WO2010130147A1 - Lactate de pyronaridine, composition pharmaceutique et son utilisation - Google Patents

Lactate de pyronaridine, composition pharmaceutique et son utilisation Download PDF

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Publication number
WO2010130147A1
WO2010130147A1 PCT/CN2010/000655 CN2010000655W WO2010130147A1 WO 2010130147 A1 WO2010130147 A1 WO 2010130147A1 CN 2010000655 W CN2010000655 W CN 2010000655W WO 2010130147 A1 WO2010130147 A1 WO 2010130147A1
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Prior art keywords
compound
pharmaceutical composition
formula
artemisinin
pharmaceutical
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PCT/CN2010/000655
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English (en)
Chinese (zh)
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郑一敏
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重庆通天药业有限公司
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Publication of WO2010130147A1 publication Critical patent/WO2010130147A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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 invention belongs to the technical field of medicine and relates to a novel pyronaridine salt.
  • the invention relates to a lactate salt of pyronaridine, and to a pharmaceutical composition comprising the lactate, a pharmaceutical composition comprising the lactate and an artemisinin analogue, comprising the lactate And a kit product of an artemisinin analog, and the use of the lactate, pharmaceutical composition or pharmaceutical composition for the preparation of a medicament for preventing and/or treating malaria.
  • Malaria is the world's most prevalent, morbidity and mortality tropical parasitic infection. According to the World Health Organization (WHO) statistics, malaria is prevalent in more than 90 countries and regions, with clinical cases of 300-500 million. People/years, between 1.5 and 2.7 million people worldwide die of malaria each year, half of whom are children under the age of five. Especially in sub-Saharan Africa, it shows the highest infection rate, prevalence and mortality. Today, malaria has become more resistant to war, environmental damage, re-migration, climate change, etc., and malaria has become more severe, especially for chloroquine and pyrimethamine/sulfadoxine.
  • WHO World Health Organization
  • chloroquine drugs provided by WHO.
  • WHO chloroquine-resistant falciparum malaria
  • Plasmodium vivax After the development of new drugs, consideration must be given to what form the drug is prepared for.
  • the preferred alternative to chloroquine is in the form of oral administration because it is readily acceptable to public health organizations such as WHO or remote residents, is easy to administer, is effective, and is safer than other forms.
  • pyronaridine phosphate form, which is available in oral form and injectable form
  • Malaridine phosphate form, which is available in oral form and injectable form
  • artesunate is the most widely used in China and Vietnam. It is effective against Plasmodium vivax and Plasmodium vivax, which are resistant to other antimalarial agents.
  • Today, 50 mg of artesunate tablets are marketed in Vietnam (Mediplantex and Khanh Hoa) and in China, and are marketed in some parts of Africa under the name Arsumax®.
  • artemisinin derivatives such as artemisinin, dihydroartemisinin, and artemether are also effective drugs for controlling the symptoms of malaria.
  • CN1238950A (Chinese Patent Application No. 98115332.1, published on December 22, 1999) discloses a compound anti-malarial drug consisting of an artemisinin-based drug and pyronaridine, which includes artemisinin, dihydrogen Artemisinin, artemether and the like.
  • CN1283458A (Chinese Patent Application No. 99109669.X, published Feb. 14, 2001) also discloses a compound anti-malarial drug consisting of an artemisinin-based drug and pyronaridine.
  • pyronaridine is a lactate which has a much higher bioavailability than existing pyronaridine phosphates and thus provides an overcoming of the clinical drawbacks of existing pyronidines. It is possible that the inventors have completed the present invention based on this finding. In addition, the present inventors have also found that a combined preparation of a combined use of pyrrolidinium and artemisinin or a derivative thereof such as dihydroartemisinin can not only improve the bioavailability of each active ingredient, but also can produce extremely remarkable Synergies and synergies. Summary of invention
  • a first aspect of the invention provides a compound of formula I:
  • n 1 to 4
  • the compound of formula I of the present invention may be referred to as carboxypyridinium lactate.
  • n is 1 to 2; preferably, wherein n is an integer from 1 to 2.
  • a second aspect of the invention provides a process for the preparation of a compound of formula I according to the first aspect of the invention, which comprises the step of forming a salt of pyronaridine with lactic acid in an organic solvent.
  • the organic solvent is selected from the group consisting of decyl alcohol, ethanol, acetone, ethylene glycol, ethyl acetate, propanol, isopropanol, propylene glycol, n-butanol, and 1,3-butyl Glycol, polyethylene glycol, chloroform, benzyl alcohol, benzyl benzoate, benzene and cyclohexane.
  • the organic solvent is selected from the group consisting of ethanol, ethyl acetate and acetone.
  • the method according to the second aspect of the invention wherein the step of forming a salt is from room temperature to 100.
  • the reflux was carried out at a temperature of C.
  • the method according to the second aspect of the invention wherein the step of forming a salt is at a solvent to room temperature of 100.
  • the reflux is performed at the temperature of C.
  • the method according to the second aspect of the invention wherein the step of forming a salt is at 50-90.
  • the reflux was carried out at a temperature of C.
