New bezafibrate salt and use thereof
By preparing a new bezafibrate salt that reacts with amino acids or choline to generate a quaternary ammonium salt, the problem of low bioavailability of bezafibrate is solved, achieving efficient lipid regulation and treatment of hepatobiliary diseases. This simplifies the preparation process and reduces the frequency of administration and toxic side effects.
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- NINGBO BESTDRUG PHARMA CO LTD
- Filing Date
- 2026-03-25
- Publication Date
- 2026-07-30
AI Technical Summary
The existing bezafibrate drug has poor bioavailability, requires multiple daily dosing, affects patient compliance, and is prone to toxic side effects. Existing improvements such as extended-release tablets have not significantly improved its pharmacokinetic properties.
The bezafibrate is prepared by reacting with amino acids or choline to form a quaternary ammonium salt, thus forming a new bezafibrate salt. This is then presented as a drug composition that does not require ultrafine powder, with the addition of pharmaceutical excipients to improve solubility and bioavailability.
It significantly improved the bioavailability and solubility of bezafibrate, simplified the preparation process, improved efficacy, and reduced the frequency of administration and toxic side effects.
Smart Images
Figure PCTCN2026086000-FTAPPB-I100001 
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Figure PCTCN2026086000-FTAPPB-I100003
Abstract
Description
A new benzabite salt and its application Technical Field
[0001] This invention relates to the field of biomedical technology, and in particular to a new bezafibrate salt and its applications. Background Technology
[0002] Bezafibrate belongs to the fibrates class of lipid-lowering drugs. It can significantly reduce triglycerides and low-density lipoprotein (LDL) levels, increase high-density lipoprotein (HDL) levels, slow the progression of coronary atherosclerosis, and reduce the incidence of coronary heart disease events. Recent studies have found that bezafibrate can also inhibit bile acid synthesis, thus having a therapeutic effect on primary biliary cholangitis. Bezafibrate is rapidly absorbed orally, with a Tmax of approximately 2 hours, but it is also rapidly excreted. After a single oral dose of conventional bezafibrate, the elimination half-life (T1 / 2β) is approximately 1.5-2.0 hours, with 95% of the drug excreted in the urine and approximately 50% excreted unchanged, resulting in poor bioavailability. Conventional bezafibrate tablets need to be taken orally three times daily at a dose of 200 mg each time to achieve good therapeutic efficacy. Bezafibrate requires long-term use; three-times-daily dosing leads to poor patient compliance and affects efficacy. A daily dose of 600 mg also easily causes toxic side effects.
[0003] To improve the pharmacokinetic properties and bioavailability of bezafibrate, researchers have conducted extensive studies on its formulation and molecular structure modification. In terms of formulation, methods include freeze-drying granulation, preparation of disintegrating tablets and solid dispersion tablets, development of sustained-release formulations, conversion of the active pharmaceutical ingredient into ultrafine powders, nanoparticles, electro-sprayed nanospheres, nanoliposomes, preparation of osmotic pump tablets using semi-solid 3D printing technology, and the use of novel pharmaceutical excipients to improve drug bioavailability. In terms of molecular structure modification, the main focus is on the preparation of prodrugs, such as WO2019168842 for N-methylamides and WO2012145899 for bezafibrate ester prodrugs. However, currently only sustained-release tablets are approved for marketing, with a daily dose of 400 mg once a day. The pharmacokinetic properties of bezafibrate still have significant room for improvement. Summary of the Invention
[0004] The purpose of this invention is to address the shortcomings of existing technologies by providing a new bezafibrate salt and its applications.
[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:
[0006] The first aspect is to provide a benzalofibrate salt as shown in structural formula (Ⅰ).
[0007] Among them, M + It is a quaternary ammonium salt or AH + A is selected from amino acids or their ester derivatives.
[0008] Furthermore, A is selected from L-type amino acids, or it can be D-type amino acids, or a mixture of L and D-type amino acids.
