WO2006049391A1 - Preparation combinee antimalaria administrable par voie orale et son procede de preparation - Google Patents

Preparation combinee antimalaria administrable par voie orale et son procede de preparation Download PDF

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Publication number
WO2006049391A1
WO2006049391A1 PCT/KR2005/003432 KR2005003432W WO2006049391A1 WO 2006049391 A1 WO2006049391 A1 WO 2006049391A1 KR 2005003432 W KR2005003432 W KR 2005003432W WO 2006049391 A1 WO2006049391 A1 WO 2006049391A1
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WO
WIPO (PCT)
Prior art keywords
pyronaridine
artesunate
preparation
composition according
derivatives
Prior art date
Application number
PCT/KR2005/003432
Other languages
English (en)
Inventor
Sung-Tae Lee
Woo-Yle Park
Jeong-Ryul Noh
Hyeon-Gun Jeong
Chul-Kyu Lee
Sung-Hyun Chun
Hyun-Kyu Jung
Original Assignee
Shin Poong Pharmaceutical Co., Ltd.
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 Shin Poong Pharmaceutical Co., Ltd. filed Critical Shin Poong Pharmaceutical Co., Ltd.
Priority to CN2005800374225A priority Critical patent/CN101052392B/zh
Priority to BRPI0517241A priority patent/BRPI0517241B8/pt
Publication of WO2006049391A1 publication Critical patent/WO2006049391A1/fr
Priority to HK08102530.5A priority patent/HK1113079A1/xx

