Memantine paroxetine cocrystal salt and its preparation method, pharmaceutical composition and application
11839607 · 2023-12-12
Assignee
Inventors
- Ke Wang (Hefei, CN)
- Qianliu Cheng (Hefei, CN)
- Zonggui Wang (Hefei, CN)
- Yan Geng (Hefei, CN)
- Xun Zhao (Suzhou, CN)
Cpc classification
C07D405/12
CHEMISTRY; METALLURGY
A61K31/265
HUMAN NECESSITIES
A61K31/4525
HUMAN NECESSITIES
International classification
A61K31/4525
HUMAN NECESSITIES
A61K31/265
HUMAN NECESSITIES
A61K31/55
HUMAN NECESSITIES
Abstract
A memantine paroxetine cocrystal salt and its preparation method, pharmaceutical composition and application thereof are provided. The cocrystal salt of the invention is memantine paroxetine sulfate hydrate. Its mechanism of action is 5-HT inhibitor and NMDA receptor antagonist. It is a multi-target drug. The preliminary pharmacokinetic experiments showed that the main pharmacokinetic parameters of cocrystal salt and memantine, such as T.sub.1/2, T.sub.max, C.sub.max and AUC.sub.(0-∞), were significantly different. The results also showed that cocrystal salt could improve drug absorption, blood drug concentration, bioavailability and curative effect. This provides a material basis for reducing dosage and adverse drug reactions. In addition to that the cocrystal salt of this invention can be used as a multi-target drug, it can also combine with other drugs of different action mechanisms to form compound preparations or be used in combination, so as to obtain unexpected clinical efficacy.
Claims
1. A memantine paroxetine cocrystal salt, wherein a molecular formula of the memantine paroxetine cocrystal salt is C.sub.19H.sub.20FNO.sub.3.Math.C.sub.12H.sub.21N.Math.H.sub.2SO.sub.4.Math.XH.sub.2O, wherein X is 3, and a memantine molecule and a paroxetine molecule are bound by a non-covalent bond, wherein the memantine paroxetine cocrystal salt comprises following lattice plane intervals d[A](±0.10 A): 19.06, 7.48, 7.13, 5.86, 4.97, 4.45, 4.20, 3.90, 3.80 determined by an X-ray powder diffractometer.
2. A preparative method for the memantine paroxetine cocrystal salt according to claim 1, comprising the following steps: step 1: dissolving a memantine and a paroxetine in a −10-25° C. solvent successively to obtain a dissolved solution, wherein a volume-mass ratio between the solvent and the paroxetine is (1-20 mL):1 g, then dropwise adding sulfuric acid with a concentration of 10%-80% to the dissolved solution to obtain a mixed solution, then stirring and crystallizing the mixed solution for 1-24 h to obtain a crystalline solid, wherein a molar ratio of the memantine, the paroxetine and the sulfuric acid of the crystalline solid is (0.8-1.2):(0.8-1.2):(0.8-1.2), step 2: filtering the crystalline solid and drying the crystalline solid at 40-80° C. for 2-12 h to obtain the memantine paroxetine cocrystal salt.
3. The preparative method for the memantine paroxetine cocrystal salt according to claim 2, wherein the temperature of the solvent in step 1 is 0-10° C.
4. The preparative method for the memantine paroxetine cocrystal salt according to claim 2, wherein the volume-mass ratio of the solvent to the paroxetine is (3-10 mL):1 g in step 1.
5. The preparative method for the memantine paroxetine cocrystal salt according to claim 2, wherein the solvent is one selected from the group consisting of tetrahydrofuran, acetone, dichloromethane, isopropanol, methanol, ethanol, n-butanol, acetonitrile, ether and ethyl acetate.
6. The preparative method for the memantine paroxetine cocrystal salt according to claim 2, wherein the concentration of the sulfuric acid is 30-40% in step 1.
7. A pharmaceutical composition, comprising the memantine paroxetine cocrystal salt according to claim 1, and at least one pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additive is one selected from the group consisting of diluents, fillers, disintegrating agents, flow aids, lubricants, adhesives, antioxidants, buffers and colorants.