[0009] Furthermore, the amino acids are selected from natural amino acids, with preference given to amino acids present in the human body. The most preferred are lysine (Formula (II)), arginine, and methionine esters (Formula (III)).
[0010] Wherein, R is a C1-C8 alkyl group, preferably a C1-C4 n-alkyl group, namely methyl, ethyl, n-propyl, or n-butyl.
[0011] Furthermore, the M + Selected from choline (formula (IV)) or N-methylnicotinamide (abbreviated as NMNAM, formula (V)):
[0012] The new bezafibrate salt provided by the present invention can be reacted directly with bezafibrate and corresponding bases such as lysine and choline hydroxide, etc., with a reaction ratio (molar ratio) of bezafibrate:base of 1:(0.2-10), preferably 1:(0.5-2), and most preferably 1:1.
[0013] The reaction temperature is -20℃ to 140℃, preferably 0℃ to 100℃, and most preferably room temperature to 80℃. The reaction solvent is not limited, but water and water-miscible solvents are preferred, including water, C1-C4 alcohols, C3-C8 ketones, tetrahydrofuran, methyltetrahydrofuran, and mixtures thereof.
[0014] The novel bezafibrate salt provided by this invention can also be prepared by first preparing bezafibrate into sodium or potassium salts, and then reacting it with corresponding coordinating salts such as NMNAM hydrochloride, D-methionine methyl ester hydrochloride, L-methionine ethyl ester hydrochloride, etc. The reaction ratio (molar ratio) is bezafibrate:base 1:(0.2-10), preferably 1:(0.5-2), and most preferably 1:1.
[0015] The reaction temperature is -20℃ to 140℃, preferably 0℃ to 100℃, and most preferably room temperature to 80℃. The reaction solvent is not limited, but water and water-miscible solvents are preferred, including water, C1-C4 alcohols, C3-C8 ketones, tetrahydrofuran and methyltetrahydrofuran and mixtures thereof.
[0016] The second aspect is to provide a pharmaceutical composition having the aforementioned bezafibrate salt as the main active ingredient.
[0017] Furthermore, the pharmaceutical composition is administered via injection, and the selected dosage form is sterile powder for injection, small-volume injection, or large-volume infusion.
[0018] Furthermore, the pharmaceutical composition is administered orally, and the selected dosage form is a tablet, coated tablet, capsule, granule, or oral solution.
[0019] The pharmaceutical composition provided by this invention does not require micronized or ultramicronized active ingredients; it only requires conventional pulverization to the level required by the pharmaceutical formulation process.
[0020] In addition to the bezafibrate salt provided by this invention, the pharmaceutical composition preferably contains a certain amount of pharmaceutical excipients. For injectable formulations, solubilizers, preservatives, chelating agents, pH adjusters, osmotic pressure adjusters, etc., are preferably added. For oral formulations, diluents, disintegrants, binders, drug release rate regulators, coating agents, etc., are preferably added. One type of pharmaceutical excipient may be used, but two or more types are preferred.
[0021] The definitions and types of the terms such as solubilizers, preservatives, chelating agents, pH adjusters, osmotic pressure adjusters, diluents, disintegrants, binders, drug release rate regulators, and coating agents are the same as those known to professionals in this field, and all are pharmaceutical excipients approved by the drug regulatory authorities for use in drug formulations.
[0022] The third aspect is to provide the application of the aforementioned bezafibrate salt in the preparation of lipid-regulating drugs, preferably for lowering high triglycerides and / or raising high-density lipoprotein.
[0023] The fourth aspect involves the application of the aforementioned bezafibrate salt in the preparation of drugs for treating hepatobiliary diseases, preferably cholangitis, cholecystitis, gallstones, cholestasis, and fatty liver. It is most preferably used for the treatment of primary biliary cholangitis and cholestasis.
[0024] The bezafibrate salt and its pharmaceutical composition provided by this invention can be used simultaneously with other drugs as needed for regulating blood lipids and treating hepatobiliary diseases. Preferably, it is used in combination with statins or ursodeoxycholic acid.