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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
    • A61K31/335—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
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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 an orally administrable antimalarial combined preparation containing artemisinine or its derivatives, and pyronaridine or its salts, as active ingredients, with pharmaceutically acceptable carriers, and to a preparation process thereof.
  • the present inventors have searched safe, effective, quality, and inexpensive an ⁇ timalarial agents to treat uncomplicated P. falciparum and P.vivax malaria by oral ad ⁇ ministration in Africa and Asia.
  • the inventors have tried various combinations of py ⁇ ronaridine or salts thereof and artemisinine or derivatives thereof which have the most effect on the resistant strains, and finally, confirmed that the combination in the weight ratio of 6:1 ⁇ 1: 1, especially 3:1, is the most effective in the efficacy and toxicity.
  • the inventors discovered that when the two drugs are simply mixed together, artemisinine or derivatives thereof are resolved by direct contact because pyronaridine salts have physicochemical properties of acidic salts.
  • the present inventors solved the problems of preparation stability, solubility, and dissolution rate through primarily formulating artemisinine or derivatives thereof by using pharmaceutically acceptable carrier such as preparing them into microcapsule or eutectic mixture, or coating them with coating agents, and then mixing them with pyronaridine acidic salts to prepare a combined preparation.
  • pharmaceutically acceptable carrier such as preparing them into microcapsule or eutectic mixture, or coating them with coating agents, and then mixing them with pyronaridine acidic salts to prepare a combined preparation.
  • the purpose of the invention is to provide an orally administrable an ⁇ timalarial combined preparation containing artemisinine or its derivatives and py ⁇ ronaridine or its salts, as active ingredients, with the pharmaceutically acceptable carriers, and a preparation process thereof.
  • Fig. 1 is a graph showing the dissolution test result of artesunate of the combined preparation of Example 1 in simulated intestinal fluid, water, and pH 4.0 of phosphate buffer;
  • Fig. 2 is a graph showing the elution test result of pyronaridine tetraphosphate of the combined preparation of Example 1 in simulated gastric fluid, simulated intestinal fluid, water, and pH 4.0 of phosphate buffer.
  • the present invention relates to an orally administrable antimalarial combined preparation containing artemisinine or its derivatives, and pyronaridine or its salts, as active ingredients, with the pharmaceutically acceptable carriers, and to preparation process thereof.
  • artemisinine derivatives include dihydroartemisinine, artesunate,, artemether, and arteether, but not limited thereto.
  • artemisinine derivative is artesunate.
  • pyronaridine salts include acidic addition salts with phosphoric acid, sulfuric aicd, hydrochloric acid, acetic acid, methansulfonic acid, toluenesulfonic acid, maleic acid, or fumaric acid, but not limited thereto.
  • pyronaridine salts are py- ronaridine phosphate.
  • composition of the present invention contains artemisinine or its derivatives, and pyronaridine or its salts, preferably in the weight ratio of 1:1 ⁇ 1:6, more preferably 1:3.
  • artemisinine or its derivatives it is preferable to formulate artemisinine or its derivatives not to contact with pyronaridine or its salts.
  • artemisinine or its derivatives can be formulated by primarily formulating them into microcapsule, particulate form of eutectic mixture, or coated preparation with pharmaceutically acceptable carrier, and then mixing them with pyronaridine or its salts added thereto in a certain ratio to artemisinine or its derivatives.
  • any conventional carriers used in the pharmaceutical field can be used as the phar ⁇ maceutically acceptable carriers for the present invention.
  • Some representative examples thereof are lactose, dextrine, sugar, microcrystalline cellulose, hydroxy propylmethyl cellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, ethyl cellulose, methyl cellulose, polyethylene glycol, silicon dioxide, hydrotalcite, aluminium magnesium silicate, aluminium hydroxide, aluminium silicate, magnesium aluminium metha silicate, bentonite, and mixture thereof.
  • the preferable melting dispersing carrier is polyethylene glycol
  • the preferable weight ratio of artemisinine or its derivatives to polyethylene glycol is 1:0.1 ⁇ 1:2. Par ⁇ ticularly, the weight ratio of artesunate to polyethylene glycol is 1:1.
  • composition of the present invention can further comprise surfactants so that the components can quickly disintegrate and dissolve at the time of contacting with aqueous medium during in vivo administration, in addition to carriers.
  • surfactants include sodium lauryl sulfate and its derivatives; poloxamer and its derivatives; saturated polyglycorized glyceride (gelucire); labrasol; all sort of polysorbate such as polyoxyethylene sorbitan mono laurate (hereinafter, Tween 20), polyoxyethylene sorbitan monopalmitate (hereinafter, Tween 40), poly ⁇ oxyethylene sorbitan monostearate (hereinafter, Tween 60), and polyoxyethylene sorbitan monooleate (hereinafter, Tween 80); sorbitan esters such as sorbitan mono laurate (hereinafter, Span 20), sorbitan monopalmitate (hereinafter, Span 40), sorbitan monostearate (hereinafter,
  • microcapsule was prepared according to the same procedure as the Preparative Example 1.
  • microcapsule was prepared according to the same procedure as the Preparative Example 1.
  • Poloxamer F 127 15 hydroxypropylmethyl cellulose 20
  • Polyethylene glycol as melting dispersing carrier and artesunate as active ingredient are mixed, and then about 20mg of ethanol is added thereto, and the mixture is suspended at room temperature. After heating the mixture to about 80 0 C for melting, Poloxamer and hydroxy propylmethyl cellulose were added thereto, which was quickly frozen and solidified. After finely grinding the mixture, microcrystalline cellulose was added thereto, and the mixture was aggregated in the method of dry granulation to prepare the desired eutectic mixture granule containing artesunate.