  • the method according to the second aspect of the invention, wherein the step of forming a salt is at 60-80.
  • the reflux was carried out at a temperature of C.
  • the reflux time can be determined depending on the reaction temperature, the reaction solvent, the nature of the reactants, and the like.
  • a method according to the second aspect of the invention comprising the steps of:
  • a third aspect of the invention provides a pharmaceutical composition comprising an effective amount of a compound of formula I according to any one of the first aspects of the invention for preventing and/or treating malaria, and optionally a pharmaceutically acceptable carrier or Shape agent.
  • the pharmaceutical composition according to the third aspect of the invention which is in unit dosage form.
  • the pharmaceutical composition according to the third aspect of the invention wherein the unit dosage form is selected from the group consisting of: a tablet, a gelatizer, a granule, an injection, a powder for injection, a transdermal patch, an ointment, a gel Agents, suppositories, oral solutions, oral suspensions, emulsions for injection, oral emulsions, sustained release tablets, controlled release tablets, and the like.
  • the pharmaceutical composition according to the third aspect of the invention wherein the amount of the compound of the formula I in the unit dosage form is pyronaridine (i.e., the base portion of the compound of formula I, C 29 H 32 C1N 5 0 2) counted as a 10 ⁇ 1000mg o according to a third aspect of the present invention is a pharmaceutical composition, wherein the amount of the compound of formula I in the unit dose forms, to pyronaridine (base compound of formula I i.e. The fraction, C 29 H 32 C1N 5 0 2 ), is 20 to 800 mg.
  • the pharmaceutical composition according to the third aspect of the invention wherein the amount of the compound of the formula I in the unit dosage form is pyronaridine (i.e., the base portion of the compound of formula I, C 29 H 32 C1N 5 0 2 ) Calculated, 25 ⁇ 500mg.
  • the pharmaceutical composition according to the third aspect of the invention wherein the amount of the compound of the formula I in the unit dosage form is pyronaridine (i.e., the base portion of the compound of formula I, C 29 H 32 C1N S 0 2 ) Calculated, it is 80 ⁇ 150mg.
  • a fourth aspect of the invention provides a pharmaceutical composition comprising a) preventing and/or treating malaria An effective amount of a compound of formula I according to any one of the first aspects of the invention, b) an effective amount of at least one artemisinin or analogue thereof for preventing and/or treating malaria, and C) optionally pharmaceutically acceptable Accepted carrier or excipient.
  • the artemisinin analogue is selected from the group consisting of dihydroartemisinin, artemether, arteether, artesunate and artemether.
  • the artemisinin analogue is selected from the group consisting of dihydroartemisinin, artemether, arteether, and artesunate.
  • the artemisinin analog is selected from the group consisting of dihydroartemisinin and artemether.
  • the artemisinin analogue is dihydroartemisinin.
  • the compound of formula I wherein the weight ratio of the compound of the formula I to artemisinin or an analogue thereof is from 5:1 to 1:1.
  • the compound of formula I wherein the weight ratio of the compound of formula I to artemisinin or its analog is from 4:1 to 1:1.
  • the compound of formula I wherein the weight ratio of the compound of the formula I to artemisinin or an analog thereof is from 3:1 to 1:1.
  • the weight ratio of the compound of formula I to artemisinin or an analog thereof is 3:1, 2.5:1, 2:1, 1.5:1 or 1: by weight: 1.
  • the compound of formula I wherein the weight ratio of the compound of the formula I to artemisinin or an analogue thereof is 3:1 or 1.5:1.
  • composition according to any of the aspects of the invention, wherein the artemisinin or an analogue thereof is in the form of a cyclodextrin inclusion compound.
  • the cyclodextrin is selected from the group consisting of: alpha-cyclodextrins, quinone-cyclodextrins, gamma-cyclodextrins.
  • the cyclodextrin is a guanidine-cyclodextrin.
  • the cyclodextrin is selected from the group consisting of: hydrazine-cyclodextrin, decyl cyclodextrin, dimethyl cyclodextrin, trimethyl-hydrazine-cyclodextrin, hydroxypropyl cyclodextrin Refined, 2-hydroxypropyl-indole-cyclodextrin, 3-hydroxypropyl-indole-cyclodextrin, 2,3-dihydroxypropyl cyclodextrin, hydroxyethyl-hydrazine-ring Dextrin, 2-hydroxyethyl-p-cyclodextrin, 3-hydroxyethyl-P-cyclodextrin, 2,3-dihydroxyethyl cyclodextrin and 3-hydroxy-P-cyclodextrin.
  • the cyclodextrin is selected from the group consisting of: hydroxypropyl- ⁇ -cyclodextrin, 2-hydroxypropyl cyclodextrin, 3-hydroxypropyl-indole-cyclodextrin, 2,3 -dihydroxypropyl- ⁇ -cyclodextrin, hydroxyethyl-hydrazine-cyclodextrin, 2-hydroxyethyl- ⁇ -cyclodextrin, 3-hydroxyethyl- ⁇ -cyclodextrin, 2,3- Dihydroxyethyl- ⁇ -cyclodextrin and 3-hydroxycyclodextrin.
