EP1267864A1 - Synergistische formulierung gegen malaria - Google Patents

Synergistische formulierung gegen malaria

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Publication number
EP1267864A1
EP1267864A1 EP00940733A EP00940733A EP1267864A1 EP 1267864 A1 EP1267864 A1 EP 1267864A1 EP 00940733 A EP00940733 A EP 00940733A EP 00940733 A EP00940733 A EP 00940733A EP 1267864 A1 EP1267864 A1 EP 1267864A1
Authority
EP
European Patent Office
Prior art keywords
formulation
rectal
arteether
treatment
oil
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
EP00940733A
Other languages
English (en)
French (fr)
Inventor
Guru Prakash Central Institute DUTTA
Dharm Chand Central Institute JAIN
Rajendra Singh Central Institute BHAKUNI
Sudhanshu Central Institute SAXENA
Sangeeta Central Institute DHAWAN
Suman Preeet Singh Central Institute KHANUJA
Sushil Central Institute KUMAR
Renu Central Drug Research Institute TRIPATHI
Aseem Central Drug Research Institute UMESH
Nuzhat Central Drug Research Institute KAMAL
Anil Kumar Central Drug Research Inst. DWIVEDI
Satyawan Central Drug Research Institute SINGH
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.)
Council of Scientific and Industrial Research CSIR
Original Assignee
Council of Scientific and Industrial Research CSIR
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 Council of Scientific and Industrial Research CSIR filed Critical Council of Scientific and Industrial Research CSIR
Publication of EP1267864A1 publication Critical patent/EP1267864A1/de
Ceased legal-status Critical Current

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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
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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 novel synergistic formulation comprising ⁇ , ⁇ -arteether together with vegetable oil, said formulation useful in the treatment of comatose and cerebral malarial cases.
  • the formulation specifically useful for rectal route treatment of highly multi-drug resistant P. falciparum and P. vivax cases and which can be used for emergency treatment of comatose and cerebral malaria.
  • the invention also provides methods of treatment of malaria affecting the brain employing the novel formulation.
  • the invention also provides process for preparation of the said novel formulation.
  • Mefloquine was reported to produce neuropsychiatric side-effects in adults who developed tonic clonic fits. Besides psychosis, delusions and hallucinations, anxiety sleep disturbances were also reported after mefloquine (Drugs 1990, 39, 160-169).
  • Multi-drug-resistance in P. falciparum malaria and high level of P. vivax resistant strains are posing a major threat to countries in South-east Asia. Africa and Southern America. Most seriously affected areas include Thai-Myanmar Burmese border, where resistance to nearly all available drugs (Chlorquine, sulfadoxine-pyrimethamine, mefloquine, quinine) has already got established, (WHO Report on Infectious Diseases, 1999, WHO/CDS/99 1)
  • Halofant ⁇ ne ts more effective but rather high doses of the drug are now required to control resistant P. falciparum (Brasseur et al 1993 Lancet 341, 901-2) which cold lead to increased risk of cardiotoxicity of this new antimalarial including sinus bradycardia, sinus arrhythmia, tall peak T waves, QT interval prolongation, ectopic beats (Karbwang et al 1993, Lancet, 342, 501, Wildling et al 1993 Lancet, 342, 55, Kremsner et al Am J Trop Med Hyg 50, 790-795) which has imposed great limitation on the antimalarial potential of this drug Several reports have recently appeared which document emergence of chloroquine resistance by P.
  • ⁇ , ⁇ -arteether is an ethylether derivative of qinghaosu (artemisinine), which is extracted from Artemisia anniia, a plant long known in traditional Chinese medicine for its antimalarial properties
  • ⁇ , ⁇ -Arteether (30 70) is one of the artemisinin derivatives that has been developed in India and shows antimalarial activity against chloroquine, mefloquine and quinine resistant P. yoeln mgenensis and cures experimental cerebral malaria infections P. knowlesilP.
