WO2011009956A1 - Solution aqueuse injectable contenant de l'artésunate - Google Patents

Solution aqueuse injectable contenant de l'artésunate Download PDF

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Publication number
WO2011009956A1
WO2011009956A1 PCT/EP2010/060757 EP2010060757W WO2011009956A1 WO 2011009956 A1 WO2011009956 A1 WO 2011009956A1 EP 2010060757 W EP2010060757 W EP 2010060757W WO 2011009956 A1 WO2011009956 A1 WO 2011009956A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
hydroxycarbohydrate
carrier
artesunate
pharmaceutically acceptable
Prior art date
Application number
PCT/EP2010/060757
Other languages
English (en)
Inventor
Frans Herwig Jansen
Original Assignee
Dafra Pharma N.V.
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 Dafra Pharma N.V. filed Critical Dafra Pharma N.V.
Publication of WO2011009956A1 publication Critical patent/WO2011009956A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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 pharmaceutical compositions comprising an anti-malarial agent. Further, the present invention relates to a unit dose comprising the present pharmaceutical compositions. Furthermore, the present invention relates to a unit dose comprising the present pharmaceutical compositions for use in the treatment of malaria.
  • malaria is a mosquito-borne disease or vector-borne
  • Novel efficient anti-malarial drugs based on artemisinin derivatives were discovered, developed and were proven to be highly efficient anti-malarial medicines, such as artemisinin and derivatives thereof.
  • artesunate is known for the treatment of malaria infected patients.
  • the efficiency of the drug generally provides clearance of the parasite induced fever within 16 to 25 hours.
  • artesunate generally is not soluble in aqueous solutions and,
  • a common formulation of artesunate is a formulation of artesunate in bicarbonate. This formulation has to be prepared immediately before use, generally using artesunic acid and bicarbonate. However, according to Ipca Laboratories Ltd in their document Crusade against Malaria, this composition needs to be vigorously mixed for several minutes in order to dissolve the ingredients and avoid cloudy solutions. In other words, artesunate is difficult to dissolve in aqueous solutions such as water.
  • Cloudy solutions or opaque suspensions, inherently imply a decrease in dosing accuracy, especially when such dosing is prepared by not adequately trained medical personnel, being the case in most regions where malaria is an issue. Further, cloudy solutions, or
  • cloudy solutions, or medicinal preparations comprising undissolved active ingredients such as artesunate are generally undesirable.
  • cloudy solutions generally do not allow parenteral, and especially intravenous, administration because the insoluble particles can easily result in, for example, pulmonary and/or capillary embolism.
  • compositions in powder form, comprising artesunate, a pharmaceutically acceptable hydroxycarbohydrate carrier and a phosphate salt, wherein in aqueous form, the composition has a pH of at least 6 and wherein the ratio between the artesunate and the pharmaceutically acceptable hydroxycarbohydrate carrier is in the range of 1:0.1 to 1:3 by weight.
  • a substantially soluble artesunate preparation as described herein, is defined as an aqueous preparation suitable for parenteral, such as intramuscular,
  • the present composition is stable, i.e., no visible precipitation is observed, over a prolonged period such as over hours to days. This stability also contributes to the beneficial properties of the present pharmaceutical compositions.
  • compositions according to the invention are surprisingly suitable to obviate the above mentioned dosage problem of the artesunate by providing pharmaceutical compositions substantially soluble in aqueous solutions .
  • the powder form of the pharmaceutical compositions is stable over months for shipping, storage and handling purposes.
  • the pH of the pharmaceutical compositions in aqueous solution is in the range of 6 to 9.2, such as 6.1, 6.2, 6.5, 6.7, 6.9, 7.0, 7.1, 7.2, 7.4, 7.6, 7.8, 8.0, 8.2, 8.4, 8.6, 8.8, or 9.0.
  • the pharmaceutical compositions according to the invention in aqueous form, have a pH in the range of 6.5 to 8.0, preferably 6.9 to 7.5, more preferably 7.2.
  • the ratio between the artesunate and the pharmaceutically acceptable hydroxycarbohydrate carrier is in the range of 1:0.1 to 1:3 by weight, such as 0.5:1.5, 0.6:1.4, 0.7:1.3, 0.8:1.2, 0.9:1.1, 1:1, 1.1:0.9, 1.2:0.8, 1.3:0.7, 1.4:0.6 and
  • compositions according to the present invention comprise a pharmaceutically acceptable
  • hydroxycarbohydrate carrier wherein the hydroxycarbohydrate carrier is mannitol.
  • compositions according to the present invention comprise a pharmaceutically acceptable
  • hydroxycarbohydrate carrier wherein the hydroxycarbohydrate carrier is micronized mannitol.
  • Micronized mannitol is a particular powder form of mannitol, wherein the grains of the powder have a diameter of 1 to 100 microns.
  • compositions according to the present invention comprise a pharmaceutically acceptable
  • hydroxycarbohydrate carrier wherein the hydroxycarbohydrate carrier is sorbitol.
  • compositions according to the present invention comprise a pharmaceutically acceptable hydroxycarbohydrate carrier, wherein the hydroxycarbohydrate carrier is xylitol.
  • the pharmaceutical compositions according to the present invention comprising artesunate are in an ultrathin powdered form.
  • Ultrathin artesunate is artesunate which has been sieved in order to select the smaller grains of the powder .
  • the present invention relates to a unit dose comprising a sealable container comprising a pharmaceutical composition in powder form according to the present invention for the treatment of malaria.
  • a unit dose is packaging of a medicament suitable for one single dose.
  • Said sealable container is generally known for pharmaceutical use and can be a vial, a capsule or a flask for example.
  • a sealable container according to the present invention is a substantially air and moisture impermeable container after sealing.
  • the unit dose according to the present invention comprises artesunate with a weight in the range of 20 to 200 mg, preferably 30 to 150 mg, more preferably 40 or 100 mg.
  • the indicated amounts of artesunate are generally accepted efficient dosages of the anti-malarial agent.
  • the unit dose according to the present invention in aqueous form, has a volume in the range of 0.25 to 5 ml, preferably 0.5 to 3 ml, more preferably 1 ml or 2 ml .
  • the indicated volumes of solution are generally accepted volumes for parenteral, such as intramuscular or intravenous, administration .
  • methods for the preparation of a pharmaceutical composition comprising: a) dissolving of a pharmaceutical composition in powder form comprising artesunate, a
  • freeze-drying process also called lyophilisation
  • lyophilisation is a dehydration method allowing better transport and handling of materials .
  • methods for the preparation of the pharmaceutical composition have a pH of 7.2 when dissolved in aqueous solutions such as water.
  • compositions or the unit doses according to the present invention are suitable for the treatment of malaria.
  • the treatment comprising parenteral, preferably intravenous, injection.
  • a unit dosage of a representative pharmaceutical composition according to the present invention was prepared comprising the following ingredients: Artesunate 40 mg
  • the vials were left at 30 0 C for 1 day. After 24 hours, the vials were visibly inspected and no precipitation was observed.
  • composition was also prepared comprising: Artesunate 100 or 200 mg
  • compositions were added to an air sealable vial and, after closing, stored for 2 months at 30 0 C.
  • the vials were left at 30 0 C for 1 day. After 24 hours, the vials were visibly inspected and no precipitation was observed.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Dermatology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques sous forme de poudre comprenant un agent antipaludique. En particulier, la présente invention concerne une composition pharmaceutique sous forme de poudre, comprenant : a) l'artésunate ; b) un transporteur glucidique hydroxylé pharmaceutiquement acceptable ; c) un sel de phosphate ; la composition, quand elle est sous forme aqueuse, ayant un pH d'au moins 6, et le rapport entre l'artésunate et le transporteur glucidique hydroxylé pharmaceutiquement acceptable étant dans la plage allant de 1 : 0,1 à 1 : 3 en poids. De plus, la présente invention concerne une dose unitaire comprenant les compositions pharmaceutiques. En outre, la présente invention concerne une dose unitaire comprenant les compositions pharmaceutiques destinées à être utilisées dans le traitement de la malaria.
PCT/EP2010/060757 2009-07-24 2010-07-23 Solution aqueuse injectable contenant de l'artésunate WO2011009956A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EPPCT/EP2009/059596 2009-07-24
EP2009059596 2009-07-24