  • the cyclodextrin is selected from the group consisting of: hydroxypropyl- ⁇ -cyclodextrin, 2-hydroxypropyl-indole-cyclodextrin, 3-hydroxypropyl- ⁇ -cyclodextrin, 2,3-dihydroxypropyl cyclodextrin and 3-hydroxycyclodextrin.
  • a pharmaceutical composition according to any one of the fourth aspects of the invention which is in unit dosage form.
  • the unit dosage form is selected from the group consisting of: tablets, capsules, granules, injections, powders for injection, transdermal patches, ointments, gels, suppositories, oral solutions, oral Suspensions, emulsions for injection, oral emulsions, sustained release tablets, controlled release tablets, and the like.
  • the amount of the compound of formula I in the unit dosage form is 10 to 1000 mg based on pyronaridine (i.e., the base portion of the compound of formula I, C 29 H 32 C1N 5 0 2 ). .
  • the amount of the compound of formula I in the unit dosage form is, in the case of pyronaridine (i.e., the base portion of the compound of formula I, C 29 H 32 C1N 5 0 2 ), 20 ⁇ 800mg. In another embodiment, the amount of the compound of formula I in the unit dosage form is 25% of pyronaridine (i.e., the base moiety of the compound of Formula I, C 29 H 32 C1N 5 0 2 ). 500mg. In another embodiment, the amount of the compound of formula I in the unit dosage form is 50% of pyronaridine (i.e., the base moiety of the compound of Formula I, C 29 H 32 C1N S 0 2 ). 250mg.
  • the amount of the compound of Formula I in the unit dosage form is 50% of pyronaridine (ie, the base moiety of the compound of Formula I, C 29 H 32 C1N 5 0 2 ). 150mg. In still another embodiment, the amount of the compound of formula I in the unit dosage form is 50 mg of pyronaridine (i.e., the base portion of the compound of formula I, C 29 H 32 C1N 5 0 2 ) 100mg.
  • a pharmaceutical composition according to any one of the fourth aspects of the present invention, wherein The amount of artemisinin or an analogue thereof in the unit dosage form can be easily determined according to the ratio of the above two types of components of the present invention and the above specific content, for example, in the unit dosage form of the pharmaceutical composition of the present invention, Formula I compound (nucleotide basis) weight ratio of artemisinin or the like 3: 150m g 1, and the compound of formula I per unit dose form (nucleotide basis) amount, the unit dosage form CY The amount of artemisinin or its analog is 50 mg.
  • artemisinin or an analog thereof in the pharmaceutical composition of the present invention is present in the form of a cyclodextrin inclusion compound
  • the amount of artemisinin or its analog is artemisinin or the like itself.
  • weight not by weight of the cyclodextrin inclusion compound.
  • a fifth aspect of the invention provides a process for the preparation of a pharmaceutical composition according to any of the four aspects of the invention, which comprises the compound of the formula I according to any one of the first aspects of the invention, b) artemisinin or the like And c) a step of intimately mixing the pharmaceutically acceptable carrier or excipient.
  • the method according to the sixth aspect of the present invention which further comprises the step of preparing the artemisinin or the analog thereof into a cyclodextrin inclusion compound before the mixing step.
  • step of preparing the cyclodextrin inclusion compound comprises the steps of:
  • a seventh aspect of the invention provides a kit product comprising at least one first pharmaceutical preparation unit and at least one second pharmaceutical preparation unit, the first pharmaceutical preparation unit and the second pharmaceutical preparation unit being optionally present independently of each other
  • the first pharmaceutical preparation unit comprises an effective amount of the present invention for preventing and/or treating malaria
  • the second pharmaceutical formulation unit comprising an effective amount of artemisinin or an analogue thereof for preventing and/or treating malaria And optionally a pharmaceutically acceptable carrier or excipient.
  • the kit product according to the seventh aspect of the invention wherein the artemisinin-like substance is selected from the group consisting of dihydroartemisinin, artemether, arteether, artesunate and artemether.
  • the kit product according to the seventh aspect of the invention wherein the artemisinin analogue is selected from the group consisting of dihydroartemisinin, artemether, arteether and artesunate.
  • the artemisinin analogue is selected from the group consisting of dihydroartemisinin and artemether.
  • the kit product according to the seventh aspect of the invention, wherein the artemisinin analogue is dihydroartemisinin.
  • kit product according to any one of the seventh aspects of the present invention, wherein the compound of the formula I in each of the first pharmaceutical preparation units is based on the pyronaridine base and the artemisinin in each of the second pharmaceutical preparation units or The weight ratio of the analog is from 6:1 to 1:1, preferably from 5:1 to 1:1, preferably from 4:1 to 1:1, preferably from 3:1 to 1:1.
  • kit product according to any one of the seventh aspect of the invention, wherein the artemisinin or the analog thereof in the second pharmaceutical preparation unit may be in the form of a cyclodextrin inclusion compound.
  • the form of the form of the cyclodextrin inclusion compound may optionally be the same as that of the form of the cyclodextrin inclusion compound in the pharmaceutical composition of the fourth aspect of the invention.
