Entecavir pharmaceutical salt and its preparation method, pharmaceutical composition and application

Abstract

The present invention provides a pharmaceutical salt of entecavir, a preparation method, a pharmaceutical composition, and uses thereof. The present invention discloses a pharmaceutical salt of entecavir, which is a salt formed by entecavir free base I and an organic acid containing at least six carbon atoms. The pharmaceutical salt of entecavir of the present invention has low solubility, good stability, high bioavailability, and promising market prospects. #imgabs0#

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 202110989524.8 and title “Pharmaceutical salt of Entecavir and its preparation method, pharmaceutical composition and application”.

[0002] This application claims priority to invention patent application No. 202010870716.2, filed with the State Intellectual Property Office of China on August 26, 2020, entitled "Pharmaceutical Salts of Entecavir, Methods of Preparation, Pharmaceutical Compositions Containing Same, and Uses thereof." The entire text of that application is incorporated herein by reference. Technical Field

[0003] The present invention relates to a pharmaceutical salt of entecavir, a preparation method thereof, a pharmaceutical composition and application thereof. Background Art

[0004] Entecavir (Formula I) is a 2'-pentadeoxyguanosine nucleoside analogue, chemically named 2-amino-9-[(1S,3S,4S)-4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl]-1,9-dihydro-6H-purin-6-one, with a molecular formula of C 12 H 15 N5O3, molecular weight 277.3, structural formula is shown below.

[0005]

[0006] Entecavir is a deoxyguanosine analog that effectively inhibits hepatitis B virus (HBV) replication and exhibits strong anti-HBV activity. In in vitro studies, extremely low concentrations of entecavir can inhibit HBV replication, while exhibiting very low cytotoxicity, demonstrating a highly selective therapeutic index.

[0007] Patent document CN1566118A discloses entecavir base salts, such as ammonium, calcium, and sodium salts, and their preparation methods. However, these base salts are not addition salts formed by organic acids and bases. Instead, entecavir undergoes enolization, resulting in a weakly acidic hydroxyl group in the enol group that reacts with a strong base, such as sodium hydroxide or potassium hydroxide, to form an enolate salt. The guanine nucleoside structure of entecavir has undergone significant changes. This enolate salt readily dissociates into entecavir molecules in solution and may be more susceptible to oxidation and degradation than entecavir itself.

[0008] Patent document CN101003536A discloses a variety of acid addition salts and base addition salts of entecavir, including acid addition salts including hydrochloride, hydrobromide, methanesulfonate, benzenesulfonate, sulfate, and phosphate, all of which have a solubility in water greater than 150 mg / mL. Base salts include magnesium salt and barium salt, which are also enolates and have the risk of easy dissociation or oxidation.

[0009] Patent document CN1872853A discloses various acid addition salts of entecavir, such as hydrobromide, hydrochloride, methanesulfonate, and maleate. Compared with entecavir, these salts have significantly enhanced solubility under the same conditions. For example, the solubility of hydrochloride in room temperature aqueous solution and neutral physiological buffer is greater than 165 mg / mL, while the solubility of entecavir is 2.4 mg / mL.

[0010] Patent document CN1907987A discloses various acid addition salts of entecavir, specifically the hydrochloride and maleate salts, and discloses their melting points. In room temperature aqueous solution or neutral physiological buffer, these salts have solubilities greater than or equal to 100 mg / mL, more than 10 times higher than that of entecavir.

[0011] Patent document CN101781300A discloses entecavir p-toluenesulfonate, which has a water solubility of greater than 130 mg / mL at room temperature and pressure, which is much greater than the water solubility of entecavir.

