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WO2022042641A1 - Sel médicinal d'entécavir, son procédé de préparation, composition pharmaceutique de celui-ci et utilisation associée - Google Patents

Sel médicinal d'entécavir, son procédé de préparation, composition pharmaceutique de celui-ci et utilisation associée Download PDF

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Publication number
WO2022042641A1
WO2022042641A1 PCT/CN2021/114753 CN2021114753W WO2022042641A1 WO 2022042641 A1 WO2022042641 A1 WO 2022042641A1 CN 2021114753 W CN2021114753 W CN 2021114753W WO 2022042641 A1 WO2022042641 A1 WO 2022042641A1
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Prior art keywords
entecavir
acid
salt
organic
pharmaceutically acceptable
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English (en)
Chinese (zh)
Inventor
应述欢
陈志祥
刘璐
张贤
朱涛
王婷婷
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Shanghai Bocimed Pharmaceutical Co Ltd
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Shanghai Bocimed Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • the present invention relates to a pharmaceutical salt of entecavir and its preparation method, pharmaceutical composition and application.
  • Entecavir is a 2'-pentacyclodeoxyguanosine analog with the chemical name 2-amino-9-[(1S,3S,4S)-4-hydroxy-3-hydroxymethyl -2-Methylenecyclopentyl]-1,9-dihydro-6H-purin-6-one, the molecular formula is C 12 H 15 N 5 O 3 , the molecular weight is 277.3, and the structural formula is shown below.
  • Entecavir is a deoxyguanosine analog that can effectively inhibit the replication of hepatitis B virus, and has a strong anti-hepatitis B (HBV) effect.
  • HBV anti-hepatitis B
  • very low concentrations of entecavir can inhibit the replication of hepatitis B virus, and its cytotoxicity is very low, has a very good selective therapeutic index.
  • Patent document CN1566118A discloses entecavir base salts, such as entecavir ammonium salt, calcium salt, sodium salt and preparation method thereof.
  • its alkali salt is not an addition salt formed by an organic acid and a base, but after the enolization of entecavir, the hydroxyl group in the enol has a weak acidity and can react with a strong base such as sodium hydroxide or potassium hydroxide to form An enolate in which the guanosine moiety of entecavir has been substantially altered.
  • the enolate is easily dissociated into entecavir molecules in solution, and may be more easily oxidized and degraded than entecavir itself.
  • Patent document CN101003536A discloses various acid addition salts and base addition salts of entecavir, wherein the acid addition salts include hydrochloride, hydrobromide, mesylate, benzenesulfonate, sulfate and phosphate, The solubility in water is all greater than 150mg/mL, and the alkali salts include magnesium salts and barium salts, which are also enolate salts, and there is a risk of easy dissociation or easy oxidation.
  • Patent document CN1872853A discloses a variety of acid addition salts of entecavir, such as hydrobromide, hydrochloride, mesylate, maleate, etc. Compared with entecavir, these salts have significantly enhanced solubility under the same conditions , for example, the solubility of hydrochloride in aqueous solution and neutral physiological buffer at room temperature is greater than 165 mg/mL, while the solubility of entecavir is 2.4 mg/mL.
  • Patent document CN1907987A discloses various acid addition salts of entecavir, especially hydrochloride and maleate, and discloses the melting points of both. In aqueous solution at room temperature or neutral physiological buffer solution, the solubility of these salts is greater than or equal to 100 mg/mL, which is more than 10 times higher than that of entecavir.
  • Patent document CN101781300A discloses entecavir p-toluenesulfonate, the water solubility at normal temperature and pressure is greater than 130 mg/mL, which is far greater than that of entecavir.
  • entecavir due to the high solubility of entecavir and various existing salts of entecavir, it is easy to cause its release rate in the preparation to be too fast, and frequent administration is required to maintain the blood drug concentration, which makes the patient's compliance poor.
  • the pharmaceutical salt form of entecavir suitable for sustained-release administration, high stability, good clinical effect and suitable for commercialization is a technical problem that needs to be solved urgently at present.