  • the eighth aspect of the invention provides the pharmaceutical composition of any one of the first aspects of the invention, or the pharmaceutical composition of any one of the third aspect of the invention, or the pharmaceutical composition of any of the fourth aspect of the invention Use in the manufacture of a medicament for the prevention and/or treatment of malaria.
  • pyronaridine is usually used primarily as an antimalarial drug for malaria control, not as a preventive drug, pyronaridine can be used in combination with malaria-preventing drugs to Produce a preventive effect.
  • a ninth aspect of the invention provides a method of preventing and/or treating malaria in a mammal suffering from malaria, comprising administering to the mammal an amount effective to prevent and/or treat malaria, according to any one of the first aspects of the invention.
  • treating has its ordinary meaning, and particularly herein refers to the treatment of a mammal having a malaria with a compound of the formula I or a pharmaceutical composition or pharmaceutical composition of the invention, with a view to Malaria produces treatment, cure, alleviation, and relief.
  • prevention has its ordinary meaning, and particularly herein refers to the use of the formula of the invention for a mammal that may be at risk of or suffering from the malaria of the invention.
  • the compound or pharmaceutical composition or pharmaceutical composition is treated to prevent, prevent, prevent, block, etc. the malaria.
  • the term "pharmaceutically acceptable” generally refers to the pharmaceutical field, which is not deleterious to the product or to the mammal, or has a reasonable or acceptable benefit/risk ratio.
  • carrier and “excipient” can be any of the conventional carriers and excipients in the pharmaceutical art.
  • the choice of the particular carrier and excipient will depend on the mode of administration or the type and state of the disease used to treat the particular patient.
  • the preparation of suitable pharmaceutical compositions for a particular mode of administration is well within the knowledge of those skilled in the pharmaceutical arts.
  • it may be a pharmaceutically acceptable carrier or excipient, including conventional carriers, excipients, diluents, fillers, solvents, support agents, binders, wetting agents, disintegrating agents, absorption promotion in the pharmaceutical field. Agents, surfactants, adsorption carriers and lubricants.
  • a flavoring agent, a preservative, a sweetener, and the like may also be included as necessary.
  • malaria has its ordinary meaning in the medical field, such as malaria caused by protozoa such as Plasmodium vivax, Plasmodium yoelii, Plasmodium vivax, and Plasmodium falciparum.
  • the term "effective amount” refers to an amount of the active ingredient of the present invention which is effective for the prevention and/or treatment of malaria according to the present invention.
  • the terms "pharmaceutical composition” or “pharmaceutical composition” or “second pharmaceutical formulation unit” in a kit product have their general meaning, and may be narrowly defined herein.
  • pharmaceutical or pharmaceutical dosage form it may or may not contain a pharmaceutical excipient.
  • the pharmaceutical composition or pharmaceutical composition of the present invention can be prepared by conventional techniques in the pharmaceutical field, particularly in the field of formulation.
  • the pharmaceutical composition according to the present invention is a pharmaceutical dosage form which can be suitably used for oral administration, parenteral administration or topical administration, or external administration.
  • the pharmaceutical dosage form includes, but is not limited to: tablets, capsules, granules, powders, injections, powders for injection, transdermal patches, ointments, gels, suppositories Oral solution, oral suspension, injectable emulsion, oral emulsion, etc., sustained release tablets, controlled release tablets, and the like.
  • the above various dosage forms of the drug can be prepared according to a conventional method in the field of pharmacy.
  • the term "mammal, (or may be referred to as "individual") has its ordinary meaning, and may be used herein to refer to an individual or mammal suffering from or likely to suffer from the malaria of the present invention, and may also refer to A mammal used for a certain purpose, for example, for scientific research purposes.
  • the mammal is, for example, a human, a pig, a dog, a cat, a cow, a sheep, a horse, a rat, a mouse, a rabbit, a guinea pig. More specifically, the mammal of the present invention is a human.
  • first pharmaceutical preparation unit and the “second pharmaceutical preparation unit” in the pharmaceutical composition or the pharmaceutical composition or the kit product of the present invention are administered as a medicament to a patient of a test animal, they may be administered by themselves, that is, The pharmaceutical composition or the pharmaceutical composition of the present invention is directly administered to a patient in a prototype without any of the above pharmaceutically acceptable carriers; or may contain, for example, 1 to 99% (more preferably, for example, 10 to 90%) A compound of formula I is administered to a human or animal in combination with a pharmaceutically acceptable carrier in a pharmaceutical composition or pharmaceutical composition.
  • the time course can be varied to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, composition and method of administration without toxicity to the subject.
  • Exemplary dose ranges can be found in the literature (eg, Chen Xinqian, et al., New Pharmacy,
  • the specific therapeutically effective dose level for any particular patient will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed. The age, weight, general health, sex and diet of the patient; the time of administration, the route of administration and the rate of excretion of the particular compound employed; duration of treatment; the drug used in combination or concurrently with the particular compound employed; And similar factors well known in the medical field.