Publications (1)

Publication Number Publication Date
WO2011009956A1 true WO2011009956A1 (fr) 2011-01-27

Family

ID=42557370

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2010/060757 WO2011009956A1 (fr) 2009-07-24 2010-07-23 Solution aqueuse injectable contenant de l'artésunate

Country Status (1)

Country Link
WO (1) WO2011009956A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3402479A4 (fr) * 2016-01-15 2018-12-19 Ming Zhao Composition contenant de l'artésunate

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030203875A1 (en) * 2002-03-07 2003-10-30 Hartell Mark G. Artemisinins with improved stability and bioavailability for therapeutic drug development and application
WO2007017646A2 (fr) * 2005-08-05 2007-02-15 Cipla Limited Composition antimalarienne
WO2007146288A2 (fr) * 2006-06-13 2007-12-21 Walter Reed Army Institute Of Research (Wrair) Méthodes de formulation et de fabrication d'acide artésunique pour injection

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030203875A1 (en) * 2002-03-07 2003-10-30 Hartell Mark G. Artemisinins with improved stability and bioavailability for therapeutic drug development and application
WO2007017646A2 (fr) * 2005-08-05 2007-02-15 Cipla Limited Composition antimalarienne
WO2007146288A2 (fr) * 2006-06-13 2007-12-21 Walter Reed Army Institute Of Research (Wrair) Méthodes de formulation et de fabrication d'acide artésunique pour injection

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3402479A4 (fr) * 2016-01-15 2018-12-19 Ming Zhao Composition contenant de l'artésunate
US10471042B2 (en) 2016-01-15 2019-11-12 Ming Zhao Composition containing artesunate
US10987338B2 (en) 2016-01-15 2021-04-27 Ming Zhao Composition containing artesunate

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