  • ⁇ / ⁇ -Arteether is relatively safer and its LD 50 dose is 1250 mg/kg in Swiss mice as compared to artemether (LD 50 263 mg/kg (im) and artesunate (LD50 475 mg/kg, im)(J Trad Chinese Med 1982,2(1) 31-38).
  • Clinical trials of intramuscular injection of this compound have been completed and marketed Data on clinical trials with injectible preparation of ⁇ , ⁇ arteether (30 70 mixtures of isomers amongst P. falciparum cases has been published (Mohapatra et al 1996 Indian J Med Res 104, 284-7, Nalecha et al 1997, Int J Clin Pharm Res XNII (1) 11-15 Mohanty et al 1997 Trans. R Soc Trop Med Hyg 91, 328-330, Mishra et / 1995, Trans R Soc. Trop Med Hyg 89, 299-301)
  • the main objective of the present invention is to provide a useful synergistic formulation of ⁇ , ⁇ -arteether for treatment of cerebral malaria.
  • Another objective of the present invention is to provide a formulation which is highly effective, easy to use, non-messy and non-cumbersome and can be administered by the rectal route to control cerebral malaria and which can also be used to clear a wide spectrum of infections resistant to most of the conventional antimalarials, antibiotic and other drug combinations.
  • Another objective of the invention is to provide a formulation effective in controlling malarial parasites in both asexual and sexual stages, in both drug sensitive and resistant malaria infections.
  • Yet another objective is to provide the rectal arteether can be effective in stopping malaria transmission and spread of the disease.
  • the present invention relates to a synergistic formulation comprising ⁇ / ⁇ arteether useful for the treatment of wide spectrum multi-drug resistant malaria and emergency treatment of comatose malaria
  • the formulation can be administered in malarial cases by rectal route in the form of rectal formulation, suppository in different doses form for infant, children, adults and pregnant woman
  • the above said formulation can be given by oral route also, for complete elimination of malaria infection.
  • the formulation would be effective in stopping the malarial transmission.
  • the invention also provides a process for the preparation of the said formulation
  • the invention provides a synergistic formulation comprising pharmaceutically effective amount of ⁇ / ⁇ arteether and a neutralized refined vegetable oil suitable for administration by rectal route
  • the vegetable oil is sterilized neutral refined oil that does not solidify in winter at room temperature
  • the ratio of ⁇ / ⁇ arteether and vegetable oil in the formulation is 0 002-0 020 1 w/w, preferably 0 0025 1 w/w
  • the vegetable oil is selected from the group comprising ground nut oil, sesame oil and tea oil.
  • ⁇ and ⁇ tautomers are present in a ratio of 10 90 to 30 70 In still another embodiment, the preferred ratio of ⁇ and ⁇ tautomers in the formulation is 30:70.
  • the formulation is used against a wide spectrum of Plasmodium yoelii nigeriensis (MDR II) parasite resistant to high oral doses of drugs selected from chloroquine, amodoquine, mepacrine, mefloquine, quinine, quinidine, pyrimethamine, pyronaridine, halofantrine, pyrimethamine+sulfadoxin, primaquine and WR 238605.
  • MDR II Plasmodium yoelii nigeriensis
  • the formulation is used against Plasmodium yoelii nigeriensis resistant to antibiotics selected from tetracycline, oxytetracycline, demeclocycline, erythromycin, ciprofloxacine, norfloxacine and doxycycline.
  • Plasmodium yoelii nigeriensis resistant to antimalarial-antibiotic combinational drugs selected from chloroquine +tetracycline, amodiaquine+tetracycline, mefloquine+tetracycline, mepacrine+tetracycline, quinine+tetracycline, quinine+oxytetracycline, quinine+doxycycline, quinine+erythromycin, cyprofloxacine +chloroquine, norfloxacine+chloroquine and quinine+tetracycline.
  • the said formulation is viscous and light yellow in colour.
