WO2010062147A2 - Forme cristalline d'adefovir fipivoxil, procédé de préparation associé et composition pharmaceutique contenant cette forme - Google Patents

Forme cristalline d'adefovir fipivoxil, procédé de préparation associé et composition pharmaceutique contenant cette forme Download PDF

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Publication number
WO2010062147A2
WO2010062147A2 PCT/KR2009/007068 KR2009007068W WO2010062147A2 WO 2010062147 A2 WO2010062147 A2 WO 2010062147A2 KR 2009007068 W KR2009007068 W KR 2009007068W WO 2010062147 A2 WO2010062147 A2 WO 2010062147A2
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WO
WIPO (PCT)
Prior art keywords
crystalline form
difficile
adefober difficile
adefober
ethyl alcohol
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PCT/KR2009/007068
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English (en)
Korean (ko)
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WO2010062147A3 (fr
Inventor
이기화
전재일
홍덕기
우병영
이영란
Original Assignee
(주)아모레퍼시픽
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Publication of WO2010062147A2 publication Critical patent/WO2010062147A2/fr
Publication of WO2010062147A3 publication Critical patent/WO2010062147A3/fr

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to a crystalline form of adefober difficile, a preparation method thereof, and a pharmaceutical composition comprising the same.
  • Adefober difficile is a bis-pivaloyloxy methyl ester of the parent compound 9- [2- (phosphonomethoxy) ethyl] adenine (PMEA) and is known to have antiviral activity against animals and humans. have:
  • the crystalline form of adefober difficile according to the present invention is characterized by being an ethyl alcohol solvent-ized type.
  • the method for producing a crystalline form of the adefober difficile includes a step of dissolving adefober difficile in anhydrous ethyl alcohol and a step of cooling and stirring the adefober difficile solution obtained by the dissolution step to form crystals. do.
  • the pharmaceutical composition comprising the ethyl alcohol solvated crystalline form of Adefober difficile in the present invention can be used as an agent for preventing and treating viral infections.
  • Adefober difficile according to the present invention has high solubility and dissolution rate, and is excellent in biosafety.
  • FIG. 1 is a graph showing an X-ray powder diffraction pattern (XRD) for the crystalline form of adefober difficile according to one embodiment
  • Figure 2 is a graph showing the results of measuring the endothermic peak of the crystalline form of adefober difficile according to another embodiment
  • Figure 3 is a graph showing the thermogravimetric analysis of the crystalline form of adefober difficile according to another embodiment.
  • Adefober difficile crystalline form is an ethyl alcohol solvent-ized crystalline form.
  • the adefober difficile crystalline form relates to a new crystalline form of adefober difficile in the ethyl alcohol solvent-formed form, and specifically relates to the adefober difficile hemiethanol solvent-formed crystalline form.
  • solventized crystalline form refers to a crystalline form according to the type of solvent used in the crystallization process
  • ethyl alcohol solvent-ized crystalline form means a form crystallized using ethyl alcohol as a crystallization solvent.
  • ethyl alcohol was used as the crystallization solvent to obtain a new crystalline form for adefober difficile.
  • Adefober difficile is 9- [2-[ ⁇ bis (pivaloyloxy) methoxy ⁇ phosphinyl] methoxy] ethyl] adenine, which can be represented by the following Chemical Formula 1. have.
  • the adefober difficile crystal form has a diffraction of 2 ⁇ of at least 7.94, 8.54, 14.32, 16.22, 19.3, 20.82, 22.3, 23.5 + 0.2 in an X-ray powder diffraction pattern It is characterized by having a peak at an angle.
  • the present invention also provides a production method in which adefober difficile is dissolved in anhydrous ethyl alcohol to form a supersaturated adefober difficile solution, followed by cooling and stirring to generate crystals.
  • the pharmaceutical composition in another embodiment, it provides a pharmaceutical composition comprising adefober difficile crystalline form and a pharmaceutically acceptable carrier and the like according to the present invention, the pharmaceutical composition is useful as a composition for the prevention and treatment of viral infections It is possible.
  • Republic of Korea Patent No. 0624214 refers to the control of drying loss and the use of alkaline excipients in order to prevent stability deterioration due to hydrolysis of adefober difficile.
  • the formulation is made by a wet granulation process using water, and when formulated by the wet granulation process, the drug is inevitably exposed to moisture from the manufacturing stage. Since adefober difficile is sensitive to moisture, hydrolysis proceeds when exposed to moisture. Therefore, when the method disclosed in the patent, there is a problem that the formulation stability can not be secured.