[0025] The present invention adopts the above technical solution and has the following technical effects compared with the prior art:
[0026] The novel bezafibrate salts of the present invention include, but are not limited to, bezafibrate NMNAM salt, bezafibrate choline salt, bezafibrate lysine salt, bezafibrate methionine methyl ester salt, and bezafibrate methionine ethyl ester salt. These novel salts significantly improve the bioavailability and water solubility of bezafibrate, eliminating the need for ultrafine powder or nanopowder preparation when developing pharmaceutical compositions, thus simplifying the process, improving efficacy, and providing new options for drug development and clinical application. Detailed Implementation
[0027] The present invention will be further described below with reference to specific embodiments, but these are not intended to limit the invention. It should be noted that, unless otherwise specified, the embodiments and features described in the embodiments of the present invention can be combined with each other.
[0028] Example 1: Preparation of bezafibrate NMNAM salt
[0029] 3.00 g of bezafibrate, 1.5 g of NMNAM hydrochloride, 0.338 g of sodium hydroxide, and 25 ml of 50% ethanol were placed in a reaction flask and stirred. The mixture was heated until all the solids were dissolved. The mixture was cooled to room temperature and placed in a refrigerator overnight. A solid precipitated out; it was filtered off, dried, and the product was obtained, with a yield of approximately 50%.
[0030] 1H NMR(400MHz,D2O)σ1.41(S,6H),2.79(T,2H),3.52(T,2H),4.39(S,3H),6.78(D,2H),7. 11(D,2H),7.39(D,2H),7.48(D,2H),8.08(T,1H),8.80(D,1H),8.87(D,1H),9.18(S,1H)
[0031] Example 2: Preparation of bezafibrate choline salt
[0032] Place 3.00 g of bezafibrate and 50 ml of anhydrous ethanol in a reaction flask and stir.
[0033] Dissolve 2.3 g of choline hydroxide aqueous solution (44%) in 10 ml of anhydrous ethanol, and add it dropwise to the above reaction solution while dissolving bezafibrate. Once the solution is completely dissolved, continue stirring for 2 hours, then concentrate under reduced pressure to dryness to obtain a gel-like substance. Add 30 ml of isopropanol and stir; a solid precipitates out. Heat until the solid is completely dissolved, then cool to allow crystals to precipitate. Filter under suction, dry the filtered solid, and obtain 1.12 g of the product.
[0034] 1H NMR(400MHz,D2O)σ1.39(S,6H),2.75(T,2H),3.09(S,9H),3.41(T,2H),3. 47(T,2H),3.92(T,2H),6.76(D,2H),7.08(D,2H),7.33(D,2H),7.44(D,2H)
[0035] Example 3: Preparation of benzalkonium lysine salt
[0036] 1.00 g of bezafibrate, 0.405 g of lysine, and 14 ml of methanol were placed in a reaction flask and stirred until dissolved within a few minutes. The solution was concentrated to dryness to obtain a gel-like substance. Anhydrous ethanol was added twice to obtain 1.3 g of a white powder.
[0037] 1H NMR(400MHz,D2O)σ1.38-1.42(m,2H),1.40(S,6H),1.62(m,2H),1.80-1.84(m,2H),2.79(T,2H), 2.94(T,2H),3.52(T,2H),3.66-3.80(m,1H),6.77(D,2H),7.11(D,2H),7.40(D,2H),7.49(D,2H)
[0038] Example 4: Preparation of bezafibrate methionine methyl ester salt
[0039] Dissolve 0.55 g of D-methionine methyl ester hydrochloride in 5 ml of water, add 0.25 g of sodium bicarbonate, stir for 0.5 hours, and extract three times with 5 ml of dichloromethane each time. Combine the extracts, dry with anhydrous magnesium sulfate, filter off the magnesium sulfate, add 1.00 g of bezafibrate to the filtrate, and stir for 1 hour. Concentrate under reduced pressure to dryness to obtain a gel. Add acetic acid to dissolve the gel, followed by the precipitation of a large amount of solid. Filter under vacuum, filter off the solid, and dry to obtain 1.3 g.