  • the ⁇ and ⁇ tautomers in the formulation are present in a ratio of 10:90 to 30:70. and maintains longer half life (22 hrs or more).
  • the same formulation can also be made into regular rectal suppository which can be administered into rectum 3-4 times daily during acute phase of malaria.
  • the formulation can be used as substitute of primaquine and WR236805 and useful for interrupting transmission of P. falciparum because of its gametocytocidal action.
  • the formulation has a half life of about 22 hrs or more.
  • the formulation provides extended bioavailability because of longer T 1/2 ⁇ (clearance) in comparison to other artemisinin derivatives such as artemether or artesunate which have short plasma half life.
  • the formulation shows no adverse gastric effects, hemorrhage etc. which are found in the rectal or oral treatment with other artemisinin derivatives in tablet form.
  • the formulation is safe (LDso > 1250 mg/kg), well tolerated and much safer than artemether and artesunate in animal toxicity tests.
  • the formulation can be administered by rectal or oral routes or as gelatin capsule, given three to four times daily, and the formulation has shelf life of more than three years.
  • the formulation has 100-300 times more accumulation in the malarial infected red blood cells than the normal red blood cells.
  • the said formulation has adequate rectal absorption of compound sufficient to arrest the rising parasitaemia and the treated animals show significant reduction/clearance of parasitaemia indicating sufficient rectal drug absorption.
  • the formulation has blood schizontocidal activity as useful for the emergency treatment of uncomplicated severe complicated/cerebral and multi-drug resistant malarial infections including comatose malaria cases (for which it is the first line of emergency treatment).
  • the said formulation has no adverse met-hemoglobin type of toxicity which is known to be associated with administration of primaquine and WR236805.
  • the invention provides methods for the treatment of comatose cerebral malarial conditions comprising the steps of rectal administration of the formulation to a subject in need thereof.
  • the formulation is effective against sexual stage of parasites selected from P. falciparum, P. vivax and P. cynomolgi.
  • the formulation for rectal/oral treatment is used in the form of rectal formulation rectal suppositories/ oral gelatin capsules of liquid formulations in different dose forms for infants, children and adults.
  • the formulation is effective and safe in pregnant malaria infected monkeys, and could be useful for treatment of severe malaria in pregnant women.
  • the formulation is administered by the rectal route in children as well as adults for longer periods of once or twice a week until transmission continues
  • the process for the preparation of a formulation useful for the control of wide spectrum of malaria comprising (a) preparation of arteether ⁇ and ⁇ from artemisinin by known methods, (b) dissolving ⁇ / ⁇ arteether in sterilized neutral refined vegetable oil heating at 70-90°C for 2-4 min. and (c) cooling the solution at room temperature to obtain the desired formulation and (d) followed by sterilization of formulation by filtration through 0.45 ⁇ m filter.
  • the major advantage of the arteether rectal formulation will be to treat very serious cases/ comatose cases of cerebral malaria with a view to reduce mortality among P. falciparum cases particularly in children, pregnant women who are at maximum risk and can prove fatal unless the emergency therapy is instituted.
  • a still another advantage of the rectal formulation of arteether will be to control multi-drug resistant infections due primarily to P. falciparum which because of problem of resistance can not be treated effectively or cured with conventional antimalarial drugs such as chloroquine, mefloquine, amodiaquine, mepacrine, quinine, quinidine, halofantrin, pyrimethhamine, pyronaridine, WR238605 to which the parasite might be resistant, or with standard suppressive antimalarial antibiotics such as tetracycline, oxytetracycline, demeclocycline, doxycycline, erythromycin, ciprofloxacin, norfloxacin to which plasmodia may be resistant or with diverse antimalarial+antibiotic combination such as chloroquine, amodiquine/ mefloquine/ mepacrine/ quinine/ quinidine+tetracycline combinations or quinine/ quinidine+oxytetracycline combination, or qui
  • Another advantage of formulation will be to control chloroquine resistant P. vivax blood infections which are presently spreading in many continents could be effectively treated initially with rectal arteether formulation to prevent deterioration of the condition of the patient, and as soon as the patient is brought to the hospital arteether formulation can also be given parenterally as intramuscular (3 doses) curative treatment. All cases of P. falciparum and P. vivax which need a life saving therapy/those in coma /serious complicated P.
