WO2014076616A2 - Formulations de 5-azacytidine - Google Patents

Formulations de 5-azacytidine Download PDF

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Publication number
WO2014076616A2
WO2014076616A2 PCT/IB2013/059992 IB2013059992W WO2014076616A2 WO 2014076616 A2 WO2014076616 A2 WO 2014076616A2 IB 2013059992 W IB2013059992 W IB 2013059992W WO 2014076616 A2 WO2014076616 A2 WO 2014076616A2
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WO
WIPO (PCT)
Prior art keywords
azacytidine
crystalline
water
solution
ray powder
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PCT/IB2013/059992
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English (en)
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WO2014076616A3 (fr
Inventor
Pradeep SHIVAKUMAR
Nagaraju DASARI
Ravi KISHORE
Rizwan Ahmed
Akshaykant CHATURVEDI
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Shilpa Medicare Limited
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 Shilpa Medicare Limited filed Critical Shilpa Medicare Limited
Priority to US14/441,517 priority Critical patent/US9765108B2/en
Publication of WO2014076616A2 publication Critical patent/WO2014076616A2/fr
Publication of WO2014076616A3 publication Critical patent/WO2014076616A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • 5-azacytidine also known as azacitidine 4-amino-l-P-D-ribofuranosyl-l, 3, 5-triazin-2(lH)- one; National Service Center designation NSC- 102816; CAS Registry Number 320-67-2) has undergone NCI-sponsored clinical trials for the treatment of myelodysplasia syndromes (MDS). See Komblith et al., J. Clin. Oncol. 20(10): 2441-2452 (2002) and Silverman et al., J. Clin. Oncol. 20(10): 2429-2440 (2002).
  • 5-azacytidine may be defined as having a formula of C8H12N4O5, a molecular weight of 244.20 and a structure of:
  • 5-azacytidine is insoluble in acetone, ethanol, and methyl ethyl ketone, slightly soluble in ethanol and water (50:50), propylene glycol, and polyethylene glycol, sparingly soluble in water, water saturated octanol, 5% dextrose in water, N-methylpyrrolidone, normal saline, and 5% TweenTM 80 in water, and soluble in dimethylsulfoxide (DMSO).
  • Azacitidine is used in the treatment of myelodysplasia syndrome.
  • Vials of the VIDAZA® product contain 100 mg of azacitidine and 100 mg of mannitol, as a sterile lyophilized powder.
  • U.S. Publication No. 2011/0042247 Chandrasekhar et al; relates to a pharmaceutical formulation for parenteral administration comprising azacitidine, prepared by a process comprising preparing an aqueous solution containing azacitidine at about -3°C to about -1°C; and lyophilizing the solution.
  • lyophilized formulations of cytidine analogs e.g., 5- azacytidine
  • methods of preparing and using such lyophilized formulations, or new polymorphs in such formulations to potentially permit, inter alia, for convenient administration to patients, and limited amount of impurities upon storage, wherein the suitable impurity profile is also to minimize potential toxicity, and ensure accurate delivery of intended dose of cytidine analogs for treating new diseases or disorders or new patient populations; and/or other potential advantageous benefits.
  • lyophilized formulations comprising 5-azacytidine crystalline forms. Also provided are methods of preparing the said formulations, and methods of using the formulations to treat disorders related to abnormal cell proliferation including cancer and hematologic disorders.
  • aspects of the present invention relate to a crystalline 5-Azacytidine designated as Form-SA-1 characterized by an X-Ray powder diffraction pattern having at least four characteristic diffraction angle peaks at about 12.00, 12.60, 13.90, 15.15 and 31.40 ⁇ 0.20 29°.
  • aspects of the present invention relate to a process for preparing crystalline 5-Azacytidine Form SA-1, comprising the steps of-
  • aspects of the present invention relate to a process for preparing Crystalline 5-Azacytidine Form SA-1, comprising the steps of-
  • aspects of the present invention relate to a lyophilized formulation comprising crystalline 5- Azacytidine Form-SA-1, characterized by an X-Ray powder diffraction pattern having at least four characteristic diffraction angle peaks at about 12.00, 12.60, 13.90, 15.15 and 31.40 + 0.20 29°, optionally a bulking agent; and having water content less than 1%.
  • aspects of the present invention relate to a process for preparing lyophilized formulation comprising Crystalline 5-Azacytidine Form SA-1, characterized by the steps:
  • step (i) Dissolving optional bulking agent and 5-azacytidine, in a stabilizing amount of solvent vehicle comprising acetonitrile and refrigerated water; in the ratio of 20:80 to 60:40.
  • step (i) Lyophilizing the solution obtained from step (i);
  • the said lyophilized formulation having l-P-D-ribofuranosyl-3-guanylurea (RGU) impurity not more than 0.2% and total impurities not more than 2%.