8. The pharmaceutical composition according to claim 7, further comprising at least one therapeutic agent wherein the therapeutic agent is one selected from the group consisting of donepezil, galantamine and Rivastigmine.
9. The preparative method for the memantine paroxetine cocrystal salt according to claim 3, wherein the solvent is one selected from the group consisting of tetrahydrofuran, acetone, dichloromethane, isopropanol, methanol, ethanol, n-butanol, acetonitrile, ether and ethyl acetate.
10. The preparative method for the memantine paroxetine cocrystal salt according to claim 4, wherein the solvent is one selected from the group consisting of tetrahydrofuran, acetone, dichloromethane, isopropanol, methanol, ethanol, n-butanol, acetonitrile, ether and ethyl acetate.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
(1)
(2)
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DETAILED DESCRIPTION OF THE EMBODIMENTS
(6) The following is a detailed description of the embodiment of the invention. The embodiment is implemented on the premise of the technical scheme of the invention, and the detailed implementation mode and specific operation process are given. However, the protection scope of the invention is not limited to the following embodiments.
(7) The apparatus for detecting the structure and performance of cocrystal salt in the embodiment of the invention is as follows: 1. X-ray powder diffractometer, RIGAKU TTR III high power X-ray diffractometer of Japanese science company, test conditions: Cu target, 40 kV, 40 mA, 3°-50°, target/filter-Cu/Ni filter, current/voltage-40.0 mA/40.0 kV, 2θ angle range: 3°-50°); 2. Fourier transform infrared spectrometer, Thermo Scientific Instrument Co. U.S.A, Nicolet 8700 Fourier transform infrared spectrometer; 3. Bruker Avance III 400 superconducting nuclear magnetic resonance instrument, determination solvent: DMSO-d, internal standard: TMS; 4. TQ/Orbitrap XL Fourier Fourier transform electrostatic field orbit mass spectrometer of Thermal Power Company.
Embodiment 1 Preparation of C.SUB.19.H.SUB.20.FNO.SUB.3..Math.C.SUB.12.H.SUB.21.N H.SUB.2.SO.SUB.4..Math.3H.SUB.2.O
(8) Add 120 g (0.282 mol) of paroxetine mesylate into the reaction flask. Add 1200 mL of 1 mol/L sodium hydroxide solution. Add 1200 mL of ethyl acetate. Keep the temperature below 30° C. Stir until it is clear and solid-free. Leave it standing and stratified. Wash the organic phase three times with water. Add anhydrous sodium sulfate to dry for 4 h. Filter and wash. Reduce the pressure to concentrate. Keep the prepared paroxetine for use;
(9) Add 60 g (0.278 mol) of memantine hydrochloride into the reaction flask. Add 200 mL of 1 mol/L sodium hydroxide solution. Add 200 mL of dichloromethane. Keep the temperature below 30° C. Stir it until it is clear and solid-free. Leave it standing and stratified. Wash the organic phase three times with water. Add anhydrous sodium sulfate to dry for 4 h. Filter and wash. Reduce the pressure and concentrate. Keep the prepared memantine for use;
(10) Dissolve 77.4 g (0.2350 mol) of paroxetine with 387 mL of tetrahydrofuran, transfer it to a reaction flask, add 42.1 g (0.235 mol) of memantine, and stir evenly. In an ice water bath, keep the temperature at 0-10° C., stir and add 69.5 g (0.235 mol) of 33% sulfuric acid. Then stir and crystalize at 5° C. for 4 h and filter. Blow the solids at 50° C. for 8 h and get 117.1 g white solids. The yield is 82.1%.