  • infants can be administered rectal arteether formulations 2-4 times daily to revive the comatose cases and rectal therapy used as emergency treatment can be changed to parenteral (oral) therapy with same arteether formulation (prepared in neutralized oil) which allows rapid drug absorption from gut and can provide effective control of parasitaemia, by oral route.
  • Rectal suppositories are simple to administer, easy to store at room temperature and administered, as it does not require any special equipment and can be given as emergency drug at rural health centers throughout the developing world. Suppository could be used in remote areas/villages incases who might not survive the long journey or delay in reporting to the hospital.
  • the formulation ( ⁇ / ⁇ -arteether and vehicle) is relatively safe as compared to other artemisinin derivatives (LDj 0 in mice>1250 mg/kg) and consequently the therapeutic index is more favorable for treatment of malaria.
  • the neutralized refined oil thus prepared was superior to commercial refined oil because it was stable even during winter on the shelf and did not solidify during overnight very low temperature. Accordingly, the present invention provides a process of the preparation of formulation useful for treatment of malaria, which comprises mixing 5 to 15% by weight of arteether with 85 to 95% by weight of neutralized refined ground nut oil which can be put into soft gelatin capsule for rectal treatment, or taking material in syringe and giving rectal administration of drug through a nozzle or catheter or prepare into standard suppository by known methods.
  • ⁇ / ⁇ arteether used may be selected from the mixture in different proportions ranging from 10-30 of ⁇ - and 70-90 of ⁇ -isomers.
  • the formulation used may be mixed with known suppository formulations such as glycerols substituted glycol, alkyl alcohol and mixture thereof.
  • the resulting composition (formulation and standard suppository materials) may be molded into desired shape and size.
  • the composition can also be made into a suppository like glycrine suppository or can be put in a soft gelatin capsule or the final formulations can be administered deep into rectum through plastic nozzle or rubber catheter 2-4 times daily for several days to reduce the parasitaemia to eliminate infection.
  • Neutralized oil Refined ground nut oil was purchased from commercial source locally. 100 ml oil was taken in separating funnel and to this 50 ml of sterile 5% sodium bicarbonate solution was added and was shaken for 10 min thoroughly to mix sodium bicarbonate with the oil. This solution was allowed to stand for 2 hrs, sodium bicarbonate layer was drawn out and fresh bicarbonate was added and process was repeated for 4 times to prepare neutralized oil. Last bicarbonate washing was continued for over night and after bicarbonate treatment, washing with sterilized deionized distilled water was started and likewise 4 washing of the treated oil were given with 50 ml distilled water. After the last washing, oil was filtered through double layered Whattman filter no.
  • Multi-drug resistant character of Plasmodium yoelii nigeriensis (MDR strain):
  • mice weighing 20 ⁇ 1 to 25 ⁇ 1 g of either sex and random laboratory bred at Central Drug Research Institute, Lucknow were used. Mice were routinely infected with lxlO 3 parasitized RBC intraperitoneally using sterile citrate saline as diluent for infected blood
  • the parasite suspension were inoculated in healthy mice by intraperitoneal route on day 0, and drugs were administered orally once a day for 4 doses (day 0 to day+ 3). From day 4 onwards, tail blood smears were examined after Giemsa staining and percent parasitaemia and mortality was recorded.
  • the parasite (MDR strain) was lethal for Swiss mice and mice died in 6-8 days after developing parasitaemia above 40% to 100% infection of RBC. Mortality was 100% in mice.
  • Table Present status of resistance pattern of P. yoelii nigeriensis (MDRII) strain to different antimalanals in Swiss mice.