[0012] However, due to the high solubility of entecavir and various existing entecavir salts, their release rate in the preparation is easily too fast, requiring frequent administration to maintain blood drug concentration, resulting in poor patient compliance. Therefore, finding a pharmaceutical entecavir salt form with low solubility, suitable for sustained-release administration, high stability, good clinical effect, and suitable for commercialization is a technical problem that needs to be urgently solved. Summary of the Invention

[0013] In order to improve the above technical problems, the present invention provides a pharmaceutically acceptable salt of entecavir, wherein the pharmaceutically acceptable salt of entecavir is a salt formed by entecavir free base (Formula I) and an organic acid having more than six carbon atoms;

[0014]

[0015] According to an embodiment of the present invention, the organic acid with more than six carbon atoms may be an organic acid with C6 to C30. The organic acid with C6 to C30 includes, but is not limited to, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid, decanoic 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, heneicosanoic acid, docosanoic acid, tricosanoic acid, tetracosanoic acid, pentacosanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid, nonacosanoic acid, triacontanol (melisic acid), triacetin, lignic acid, pamoic acid (palmitate), 1-hydroxy-2-naphthoic acid, and naphthoic acid derivatives (including but not limited to naphthoic acid esters).

[0016] According to an embodiment of the present invention, the palmitate refers to a structure in which palmitic acid forms an ester with at least one hydroxyl group of a compound containing both a carboxyl group and a hydroxyl group (such as pamoic acid); the naphthoate refers to a structure in which naphthoic acid forms an ester with at least one hydroxyl group of a compound containing both a carboxyl group and a hydroxyl group (such as pamoic acid).

[0017] According to an embodiment of the present invention, the pharmaceutically acceptable salt of entecavir may be in a crystalline, polycrystalline or amorphous form.

[0018] According to an embodiment of the present invention, the term "polymorph" refers to different crystal forms and other solid molecular forms of the same compound, such as a solid comprising two or more crystal forms and / or amorphous forms of the pharmaceutically acceptable salt of entecavir.

[0019] According to an embodiment of the present invention, the pharmaceutically acceptable salt of entecavir includes a solvate formed with a solvent. The solvate includes a hydrate of the pharmaceutically acceptable salt of entecavir and a solvate formed with an organic solvent. The "organic solvent" in the "solvate formed with the pharmaceutically acceptable salt of entecavir and an organic solvent" includes, but is not limited to, one, two, or more solvents selected from ethanol, acetone, and dimethyl sulfoxide.

[0020] According to an embodiment of the present invention, in the pharmaceutically acceptable salt of entecavir, the molar ratio of entecavir to the organic acid with more than six carbon atoms is preferably 1:1.

[0021] According to an embodiment of the present invention, the pharmaceutically acceptable salt of entecavir is entecavir 1-hydroxy-2-naphthoate having a structure shown in the following formula II.

[0022]

[0023] The present invention also provides a method for preparing the pharmaceutical salt of entecavir, which comprises the following steps: forming an entecavir free base solution and an organic acid solution in a first solvent, respectively, mixing the two, reacting them, and adding a second solvent or removing the first solvent to obtain the pharmaceutical salt of entecavir.

[0024] According to an embodiment of the present invention, the first solvent is selected from ethanol, water, N,N-dimethylformamide or a mixture thereof.

[0025] According to an embodiment of the present invention, the second solvent is isopropyl ether, methyl tert-butyl, n-heptane, toluene or a mixture thereof.

[0026] According to an embodiment of the present invention, the molar ratio of entecavir to organic acid is 1:1.1 to 1:1.2.

[0027] According to an embodiment of the present invention, the mixing is adding the organic acid solution into the entecavir free base solution.

[0028] According to an embodiment of the present invention, the reaction is carried out at room temperature.

[0029] According to an embodiment of the present invention, the method for preparing the pharmaceutically acceptable salt of entecavir can also be carried out in the absence of a solvent.

[0030] According to an embodiment of the present invention, in the method for preparing a pharmaceutically acceptable salt of entecavir, the organic acid having more than six carbon atoms may be a C6-C30 organic acid. The C6-C30 organic acid includes, but is not limited to, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid, decanoic 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, heneicosanoic acid, docosanoic acid, tricosanoic acid, tetracosanoic acid, pentacosanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid, nonacosanoic acid, triacontanol (melisic acid), triacetin, lignic acid, pamoic acid (palmitate), 1-hydroxy-2-naphthoic acid, and naphthoic acid derivatives (including but not limited to naphthoic acid esters).