(11) The reaction flow diagram is as follows:
(12) ##STR00003##
(13) The cocrystal salt of C.sub.19H.sub.20FNO.sub.3.Math.C.sub.12H.sub.21N.Math.H.sub.2SO.sub.4.Math.3H.sub.2O prepared in this embodiment has the following structural formula:
(14) ##STR00004##
(15) The product prepared in this embodiment is characterized by:
(16) 1. X-Ray Powder Diffraction Characterization
(17) X-ray diffraction analysis is performed on the samples using a Rigaku TTR III high-power X-ray diffractometer from RIGAKU Company. Test conditions: Cu target, 40 kV, 40 mA, 3°-50°, target/filter: Cu/Ni filter, current/voltage: −40.0 mA/40.0 kV, 2θ Angle range: 3°-50°). The measured d(Å) value of X-ray powder diffraction is: 19.0629, 7.4792, 7.1407, 5.9035, 4.9778, 4.4550, 4.1107, 3.8866, 3.7882. The X-ray diffraction pattern is shown in
(18) 2. Infrared Spectrum Characterization
(19) The cocrystal salt is characterized by infrared absorption spectrum obtained by Fourier transform infrared spectroscopy (FT-IR), using the following important bands (expressed by the reciprocal of wavelength data (cm.sup.−1)): Nicolet 8700 FT-IR spectrometer of Thermo Scientific Instrument Co. U.S.A. Test samples are made by KBr tablet. The main absorption peak positions (cm.sup.−1): 3433 (s), 2920 (s), 1633 (m), 1606 (m), 1511 (m), 1489 (m), 1471 (m), 1226 (m), 1186 (m), 1125 (m), 1038 (m), 933 (m), 835 (m), 620 (m). The infrared spectrum is shown in
(20) 3. NMR Characterization
(21) The sample is tested by Bruker Avance III 400 superconductive nuclear magnetic resonance instrument. The solvent to be tested: DMSO-d. The internal standard: TMS.
(22) The .sup.13C NMR data (ppm): 162.08, 159.68, 153.79, 147.76, 141.21, 139.48, 129.34, 129.26, 115.24, 115.03, 107.82, 105.45, 100.93, 97.68, 68.48, 51.62, 49.58, 46.35, 45.78, 4 3.83, 41.64, 41.58, 38.79, 38.33, 31.82, 30.48, 29.66, 29.15. The pattern is shown in
(23) The .sup.1H NMR data are as follows: 8.32 (Brs, 1H), 7.34 (dd, 2H), 7.08 (t, 2H), 6.67 (d, 1H), 6.38 (d, H), 6.11 (dd, 1H), 5.89 (s, 2H), 4.04 (Brs, 2H), 3.57-3.39 (m, 3H), 3.32 (d, 1H), 2.82 (dt, 3H), 2.60 (s, 1H), 2.25 (d, 1H), 2.06 (s, 1H), 1.73 (m, 3H), 1.50 (dd, 4H), 1.33-1.16 (m, 4H), 1.13-1.00 (m, 2H), 0.78 (s, 6H). The pattern is shown in
(24) In order to further explain the structural features of the memantine paroxetine cocrystal salt of the invention, 1 g white solid cocrystal salt is taken, dissolved with 100 mL dichloromethane, placed at room temperature for slow crystallization, separated and filtered to obtain transparent block crystal. The block crystal is characterized by single crystal structure test, X-ray powder diffraction, infrared, nuclear magnetic resonance and mass spectrometry, and the characterization results are as follows:
(25) 1. Single Crystal Structure Test
(26) Test conditions: single crystal data single crystal X-ray diffractometer, light source: Cu Ka (λ=1.54184 Å); temperature: room temperature; θ angle collection range: 3.60˜69.44°
(27) Data and Parameters:
(28) Molecular formula: Each unit of molecular formula: C.sub.19H.sub.21FNO.sub.3, C.sub.12H.sub.22N, O.sub.4S, 3(H.sub.2O); Total molecular formula: C.sub.31H.sub.49FN.sub.2O.sub.10S
(29) Molecular weight: 660.78
(30) Crystal color: colorless
(31) Crystal shape: blocky crystal
(32) Crystal system: orthorhombic system
(33) Space group: P212121
(34) Unit cell parameter: A=7.2618(1)
(35) b=11.9317(1)
(36) c=38.3731(4)
(37) alpha=90
(38) beta=90
(39) gamma=90
(40) Z (number of asymmetric units in unit cell): 4
(41) Calculated strength: 1.320 g/cm.sup.3
(42) According to the crystal composition and molecular formula provided by the entrusting party, C.sub.31H.sub.49FN.sub.2O.sub.10S, on the basis of the measured single crystal diffraction data, the possible spatial structure of the crystal obtained through analysis and refinement by WinGX(v1.80.05) software is shown in
(43) 2. X-Ray Powder Diffraction Characterization
(44) The samples are analyzed by RIGAKU TTR III high power X-ray diffractometer of RIGAKU Company. Test conditions: Cu target, 40 kV, 40 mA, 3°-50°, target/filter: Cu/Ni filter, current/voltage: −40.0 mA/40.0 kV, 2θ angle range: 3°-50°). The measured X-ray powder diffraction data d(Å) value: 19.050, 7.461, 7.147, 5.9091, 4.9849, 4.4568, 4.1587, 3.8983, 3.8052.
