WO2011014541A1 - Compositions stables à base d'azacitidine - Google Patents

Compositions stables à base d'azacitidine Download PDF

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Publication number
WO2011014541A1
WO2011014541A1 PCT/US2010/043503 US2010043503W WO2011014541A1 WO 2011014541 A1 WO2011014541 A1 WO 2011014541A1 US 2010043503 W US2010043503 W US 2010043503W WO 2011014541 A1 WO2011014541 A1 WO 2011014541A1
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WO
WIPO (PCT)
Prior art keywords
azacitidine
surfactant
containing composition
polysorbate
propylene glycol
Prior art date
Application number
PCT/US2010/043503
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English (en)
Inventor
Nagesh R. Palepu
Philip Christopher Buxton
Bulusu Bhanu Teja
Original Assignee
Eagle Pharmaceuticals, Inc.
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 Eagle Pharmaceuticals, Inc. filed Critical Eagle Pharmaceuticals, Inc.
Publication of WO2011014541A1 publication Critical patent/WO2011014541A1/fr

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • 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
    • A61K9/0012—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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • Azacitidine is a pyrimidine nucleoside analog.
  • the structure of azacitidine is
  • Azacitidine is used in the treatment of myelodysplastic syndrome subtypes:
  • refractory anemia or refractory anemia with ringed sideroblasts if accompanied by neutropenia or thrombocytopenia or requiring transfusions
  • refractory anemia with excess blasts refractory anemia with excess blasts in transformation
  • chronic myelomonocytic leukemia azacitidine causes hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in bone marrow.
  • Azacitidine (ACD) use is not widespread due to limitations of the formulation, specifically the chemical stability of the reconstituted lyophile is very short. A simple solution in water loses around 30% of its drug content over a period of 16 hours and at least 9% over the first 2 hours.
  • Azacitidine is commercially available as VidazaTM for intravenous or subcutaneous treatment of acute forms of leukemia.
  • VidazaTM which is formulated at a pH of about 6.5, contains a small quantity of sodium hydroxide and delivers lOOmg of azacitidine in 10ml of water when the lyophile is reconstituted. This concentrate is further diluted with normal saline or Ringer's Lactate to yield a finally
  • the reconstituted azacitidine product is stable only for about 1 hour under ambient conditions and about 8 hours at 5 0 C.
  • a hospital environment requires a minimum of about 8 hours of reconstitution stability under ambient conditions.
  • azacitidine formulations with increased stability after reconstitution, especially at ambient conditions.
  • the invention is generally directed to azacitidine-containing compositions that are stable for at least about 24 hours at room temperature, i.e. temperatures of less than or equal to about 25 0 C.
  • the inventive compositions contain azacitidine or a pharmaceutically acceptable salt thereof and a pharmacologically suitable fluid which includes (i) propylene glycol (PG), polyethylene glycol (PEG), or mixtures thereof and (ii) an ef 4 ⁇ 4 ""* amoun t o f a surfactant which, in many preferred embodiments, is at least //w).
  • the fluid can be about 99.5% propylene glycol or PEG and about 0.5% of a surfactant such as polysorbate 80.
  • Still further aspects include fluids with about equal portions of PG and PEG, with about 0.5% surfactant.
  • the amount of surfactant included is at least about 0.5% and less than about 10% with amounts of less than or equal to 2.5% being preferred.
  • kits containing an amount of azacitidine or a pharmaceutically acceptable salt thereof, preferably in lyophilized form, in a first vial or container and a pharmacologically suitable fluid which contains at least one of PG or PEG, or mixtures thereof and an effective amount of a surfactant, i.e. at least about 0.5%, in a second vial or container.
  • inventive compositions can also include dispersions of a lyophilized azacitidine in the pharmacologically suitable fluids, forming homogenous suspensions.
  • inventive compositions are substantially free of hydrolysis products, including formamide, guanidine and urea based derivatives for periods of at least about 24 hours or more.
  • stable compositions according to the invention include those in which the formulation is substantially free of, i.e. less than about 2% but preferably less than about 0.2-0.5%, hydrolysis products, including formamide, guanidine and urea based derivatives for a period of at least about 24 hours at temperatures of less than or equal to about 25°C, hereinafter "room temperature".
  • Still further aspects of the invention include methods for making azacitidine formulations suitable for parenteral administration.
  • the methods include dispersing a lyophilized azacitidine such as that described herein into a pharmacologically suitable, non-aqueous fluid as defined herein and forming a dispersion that is suitable for intramuscular, subcutaneous or subdermal injection and an extended shelf life.
  • stable refers to azacitidine-containing compositions in which there is not more than about 2% hydrolysis products after a period of at least about 24 hours at a temperature of less than or equal 25°C.
  • pharmaceutically suitable fluid is a solvent suitable for a pharmaceutically suitable fluid
  • azacitidine also includes pharmaceutically acce ⁇ table salts thereof or derivatives of the compound, including esters, enol ethers ⁇ ds, bases, solvates, hydrates or prodrugs thereof.