  • adefober difficile dissolved by moisture can be converted into an unintended crystalline form such as a hydrate during drying.
  • the wet granulation method is a very general manufacturing process, and the solvent used to form the wet granules is limited to water or ethyl alcohol.
  • the use of water as a solvent can cause serious problems in physicochemical stability such as decomposition product formation and crystalline change by hydrolysis.
  • ethyl alcohol is used as the solvent, a change in crystal form may be caused in the manufacturing process.
  • Adefober difficile crystalline form according to an embodiment of the present invention is characterized in that the solvent-soluble crystalline form after the process of dissolving in anhydrous ethyl alcohol. Therefore, even if the wet granulation method using ethyl alcohol in the manufacturing process of the therapeutic product can be maintained a very stable state does not cause physicochemical changes.
  • Adefober difficile crystalline form according to an embodiment of the present invention is a new crystalline form of the ethyl alcohol solvent-formed form.
  • the ethyl alcohol solvated crystalline form of Adefober difficile contains about 0.3 to about 0.7 equivalents of ethyl alcohol in the crystal lattice. More specifically, the crystalline form P of the adefober difficile may contain about 0.5 equivalents of ethyl alcohol in the crystal lattice, which means that the adefober difficile crystalline form is (adefover difficile). (1 ⁇ 2EtOH) It exists in the form of (formular weight: 524.51). Theoretical value of the content of ethyl alcohol for Form P of Adefober difficile to contain 0.5 equivalent of ethyl alcohol is about 4.39%. Residual ethyl alcohol analysis and thermogravimetric analysis (TGA) yielded about 4.4% and 4.0%, respectively.
  • TGA thermogravimetric analysis
  • the crystalline form P of the adefober difficile is present in the form of (adefover difficile) ⁇ (1 ⁇ 2EtOH), which is essentially free of other detectable solvents or water. have.
  • Ethyl alcohol contained in the crystalline form P of the Adefober difficile is managed as a solvent of Class 3 by a process such as ICH guideline Q3C (Impurities: Guideline for residual solvents), and is classified as a solvent of Class 2 Higher biosafety than methyl alcohol. Therefore, crystalline form P of adefober difficile according to an embodiment of the present invention has an advantage of higher biostability than a conventional methyl alcohol-solvated form.
  • the crystalline form P of the adefober difficile is at least 7.94, 8.54, 14.32, 16.22, 19.3, 20.82, 22.3, 23.5 + 0.2, as measured by X-ray powder diffraction using Cu-K ⁇ radiation. Has a peak at a diffraction angle of 2 ⁇ .
  • the measurement result by the specific X-ray powder diffraction method is shown in Figure 1 below.
  • the crystalline form P of the adefober difficile has a melting point at about 66 + 2.0 ° C. and about 78 + 2.0 ° C. when observing the endothermic transition property measured by the differential scanning calorimetry method. Specific measurement results of the endothermic transition characteristics by the differential scanning calorimetry is shown in Figure 2 below.
  • the present invention also provides a process for preparing Form P of adefober difficile.
  • the preparation method includes a step of dissolving adefober difficile, and a step of forming crystals from the adefober difficile solution obtained in the step.
  • adefober difficile is dissolved in anhydrous ethyl alcohol.
  • the amount of anhydrous ethyl alcohol used at this time is 1 or more, based on the weight to volume ratio of the dissolved adefober difficile [the weight of the anhydrous ethyl alcohol (ml) / adefober difficile (g)], specifically It may be 1.5 to 3.
  • adefober difficile may be warmed to an appropriate temperature, for example 25 to 40 ° C., in order to readily dissolve in anhydrous ethyl alcohol, and if there is an insoluble solid, it may be filtered.
  • the adefober difficyl ethyl alcohol solution obtained in the dissolution step is cooled to form crystals. Cooling the adefober difficile ethylalcohol solution warmed to a temperature of about 25-40 ° C. in the dissolution process results in precipitation of the supersaturated adefober difficile, resulting in crystals. In one embodiment, to increase the yield of the resulting crystals, the solution can be cooled and stirred, for example, in the range of about 5 to -10 ° C.
  • Crystals obtained by the preparation method as described above have peaks at diffraction angles of at least 7.94, 8.54, 14.32, 16.22, 19.3, 20.82, 22.3, 23.5 + 0.2 when measured by X-ray powder diffraction method, and differential scanning Observing the endothermic transition properties measured by calorimetry, it has a melting point at about 66 + 2.0 ° C and about 78 + 2.0 ° C.
  • the present invention also provides a pharmaceutical composition containing Form P of the above adefober difficile.