(45) 3. Infrared Spectral Characterization
(46) The cocrystal is characterized by the infrared absorption spectrum obtained by Fourier transform infrared spectroscopy (FT-IR) spectrometer, and the important bands (expressed as the reciprocal of wavelength data (cm.sup.−1)) described below: Thermo Scientific Instrument Co. U.S.A., Nicolet 8700 Fourier transform infrared spectrometer is used to test the samples prepared by KBr tablet. The main absorption peak positions (cm.sup.−1): 3432 (s), 2920 (s), 1633 (m), 1606 (m), 1510 (m), 1489 (m), 1471 (m), 1186 (m), 1125 (m), 1038 (m), 933 (m), 620 (m). Compared with the infrared absorption spectra of physical mixtures, the absorption peaks and shifts are very obvious.
(47) 4. NMR Spectrum Characterization
(48) The samples are tested by Bruker Avance III 400 superconductive nuclear magnetic resonance. The solvent: DMSO-d. The internal standard: TMS.
(49) The .sup.13C nuclear magnetic resonance (NMR) spectral data (PPM): 160.93, 153.79, 147.77, 141.24, 139.38, 129.36, 115.26, 115.06, 107.80, 105.44, 100.96, 97.68, 68.41, 51.69, 49.61, 46.05, 45.67, 43.65, 41.60, 41.42, 38.50, 38.23, 31.82, 30.06, 29.68, 29.18.
(50) The .sup.1H NMR spectrum data are as follows: 8.35 (Brs, 1H), 7.35 (dd, 2H), 7.09 (t, 2H), 6.68 (d, 1H), 6.39 (d, 1H), 6.12 (dd, 1H), 5.90 (s, 2H), 4.06 (Brs, 2H), 3.58-3.40 (m, 3H), 3.33 (d, 1H), 2.83 (dt, 3H), 2.61 (s, 1H), 2.26 (d, 1H), 2.07 (s, 1H), 1.74 (m, 3H), 1.51 (dd, 4H), 1.34-1.17 (m, 4H), 1.14-1.01 (m, 2H), 0.79 (s, 6H).
(51) 5. Mass Spectrometry Characterization:
(52) Thermo Scientific Instrument Co. U.S.A. TQ/Orbitrap XL Fourier transform electrostatic field orbital trap mass spectrometer is used. Test method: GB/T 6041-2002 general principles of mass spectrometry analysis method. See Table 1 for test results.
(53) TABLE-US-00001 TABLE 1 Position and relative abundance of the major fragmentation peaks in the sample quality spectra Mass charge Mass charge ratio (M/Z) ratio (M/Z) Relative Molecular (measured value) (theoretical value) abundance (%) formula 180.17444 180.17468 100.00 C.sub.12H.sub.22N.sub.4 330.15002 330.15000 10.19 C.sub.19H.sub.21O.sub.3NF
(54) From the above characterization data, it can be seen that the C.sub.19H.sub.20FNO.sub.3.Math.C.sub.12H.sub.21N.Math.H.sub.2SO.sub.4.Math.3H.sub.2O prepared in this embodiment has the same phase and structure as the single crystal, and is quite different from the phase and structure of the mixture obtained by mixing the two active ingredients of memantine and paroxetine through simple materials.
Embodiment 2 Prepares C.SUB.19.H.SUB.20.FNO.SUB.3..Math.C.SUB.12.H.SUB.21.N.Math.H.SUB.2.SO.SUB.4..Math.3H.SUB.2.O
(55) Paroxetine and memantine is prepared by taking 50 g paroxetine mesylate and 30 g memantine hydrochloride respectively.