  • the present invention provides a kind of entecavir medicinal salt, and the entecavir medicinal salt is the salt formed by entecavir free base (formula I) and an organic acid having more than six carbons;
  • the organic acid with more than six carbons can be a C6-C30 organic acid.
  • C6 ⁇ C30 organic acids include but are not limited to: caproic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid, capric acid, undecanoic acid, lauric acid (dodecanoic acid), tridecanoic acid , myristic acid (tetradecanoic acid), pentadecanoic acid, palmitic acid (hexadecanoic acid), heptadecanoic acid, stearic acid (octadecanoic acid), nonadecanoic acid, eicosanoic acid ( arachidic acid), oleic acid, behenic acid, behenic acid, behenic acid, behenic acid, behenic acid, heptacosanoic acid, Octadecanoic acid, nonaco
  • the palmitate refers to a structure after palmitic acid is esterified with at least one hydroxyl group of a compound containing both carboxyl and hydroxyl groups (such as pamoic acid);
  • the naphthalate refers to naphthalene A structure in which an acid is esterified with at least one hydroxyl group of a compound containing both carboxyl and hydroxyl groups, such as pamoic acid.
  • the pharmaceutically acceptable salt of entecavir may be in crystalline, polymorphic or amorphous form.
  • polymorphism refers to different crystal forms and other solid-state molecular forms of the same compound, for example, comprising two or more crystal forms and/or the pharmaceutically acceptable salts of entecavir. Amorphous form of solid.
  • the pharmaceutically acceptable salt of entecavir includes its solvate formed with a solvent.
  • the solvates include hydrates of entecavir pharmaceutically acceptable salts and solvates formed by entecavir pharmaceutically acceptable salts and organic solvents.
  • the "organic solvent” described in the "solvate formed by a pharmaceutical salt of entecavir and an organic solvent” includes but is not limited to one, two or more selected from ethanol, acetone and dimethyl sulfoxide. kind.
  • the molar ratio of entecavir to the organic acid with more than six carbons is preferably 1:1.
  • the pharmaceutically acceptable salt of entecavir is entecavir 1-hydroxy-2-naphthoate salt having the structure shown in the following formula II.
  • the present invention also provides the preparation method of the pharmaceutical salt of entecavir, which comprises the following steps: respectively forming an entecavir free base solution and an organic acid solution in a first solvent, then mixing and reacting the two, adding a second solvent or removing The first solvent obtains the medicinal salt of entecavir.
  • the first solvent is selected from ethanol, water, N,N-dimethylformamide or a mixture thereof.
  • the second solvent is isopropyl ether, methyl tert-butyl, n-heptane, toluene, or a mixture thereof.
  • the molar ratio of entecavir and organic acid is 1:1.1 ⁇ 1:1.2.
  • the mixing is adding the organic acid solution to the entecavir free base solution.
  • the reaction is carried out at room temperature.
  • the preparation method of the pharmaceutically acceptable salt of entecavir can also be carried out under solvent-free conditions.
  • the organic acid with more than six carbons can be a C6-C30 organic acid.
  • Described C6 ⁇ C30 organic acids include but are not limited to: caproic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid, capric acid, undecanoic acid, lauric acid (dodecanoic acid), tridecanoic acid , myristic acid (tetradecanoic acid), pentadecanoic acid, palmitic acid (hexadecanoic acid), heptadecanoic acid, stearic acid (octadecanoic acid), nonadecanoic acid, eicosanoic acid ( arachidic acid), oleic acid, behenic acid, behenic acid, behenic acid, behenic acid, behenic acid, behenic acid, heptacosanoi
  • the present invention also provides a pharmaceutical composition comprising the entecavir pharmaceutically acceptable salt.
  • the pharmaceutical composition comprises a therapeutically effective amount of the pharmaceutically acceptable salt of entecavir and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of a compound to an organism such as a human or other mammal.
  • the dosage form of the pharmaceutical composition is selected from injections, such as long-acting injections.