  • ⁇ , ⁇ -Arteether mixture dissolved in neutralized ground-nut oil was administered to P. yoelh nigeriensis (MDR II) infected mice at 10 mg/kg to 20 mg/kg dose from day 0 to day 2 (for 3 consecutive days) by intra-rectal route
  • Drug was administered with 0 05-0 25 ml oil (vehicle) in single dose or in 2 divided dose daily
  • Parasitaemia was recorded daily from tail blood smears stained with Giemsa stain and results are given as % parasitaemia (means ⁇ SD) All the doses of arteether namely 10 0, 15 0 and 20 0 mg/kg suppressed the parasitaemia even after treatment (upto 5 days) as shown by blood smear examination The study shows that till day 5, the control mice had developed very high level of parasitaemia (57 6 ⁇ 24 7) and had starting dying whereas the groups of mice administered 15-20 mg/kg ⁇ , ⁇ -arteether formulation by rectal route treatment were fully protected as shown
  • Rectal formulation can easily control highly multi drug resistant malaria infections which do not respond to drugs like chloroquine, amodiaquine, mepacrine, mefloquine, halofantrine, quinine, quinidine, pyrimethamine +sulfadoxin etc. in MDR areas. Rectal route ⁇ / ⁇ arteether formulation remains 1 st line of emergency treatment of comatose P. falciparum cases in areas of MDR.
  • Swiss mice 25 ⁇ 1 gm infected intraperitoneally with 1x10 parasitized rbcs were administered ⁇ / ⁇ formulation, prepared in DMSO (3-4 drop) and then suspended in distilled water by oral administration at various doses ranging between 40-100 mg/kg for 5 consecutive days
  • Curative dose 60 mg/kg x 5 doses
  • yoelii nigeriensis MDR II was achieved As discussed above the bioavailability of oral arteether ⁇ / ⁇ (powder) prepared into dosage form in DMSO and distilled water is of lower order and a dose of 60 mg/kg x 5 days is needed for multi-drug resistant P. yoelii nigeriensis (MDRII) total clearance, whereas oral arteether ( ⁇ / ⁇ ) formulation in neutralized refined ground nut oil is much more effective and 50% drug dose (30 mg/kg x 5) is effective in 100% parasite clearance. Thus formulation in oil is superior for treatment of malaria.
  • P. falciparum clinical cases which were ganetocyte carriers were administered arteether formulation parenterally (intramuscular) at 150 mg dose (in neutralized ground nut oil) x 3 days for treatment of malaria, and within 48 h both asexual parasitaemia and gametocytes were completely cleared from the blood stream.
  • 8 cases 7 cases were cleared of gametocytes within 24 h of treatment while in the 8 th case gametocytes were cleared by 48 h.
  • the study shows strong gametocytocidal action of arteether formulation. All cases remained parasite free upto 28 days observation and drug cure rate was 100 percent.

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EP00940733A 2000-03-31 2000-03-31 Synergistische formulierung gegen malaria Ceased EP1267864A1 (de)

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PCT/IN2000/000039 WO2001074353A1 (en) 2000-03-31 2000-03-31 A synergistic anti-malarial formulation

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US20040023897A1 (en) * 2001-11-13 2004-02-05 Caplan Michael J. Methods for preventing or treating disease mediated by toxin-secreting bacteria

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ES2054975T3 (es) * 1988-10-07 1994-08-16 Hoechst Ag Composiciones antimalaricas que emplean quinidina, artemisinina y sus derivados.
CN1058717A (zh) * 1990-08-08 1992-02-19 中国人民解放军军事医学科学院微生物流行病研究所 抗疟新药—复方蒿甲醚及其制备方法
CH692321A5 (de) * 1997-11-03 2002-05-15 Mepha Ag Pharmazeutisch wirksame Zusammensetzung, welche eine gegen Malariaparasiten wirksame Substanz enthält.
IN191696B (de) * 1999-02-12 2003-12-20 Council Scient Ind Res

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