  • First pharmaceutical formulation unit and “second pharmaceutical formulation unit” in a compound of the formula I or a pharmaceutical composition or kit of the invention, as described above, their specific dosages may be skill in the art Personnel are determined based on prior knowledge. If desired, an effective daily dose may be divided into multiple doses for administration purposes; therefore, a single dose composition or pharmaceutical formulation unit may contain such amounts or sub-doses thereof to constitute Daily dose.
  • the kit product of the present invention the "first pharmaceutical preparation unit” and the "second pharmaceutical preparation unit” are applied to the test subject in a certain chronological order, for example, the two are simultaneously administered, in an optional sequence of intervals. Application, etc.
  • first pharmaceutical preparation unit and the “second pharmaceutical preparation unit” in the pharmaceutical composition or the kit product of the present invention may be specifically formulated to be administered orally, in a solid or liquid form, for parenteral injection or for rectal administration. medicine.
  • first pharmaceutical preparation unit and the “second pharmaceutical preparation unit” in the pharmaceutical composition or the kit product of the present invention may be administered orally, rectally, parenterally, intrapool, intravaginally, intraperitoneally, or locally (e.g., by powder, Ointments or drops), administered to humans and other mammals by buccal, or as an oral spray or nasal spray.
  • parenteral refers to administrations which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injections and infusions.
  • first pharmaceutical formulation unit and “second pharmaceutical formulation unit” in the pharmaceutical or kit product of the invention may be diluted with one or more non-toxic physiologically tolerable or acceptable dilutions.
  • Agents, carriers, adjuvants or vehicles (which may be referred to herein collectively as carriers) are formulated together for parenteral injection, intranasal delivery, oral administration in solid or liquid form, rectal or topical administration, and the like .
  • first pharmaceutical preparation unit and the “second pharmaceutical preparation unit” in the pharmaceutical composition or kit product of the present invention suitable for parenteral injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersing agents. , Suspensions or emulsions, and aseptic powders which constitute a sterile injectable solution or dispersion.
  • suitable aqueous or nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), vegetable oils (such as olive oil), injectable organic esters such as oleic acid. Ethyl esters and suitable mixtures thereof.
  • first pharmaceutical preparation unit and the “second pharmaceutical preparation unit” in the pharmaceutical composition or the kit product of the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersing agents. And antifungal agents, such as parabens, three Chlorobutanol, phenol, sorbic acid, etc., ensure the prevention of the action of microorganisms. It is also desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of materials which delay absorption, such as aluminum monostearate and gelatin.
  • Suspensions may contain suspending agents in addition to the active compound, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite , agar and tragacanth or a mixture of these substances.
  • suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite , agar and tragacanth or a mixture of these substances.
  • first pharmaceutical preparation unit and “second pharmaceutical preparation unit” in the pharmaceutical composition or kit product of the present invention may be in the form of an injectable preparation which can be filtered or passed, for example, by a bacteria filter. Sterilization is carried out by incorporating a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.
  • first pharmaceutical preparation unit and the “second pharmaceutical preparation unit” in the pharmaceutical composition or the kit product of the present invention may be in a solid dosage form for oral administration, and the solid dosage form for oral administration includes a capsule, Tablets, pills, powders and granules.
  • the active compound may be mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or the following: a) filler or extender such as starch, Lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginate, gelatin, like vinylpyrrolidone, sucrose and gum arabic; c) humectants such as glycerol; d) disintegration Such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl wax Alcohol and glycerol monostearate; h) adsorbents such as kaolin and bentonite and i) lubricants such as tal
  • the “second pharmaceutical preparation unit” may be in a liquid dosage form for oral administration, and the liquid dosage form for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage form may contain, in addition to the active compound, an inert diluent commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid.
  • Benzyl ester propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol ( Tetrahydrofurfuryl alcohol), fatty acid esters of polyethylene glycol and sorbitan and mixtures thereof.
  • the compounds of the formula I, pharmaceutical compositions, pharmaceutical compositions and kits provided by the present invention are subjected to pharmacodynamics, toxicology, general pharmacological tests, preparation techniques, quality testing and stability studies.
  • the inventors have found through repeated experiments that the bioavailability can be increased by more than three times compared with the pyrrolizidine of the formula I of the present invention, and the dihydroartemisinin 3-hydroxy P-cyclodextrin inclusion Compared with dihydroartemisinin, the bioavailability increased by more than 1.5 times.
  • the research results show that the invention has good safety, has a good therapeutic effect on malaria, has simple process and good stability, and particularly uses a combination of nalbuminyl lactate and dihydroartemisinin inclusion compound, which can significantly reduce the dosage and reduce the dosage.
  • the cost is suitable for solid and liquid dosage forms, and the practical application value is large.
  • the group can play a very significant synergy and synergy, and the efficiency index reaches 7 or above.