[0031] The present invention also provides a pharmaceutical composition comprising the pharmaceutically acceptable salt of entecavir.

[0032] According to an embodiment of the present invention, the pharmaceutical composition comprises a therapeutically effective amount of the pharmaceutical salt of entecavir and pharmaceutically acceptable excipients.

[0033] According to an embodiment of the present invention, the purpose of the pharmaceutical composition is to facilitate administration of a compound to an organism such as a human or other mammal.

[0034] According to an embodiment of the present invention, the dosage form of the pharmaceutical composition is selected from injections, such as long-acting injections. The injections can be aqueous suspensions, oil suspensions, or suspension powders.

[0035] According to an embodiment of the present invention, the suspension powder can be dispersed into a suspension using a specific diluent before use.

[0036] According to an embodiment of the present invention, the concentration of the pharmaceutically acceptable salt of entecavir in the long-acting entecavir injection is not less than 5 mg / mL, wherein the concentration refers to the ratio of the mass of the pharmaceutically acceptable salt of entecavir to the volume of the long-acting entecavir injection.

[0037] According to an embodiment of the present invention, the particle size of the powder in the mixed powder may be, for example, ≤1 mm.

[0038] According to an embodiment of the present invention, the pharmaceutically acceptable excipients include one or more physiologically or pharmaceutically acceptable carriers, diluents, vehicles and / or excipients.

[0039] The present invention also provides use of the pharmaceutically acceptable salt of entecavir in preparing a drug for treating and / or preventing hepatitis B.

[0040] The present invention also provides use of the pharmaceutical salt of entecavir in preparing a drug for inhibiting hepatitis B virus.

[0041] The present invention also provides the use of the pharmaceutical composition in preparing a drug for treating and / or preventing hepatitis B, which comprises administering the pharmaceutical composition to an administrator.

[0042] According to an embodiment of the present invention, the use may include administering the pharmaceutically acceptable salt of entecavir or the pharmaceutical composition thereof to an administrator.

[0043] The present invention also provides a method for treating and / or preventing hepatitis B, comprising administering the pharmaceutically acceptable salt of entecavir or the pharmaceutical composition thereof to an administrator.

[0044] The present invention also provides a method for inhibiting hepatitis B virus, comprising administering the pharmaceutically acceptable salt of entecavir or the pharmaceutical composition thereof to an administrator.

[0045] Unless otherwise specified, the following terms appearing in the present specification and claims have the following meanings:

[0046] According to an embodiment of the present invention, the term "pharmaceutically acceptable", "carrier", "diluent", "vehicle" or "excipient" refers to a substance (or substances) that can be included with a specific agent to form a pharmaceutical composition and can be solid or liquid. The solid carrier includes but is not limited to starch, calcium sulfate dihydrate, gypsum powder, talc, lactose, sucrose, mica, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid, etc. The liquid carrier includes but is not limited to syrup, peanut oil, olive oil, saline solution and water, etc. The carrier or diluent may include delayed or timed release materials known in the art, such as glyceryl monostearate or glyceryl distearate alone or with wax, ethyl cellulose, hydroxypropyl methylcellulose, methyl methacrylate, etc.

[0047] According to an embodiment of the present invention, the term "solvate" includes a molecular complex of a drug and a stoichiometric or non-stoichiometric amount of one or more solvent molecules (such as ethanol). When the solvent is tightly bound to the drug, the resulting complex will have a well-defined stoichiometry that is independent of humidity. However, when the solvent is weakly bound to the drug, as in channel solvates and hygroscopic compounds, the solvent content will depend on humidity and drying conditions. In such cases, the complex will typically be non-stoichiometric.

[0048] According to an embodiment of the present invention, the term "hydrate" describes a solvate comprising a drug and a stoichiometric or non-stoichiometric amount of water. The term "relative humidity" refers to the ratio of the amount of water vapor at a specified temperature to the maximum amount of water vapor that can be retained at that temperature and pressure, expressed as a percentage.