  • Such salts and derivatives may be readily prepared by those of skill in the art using known methods.
  • the salts and derivatives produced may be administered to animals or humans without substantial toxic effects and are either pharmaceutically active or are prodrugs.
  • the azacitidine can be prepared and lyophilized in conventional methods known in the art, such as that described in the package insert for VidazaTM, the contents of which are incorporated herein by reference.
  • the azacitidine is obtained from commercial sources, hi either case, the azacitidine is understood by those of ordinary skill to be suitable for inclusion in the formulations described herein.
  • azacitidine-containing compositions which have improved stability and dispersibility.
  • the invention includes azacitidine-containing compositions, including:
  • an effective amount i.e. preferably at least about 0.5%, of a surfactant (w/w).
  • effective amount shall be understood to be an amount which is sufficient, when combined with the propylene glycol or polyethylene glycol to confer not only suitable dispersability upon the azacitidine included in the inventive formulations, but will also sufficient to impart the unexpected increase in stability thereon. While in many preferred aspects, the amount of surfactant is at least about 0.5%, it will be appreciated that some surfaciants, when included in amounts below 0.5% will none +1if>1(iQ ⁇ i ⁇ f sufficient to impart the desired qualities upon the formulation.
  • the surfactant is apoloxamer of the general formula (I),
  • R fatty acid
  • the surfactant is selected from the non-limiting list of materials which includes polysorbate 80, poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 85, polysorbate 81, polysorbate 21, polysorbate 61 and Cremophor ELTM.
  • the pharmacologically suitable fluid includes polysorbate 80 as the surfactant.
  • the pharmacologically suitable fluid includes poloxamer 188 as the surfactant.
  • the pharmaceutically suitable fluids used herein are preferably non-aqueous or substantially non-aqueous.
  • the PG and PEG used in the fluids will be pharmaceutically acceptable (as such term is understood by those of ordinary skill in the art) and meet all necessary pharmacopeial (USP, JP, PhEur, etc.) standards.
  • the molecular weight of polyethylene glycol is from about 190 to about 9,000 or higher, as known to be used by those of ordinary skill in the art. More preferably, the polyethylene glycol is PEG 400.
  • This invention is not limited to the aforementioned fluids and can optionally also include all pharmacologically acceptable organic solvents that are miscible in water such as ethanol, benzyl alcohol, etc.
  • the surfactants described herein allow the azacitidine to be more readily dispersed in the preferably non-aqueous fluids.
  • the pharmacologically suitable fluid includes a combination of propylene glycol and a surfactant.
  • the ratio of propylene glycol to surfactant can be from about 99.6/0.4 to about 90/10 (w/w).
  • the ratio of propylene glycol to surfactant is from about 99.5/0.5 to about 97.5/2.5 (w/w) or, more preferably, from about 99.5/0.5 to about 98.5/1.5
  • One particularly preferred fluid useful herein includes 99.5% PG and 0.5% surfactant.
  • the azacitidine-containing composition includes azacitidine or a pharmaceutically acceptable salt thereof; a
  • pharmacologically suitable fluid including propylene glycol, and polysorbate 80; wherein the ratio of propylene glycol to polysorbate 80 is about 99.5/0.5 (w/w).
  • One particularly preferred fluid useful herein includes 99.5% PG and 0.5% surfactant.
  • Other preferred aspects of the invention are those in which the pharmacologically suitable fluid includes a combination of polyethylene glycol and surfactant.
  • the ratio of polyethylene glycol to surfactant can be from about 99.6/0.4 to about 90/10 (w/w).
  • the ratio of polyethylene glycol to surfactant is from about 99.5/0.5 to about 97.5/2.5 (w/w) or from about 99.5/0.5 to about 98.5/1.5 (w/w).
  • One particularly preferred fluid useful herein includes 99.5% PEG and 0.5% surfactant.
  • the azacitidine-containing composition includes azacitidine or a pharmaceutically acceptable salt thereof; a
  • pharmacologically suitable fluid including polyethylene glycol, and polysorbate 80; wherein the ratio of polyethylene glycol to polysorbate 80 is about 99.5/0.5
  • the pharmacologically sv ⁇ hl p fluid includes a mixture of propylene glycol and polyethylene glycol.
  • the r ⁇ ae glycol to polyethylene glycol is from about 1/99 to about 99/1 (w/w).
  • the ratio of propylene glycol to polyethylene glycol is about 50/50 (w/w).
  • the fluid will include PG:PEG:surfactant in a ratio of about 49.25:49.25:0.5.
  • the azacitidine concentration is from about 0.5 mg/ml to about 120 mg/mL. In another embodiment of the invention, the azacitidine concentration is from about 1 mg/ml to about 34 mg/ml. Preferably, the azacitidine concentration is from about 20 mg/ml to about 31 mg/ml. More preferably, the azacitidine concentration is from about 25 to about 30 mg/ml. In alternative embodiments, there are provided formulations in accordance with the invention where the azacitidine concentration is about 100 mg/ml.
  • Still further aspects of the invention include methods for making azacitidine formulations suitable for parenteral administration.
  • the methods include dispersing azacitidine as described herein, i.e. lyophilized or not, into a