[0040] 1HNMR(400MHz,DCCl3)σ1.58(s,6H),1.86-1.92(m,2H),2.07(s,3H),2.62-2.64(m,2H),2.88(t,2H),3.69(t,2H) ,3.67-3.70(m,1H),3.75(s,3H),6.15(br,1H),6.89(d,2H),7.12(d,2H),7.38(d,2H),7.62(d,2H),8.86(br,3H)
[0041] Example 5: Preparation of Zafibrate Methionine Ethyl Ester Salt
[0042] Dissolve 0.56 g of L-methionine ethyl ester hydrochloride in 5 ml of water, add 0.25 g of sodium bicarbonate, stir for 0.5 hours, and extract three times with 5 ml of dichloromethane each time. Combine the extracts, dry with anhydrous magnesium sulfate, filter off the magnesium sulfate, add 1.00 g of bezafibrate to the filtrate, and stir for 1 hour. Concentrate under reduced pressure to dryness to obtain a gel. Add acetic acid to dissolve the gel, followed by the precipitation of a large amount of solid. Filter under vacuum, filter off the solid, and dry to obtain 1.4 g.
[0043] 1HNMR(400MHz,DCCl3)σ1.28(t,3H),1.57(s,6H),1.86-1.87(m,2H),2.10(s,3H),2.62(br,2H),2.86(t,2H),3.64 (t,2H),3.43(br,1H),4.20(q,2H),6.21(s,1H),6.88(d,2H),7.10(d,2H),7.37(d,2H),7.63(d,2H),8.80(br,3H)
[0044] Comparative Example 1: Preparation of Sodium Benzalfibrate
[0045] Place 3.00 g of bezafibrate, 0.338 g of sodium hydroxide, and 75 ml of methanol in a reaction flask and stir until the solid is completely dissolved. Concentrate under reduced pressure to dryness to obtain sodium bezafibrate.
[0046] Comparative Example 2: Preparation of Calcium Benzalfibrate
[0047] Place 1.00g of bezafibrate, 0.112g of sodium hydroxide, and 15ml of water in a reaction flask and stir briefly until dissolved.
[0048] Dissolve 0.155g of calcium chloride in 5ml of water and add it dropwise to the above reaction solution. As the solution is added, a solid precipitates out. After the addition is complete, continue stirring for 2 hours, filter, filter out the solid, and dry it to obtain bezafibrate calcium salt (1g).
[0049] Comparative Example 3: Preparation of magnesium bezafibrate
[0050] Place 1.00g of bezafibrate, 0.112g of sodium hydroxide, and 15ml of water in a reaction flask and stir briefly until dissolved.
[0051] Dissolve 0.15 g of magnesium chloride in 5 ml of water and add it dropwise to the above reaction solution. As the solution is added, solid precipitates out. After the addition is complete, heat the solution and some of the solid dissolves. Continue stirring for 2 hours, then cool. Solid precipitates out again. Filter the solution and dry it to obtain bezafibrate magnesium salt (0.90 g).
[0052] Verification Example 1: Bioavailability Study
[0053] animal
[0054] Sprague-Dawley rats, male, weighing 200-250g. They were fasted for 12 hours before the experiment but allowed free access to water.
[0055] drug
[0056] Control drug: Bezafibrate. Since bezafibrate is insoluble in water, it was prepared into a suspension with a concentration of 0.6 mg / ml using a 0.5% methylcellulose saline solution. Test drug: The bezafibrate salts prepared in Examples 1-5 and Comparative Example 1 above. Solutions equivalent to 0.6 mg / ml of bezafibrate were prepared using physiological saline. Specific concentrations are shown in Table 1.
[0057] Table 1
[0058] Grouping and Sample Collection and Preservation
[0059] Rats were randomly divided into seven groups of eight each. Group 1 received 1 ml of bezafibrate suspension orally, equivalent to a bezafibrate dose of 3 mg / kg. Groups 2 through 7 received 1 ml each of bezafibrate sodium salt, NMNAM salt, choline salt, lysine salt, methionine ethyl ester salt, and methionine methyl ester salt orally, equivalent to a bezafibrate dose of 3 mg / kg. All formulations were freshly prepared before administration.