[0049] The reagents and raw materials used in the present invention are commercially available.

[0050] According to an embodiment of the present invention, the room temperature refers to an ambient temperature of 10°C to 35°C.

[0051] Beneficial effects

[0052] The pharmaceutical salt of entecavir disclosed herein achieves low solubility, unexpectedly resolving the technical issue of rapid drug release and the need for frequent dosing to maintain blood drug concentrations, significantly improving patient compliance. The pharmaceutical salt of entecavir exhibits excellent stability, and the use of an organic acid for salt formation avoids the adverse effects of the enol structure formed when entecavir reacts with a base on stability. Furthermore, the salt exhibits high bioavailability and promising market prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 Entecavir 1-hydroxy-2-naphthoate of the present invention 1 H-NMR spectrum;

[0054] Figure 2 1-Hydroxy-2-naphthoate of entecavir according to the present invention is an XRPD pattern. DETAILED DESCRIPTION

[0055] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0056] Nuclear magnetic resonance ( 1The salt compounds of the examples were tested by H-NMR, high performance liquid chromatography (HPLC) and X-ray powder diffraction (XRPD), and the test parameters were as follows:

[0057] (1) 1 The H-NMR measurements were performed on a Bruker Advance III 500M nuclear magnetic resonance spectrometer at a measurement frequency of 400 MHz using deuterated DMSO as the solvent.

[0058] (2) XRPD measurements were performed on a Bruker D8 Advance X-ray powder diffractometer using a circular zero-background single-crystal silicon stage. Scan parameters were as follows: voltage 40 kV, current 40 mA, scan range 3°–45°, scan step size 0.02°, and continuous scan mode.

[0059] (3) HPLC measurements were performed in a Waters high performance liquid chromatograph using a Waters SymmetryShield column. TM RP18, 4.6mm*250mm, 5μm, detection wavelength is 254nm, mobile phase is water / acetonitrile (90 / 10v / v), flow rate is 1mL / min, column temperature is 30℃, injection plate temperature is 37℃, injection volume is 5μL, and elution time is 20min.

[0060] Example 1 Preparation of Entecavir 1-Hydroxy-2-Naphthoate

[0061] Take 500 mg of entecavir and add 20 mL of DMF to dissolve to obtain an entecavir free base solution; take 360 mg of 1-hydroxy-2-naphthoic acid and add 12 mL of DMF to dissolve to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, stir to react for 18 to 24 hours, add 180 mL of methyl tert-butyl ether, stir for 18 to 24 hours, filter, and dry in vacuo at 40°C to obtain 780 mg of entecavir 1-hydroxy-2-naphthoate.

[0062] The structure and molar ratio of the entecavir 1-hydroxy-2-naphthoate salt of the present invention were confirmed by hydrogen nuclear magnetic resonance spectroscopy.

[0063] 1H-NMR (400MHz, DMSO-d6): δ10.63(s,1H),8.28(dd,2H),7.89(d,2H),7.78–7.71(m,3H),7.67(ddd,2H),7.57(ddd,2H),7.38(d,2H) ,6.46(s,2H),5.37(ddd,1H),5.11(t,1H),4.58(t,1H),4.24(dt,1H),3.54(d,2H),2.54(d,1H),2.23(ddd,1H),2.10–2.00(m,1H).

[0064] 1 H-NMR showed that entecavir and 1-hydroxy-2-naphthoic acid formed a salt at a molar ratio of 1:1.

[0065] XRPD analysis of the above sample showed that it was amorphous.

[0066] Example 2 Preparation of Entecavir 1-Hydroxy-2-Naphthoate

[0067] Take 10 mg of entecavir and add 2 mL of ethanol to dissolve it to obtain an entecavir free base solution; take 7.2 mg of 1-hydroxy-2-naphthoic acid and add 0.5 mL of ethanol to dissolve it to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, stir and react for 18 to 24 hours, add 8 mL of toluene, stir for 18 to 24 hours, filter, and dry in vacuo at 40°C to obtain 15 mg of entecavir 1-hydroxy-2-naphthoate.