  • the pharmaceutical composition may include a pharmaceutically acceptable carrier, and may be used as an agent for preventing and treating viral infections, for example, for preventing and treating AIDS or hepatitis B.
  • the pharmaceutical composition according to the present invention may be administered via an appropriate route depending on the conditions prescribed. Suitable routes include oral, rectal, nasal, topical (eye, mouth and sublingual), vaginal and parenteral (subcutaneous, intramuscular, intravenous, intradermal, intradermal, intrathecal and dural) routes. Generally, the pharmaceutical composition is administered orally, but may be administered via any of the other routes mentioned above.
  • Forms of oral administration can be, for example, tablets, capsules, granules, powders or solutions, and the like, specifically, tablets or capsules.
  • a pharmaceutically acceptable carrier may be used in addition to the adefober difficile crystalline form of the present invention.
  • it can be compressed by direct compression after mixing the adefober difficile crystalline form and the carrier, it can be carried out dry or wet granulation process for the production of tableting granules.
  • the pharmaceutically acceptable carriers are organic and inorganic compounds, and include those for preparing oral solid preparations, such as diluents, binders, disintegrants, lubricants and other additives.
  • Specific diluents include one or more selected from the group consisting of lactose (monohydrate or anhydride), dicalcium phosphate (dihydrate or anhydride), calcium carbonate, starch, cellulose, sucrose, dextrose, mannitol and sorbitol It includes.
  • a binder gelatin, sugar (sucrose, glucose, dextrose, lactose), starch, acacia, sodium alginate, polyvinylpyrrolidone, celluloses (carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, Hydroxypropylmethylcellulose or polyethylene glycol, etc.
  • Disintegrants include pregelatinized starch, microcrystalline cellulose, alginic acid, sodium starch glycolate, croscarmellose sodium or crosslinked polyvinylpyrrolidone (crospovidone). Glidants also include magnesium stearate, stearic acid, talc, sodium stearyl fumarate, glyceryl behenate, sodium lauryl sulfate.
  • adefober difficile 30 g was dissolved in 60 ml of anhydrous ethyl alcohol at 35 ° C. to obtain an adefober difficile solution. Insolubles were filtered off and stirred for 30 minutes in a salt-ice water bath (-5 ° C). The solid produced through stirring was filtered and washed with n-hexane. The reaction product was vacuum dried at 25 ° C. to obtain 28.3 g of adefober difficile crystals.
  • adefober difficile 100 g was dissolved in 200 ml of anhydrous ethyl alcohol at 37 ° C. to obtain an adefober difficile solution. The resulting solution was stirred at 1.5 ° C. for 2 hours. The resulting solid was filtered and dried in vacuo at 25 ° C. to yield 91 g of adefober difficile crystals.
  • XRD analysis was performed on the crystalline form of the adefober difficile obtained in Examples 1 and 2 by Rigaku, MiniFlex X-ray powder diffractometer.
  • CuK ⁇ 1 wire ( ⁇ 1 1.54056 Hz) operated at 30 kV and 15 mA was used to measure the scan speed of 10.0 ° per minute between 2 ⁇ values of 4 to 40 degrees.
  • the XRD pattern of Example 1 is shown in Figure 1 as a representative drawing.
  • the crystalline form of the adefober difficile of Example 1 has a peak at a diffraction angle of at least 7.94, 8.54, 14.32, 16.22, 19.3, 20.82, 22.3, 23.5 + 0.2 in an X-ray powder diffraction pattern You can check it.
  • the endothermic peak of the adefober difficile crystals obtained in Examples 1 and 2 was measured using a TA Instruments, DSC Q1000 differential scanning calorimeter. Measurement conditions were made into 20 degreeC of start temperature, 120 degreeC of end temperature, and a temperature increase rate of 10 degreeC / min.
  • the DSC thermogram of Example 1 is shown in FIG. 2 as a representative figure.
  • the crystalline form of the adefober difficile of Example 1 has a melting point at 66 + 2.0 °C and about 78 + 2.0 °C.
  • thermogravimetric analyzer was used to determine the weight change with temperature rise for the crystalline form of adefober difficile obtained in Examples 1 and 2. It measured at the start temperature of 35 degreeC, the end temperature of 200 degreeC, and a temperature increase rate: 5 degreeC / min.
  • the TGA thermogravimetric diagram of Example 1 is shown in FIG. 3 as a representative drawing.
  • Ethyl alcohol standard was weighed to 200,000 ⁇ g / ml, and placed in a 100 ml flask, filled with acetonitrile to the mark. 30 ml of this solution was taken and placed in a 50 ml flask to obtain a first standard solution. The first standard solution was diluted 10 and 100 times to obtain a second and third standard solution, respectively.
  • a sample solution was prepared by dissolving 100 mg of crystalline form P of each adefober difficile obtained in Examples 1 and 2 in 10 ml of acetonitrile.
  • the adefober difficile crystal form according to the present invention has high solubility and dissolution rate, shows excellent biosafety, and can be widely used in medicine.