[0060] Blood samples were collected from the posterior orbital vein at predetermined time points: 5, 15, and 30 minutes, and 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 48, and 72 hours after drug administration. Blood samples were collected in tubes pre-filled with 0.5 mL of heparin sodium and centrifuged (3000 rpm) for 10 minutes to obtain plasma. All plasma samples were stored at -20°C before analysis.
[0061] Extraction and separation of plasma samples
[0062] Take a plasma sample (50 μL), add 10 μL of 10% perchloric acid solution, shake for 10 minutes, centrifuge for 10 minutes, take 10 μL of supernatant and enter the high performance liquid chromatograph to determine the peak area of bezafibrate, and calculate the blood concentration at each time point using the external standard method.
[0063] High performance liquid chromatography determination conditions
[0064] Mobile phase: Composed of methanol-0.01 mol / L acetate buffer (pH 4.0)-0.5 mol / L tetrabutylammonium bromide (74:26:0.2); Flow rate: 1.0 ml / min; Column: Agilent ZORBAX ODS C18 (5.0 μm, 250 nm x 4.6 mm); Detection wavelength: 232 nm; Column temperature: 40 °C.
[0065] Data processing and statistical analysis
[0066] Data processing employed the 3P97 pharmacokinetic program, using a two-tailed t-test to compare AUCs and evaluate bioavailability. Pharmacokinetic parameters are shown in Table 2 below.
[0067] Table 2
[0068] As shown in Table 2, sodium bezafibrate did not significantly alter the pharmacokinetic parameters of bezafibrate. NMNAM, choline, lysine, and methionine salts of bezafibrate, however, significantly altered the pharmacokinetic parameters and substantially improved bioavailability.
[0069] Verification Example 2: Solubility Test
[0070] Weigh a certain amount of bezafibrate and an equivalent amount of bezafibrate salt, add water and shake, observe the dissolution of the sample, and the test results are shown in Table 3.
[0071] Table 3
[0072] Table 3 shows that the solubility of bezafibrate sodium salt, NMNAM salt, choline salt, lysine salt, and methionine ester salt in water is significantly higher than that of bezafibrate. The effects on bezafibrate calcium and magnesium salts are minimal.
[0073] The above description is merely a preferred embodiment of the present invention and does not limit the implementation and protection scope of the present invention. Those skilled in the art should realize that any equivalent substitutions and obvious changes made based on the content of the present invention specification should be included within the protection scope of the present invention.
Claims
1. A salt of bezafibrate represented by the following structural formula (I) : ###00001### (I) wherein R is a C1-4 alkyl group, and X is a halogen atom, characterized in that, wherein M + is a quaternary ammonium salt or AH + , A is selected from an amino acid or an ester derivative thereof.
2. The salt of bezafibrate according to claim 1, characterized in that, A is selected from the group consisting of lysine, arginine, methionine ester.
3. The bezafibrate salt of claim 1, wherein M + selected from choline or N-methyl nicotinamide.
4. A pharmaceutical composition, characterized by, The bezafibrate salt of claim 1 is used as the main active ingredient.
5. The pharmaceutical composition of claim 4, wherein, The selected dosage form is sterile powder injection or small water injection or large infusion by injection route.
6. The pharmaceutical composition of claim 4, wherein, The selected dosage form is tablet, coated tablet, capsule, granule, oral solution by oral route.
7. Use of the bezafibrate salt of claim 1 in the preparation of a medicament for regulating blood lipid.
8. Use of the bezafibrate salt of claim 1 in the preparation of a medicament treating hepatobiliary diseases.
9. Use of the pharmaceutical composition of claim 4 in the preparation of a medicament for regulating blood lipid.
10. Use of the pharmaceutical composition of claim 4 in the preparation of a medicament treating hepatobiliary diseases.