  • the dispersion can be transferred into an IV container or bag containing infusion fluid such as normal saline, dissolved and administered as IV infusion.
  • infusion fluid such as normal saline
  • the dosage form of azacitidine can be packaged with the Add-vantageTM system for dispersion and administration by IV.
  • a further aspect of the invention includes a reconstituted dispersion that is ready to administer.
  • Another embodiment of the invention includes methods of t ⁇ TM ⁇ " "'””itidine sensitive disease in mammals, including administering an efi of an azacitidine-containing composition as described herein, i.e. including azacitidine or a pharmaceutically acceptable salt thereof; and a pharmacologically suitable fluid including propylene glycol, polyethylene glycol, or mixtures thereof; and an effective amount of a surfactant, to a mammal in need thereof.
  • an efi of an azacitidine-containing composition as described herein i.e. including azacitidine or a pharmaceutically acceptable salt thereof
  • a pharmacologically suitable fluid including propylene glycol, polyethylene glycol, or mixtures thereof
  • an effective amount of a surfactant to a mammal in need thereof.
  • the azacitidine sensitive disease is, but not limited to,
  • kits including:
  • the kit may also include instructions for use in/administration of the drug and/or ancillary materials useful in the administration of the drug to a patient in need thereof.
  • the amount of azacitidine included in the container will vary, depending upon need but generally is an amount suffient for one or more therapeutic doses to a patient. Examples
  • RRT relative retention time
  • Table 1 shows that azacitidine in water loses about 30% of its drug content over a period of 16 hours, and at least 9% over the first two hours. Thus, azacitidine exhibits poor stability in water.
  • Table 1 Stability of ACD (0.5mg/ml) in Water (Ambient Laboratory Temperature, about 25 0 C)
  • % HP is the area normalized percentage of the hydrolysis product at RRT
  • VidazaTM which contains lyophilized azacitidine and sodiuresti
  • the final concentration of azacitidine was lmg/ml and the pH was 6.5.
  • the vials were sealed and stored at 5 0 C for over 13 hours.
  • the samples were tested via HPLC, and the relative retention time (RRT) is reported in Table 3 below.
  • Table 3 shows that azacitidine plus sodium hydroxide is stable only for about 8 hours at 5 0 C in saline and in lactated Ringers Solution, and thus, exhibits poor stability.
  • Table 3 Stability of VidazaTM (lmg/ml) in Normal Saline and Lactated Ringers
  • % HP is the area normalized percentage of the hydrolysis product at RRT 0.66
  • the amount of degradation over a 24 hour period at room temperature is reported in Table 5 below.
  • the addition of 10% water provided excellent reconstitution and stability.
  • the ACD-containing preparation of Example 4 was made by adding a mixture of 80% propylene glycol and 20% water (w/w) instead of 100% propylene glycol and the lyophilized ACD was reconstituted at a concentration of 27.3 mg/mL.
  • the amount of degradation over a 24 hour period at room temperature is reported in Table 6 below.
  • the addition of 20% water provided excellent reconstitution and stability.
  • the ACD-containing preparation of Example 4 was made by adding a mixture of 70% propylene glycol and 30% water (w/w) instead of 100% propylene glycol and the lyophilized ACD was reconstituted at a concentration of 29.1 mg/mL.
  • the amount of degradation over a 24 hour period at room temperature is reported in Table 7 below.
  • the addition of 30% water provided excellent reconstitution and stability.
  • Table 7 24 hour stability of ACD lyophile reconstituted with 70% Propylene
  • Examples 5-7 demonstrate that alternative embodiments in which some water is included can provide useful formulations.
  • Table 8 24 hour stability of ACE) lyophile. reconstituted with 100% PEG 400
  • a mixture containing 50% propylene glycol and 50% PEG 400 was added to vials containing lyophilized ACD.
  • the lyophilized ACD was reconstituted at a concentration of 29.4 mg/mL.
  • the vials were sealed and stored at room temperature for 24 hours.
  • the samples were tested via HPLC, and the relative retention time (RRT) is reported in Table 9 below. Although the samples do not show substantial degradation, the reconstitution time to disperse the azacitidine in the samples was long and required vigorous mixing.
  • Example 10 The ACD-containing preparation of Example 10 was made with 98.5% propylene glycol and 1.5% polysorbate 80 (w/v) instead of 99.5% prop ' ' * id 0.5% polysorbate 80 (w/v), and the lyophilized ACD was reconstii
  • Example 10 The ACD-contarnrng preparation of Example 10 was made with a mixture of 97.5% propylene glycol and 2.5% polysorbate 80 (w/v) instead of 99.5% propylene glycol and 0.5% polysorbate 80 (w/v), and the ly C ⁇ t -- 1 ---' ⁇ ⁇ ⁇ was reconstituted at a concentration of 31.2 mg/mL.
  • the amoun n over a one week period at room temperature is reported in Table 12 below. The data shows that the presence of small amount of polysorbate 80 improved the reconstitution time as well as dispersibility of the lyophile without negatively affecting long-term stability.
  • Table 12 One week stability of ACD lyophile reconstituted with 97.5% Propylene Glycol containing 2.5% polysorbate 80 (w/v)
  • the reconstituted dispersion may be stable for 18 months either under ambient storage conditions or under refrigerated conditions.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Oil, Petroleum & Natural Gas (AREA)
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Abstract