  • RGU l-P-D-ribofuranosyl-3-guanylurea
  • aspects of the present invention relate to a crystalline 5 -Azacytidine designated as Form-SA-2, characterized by an X-Ray powder diffraction angle peaks at about 6.9, 14.0, 17.9 and 24.2° +0.20 2 ⁇ 0 , and having water content less than 1%.
  • aspects of the present invention relate to a process for preparing lyophilized formulation comprising Crystalline 5-Azacytidine Form SA-2, characterized by the steps:
  • aspects of the present invention relate to a lyophilized formulation comprising crystalline 5- Azacytidine Form-SA-2, characterized by an X-Ray powder diffraction pattern having at least four characteristic diffraction angle peaks at about 6.9, 14.0, 17.9 and 24.2° +0.20 2 ⁇ 0 , optionally a bulking agent; and having water content less than 1%.
  • a lyophilized formulation comprising 5-Azacytidine Form SA-1 or 5-Azacytidine Form SA-2 for parenteral administration, in a sterile vessel is provided, comprising 5-azacytidine for administration to a subject in need thereof.
  • the sterile vessel comprising a pharmaceutical formulation according to the present invention; for example, may be a vial, syringe, or ampoule.
  • aspects of the present invention herein relates to methods of using the lyophilized formulation comprising 5-Azacytidine Form SA-1 or 5-Azacytidine Form SA-2 for parenteral administration, provided herein to treat diseases or disorders including, e.g., cancer, disorders related to abnormal cell proliferation, hematologic disorders, or immune disorders, among others.
  • the pharmaceutical compositions of 5-azacytidine which are parenterally administered to subjects in need thereof to treat a cancer or a hematological disorder, such as, for example, Myelodysplastic syndromes (MDS), acute myelogenous leukemia (AML).
  • MDS Myelodysplastic syndromes
  • AML acute myelogenous leukemia
  • Fig.l is Illustration of X-ray powder diffraction (XRPD) pattern of Crystalline 5-Azacytydine Form I.
  • Fig.2 is Illustration of X-ray powder diffraction (XRPD) pattern of 5-Azacytydine formulation of example 1 containing 5-Azacytydine SA-1.
  • Fig.3 is Illustration of X-ray powder diffraction (XRPD) pattern of placebo formulation of example 1.
  • Comparative X-Ray powder diffraction patterns of lyophilized formulation of example 1 containing crystalline Form-SA-1, as against Form I, and placebo lyophilized formulation of example 1; are provided under the below table:
  • Fig.4 is Illustration of X-ray powder diffraction (XRPD) pattern of 5-Azacytydine formulation of example 2 containing 5-Azacytydine SA-2.
  • XRPD X-ray powder diffraction
  • Fig.5 is Illustration of X-ray powder diffraction (XRPD) pattern of placebo formulation of example 2.
  • Comparative X-Ray powder diffraction patterns of lyophilized formulation of example 2 containing crystalline Form-SA-2, as against Form I, and placebo lyophilized formulation of example 2; are provided under the below table:
  • Fig.6 is Illustration of X-ray powder diffraction (XRPD) pattern of formulation containing Neat Crystalline 5-Azacytidine Form SA-1 prepared in example 3.
  • X-Ray powder diffraction pattern of Neat Crystalline 5-Azacytidine Form SA-1 provided under the table below:
  • emboidment of the present invention provides a crystalline 5-Azacytidine designated as Form-SA-1 characterized by an X-Ray powder diffraction pattern having at least four characteristic diffraction angle peaks at about 12.00, 12.60, 13.90, 15.15 and 31.40 +0.20 2 ⁇ 0 .
  • step (ii) Lyophilizing the solution obtained from step (i); wherein the said lyophilized formulation having l-P-D-ribofuranosyl-3-guanylurea (RGU) impurity not more than 0.2% and total impurities not more than 2%.
  • RGU l-P-D-ribofuranosyl-3-guanylurea
  • pharmaceutically acceptable refers to an ingredient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes those acceptable for veterinary use as well as human pharmaceutical use.
  • organic solvent means an organic material, usually a liquid, capable of dissolving other substances.
  • the organic solvent selected from acetonitrile, tertiary-butyl alcohol, Ethanol, Acetone, Dimethylsulfoxide (DMSO) and Dimethylformamide (DMF).
  • RGU-CHO N-(formylamidino) ⁇ '- ⁇ -D-ribofuranosylurea
  • RGU is l-P-D-ribofuranosyl-3-guanylurea
  • Impurity-2 as referred in the specification relates to l-O-Acetyl-2, 3, 5-Tri-O- benzoyl- ⁇ -D-ribofuranose.
  • Total impurity as referred in the specification relates to sum of all known impurities like “Impurity- 1", “Impurity-2”, “Impurity-3” and RGU; but excluding RGU-CHO.
  • stabilizing amount of solvent vehicle means the ratio of organic solvent and water which would reduce the level of degradation products of 5-azacytidine in the invention compositions. For example, a concentration of 30:70 of stabilizing amount of solvent vehicle would limit the levels of l-P-D-ribofuranosyl-3-guanylurea (RGU) is NMT 0.2%w/w of 5- AZT.