  • the injection can be an aqueous suspension, an oil suspension or a suspension powder.
  • the suspension powder can be dispersed into a suspension by using a specific diluent immediately before use.
  • the concentration of the entecavir pharmaceutical salt in the entecavir long-acting injection is not less than 5 mg/mL, wherein the concentration refers to the ratio of the mass of the entecavir pharmaceutical salt to the volume of the entecavir long-acting injection .
  • the particle size of the powder in the compounded powder may be, for example, ⁇ 1 mm.
  • the pharmaceutically acceptable adjuvants include one or more of physiologically or pharmaceutically acceptable carriers, diluents, vehicles and/or excipients.
  • the present invention also provides the application of the entecavir medicinal salt in preparing a medicine for treating and/or preventing hepatitis B.
  • the present invention also provides the application of the pharmaceutical salt of entecavir in the preparation of a medicine for inhibiting hepatitis B virus.
  • the present invention also provides the application of the pharmaceutical composition in the preparation of a medicine for treating and/or preventing hepatitis B, which comprises administering the pharmaceutical composition to the user.
  • the application may comprise administering the pharmaceutically acceptable salt of entecavir or a pharmaceutical composition thereof to the user.
  • the present invention also provides a method for treating and/or preventing hepatitis B, comprising administering the entecavir pharmaceutically acceptable salt or its pharmaceutical composition to the user.
  • the present invention also provides a method for inhibiting hepatitis B virus, comprising administering the entecavir pharmaceutically acceptable salt or its pharmaceutical composition to the user.
  • the terms "pharmaceutically acceptable”, “carrier”, “diluent”, “vehicle” or “excipient” refer to a substance (or substances), It can be included with certain pharmaceutical agents to form a pharmaceutical composition, and can be solid or liquid.
  • the solid carriers include but are not limited to starch, calcium sulfate dihydrate, terra alba, talc, lactose, sucrose, mica, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • the liquid carrier includes, but is not limited to, syrup, peanut oil, olive oil, saline solution, water, and the like.
  • the carrier or diluent may include delayed or timed release materials known in the art, such as monostearic acid alone or in combination with waxes, ethyl cellulose, hypromellose, methyl methacrylate, and the like Glycerides or Glyceryl Distearate.
  • the term "solvate” includes a molecular complex of a drug and a stoichiometric or non-stoichiometric amount of one or more solvent molecules (eg, ethanol).
  • solvent molecules eg, ethanol
  • the solvent content will depend on humidity and drying conditions. In such cases, the complex will generally be non-stoichiometric.
  • the term “hydrate” describes a solvate comprising a drug with a stoichiometric or non-stoichiometric amount of water.
  • relative humidity refers to the ratio, expressed as a percentage, of the amount of water vapor at a specified temperature to the maximum amount of water vapor that can be held at that temperature and pressure.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the room temperature refers to an ambient temperature ranging from 10°C to 35°C.
  • the entecavir medicinal salt of the present invention achieves lower solubility, unexpectedly improves the technical problem that the drug is released too fast and needs frequent administration to maintain the blood drug concentration, and significantly improves the medication compliance of patients.
  • the entecavir medicinal salt has good stability, and adopts organic acid to form a salt, which avoids the adverse effect on stability caused by the enol structure formed by entecavir and an alkali salt, and has high bioavailability and marketization prospects. good.
  • Fig. 1 is the 1 H-NMR chart of entecavir 1-hydroxy-2-naphthoate of the present invention
  • Fig. 2 is the XRPD pattern of entecavir 1-hydroxy-2-naphthoate of the present invention.
  • the salt compounds of the examples were tested by nuclear magnetic resonance ( 1 H-NMR), high performance liquid chromatography (HPLC) and X-ray powder diffraction (XRPD) respectively, and the test parameters were as follows:
  • entecavir Take 500mg of entecavir, add 20mL of DMF to dissolve to obtain entecavir free base solution; take 360mg of 1-hydroxy-2-naphthoic acid, add 12mL of DMF to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution, stir After the reaction was carried out for 18-24 hours, 180 mL of methyl tert-butyl ether was added, stirred for 18-24 hours, filtered, and dried under vacuum at 40° C. to obtain 780 mg of entecavir 1-hydroxy-2-naphthoate.