La présente invention concerne des compositions contenant de l'azacitidine et un liquide pharmacologiquement acceptable. Ledit liquide pharmacologiquement acceptable est, de préférence, non aqueux et contient du propylèneglycol, du polyéthylèneglycol ou un mélange de ceux-ci, ainsi qu'un tensioactif.
PCT/US2010/043503 2009-07-30 2010-07-28 Compositions stables à base d'azacitidine WO2011014541A1 (fr)

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US61/229,832 2009-07-30

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Cited By (8)

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US8211862B2 (en) 2003-03-17 2012-07-03 Pharmion Llc Pharmaceutical compositions comprising crystal forms of 5-azacytidine
WO2013012135A1 (fr) * 2011-07-15 2013-01-24 Boryung Pharmaceutical Co., Ltd Préparation d'azacitidine pré-lyophilisée, préparation d'azacitidine lyophilisée et procédé de fabrication associé
WO2013117969A1 (fr) 2012-02-06 2013-08-15 Fresenius Kabi Oncology Ltd. Procédé pour préparer des compositions pharmaceutiques stables de composés sensibles à l'hydrolyse
US8513406B2 (en) 2003-03-17 2013-08-20 Pharmion Llc Pharmaceutical compositions comprising forms of 5-azacytidine
US8846628B2 (en) 2008-05-15 2014-09-30 Celgene Corporation Oral formulations of cytidine analogs and methods of use thereof
US9393255B2 (en) 2011-01-31 2016-07-19 Celgene Corporation Pharmaceutical compositions of cytidine analogs and methods of use thereof
CN107961216A (zh) * 2018-01-22 2018-04-27 宁波蒙曼生物科技有限公司 一种阿扎胞苷的制剂及其制备方法
CN109646410A (zh) * 2019-02-27 2019-04-19 江苏豪森药业集团有限公司 稳定的阿扎胞苷冻干制剂及其制备方法