(56) 15.98 g (0.0485 mol) paroxetine is added to 80 mL tetrahydrofuran, which is evenly dissolved by stirring; 8.70 g (0.0485 mol) memantine is added and evenly stirred; The solution temperature is maintained at 0-10° C., and 14.4 g of 33% sulfuric acid (0.0485 mol) is added into the solution. After the solution is added, stir and crystalize for 2 h, filter, and the resulting solid is dried at 50° C. for 6 h by air blast, and 21.2 g of white solid is obtained.
(57) NMR data is: .sup.1HNMR (400 MHZ, DMSO-d): 7.37 (2H), 7.13 (2H), 6.70 (1H), 6.42 (1H), 6.14 (1H, 5.93 (2H), 3.54-3.46 (3H), 3.33 (1H), 2.86 (3H), 2.26 (1H), 2.10 (1H), 1.75 (3H), 1.56 (4H), 1.28 (4H), 1.14-1.07 (2H), 0.82 (6H); The X-ray powder diffraction characteristic d(Å) value of the prepared white solid: 19.0648, 7.4908, 7.1171, 5.8144, 4.9614, 4.4404, 4.2498, 3.9010, 3.7913.
Embodiment 3 Prepares C.SUB.19.H.SUB.20.FNO.SUB.3..Math.C.SUB.12.H.SUB.21.N H.SUB.2.SO.SUB.4..Math.3H.SUB.2.O
(58) Paroxetine and memantine are prepared by taking 50 g paroxetine mesylate and 30 g memantine hydrochloride respectively;
(59) 12.35 g (0.0375 mol) paroxetine is added to 62 mL acetone, stirred and dissolved evenly. 6.72 g (0.0375 mol) memantine is added and stirred evenly; The solution temperature is maintained at 0˜10° C., and 33% sulfuric acid of 11.13 g (0.0375 mol) is added into the solution. After the solution is added, stir and crystalize for 2 h and filter. The resulting solid is dried at 50° C. by blast air for 6 h, and 10.34 g of white solid is obtained.
(60) The powder X-ray diffraction of the memantine paroxetine cocrystal salt obtained in embodiment 3 has the same characteristic value as the cocrystal salt in embodiment 1.
(61) The HNMR of the memantine paroxetine cocrystal salt obtained in embodiment 3 has the same absorption peak as that in embodiment 1.
Embodiment 4 Prepares C.SUB.19.H.SUB.20.FNO.SUB.3..Math.C.SUB.12.H.SUB.21.N H.SUB.2.SO.SUB.4..Math.3H.SUB.2.O
(62) Take 50 g of paroxetine mesylate and 30 g of memantine hydrochloride respectively, and prepare paroxetine and memantine according to the method of embodiment 1;
(63) Add 9.80 g (0.0298 mol) of paroxetine to 49 mL of dichloromethane, stir and dissolve evenly, add 5.34 g (0.0298 mol) of memantine, stir evenly; keep the solution temperature at 0-10° C., add 8.85 g (0.0298 mol) of 33% sulfuric acid into the solution, stir and crystallize for 2 h, filter, dry the solid at 50° C. for 6 h by blast, and obtain 6.38 g of white solid.
(64) The powder X-ray diffraction of the memantine paroxetine cocrystal salt obtained in embodiment 4 has the same characteristic value as that in embodiment 1.
(65) The HNMR of the memantine paroxetine cocrystal salt obtained in embodiment 4 has the same absorption peak as that in embodiment 1.
Embodiment 5 Prepares C.SUB.19.H.SUB.20.FNO.SUB.3..Math.C.SUB.12.H.SUB.21.N.Math.H.SUB.2.SO.SUB.4..Math.3H.SUB.2.O
(66) Take 50 g of paroxetine mesylate and 30 g of memantine hydrochloride respectively, and prepare paroxetine and memantine according to the method of embodiment 1;
(67) Add 11.25 g (0.0342 mol) of paroxetine to 57 mL of isopropanol, stir and dissolve evenly, add 6.13 g (0.0342 mol) of memantine, stir evenly; keep the solution temperature at 0˜10° C., add 10.16 g (0.0342 mol) of 33% sulfuric acid to the solution, stir and crystallize for 2 h, filter, and dry the solid at 50° C. by blast for 6 h to obtain 9.74 g of white solid.