  • the above sample was tested by XRPD and showed to be amorphous.
  • entecavir Take 10mg of entecavir, add 2mL of ethanol to dissolve to obtain entecavir free base solution; take 7.2mg of 1-hydroxy-2-naphthoic acid, add 0.5mL of ethanol to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution , stir the reaction for 18-24 hours, add 8 mL of toluene, stir for 18-24 hours, filter, and vacuum dry at 40°C to obtain 15 mg of entecavir 1-hydroxy-2-naphthoate.
  • entecavir Take 25 mg of entecavir, add 5 mL of water, dissolve at 60 °C to obtain entecavir free base solution; take 20 mg of 1-hydroxy-2-naphthoic acid, add 1 mL of methanol to dissolve to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution , the reaction was stirred for 18-24 hours, filtered, and dried under vacuum at 40° C. to obtain 37 mg of entecavir 1-hydroxy-2-naphthoate.
  • entecavir Take 25mg of entecavir, add 10mL of ethanol to dissolve to obtain entecavir free base solution; take 18mg of 1-hydroxy-2-naphthoic acid, add 2mL of ethanol to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution, stir The reaction was carried out for 18 to 24 hours, and concentrated under reduced pressure at 40° C. until the solvent was dry to obtain 35 mg of entecavir 1-hydroxy-2-naphthoate.
  • entecavir Take 25mg of entecavir, add 10mL of ethanol to dissolve to obtain entecavir free base solution; take 18mg of 1-hydroxy-2-naphthoic acid, add 2mL of ethanol to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution, stir The reaction was carried out for 18-24 hours, and the solvent was evaporated to dryness at 40° C. to obtain 38 mg of entecavir 1-hydroxy-2-naphthoate.
  • entecavir Take 25mg of entecavir, add 10mL of ethanol to dissolve to obtain entecavir free base solution; take 18mg of 1-hydroxy-2-naphthoic acid, add 2mL of ethanol to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution, stir The reaction was carried out for 18 to 24 hours, 20 mL of n-heptane was added, and the mixture was stirred and crystallized for 18 to 24 hours, filtered, and dried under vacuum at 40° C. to obtain 28 mg of entecavir 1-hydroxy-2-naphthoate.
  • the samples prepared in Examples 2-6 have the same or similar 1 H-NMR and XPRD spectra as those in Example 1, indicating that the samples in Examples 2-6 are the same salt as the sample in Example 1.
  • entecavir Take 50 mg of entecavir, add 7 mL of methanol to dissolve, to obtain entecavir free base solution; take 38 mg of sebacic acid, add 0.4 mL of methanol to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution, stirring and reacting for 18-24 After 1 hour, after volatilizing until a large amount of solid was precipitated, it was filtered and dried under vacuum at 40°C to obtain 61 mg of entecavir sebacate.
  • entecavir Take 50 mg of entecavir, add 7 mL of methanol to dissolve, to obtain entecavir free base solution; take 25 mg of heptanoic acid, add 0.1 mL of methanol to dissolve to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, and stir for 18 to 24 hours. , 21 mL of methyl tert-butyl ether was added, stirred for 18 to 24 hours, filtered, and dried under vacuum at 40° C. to obtain 51 mg of entecavir enanthate.
  • entecavir Take 50 mg of entecavir, add 7 mL of methanol to dissolve, to obtain entecavir free base solution; take 35 mg of heptanoic acid, add 0.5 mL of methanol to dissolve to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, stirring and reacting for 18 to 24 hours , 21 mL of toluene was added, stirred for 18 to 24 hours, filtered, and dried under vacuum at 40° C. to obtain 51 mg of entecavir undecanoate.