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US20080182806A1 (en) * 2007-01-25 2008-07-31 Nevada Cancer Institute Use of acetylated or esterificated azacytidine, decitabine, or other nucleoside analogs as oral agents for the treatment of tumors or other dysplastic syndromes sensitive to hypomethylating agents
US20090004189A1 (en) * 2007-06-18 2009-01-01 Genentech, Inc. Biological markers predictive of rheumatoid arthritis response to b-cell antagonists

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US20040005592A1 (en) * 2001-03-05 2004-01-08 Emtage Peter C.R. Materials and methods relating to therapy and diagnosis using targeting of cells that express DCAL-Hy polypeptides
US20080182806A1 (en) * 2007-01-25 2008-07-31 Nevada Cancer Institute Use of acetylated or esterificated azacytidine, decitabine, or other nucleoside analogs as oral agents for the treatment of tumors or other dysplastic syndromes sensitive to hypomethylating agents
US20090004189A1 (en) * 2007-06-18 2009-01-01 Genentech, Inc. Biological markers predictive of rheumatoid arthritis response to b-cell antagonists

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9192620B2 (en) 2003-03-17 2015-11-24 Pharmion Llc Pharmaceutical compositions comprising forms of 5-azacytidine
US8481715B2 (en) 2003-03-17 2013-07-09 Pharmion Llc Methods for isolating crystalline form I of 5-azacytidine
US8211862B2 (en) 2003-03-17 2012-07-03 Pharmion Llc Pharmaceutical compositions comprising crystal forms of 5-azacytidine
US8975392B2 (en) 2003-03-17 2015-03-10 Pharmion Llc Methods for isolating crystalline form I of 5-azacytidine
US8779117B2 (en) 2003-03-17 2014-07-15 Pharmion Llc Pharmaceutical compositions comprising 5-azacytidine monohydrate
US8513406B2 (en) 2003-03-17 2013-08-20 Pharmion Llc Pharmaceutical compositions comprising forms of 5-azacytidine
US8614313B2 (en) 2003-03-17 2013-12-24 Pharmion Llc Pharmaceutical compositions comprising forms of 5-azacytidine
US8846628B2 (en) 2008-05-15 2014-09-30 Celgene Corporation Oral formulations of cytidine analogs and methods of use thereof
US10463683B2 (en) 2008-05-15 2019-11-05 Celgene Corporation Isotopologues of 5-azacytidine
US10220050B2 (en) 2008-05-15 2019-03-05 Celgene Corporation Isotopologues of 5-azacytidine
US11571436B2 (en) 2008-05-15 2023-02-07 Celgene Corporation Oral formulations of cytidine analogs and methods of use thereof
EP3782611B1 (fr) 2008-05-15 2022-07-06 Celgene Corporation Formulations orales d'analogues de cytidine et leurs procédés d'utilisation
EP3692983B1 (fr) 2008-05-15 2021-08-11 Celgene Corporation Formulations orales d'analogues de cytidine et leurs procédés d'utilisation
US10646503B2 (en) 2008-05-15 2020-05-12 Celgene Corporation Isotopologues of 5-azacytidine
EP2695609B1 (fr) 2008-05-15 2019-12-11 Celgene Corporation Formulations orales d'analogues de cytidine et leurs procédés d'utilisation
US9393255B2 (en) 2011-01-31 2016-07-19 Celgene Corporation Pharmaceutical compositions of cytidine analogs and methods of use thereof
WO2013012135A1 (fr) * 2011-07-15 2013-01-24 Boryung Pharmaceutical Co., Ltd Préparation d'azacitidine pré-lyophilisée, préparation d'azacitidine lyophilisée et procédé de fabrication associé
KR101286802B1 (ko) * 2011-07-15 2013-07-23 보령제약 주식회사 아자시티딘의 전―동결건조 제제, 아자시티딘의 동결건조 제제 및 이의 제조방법
WO2013117969A1 (fr) 2012-02-06 2013-08-15 Fresenius Kabi Oncology Ltd. Procédé pour préparer des compositions pharmaceutiques stables de composés sensibles à l'hydrolyse
CN108451901A (zh) * 2018-01-22 2018-08-28 宁波蒙曼生物科技有限公司 一种阿扎胞苷的制剂及其制备方法
CN107961216A (zh) * 2018-01-22 2018-04-27 宁波蒙曼生物科技有限公司 一种阿扎胞苷的制剂及其制备方法
CN109646410A (zh) * 2019-02-27 2019-04-19 江苏豪森药业集团有限公司 稳定的阿扎胞苷冻干制剂及其制备方法

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