[0068] Example 3 Preparation of Entecavir 1-Hydroxy-2-Naphthoate

[0069] Take 25 mg of entecavir, add 5 mL of water, and dissolve at 60°C to obtain an 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, stir and react for 18 to 24 hours, filter, and dry in vacuo at 40°C to obtain 37 mg of entecavir 1-hydroxy-2-naphthoate.

[0070] Example 4 Preparation of Entecavir 1-Hydroxy-2-Naphthoate

[0071] Take 25 mg of entecavir and add 10 mL of ethanol to dissolve it to obtain an entecavir free base solution; take 18 mg of 1-hydroxy-2-naphthoic acid and add 2 mL of ethanol to dissolve it to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, stir and react for 18 to 24 hours, and concentrate under reduced pressure at 40°C to dryness of the solvent to obtain 35 mg of entecavir 1-hydroxy-2-naphthoate.

[0072] Example 5 Preparation of Entecavir 1-hydroxy-2-naphthoate

[0073] Take 25 mg of entecavir and add 10 mL of ethanol to dissolve it to obtain an entecavir free base solution; take 18 mg of 1-hydroxy-2-naphthoic acid and add 2 mL of ethanol to dissolve it to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, stir and react for 18 to 24 hours, and evaporate it open at 40°C until the solvent is dry to obtain 38 mg of entecavir 1-hydroxy-2-naphthoate.

[0074] Example 6 Preparation of Entecavir 1-Hydroxy-2-Naphthoate

[0075] Take 25 mg of entecavir and add 10 mL of ethanol to dissolve it to obtain an entecavir free base solution; take 18 mg of 1-hydroxy-2-naphthoic acid and add 2 mL of ethanol to dissolve it to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, stir and react for 18 to 24 hours, add 20 mL of n-heptane, stir and crystallize for 18 to 24 hours, filter, and dry in vacuo at 40°C to obtain 28 mg of entecavir 1-hydroxy-2-naphthoate.

[0076] The samples prepared in Examples 2 to 6 have the same or similar properties as those in Example 1. 1 H-NMR and XPRD spectra indicate that the samples of Examples 2 to 6 are the same salt as the sample of Example 1.

[0077] Example 7 Preparation of Entecavir Sebacate

[0078] Take 50 mg of entecavir and add 7 mL of methanol to dissolve it to obtain an entecavir free base solution; take 38 mg of sebacic acid and add 0.4 mL of methanol to dissolve it to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, stir and react for 18 to 24 hours, evaporate until a large amount of solid is precipitated, filter, and dry in vacuo at 40°C to obtain 61 mg of entecavir sebacate.

[0079] 1 H-NMR analysis showed that entecavir and sebacic acid formed a salt with a molar ratio of 1:1.

[0080] Example 8 Preparation of Entecavir Decanoate

[0081] Take 50 mg of entecavir and add 7 mL of methanol to dissolve it to obtain an entecavir free base solution; take 22 mg of succinic acid and add 0.2 mL of methanol to dissolve it to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, stir and react for 18 to 24 hours, evaporate until a large amount of solid is precipitated, filter, and dry in vacuo at 40°C to obtain 50 mg of entecavir succinate.

[0082] 1 H-NMR analysis showed that entecavir and succinic acid formed a salt with a molar ratio of 1:1.

[0083] Example 9 Preparation of Entecavir Hexanoate

[0084] Take 50 mg of entecavir and add 7 mL of methanol to dissolve it to obtain an entecavir free base solution; take 22 mg of hexanoic acid and add 0.1 mL of methanol to dissolve it to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, stir and react for 18 to 24 hours, add 21 mL of methyl tert-butyl ether, stir for 18 to 24 hours, filter, and dry in vacuo at 40°C to obtain 40 mg of entecavir hexanoate.

[0085] 1 H-NMR analysis showed that entecavir and hexanoic acid formed a salt with a molar ratio of 1:1.