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Abstract

Une forme cristalline d'Adefovir Dipivoxil selon la présente invention consiste en une forme solvatée d'alcool éthylique. L'invention concerne un procédé permettant de préparer la forme cristalline d'Adefovir Dipivoxil, lequel procédé comprend les étapes qui consistent à dissoudre l'Adefovir Dipivoxil dans un alcool éthylique anhydre, puis à refroidir et à agiter la solution d'Adefovir Dipivoxil obtenue à l'étape de dissolution afin de former des cristaux. La forme cristalline d'Adefovir Dipivoxil selon l'invention présente une plus grande solubilité et une plus grande vitesse de dissolution ainsi qu'une excellente biosécurité et elle peut être largement utilisée dans des domaines médicaux.
PCT/KR2009/007068 2008-11-28 2009-11-30 Forme cristalline d'adefovir fipivoxil, procédé de préparation associé et composition pharmaceutique contenant cette forme WO2010062147A2 (fr)

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KR10-2008-0119238 2008-11-28

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WO2010062147A3 WO2010062147A3 (fr) 2010-09-10

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012032541A1 (fr) 2010-09-06 2012-03-15 Matrix Laboratories Ltd Pseudopolymorphe d'adéfovir dipivoxil
CN111689936A (zh) * 2019-03-15 2020-09-22 罗欣药业(上海)有限公司 达格列净新晶型及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20010014284A (ko) * 1997-07-25 2001-02-26 헨슬레이 맥스 디. 뉴클레오티드 동족체 조성물
KR20050086519A (ko) * 2002-11-12 2005-08-30 티안진 킨슬리 파마슈티컬 컴퍼니 리미티드 새로운 결정 형태를 가진 아데포비어 디피복실 및 그조성물

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20010014284A (ko) * 1997-07-25 2001-02-26 헨슬레이 맥스 디. 뉴클레오티드 동족체 조성물
KR20050086519A (ko) * 2002-11-12 2005-08-30 티안진 킨슬리 파마슈티컬 컴퍼니 리미티드 새로운 결정 형태를 가진 아데포비어 디피복실 및 그조성물

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HOU, G. ET AL.: 'Solubilties of Adeforvir Dipovoxil in different binary solvents at 298.15K' J. CHEM. ENG. DATA vol. 53, 2008, pages 1021 - 1023 *
RUIZ, J. C. ET AL.: 'Synthesis and antiviral evaluation of alkoxyalkyl esters of phosphonopropoxymethyl-guanine and phosphonopropoxymethyl-diaminopurine' ANTIVIRAL CHEMISTRY & CHEMOTHERAPY vol. 17, 2006, pages 89 - 95 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012032541A1 (fr) 2010-09-06 2012-03-15 Matrix Laboratories Ltd Pseudopolymorphe d'adéfovir dipivoxil
CN111689936A (zh) * 2019-03-15 2020-09-22 罗欣药业(上海)有限公司 达格列净新晶型及其制备方法

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KR20100061401A (ko) 2010-06-07

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