  • composition or kit product of the present invention has the following advantages:
  • the invention is compared to a combination of pyronaridine and dihydroartemisinin (for example a combination of 4:1) or a combination of pyronarin and dihydroartemisinin (for example a combination of 4:1)
  • the bioavailability of each active ingredient in the pharmaceutical composition or the kit product can be stably increased by 1.5 times or more, thereby reducing the dosage;
  • the pharmaceutical composition or the kit product of the present invention has a shorter antipyretic time and no re-ignition;
  • the antipyretic time of the pharmaceutical composition of the present invention is 9-42 hours, which is superior to the 19-49 hours of the pyrazolidine single-use group, which is significantly faster than the 15-75 hours of the dihydroartemisinin single use group;
  • the disappearance time of the asexual protozoa of the pharmaceutical composition is 20-33 hours, which is better than that of the dihydroartemisinin single use group for 25-42 hours, which is significantly faster than the 27-65 hours of the pyramidine single use group;
  • the gametophytic appearance rate, duration and density were 9.1%, 5.2 days and 2/L blood, respectively, which was better than 10.3%, 5.8 days and 3 blood of the dihydroartemisinin single use group, significantly less than the naphthalene 44.5%, 13.8 days, and 11/ ⁇ blood of the pyridine group; no re-ignition of the pharmaceutical composition of the present invention and the pyronidine single-use group within 28 days after the treatment, and the dihydroartemisinin alone
  • the pyrrolizidine O.lmol was accurately taken, 1 liter of ethyl acetate was placed in a container, dissolved in heat, and 0.13 mol of lactic acid was added thereto, and refluxed for 1.5 hours; concentrated in vacuo, allowed to stand for 12-24 hours, collected and crystallized, and dried to obtain lactic acid. Naphthyridine.
  • the butyl lactamidine lactate was prepared by using "pyridinyl lactate" prepared by "Compound Preparation Example 1-4" as a raw material.
  • the formula for 1000 is as follows:
  • lactoylpyridinium in terms of pyrrolidine base
  • Add appropriate amount of water for injection stir to dissolve
  • add water for injection to the full amount of 2000 ml, remove the bacteria, filter, dispense, and package.
  • Formulation of lactamidine lactate Example 2 Preparation of pyronaridine for injection
  • the pyrrolidinium lactate is prepared by using "pyridinyl lactate" prepared in "Compound Preparation Example 1" as a raw material.
  • the formula for 1000 bottles is as follows: Preparation of Compounds Carbarylpyridinium (based on pyronaridine) (g)
  • the propranolidine lactate tablets were prepared by using the compound naphthylpyridinium prepared by "Compound Preparation Example 1-4", and the formulation of 1000 tablets was as follows:
  • the formula of the compound of the compound of Preparation Example 1-4 was prepared by using the compound of the compound of Preparation 1-4, and the formulation of 1000 tablets of the capsule was as follows:
  • the compound capsule preparation is prepared by using the compound naphthoate and the dihydroartemisinin prepared by the "Compound Preparation Example 1", and the formula of 1000 capsules is as follows:
  • the original and auxiliary materials are pulverized and passed through 100 mesh. According to the formula, the components are uniformly mixed, and the rubber is sprayed and packaged.
  • the recommended usage and dosage of the compound lactic acid naphthoquinone capsule prepared in this preparation example can be: Adult one course of treatment for 2 days, 3 capsules per day. After more than 100 clinical trials, the drug has been proven to be fast-acting, highly effective, safe, short-course and relatively small in dose, and its therapeutic effect is superior to similar drugs at home and abroad.
  • the compound tablet preparation is prepared by using "the compound preparation example 1, the prepared pyrrolizidine lactate and the dihydroartemisinin cyclodextrin inclusion compound", and the formulation of 1000 tablets is as follows:
  • the original and auxiliary materials are pulverized, passed through a 100 mesh sieve, and taken according to the formula.
  • the components are mixed and granulated, tableted, and packaged.
  • the preparation method of the dihydroartemisinin cyclodextrin inclusion compound is as follows:
  • the recommended usage and dosage of the compound lactapyridine tablets prepared in this preparation example can be: Adults for 2 days, 3 capsules per day. After more than 100 clinical trials, the drug has been proven to be fast-acting, highly effective, safe, short-course and relatively small in dose, and its therapeutic effect is superior to similar drugs at home and abroad.
  • the compound tablet preparation is prepared by using "Compound Preparation Example 1, the prepared carboxypyridinium lactate and dihydroartemisinin", and the formulation of 1000 tablets is as follows:
  • the compound tablets are prepared by using the compound of the compound of the preparation of the compound 1 and the dihydroartemisinin cyclodextrin inclusion compound, and the formulation of the 1000 tablets is as follows:
  • the recommended usage and dosage of the compound lactapyridine tablets prepared in this preparation example can be: oral, adult once a day, 5 tablets each time, the course of treatment is 2 days.
  • the preparation method of the dihydroartemisinin cyclodextrin inclusion compound is as follows: (1) taking a certain amount of 0.03 mol of dihydroartemisinin, and placing it in a container filled with 1000 ml of 95% ethanol, and then adding 0.1 g of molecular weight. 3-hydroxypropyl cyclodextrin, stirred for 3 hours;
  • the compound capsule preparation is prepared by using "compound preparation example 1, the prepared butyl lactadrolate and dihydroartemisinin cyclodextrin inclusion compound", and the formula of 1000 capsules is as follows: L-naphthyl lactate (based on pyronaridine) 30g
  • Dihydroartemisinin inclusion complex (based on dihydroartemisinin) 10g
  • Polyethylene glycol 500ml Mix the ingredients and prepare them into a liquid. Take 100g of gelatin, 55ml of glycerin and 120ml of water. Mix and prepare gelatin solution. At 28 ⁇ 2°C, relative humidity 40%, liquid medicine and gelatin. 1000 pellets were prepared by an automatic rotary tamping machine; and at 28 ⁇ 2 e C, 40% relative humidity, the glue was dried for 20 hours.