[0086] Example 10 Preparation of Entecavir Enanthate

[0087] Take 50 mg of entecavir and add 7 mL of methanol to dissolve it to obtain an entecavir free base solution; take 25 mg of heptanoic acid and add 0.1 mL of methanol to dissolve it to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, stir and react for 18 to 24 hours, add 21 mL of methyl tert-butyl ether, stir for 18 to 24 hours, filter, and vacuum dry at 40°C to obtain 51 mg of entecavir heptanoate.

[0088] 1 H-NMR analysis showed that entecavir and heptanoic acid formed a salt with a molar ratio of 1:1.

[0089] Example 11 Preparation of Entecavir Undecanoate

[0090] Take 50 mg of entecavir and add 7 mL of methanol to dissolve it to obtain an entecavir free base solution; take 35 mg of heptanoic acid and add 0.5 mL of methanol to dissolve it to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, stir and react for 18 to 24 hours, add 21 mL of toluene, stir for 18 to 24 hours, filter, and dry in vacuo at 40°C to obtain 51 mg of entecavir undecanoate.

[0091] 1 H-NMR analysis showed that entecavir and undecanoic acid formed a salt with a molar ratio of 1:1.

[0092] Example 12 Preparation of Entecavir Palmitate

[0093] Take 50 mg of entecavir and add 7 mL of methanol to dissolve it to obtain an entecavir free base solution; take 48 mg of palmitic acid and add 0.5 mL of methanol to dissolve it to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, stir and react for 18 to 24 hours, filter, and vacuum dry at 40°C to obtain 70 mg of entecavir palmitate.

[0094] 1 H-NMR analysis showed that entecavir and palmitic acid formed a salt with a molar ratio of 1:1.

[0095] Example 13 Preparation of Entecavir Oleate

[0096] Take 50 mg of entecavir and add 7 mL of methanol to dissolve it to obtain an entecavir free base solution; take 53 mg of oleic acid and add 1 mL of methanol to dilute it to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, stir and react for 18 to 24 hours, filter, and vacuum dry at 40°C to obtain 45 mg of entecavir oleate.

[0097] 1 H-NMR analysis showed that entecavir and oleic acid formed a salt with a molar ratio of 1:1.

[0098] Example 14 Preparation of Entecavir Laurate

[0099] Take 50 mg of entecavir and add 7 mL of methanol to dissolve it to obtain an entecavir free base solution; take 38 mg of lauric acid and add 1 mL of methanol to dilute it to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, stir and react for 18 to 24 hours, add 21 mL of toluene, stir for 18 to 24 hours, filter, and dry in vacuo at 40°C to obtain 56 mg of entecavir laurate.

[0100] 1 H-NMR analysis showed that entecavir and lauric acid formed a salt with a molar ratio of 1:1.

[0101] Example 15 Pharmaceutical composition of entecavir

[0102]

[0103]

[0104] According to the above prescription, entecavir 1-hydroxy-2-naphthoate and various excipients are mixed under sterile conditions and ground to obtain entecavir 1-hydroxy-2-naphthoate suspension injection.

[0105] Test Example 1 Solubility Comparison

[0106] The solubility of the pharmaceutically acceptable salt of entecavir of the present invention was compared with that of entecavir (the solubility of known entecavir addition salts is higher than that of entecavir, so entecavir with the lowest solubility was selected for comparison).

[0107] Entecavir 1-hydroxy-2-naphthoate prepared in Example 1, entecavir palmitate prepared in Example 11, entecavir oleate prepared in Example 12, entecavir laurate prepared in Example 13, and entecavir were added to the corresponding media, shaken at 37°C for 24 hours, filtered through a 0.45 μm aqueous filter membrane, and the filtrate collected for solubility determination using high-performance liquid chromatography. Acetate buffer solutions were used at pH 3 and 5, and phosphate buffer solutions were used at pH 7 and 9. The solubility test results are shown in Table 1.