  • RGU l-P-D-ribofuranosyl-3-guanylurea
  • Injectable formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspending in liquid prior to injection, or as emulsions.
  • Sterile injectable formulations can be prepared according to techniques known in the art using suitable carriers, dispersing or wetting agents, and/or suspending agents.
  • the injectable formulations may be sterile injectable solutions or suspensions in a nontoxic, parenterally acceptable diluent or solvent.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
  • Lyophilization or freeze-drying is a process in which water is removed from a product after it is frozen and placed under a vacuum, allowing the ice to change directly from a solid to a vapor, without passing through a liquid phase.
  • the process consists of three separate, unique, and interdependent processes; a freezing phase, a primary drying phase (sublimation), and a secondary drying phase (desorption). These processes may be optimized to enhance the product stability as well as decrease the manufacturing costs.
  • a primary function of the freezing phase is to ensure that the entire container having the complex solution is completely frozen, prior to proceeding to a subsequent phase. Additionally, it is usually desired that these containers freeze in a uniform manner. While there are different ways that this can be accomplished, one option is to chill the containers after they are loaded onto the lyophilizer shelves and holding for 30-60 minutes prior to initiation of the freezing cycle. It is generally not practical to equilibrate the shelves to a freezing temperature, because of frost accumulation during the filling and loading of the containers.
  • the primary drying phase involves the removal of bulk water at a product temperature below the ice transition temperature under a vacuum (pressures typically between 50-300 mTorr).
  • This phase can be a critical one for stabilizing an active.
  • the goal is to identify the glass transition temperature (Tg') for the formulation.
  • Tg' is the temperature at which there is a reversible change of state between a viscous liquid and a rigid, amorphous glassy state.
  • DSC differential scanning calorimeter
  • the collapse temperature is observed to be about 2-5°C greater than the Tg'.
  • the shelf temperature is set such that the target product temperature is maintained near or below the Tg' of the formulation throughout the removal of solvent during the primary dry phase.
  • the removal of solvent vapor can be tracked using a moisture detector, or by monitoring the decrease in pressure difference between a capacitance manometer and a thermocouple pressure gauge or by a pressure drop measurement.
  • the optimization of the primary dry cycle involves a removal of solvent as quickly as possible without causing cake collapse and subsequent product instability.
  • the secondary drying phase is the final segment of the lyophilization cycle, where residual moisture is removed from a formulation's interstitial matrix by desorption with elevated temperatures and/or reduced pressures.
  • the final moisture content of a lyophilized formulation which can be measured by Karl Fischer or other methods, is important because if the solid cake contains too much residual moisture, the stability of the active can be compromised. Hence, it is imperative that one achieves a moisture level as low as possible.
  • the shelf temperature is typically elevated to accelerate desorption of water molecules.
  • the duration of the secondary drying phase is usually short.
  • the residual moisture is generally significantly greater than desired.
  • One alternative is to purge the sample chamber of the lyophilizer with alternating cycles of an inert gas such as nitrogen, to facilitate displacement of bound water.
  • an inert gas such as nitrogen
  • the advantages of lyophilization include: ease of processing a liquid, which simplifies aseptic handling; enhanced stability of a dry powder; removal of water without excessive heating of the product; enhanced product stability in a dry state; and rapid and easy dissolution of reconstituted product.
  • the product is dried without elevated temperatures, thereby eliminating adverse thermal effects, and then stored in the dry state in which there are relatively few stability problems.
  • freeze dried products are often more soluble, dispersions are stabilized, and products subject to degradation by oxidation or hydrolysis are protected.
  • compositions to be freeze dried are frequently in aqueous solutions, ranging from about 0.01 to 40% by weight concentrations of total solids.
  • aqueous solutions ranging from about 0.01 to 40% by weight concentrations of total solids.
  • an improvement in stability of the lyophilizate, compared to a solution, is due to the absence of water in the lyophilizate.