  • the recommended usage and dosage of the compound lactic acid naphthoquinone capsule prepared in the preparation example can be: oral, adult once a day, 5 capsules per month, and the course of treatment is 2 days.
  • the preparation method of the dihydroartemisinin cyclodextrin inclusion compound is as follows: (1) taking a certain amount of 0.03 mol of dihydroartemisinin, and placing it in a container filled with 1000 ml of 95% ethanol, and then adding 0.1 g of molecular weight. 3-hydroxypropyl cyclodextrin, stirred for 3 hours;
  • the compound self-microemulsifying drug release soft gel is prepared by using the compound preparation example 1, the prepared pyrrolizidine lactate and the dihydroartemisinin cyclodextrin inclusion compound as raw materials.
  • the formula of the cockroach preparation, 1000 capsules is as follows:
  • the ingredients are mixed and mixed to prepare a chemical solution, and 100 g of gelatin, 55 ml of glycerin and 120 ml of water are mixed, and the mixture is mixed into a gelatin liquid. Under the condition of 28 ⁇ 2° C. and relative humidity of 40%, the liquid medicine and the gelatin are automatically rotated. The machine was made into 1000 tablets; and at 28 soils 2. C, under the condition of 40% relative humidity, the capsule is dried for 20 hours.
  • the recommended usage and dosage of the compound lactic acid naphthoquinone capsule prepared in this preparation example can be: Oral, once a day for adults, 4 capsules per time, and the course of treatment is 2 days.
  • the preparation method of the dihydroartemisinin cyclodextrin inclusion compound is as follows: (1) taking a certain amount of 0.03 mol of dihydroartemisinin, and placing it in a container filled with 1000 ml of 95% ethanol, and then adding 0.1 g of molecular weight. 3-hydroxypropyl- ⁇ -cyclodextrin, stirred for 3 hours;
  • the compound tablets are prepared by using the pyrrolizinium lactate and artemisinin cyclodextrin inclusion compound prepared in "Compound Preparation Example 1" as a raw material, and the formulation of 1000 tablets is as follows:
  • the compound tablet preparation is prepared by using "Compound Preparation Example 1, the prepared carboxypyridinium lactate and artemisinin", and the formulation of 1000 tablets is as follows:
  • the compound tablets are prepared by using the compound of the compound of the preparation of the compound 1 and the amyl ether butyl benzoate cyclodextrin as a raw material, and the formulation of the 1000 tablets is as follows:
  • the preparation method of the artemether cyclodextrin inclusion compound is as follows:
  • the compound tablets are prepared by using the "naphthylpyridinium lactate” and the artemether prepared in "Compound Preparation Example 1" as a raw material, and the formulation of 1000 tablets is as follows:
  • the compound tablets are prepared by using the compound of the compound of the preparation of the compound 1 and the preparation of the compound of the compound of the compound, and the formulation of the 1000 tablets is as follows:
  • the preparation method of the artemisinin cyclodextrin inclusion compound is as follows:
  • the compound tablet preparation is prepared by using "the compound preparation example 1, the prepared carboxypyridinium lactate and artemisinin", and the formulation of 1000 tablets is as follows:
  • naloxalidine lactate, artesunate and starch mixed with starch use 8-10% starch slurry as binder, make soft material, sieve through 12-14 mesh, 70-80 ⁇ dry, whole grain Add magnesium stearate and mix it into a tablet to form a package.
  • the compound tablet preparation is prepared by using “pyridinyl lactate” and sodium artesunate sodium prepared by "Compound Preparation Example 1", and the formulation of 1000 tablets is as follows: L-naphthyl lactate (based on pyronaridine) 30g
  • Starch 70g Take lactamidine lactate, artemisinin and starch mixed, use 8-10% starch slurry as binder, make soft material, sieve through 12-14 mesh, 70-80'C Dry, whole grain, add magnesium stearate and mix it, then press it into shape and package it.