[0108] Table 1 Solubility test results

[0109]

[0110] The above experimental results demonstrate that the entecavir 1-hydroxy-2-naphthoate, entecavir palmitate, entecavir oleate, and entecavir laurate salts of the present invention all have lower solubility in media than entecavir, making them more suitable for preparing various sustained-release dosage forms, improving patient compliance and bioavailability, and possessing promising market prospects. Furthermore, the pharmaceutically acceptable entecavir salts of the present invention each independently achieve comparable solubility in media with varying pH values, minimizing pH dependence on release rate. This avoids the effects of pH environments in different regions of the body on the release rate, prevents burst release or excessively high blood drug concentrations in localized regions of the body, and reduces inter-individual variability in drug release. Excessive solubility can easily lead to excessively rapid release from the formulation, necessitating frequent dosing to maintain blood drug concentrations and resulting in poor patient compliance. Conversely, excessively low solubility can easily lead to excessively slow release from the formulation, resulting in low blood drug concentrations and a failure to achieve therapeutic effects. Therefore, taking 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 the influence of the pH environment in different regions of the body on its release rate, avoiding the occurrence of burst release or excessively high blood drug concentration in local areas of the body, and reducing the difference in drug release between individuals.

[0111] Test Example 2 Stability Comparison

[0112] Entecavir 1-hydroxy-2-naphthoate and entecavir prepared in Example 1 were respectively placed in an environment of 2-8° C., and samples were taken at corresponding time points for XRPD detection to investigate their stability.

[0113] The results are shown in Table 2, which show that the entecavir 1-hydroxy-2-naphthoate salt of the present invention has good stability and remains amorphous after being stored at 2-8°C for 30 days.

[0114] Table 2 Stability test results

[0115]

Claims

1. A pharmaceutically acceptable salt of entecavir, characterized in that: The pharmaceutically acceptable salt of entecavir is a salt formed by entecavir free base I and an organic acid with more than six carbon atoms; Wherein, the organic acid with more than six carbon atoms is selected from the group consisting of lauric acid, palmitic acid, and oleic acid.

2. The pharmaceutically acceptable salt of entecavir according to claim 1, wherein: In the pharmaceutically acceptable salt of entecavir, the molar ratio of entecavir to the organic acid having more than six carbon atoms is 1:

1.

3. A method for preparing the pharmaceutically acceptable salt of entecavir according to claim 1 or 2, characterized in that: forming an entecavir free base solution and an organic acid solution in a first solvent respectively, mixing the two for reaction, and adding a second solvent or removing the first solvent to obtain a pharmaceutically acceptable entecavir salt; The first solvent is selected from methanol, ethanol, water, N,N-dimethylformamide or a mixture thereof; The second solvent is selected from isopropyl ether, methyl tert-butyl, n-heptane, toluene or a mixture thereof.

4. The method for preparing a pharmaceutically acceptable salt of entecavir according to claim 3, wherein: The molar ratio of entecavir to the organic acid is 1:1.1 to 1:1.

2.

5. The method for preparing the pharmaceutically acceptable salt of entecavir according to claim 3, wherein: The mixing is to add the organic acid solution into the entecavir free base solution.

6. The method for preparing the pharmaceutically acceptable salt of entecavir according to any one of claims 3 to 5, wherein: The reaction was carried out at room temperature.

7. A pharmaceutical composition, characterized in that The invention comprises the pharmaceutically acceptable salt of entecavir according to claim 1 or 2 and pharmaceutically acceptable excipients.

8. The pharmaceutical composition according to claim 7, wherein: The pharmaceutical composition is selected from injections.

9. The pharmaceutical composition according to claim 7, wherein: The pharmaceutical composition is selected from long-acting injections.

10. The pharmaceutical composition according to any one of claims 7 to 9, wherein: The pharmaceutical composition is an aqueous suspension, an oil suspension or a suspension powder.

11. Use of the pharmaceutically acceptable entecavir salt according to claim 1 or 2 or the pharmaceutical composition according to any one of claims 7 to 10 in the preparation of a medicament for treating and / or preventing hepatitis B.

Images