  • Polyethylene glycol as melting dispersing carrier and artesunate as active ingredient are mixed, and then about 20mg of ethanol is added thereto, and the mixture is suspended at room temperature. After heating the mixture to about 80 0 C for melting, Poloxamer and ethyl cellulose were added thereto, and the mixture was quickly frozen and solidified. After finely grinding the mixture, microcrystalline cellulose was added thereto, and the mixture was aggregated in the method of dry granulation to prepare the desired eutectic mixture granule containing artesunate.
  • Example 1 Preparation of artesunate/pyronaridine tetraphosphate (1:3) combination tablet (1)
  • Example 2 Preparation of artesunate/pyronaridine tetraphosphate (1:3) combination tablet (2) [72]
  • Example 3 Preparation of artesunate/pyronaridine tetraphosphate (1:3) combination tablet (3) [76]
  • Example 5 Preparation of artesunate/pyronaridine tetraphosphate (2:3) combination tablet [84]
  • Example 1 Using the above ingredients, the tablet was prepared according to the s procedure as Example 1.
  • Example 7 Preparation of artesunate/pyronaridine tetraphosphate (1:7) combination tablet [92]
  • Example 8 Preparation of artesunate/pyronaridine tetraphosphate (1:3) combination hard capsule [96]
  • Example 10 Preparation of artesunate/pyronaridine tetraphosphate (1:4) combination hard capsule [104]
  • Example 11 Preparation of artesunate/pyronaridine tetraphosphate (1:6) mixture hard capsule
  • Example 12 Preparation of artesunate/pyronaridine tetraphosphate (1:1) combination tablet [112]
  • pH 3.0 buffer 1.36g of Potassium dihydrogenphosphate was dissolved in IL of water and adjusted to a pH 3.0+0.05 with phosphoric acid.
  • Fig. 1 shows the result of the above-Dissolution test.
  • Fig. 2 shows the result of the above-dissolution test.
  • pH 3.0 buffer 1.36g of Potassium dihydrogenphosphate was dissolved in lLof water, and phosphoric acid was added thereto to adjust to pH 3.0+0.05.
  • Detector Ultraviolet absorption spectrometer (wavelength : 278nm)
  • the protozoa was put into in a tissue culture flask containing the culture media (RPMI- 1640:Rh+ red blood cell, 5% of Hematocrit, 25mM of HEPES, 24 mM of NaHCO , 0.2% of glucose, 0.03% of L-glutamine, 150 ⁇ M of H ypoxantin, and 0.5% of albumax II), and cultured in a tissue culture incubator (at 37 0 C with supplying 5% CO 2 /95% air).
  • the culture media RPMI- 1640:Rh+ red blood cell, 5% of Hematocrit, 25mM of HEPES, 24 mM of NaHCO , 0.2% of glucose, 0.03% of L-glutamine, 150 ⁇ M of H ypoxantin, and 0.5% of albumax II
  • [196] Drug-sensitivity test was conducted according to a modified method from Deszardin et al. (Antimicorb. Agents Chemother. 1979, 16, 710). That is, the drug was dissolved in 100% of DMSO, and repeatedly diluted with the culture media (RPMI- 1640: 0.5% of albumax II, 0.2% of glucose, 0.03% of L-glutamine, and 150 ⁇ M of H ypoxantin) in 96 well-plate. The ratio of the two drugs was fixed to 1 :0, 4: 1 , 3 :2, 2:3, 1:4, and 0:1 for the combination test. The same amount of P.
  • chabaudi ASS parasitised erythrocytes was conducted by a three-day course of treatment starting 2 days after the infection as follows: the mice were infected with P. chabaudi protozoa; pyronaridine/ artesunate (3:1) obtained in Example 1 was subcutaneously administrated; the infection process was observed for 28 days; every day, blood was taken from each animal, and thin blood film thereof was prepared; after Giemsa stains, it was examined whether the animal was infected or not with a microscope; the blood of mice which showed negative reaction after 28 days was pooled and sub-inoculated into na ⁇ ve mice ; pooled blood was diluted with 0.9% of saline solution to 2-fold volume; 0.2mL thereof was intravenously administrated to 5 na ⁇ ve mice to re-infect them; and observation was continued for 28 days more.
  • mice were infected intravenously with 2 x 10 of infected erythrocytes.
  • mice Two hours post-infection treated groups received the first treatment at the doses specified. Mice were administered once a day on Days 1 to 3. At day 4, blood was taken from their tail vein, and thin blood film was prepared therefrom. After Giemsa stains, it was examined whether they were infected or not, with a microscope. The lines used therein were P. berghei NY- drug sensitiveness, P. berghei PNY- py ⁇ ronaridine resistance, and P. berghei SANA- Artesunate resistance. The next day after completing the administration, the bloods were taken, thin blood film was prepared therefrom, and the frequency of occurrence was measured by a microscope to observe bacteriostatic effect. The bacteriostatic activity was assessed by comparing the level of parasitemia between the drug-treated group and the control group. The 50% and 90% effective levels (ED , ED ) were calculated from the log-drug concentration and bac-
  • the pharmaceutical composition of the present invention can provide antimalarial agent showing remarkable treatment effect on the resistant strains, with securing the drug stability and having synergic effect of the two drugs.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une préparation combinée antimalaria administrable par voie orale contenant de l'artémisinine ou ses dérivés, et de la pyronaridine ou ses sels, en tant que principes actifs, et des excipients pharmaceutiquement acceptables, ainsi qu'un procédé de préparation de cette préparation.
PCT/KR2005/003432 2004-11-02 2005-10-14 Preparation combinee antimalaria administrable par voie orale et son procede de preparation WO2006049391A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN2005800374225A CN101052392B (zh) 2004-11-02 2005-10-14 可口服给药的抗疟药组合制剂及其制备方法
BRPI0517241A BRPI0517241B8 (pt) 2004-11-02 2005-10-14 composição farmacêutica, e, método para preparar a mesma
HK08102530.5A HK1113079A1 (en) 2004-11-02 2008-03-05 Orally administrable antimalarial combined preparation and preparation process thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2004-0088413 2004-11-02
KR1020040088413A KR100623322B1 (ko) 2004-11-02 2004-11-02 경구투여용 항말라리아 배합 제제 및 그의 제조방법