  • Biological Example 1 Comparison of Bioavailability of L-Naphthyl Lactate
  • N-naphthyl lactate and pyrrolizidine prepared by "Compound Preparation Example 1" were administered orally to Kunming mice at 1.56 g/kg (in terms of pyronaridine), 5, 10, 15, 30, 60, Blood was taken at 90, 120, 240, 360, 480, 720, and 1440 minutes. The plasma concentration was determined by high performance liquid chromatography, and the bioavailability was calculated. The relative bioavailability was calculated based on pyrroxypyridinium. The test results are as follows: :
  • N-naphthyl lactate and pyrrolizidine prepared by "Compound Preparation Example 1" were administered orally to rabbits at 0.56 g/kg (in terms of pyronaridine), 5, 10, 15, 30, 60, 90, 120, 240, 360, 480, 720, 1440 minutes of blood was taken, the blood concentration was measured by high performance liquid chromatography, and the bioavailability was calculated. The relative bioavailability was calculated based on the pyrrolizidine. The test results are as follows: Processing relative bioavailability
  • the rabbits were administered by dihydroartemisinin inclusion complex and dihydroartemisinin at 225 mg/kg, respectively, and then at 5, 10, 15, 30, 60, 90, 120, 240, 360, 480, Blood was taken at 720 and 1440 minutes, and the plasma concentration was determined by high performance liquid chromatography. The relative bioavailability of dihydroartemisinin was calculated as the standard. The results of the test were as follows:
  • Biological Example 3 Synergism of compound lactamidine According to the above "Compound Preparation Example 1", butyl naphthyl lactate was obtained. Eighty-eight patients with current falciparum malaria were randomly divided into 4 groups and administered orally. In the first group, 22 cases were pyronaridine, 3 days of treatment, 400 mg daily, 2 times on the first day, the total dose was 1600 mg. In the second group, 22 cases were dihydroartemisinin, 8 days of treatment, and dihydroartemisinin 80 mg per day, with a total dose of 640 mg. In the third group, 22 cases were treated with dihydroartemisinin and pyronaridine. The course of treatment was 2 days.
  • the total dose was dihydroartemisinin 300 mg and pyronaridine 800 mg.
  • 22 cases were treated with dihydroartemisinin and cyproterenol.
  • the course of treatment was 2 days.
  • the total dose was dihydroartemisinin 200 mg and pyronaridine 300 mg.
  • the results of the test face are as follows:
  • the drug combination of the present invention not only has a good effect, but also has a significantly reduced dosage per person compared with one of the combination drugs, and the incorporation of cyprodinil with dihydroartemisinin and dihydroartemisinin.
  • the combination is also better than the combination of pyrrolizinium and dihydroartemisinin.
  • the test results are as follows: Drug combination nalbufene lactate + pyrazolidine phosphate + carboxypyridinium lactate +
  • Synergistic index 8 (4 + 8 ) / (8 88-8 ⁇ 8 ⁇ , > 1 indicates synergy

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Abstract

La présente invention concerne un lactate de pyronaridine de formule (I), dans laquelle: n est 1 à 4, solvate, cristal ou un amorphisme de celui-ci. L'invention concerne également une composition pharmaceutique comportant le composé de formule (I), une composition pharmaceutique comportant le composé de formule (I) et un analogue d'artémisinine, une trousse pharmaceutique comportant le composé de formule (I) et un analogue d'artémisinine et l'utilisation dudit composé de formule (I) ou de ladite composition pharmaceutique dans la préparation d'un médicament pour la prévention et/ou le traitement du paludisme.
PCT/CN2010/000655 2009-05-12 2010-05-10 Lactate de pyronaridine, composition pharmaceutique et son utilisation WO2010130147A1 (fr)

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US9221760B2 (en) 2011-05-09 2015-12-29 Van Andel Research Institute Autophagy inhibitors
WO2021209477A1 (fr) * 2020-04-17 2021-10-21 Merck Patent Gmbh Formes cristallines de 4-[(7-chloro-2-méthoxybenzo[b][1,5]naphtyridin-10-yl)amino]-2,6-bis(pyrrolidin-1-ylméthyl)phénol et leurs sels

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CN101544638B (zh) * 2009-05-12 2012-05-30 重庆通天药业有限公司 乳酸咯萘啶及其药物组合物
CN113350334A (zh) * 2021-02-05 2021-09-07 中国中医科学院中药研究所 一种含有双氢青蒿素的抗疟药物

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CN1238950A (zh) * 1998-06-17 1999-12-22 中国预防医学科学院寄生虫病研究所 青蒿素类药物与咯萘啶的复方制剂抗疟药物
CN101052392A (zh) * 2004-11-02 2007-10-10 新丰制药株式会社 可口服给药的抗疟药组合制剂及其制备方法
CN101544638A (zh) * 2009-05-12 2009-09-30 重庆通天药业有限公司 乳酸咯萘啶及其药物组合物

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CN1238950A (zh) * 1998-06-17 1999-12-22 中国预防医学科学院寄生虫病研究所 青蒿素类药物与咯萘啶的复方制剂抗疟药物
CN101052392A (zh) * 2004-11-02 2007-10-10 新丰制药株式会社 可口服给药的抗疟药组合制剂及其制备方法
CN101544638A (zh) * 2009-05-12 2009-09-30 重庆通天药业有限公司 乳酸咯萘啶及其药物组合物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9221760B2 (en) 2011-05-09 2015-12-29 Van Andel Research Institute Autophagy inhibitors
WO2021209477A1 (fr) * 2020-04-17 2021-10-21 Merck Patent Gmbh Formes cristallines de 4-[(7-chloro-2-méthoxybenzo[b][1,5]naphtyridin-10-yl)amino]-2,6-bis(pyrrolidin-1-ylméthyl)phénol et leurs sels

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