  • entecavir Take 50mg of entecavir, add 7mL of methanol to dissolve, to obtain entecavir free base solution; take 48mg of palmitic acid, add 0.5mL of methanol to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution, stir and react for 18-24 hours, filtered, and dried under vacuum at 40°C to yield 70 mg of entecavir palmitate.
  • Example 15 Pharmaceutical composition of entecavir
  • Entecavir 1-hydroxy-2-naphthoate suspension injection is obtained by mixing entecavir 1-hydroxy-2-naphthoate and each auxiliary material under aseptic conditions according to the above-mentioned prescription amount, and grinding by grinding.
  • Entecavir 1-hydroxy-2-naphthoate prepared in Example 1 Entecavir palmitate prepared in Example 11, Entecavir oleate prepared in Example 12, and Entecavir prepared in Example 13.
  • Laurate and entecavir were added to the corresponding medium respectively, shaken at 37°C for 24 hours, filtered with a 0.45 ⁇ m aqueous filter, collected the filtrate, and used high performance liquid phase for solubility determination.
  • pH3 and pH5 are acetate buffer solutions
  • pH7 and pH9 are phosphate buffer solutions
  • Table 1 the solubility test results are shown in Table 1.
  • the entecavir 1-hydroxy-2-naphthoate salt of the present invention as an example, its solubility is moderate, and the release rate can be less dependent on pH, thereby avoiding its release rate in the pH environment of different regions in the body It can avoid the sudden release phenomenon or the high blood drug concentration in the local area of the body, and reduce the drug release variability among individuals.
  • the entecavir 1-hydroxy-2-naphthoate and entecavir prepared in Example 1 were respectively taken, placed in an environment of 2-8° C., and sampled at corresponding time points for XRPD detection to investigate their stability.
  • Table 2 shows that the entecavir 1-hydroxy-2-naphthoate salt of the present invention has good stability and remains amorphous after being placed at 2-8° C. for 30 days.

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Abstract

L'invention concerne un sel médicinal d'entécavir, son procédé de préparation, une composition pharmaceutique de celui-ci et une utilisation associée. Le sel médicinal d'entécavir est un sel formé par une base libre d'entécavir (I) et un acide organique ayant plus de six atomes de carbone. Le sel médicinal d'entécavir a une faible solubilité, une bonne stabilité, une biodisponibilité élevée et de bonnes perspectives commerciales.
PCT/CN2021/114753 2020-08-26 2021-08-26 Sel médicinal d'entécavir, son procédé de préparation, composition pharmaceutique de celui-ci et utilisation associée Ceased WO2022042641A1 (fr)

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WO2023249465A1 (fr) * 2022-06-23 2023-12-28 주식회사 지투지바이오 Formulation de microsphères à action prolongée contenant de l'entécavir, et son procédé de préparation

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CN108699060A (zh) * 2016-10-07 2018-10-23 檀国大学天安校区产学合作团 结合有脂肪酸的恩替卡韦衍生化合物及其药学用途
CN108969478A (zh) * 2018-08-29 2018-12-11 江南大学 一种美金刚难溶盐缓释注射剂及其制备方法

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WO2023249465A1 (fr) * 2022-06-23 2023-12-28 주식회사 지투지바이오 Formulation de microsphères à action prolongée contenant de l'entécavir, et son procédé de préparation
KR20240000406A (ko) * 2022-06-23 2024-01-02 주식회사 지투지바이오 엔테카비르를 포함하는 장기지속성 미립구 제제 및 이의 제조방법
KR102706487B1 (ko) 2022-06-23 2024-09-12 주식회사 지투지바이오 엔테카비르를 포함하는 장기지속성 미립구 제제 및 이의 제조방법
CN116650497A (zh) * 2022-09-30 2023-08-29 广州帝奇医药技术有限公司 一种抗病毒药物组合物及其制备工艺与应用
WO2024066765A1 (fr) * 2022-09-30 2024-04-04 广州帝奇医药技术有限公司 Composition pharmaceutique antivirale, son procédé de préparation et son utilisation

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