  • a pharmacologically active constituent of many pharmaceutical products is present in such small quantities that, if freeze dried alone, it may not give a composition of suitable mass, and in some cases its presence would be hard to detect visually. Therefore, excipients are often added to increase the amount of solids present. In most applications it is desirable for a dried product cake to occupy essentially the same volume as that of the original solution. To achieve this, the total solids content of the original solution is frequently about 10 to 25% by weight.
  • Bulking substances that are useful for this purpose include, but are not limited to, sodium or potassium phosphates (monobasic potassium phosphate, potassium dihydrogen phosphate, etc.), citric acid, tartaric acid, gelatin, lactose and other carbohydrates such as dextrose, mannitol and dextran, and occasionally preservatives.
  • Various excipients contribute appearance characteristics to the cake, such as dull and spongy, sparkling and crystalline, firm or friable, expanded or shrunken, and uniform or striated. Therefore formulations of a composition to be freeze dried should be a result of consideration not only of the nature and stability characteristics required during the liquid state, both freshly prepared and when reconstituted before use, but also the characteristics desired in the final lyophilized cake.
  • the injectable pharmaceutical formulations may optionally include one or more other pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may include any one or more of: antibacterial preservatives, such as one or more of phenylmercuric nitrate, thiomersal, benzalkonium chloride, benzethonium chloride, phenol, cresol, and chlorobutanol; antioxidants including one or more of ascorbic acid, sodium sulfite, sodium bisulfite and sodium metabisulfite; chelating agents such as ethylenediamine tetraacetic acid (EDTA); buffers including one or more of acetate, citrate, tartarate, phosphate, benzoate and bicarbonate buffers; tonicity contributors including one or more of sodium chloride, potassium chloride, dextrose, mannitol, sorbitol and lactose; and alkaline substances including one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and meglu
  • kits provided for delivery of the azacitidine or its salts.
  • a kit according to the present invention comprises a container holding the drug composition, a sterile reconstitution vehicle, and a sterile syringe.
  • Example 1 Azacitidine for injection lOOmg/Vial
  • step 6 The solution of step 5 was filtered through 0.2 ⁇ PES Filter and filtrate was filled into 30ml/20mm flint moulded Vial with a fill volume of 20.0mL, half stoppered with dark grey Bromobutyl rubber stopper and loaded into precooled Lyophilizer.
  • a placebo formulation of example 1 is prepared with the same formula and manufacturing process by excluding 5-azacytidine.
  • example 1 & its corresponding placebo formulations were subjected to X-ray powder diffraction (XRPD) and as illustrated in Fig 2&3; it was observed that 5-azacytidine SA-1 found in the example 1 formulation.
  • XRPD X-ray powder diffraction
  • step 6 The solution of step 5 was filtered through 0.2 ⁇ PES Filter and filtrate was filled into 30ml/20mm flint moulded Vial with a fill volume of 20.0mL, half stoppered with dark grey Bromobutyl rubber stopper and loaded into precooled Lyophilizer.
  • a placebo formulation of example 2 is prepared with the same formula and manufacturing process by excluding 5-azacytidine.
  • example 2 & its corresponding placebo formulations were subjected to X-ray powder diffraction (XRPD) and as illustrated in Fig 4&5; it was observed that 5-azacytidine SA-2 found in the example 2 formulation.
  • Example 3 Preparation of lyophilized formulation containing Neat 5-Azacytidine Form-SA-1.
  • step 4 was filtered through 0.2 ⁇ PES Filter and filtrate was filled into 30ml/20mm flint moulded Vial with a fill volume of 20.0mL, half stoppered with dark grey Bromobutyl rubber stopper and loaded into precooled Lyophilizer.
  • the Lyophilization cycle was carried out as per recipe defined under Example 1.
  • Example 3 formulation was subjected to X-ray powder diffraction (XRPD) and as illustrated in Fig 6; 5-azacytidine SA-1 was found in the example 3 formulation.
  • XRPD X-ray powder diffraction
  • Example 4 Preparation of lyophilized formulation containing Neat 5-Azacytidine Form-SA-2.
  • step 4 was filtered through 0.2 ⁇ PES Filter and filtrate was filled into 30ml/20mm flint moulded Vial with a fill volume of 20.0mL, half stoppered with dark grey Bromobutyl rubber stopper and loaded into precooled Lyophilizer.
  • the Lyophilization cycle was carried out as per recipe defined under Example 2.
  • example 4 formulation was subjected to X-ray powder diffraction (XRPD) and as illustrated in Fig 7; 5-azacytidine SA-2 was observed in the example 4 formulation.
  • XRPD X-ray powder diffraction