Publications (1)

Publication Number Publication Date
WO2006049391A1 true WO2006049391A1 (fr) 2006-05-11

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PCT/KR2005/003432 WO2006049391A1 (fr) 2004-11-02 2005-10-14 Preparation combinee antimalaria administrable par voie orale et son procede de preparation

Country Status (8)

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KR (1) KR100623322B1 (fr)
CN (1) CN101052392B (fr)
AP (1) AP2419A (fr)
BR (1) BRPI0517241B8 (fr)
HK (1) HK1113079A1 (fr)
OA (1) OA13155A (fr)
WO (1) WO2006049391A1 (fr)
ZA (1) ZA200703467B (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP3498279A4 (fr) 2016-08-12 2020-04-29 Novmetapharma Co., Ltd. Composition pharmaceutique comprenant comme principes actifs de l'amodiaquine et un médicament anti-diabète, destinée à la prévention ou le traitement du diabète
PE20230041A1 (es) * 2020-03-26 2023-01-10 Shin Poong Pharmaceutical Co Ltd Composicion farmaceutica para la prevencion o tratamiento de enfermedad infecciosa viral de arn epidemica
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
WO2022231238A1 (fr) * 2021-04-26 2022-11-03 심민보 Composition pharmaceutique contenant de l'artésunate ou un sel de celui-ci et de la pyronaridine ou un sel de celle-ci, utilisée à des fins antipyrétiques, anti-inflammatoires, antivirales et pour le traitement ou la prévention de la covid-19, et procédé l'utilisant
KR20230076573A (ko) 2021-11-24 2023-05-31 장은혜 야생쑥 추출 천연 아르테미시닌을 함유한 항말라리아용 구강붕해성 필름제제

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1200925A (zh) * 1997-05-30 1998-12-09 北京市科泰新技术公司 一种治疗抗药性恶性疟疾的药物组合物及其制备方法

Non-Patent Citations (4)

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Title
LIU ET AL: "Study on treatment of multi-drug resistant falciparum malaria by using a combination of dihydroartemisinin and pyronaridine", ZHONGGUO JI SHENG CHONG XUE YU JI SHENG CHONG BING ZA ZHI, vol. 20, no. 4, 2002, pages 193 - 196 *
PETERS ET AL: "The chemotherapy of rodent malaria. IV. Interactions between pyronaride and artemisinin", ANN.TROP.MED.PARASITOL., vol. 91, no. 2, 1997, pages 141 - 145 *
YANG ET AL: "Effect of pyronaridine, mefloquine and quinine on artesunate-sensitive and artesunate resistant Plasmodium falciparum", ZHONGGUO JI SHENG CHONG XUE YU JI SHENG CHONG BANG ZA ZHI, vol. 18, no. 1, 2000, pages 5 - 7 *
ZHANG ET AL: "Studies on the establishment of malarial animal model of short-term relapse. III. Combined therapy with pyronaridine-artemether-chloroquine for parasitemia clearance", ZHONGGUO JI SHENG CHONG XUE YU JI SHENG CHONG BING ZA ZHI, vol. 11, no. 3, 1993, pages 180 - 184 *

Also Published As

Publication number Publication date
CN101052392A (zh) 2007-10-10
KR100623322B1 (ko) 2006-09-19
BRPI0517241B1 (pt) 2019-10-22
BRPI0517241B8 (pt) 2021-05-25
OA13155A (en) 2006-12-13
BRPI0517241A (pt) 2008-10-07
AP2419A (en) 2012-06-05
ZA200703467B (en) 2008-09-25
CN101052392B (zh) 2010-12-15
KR20060039286A (ko) 2006-05-08
HK1113079A1 (en) 2008-09-26

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