration ranging from 0.1 to 100 mg / mL.
• Artesunate Suspension (Artesunate from Sanofi-Synthelabo, Lot 1.04) Artesunate is mixed with methylcellulose (0/5 (w / w)) and Polysorbate 80 (0/5 (w / w)). The preparation is stable for 4 hours, in the dark and at room temperature. The final suspension of artesunate has a concentration ranging from 0.8 to 20 mg / mL.
• Cl 50 is defined as the concentration in mg / kg / day that inhibits blood parasitaemia by 50% at day 4 (D4) after infection (OJ) and 4 days of treatment (D0, D1, D2, D3).
• D4 day 4
• OJ 4 days of treatment
• the 0% inhibition corresponds to the mean parasitaemia observed in untreated infected mice.
• the 100% inhibition corresponds to a very low parasitaemia or zero, less than 0.1%.
• Cl 50's are determined by linear interpolation of the dose response curve plotted as logarithm concentrations.
• Cl 50 of ferroquine is determined after administration of concentrations between 1 and 10 mg / kg / day.
• concentrations used are 0; 1; 1, 47; 2.1; 3.2; 4.6; 6.8 and 10 mg / kg / day for 4 days.
• the IC 50 of artesunate is determined after administration of concentrations between 1 and 15 mg / kg / day.
• the concentrations used are 0; 1; 1.6; 2.5; 3.9; 6.1; 9.5 and 15 mg / kg / day for 4 days.
• the curative dose is 10 mg / kg / day.
• Table II shows the mean parasitaemia (percentage of infected erythrocytes) observed on the fourth day after infection.
• the curative dose is the first dose where all the mice in the batch survive.
• FIGURE 1 shows the percentage of survival of the animals from the fifth day after infection.
• the survival time of the animals is improved by the associated administration of suboptimal doses of compounds (ferroquine at a dose of 3 mg / kg / day and artesunate at a dose of 6 mg / kg / day). day for 4 days) compared to separate administrations (ferroquine at a dose of 3 mg / kg / day or artesunate at a dose of 6 mg / kg / day for 4 days).

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• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Tropical Medicine & Parasitology (AREA)
• Inorganic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Dermatology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Medicinal Preparation (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)

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• 2005
  • 2005-04-20 FR FR0503932A patent/FR2884715B1/fr not_active Expired - Fee Related
• 2006
  • 2006-04-17 PE PE2010000537A patent/PE20110119A1/es not_active Application Discontinuation
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  • 2006-04-18 WO PCT/FR2006/000842 patent/WO2006111647A1/fr active Application Filing
  • 2006-04-18 EP EP06743711A patent/EP1874293A1/de not_active Withdrawn
  • 2006-04-18 CA CA002605385A patent/CA2605385A1/fr not_active Abandoned
  • 2006-04-18 CN CN201210369240XA patent/CN102836163A/zh active Pending
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