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Abstract

Cette invention concerne des formulations lyophilisées comprenant une 5-azacytidine cristalline et un procédé de préparation desdites formulations lyophilisées comprenant la 5-azacytidine cristalline.
PCT/IB2013/059992 2012-11-19 2013-11-08 Formulations de 5-azacytidine WO2014076616A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/441,517 US9765108B2 (en) 2012-11-19 2013-11-08 Formulation of 5-azacytidine

Applications Claiming Priority (4)

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INCH48012012 2012-11-19
IN4801/CHE/2012 2012-11-19
IN2148CH2013 2013-05-15
IN2148/CHE/2013 2013-05-15

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WO2014076616A3 WO2014076616A3 (fr) 2014-07-10

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108295034A (zh) * 2018-03-29 2018-07-20 健进制药有限公司 一种注射用阿扎胞苷冻干粉针及其制备方法
WO2019231225A1 (fr) * 2018-05-30 2019-12-05 주식회사 삼양바이오팜 Procédé de préparation d'une composition pharmaceutique contenant de l'azacitidine stable

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040186065A1 (en) * 2003-03-17 2004-09-23 Dumitru Ionescu Forms of 5-azacytidine
WO2004082822A2 (fr) * 2003-03-17 2004-09-30 Pharmion Corporation Procedes permettant d'isoler la forme i cristalline de la 5-azacytidine
US20080287378A1 (en) * 2007-01-11 2008-11-20 Ales Gavenda Solid state forms of 5-azacytidine and processes for preparation thereof
US20110042247A1 (en) * 2009-06-25 2011-02-24 Chandrasekhar Kocherlakota Formulations of azacitidine and its derivatives

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040186065A1 (en) * 2003-03-17 2004-09-23 Dumitru Ionescu Forms of 5-azacytidine
WO2004082822A2 (fr) * 2003-03-17 2004-09-30 Pharmion Corporation Procedes permettant d'isoler la forme i cristalline de la 5-azacytidine
EP2270023A1 (fr) * 2003-03-17 2011-01-05 Celgene International Sarl Nouvelle forme polymorphique de la 5-azacytidine
US20130059810A1 (en) * 2003-03-17 2013-03-07 Pharmion Llc Pharmaceutical compositions comprising forms of 5-azacytidine
US20080287378A1 (en) * 2007-01-11 2008-11-20 Ales Gavenda Solid state forms of 5-azacytidine and processes for preparation thereof
EP2644614A2 (fr) * 2007-01-11 2013-10-02 IVAX Pharmaceuticals s.r.o. Formes à l'état solide de 5-azacytidine et leurs procédés de préparation
US20110042247A1 (en) * 2009-06-25 2011-02-24 Chandrasekhar Kocherlakota Formulations of azacitidine and its derivatives

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108295034A (zh) * 2018-03-29 2018-07-20 健进制药有限公司 一种注射用阿扎胞苷冻干粉针及其制备方法
WO2019231225A1 (fr) * 2018-05-30 2019-12-05 주식회사 삼양바이오팜 Procédé de préparation d'une composition pharmaceutique contenant de l'azacitidine stable
JP7148642B2 (ja) 2018-05-30 2022-10-05 サムヤン ホールディングス コーポレイション 安定したアザシチジン含有医薬組成物の製造方法

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