(68) The powder X-ray diffraction of the memantine paroxetine cocrystal salt obtained in embodiment 5 has the same characteristic d(Å) value as that in embodiment 1.
(69) The hydrogen NMR of the memantine paroxetine cocrystal salt obtained in embodiment 5 has the same absorption peak as that in embodiment 1.
Embodiment 6: Pharmacokinetic Experiment of Memantine Paroxetine Cocrystal Salt
(70) 1. Experimental objective
(71) Determination of the pharmacokinetic parameters of amantadine and paroxetine in rat plasma by LC-MS/MS method
(72) 2. Experimental Material
(73) 2.1 Main Reagents
(74) The memantine paroxetine cocrystal salt prepared in embodiment 1; memantine hydrochloride; dexamethasone (Intermediate inspection office); ammonium formate; methanol is all chromatographic pure (Merck Company); formic acid is all chromatographic pure (Aladdin Company); acetonitrile is all chromatographic pure (Merck Company); experimental water is deionized purified water.
(75) 2.2 Animal
(76) SD rat, SPF grade, male, weight 200-250 g, purchased from Zhejiang Experimental Animal Center, production license No.: SCXK (Zhejiang) 2014-0001.
(77) 3. Instrument and Equipment
(78) Liquid mass spectrometer: Thermo Finnigan TSQ Quantum, composed of Surveyor As, Surveyor MS Pump Plus and TSQ Quantum, Thermo Fisher Scientific Company; Sartorius BP-211D electronic balance; Thermo STRATOS high speed freezing centrifuge; Eppendorf PCB-11 micro vortex mixer; Milli-Q Grandient pure water meter.
(79) 4. Chromatography-Mass Spectrometry Conditions
(80) 4.1 Chromatographic Conditions:
(81) Chromatographic column: Waters Cortecs C18 (2.1 mm×50 mm, 2.7 μm); column temperature: 35° C.; mobile phase: acetonitrile-10 mm ammonium formate containing 0.1% formic acid (10:90); flow rate: 0.2 mL.Math.min.sup.−1; sample injection volume: 5 μL.
(82) 4.2 Mass Spectrum Conditions:
(83) Ion detection method: multiple reaction monitoring (MRM); ionic polarity: positive ion (Positive); ionization mode: electrospray ionization (ESI); ionization voltage (IS): 3000.0V; temperature: 300° C.; sheath gas: 35; auxiliary gas: 30. See Table 2 for test results.
(84) TABLE-US-00002 TABLE 2 Detection object Detection ion CE(eV) Memantine 180.2.fwdarw.163.0 15 hydrochloride Internal standard 393.2.fwdarw.355.2 11 (dexamethasone)
(85) 5. Collection of Rat Blood Samples
(86) 10 rats are randomly divided into 2 groups, 5 rats in each group: group A: 5.6 mg/kg memantine hydrochloride; group B: 17.4 mg/kg cocrystal salt;
(87) The rats are fasted for 12 h before the experiment, and the tested drugs re given by gavage with the volume of 1 mL/100 g. Before and 5, 10, 20, 40, 60, 120, 180, 240, 360 and 480 min after administration, 0.5 mL of blood is collected through the fundus vein plexus. Anticoagulate the heparin. Centrifugate at 4000 rpm for 10 min, and separate the plasma. It can be used for the determination of memantine concentration.
(88) TABLE-US-00003 TABLE 3 Estimated memantine and cocrystal salt and pharmacokinetic parameters after administration in rats Average Standard Group Parameter Unit value deviation Group A AUC.sub.(0-t) ng/L * h 713.726 109.856 Group B 1982.124 155.293 Group A AUC.sub.(0-∞) ng/L * h 773.35 113.602 Group B 3167.23 637.631 Group A MRT.sub.(0-t) h 2.429 0.267 Group B 3.298 0.126 Group A MRT.sub.(0-∞) h 3.054 0.328 Group B 8.1 2.474 Group A T.sub.1/2z h 2.009 0.268 Group B 5.605 1.861 Group A T.sub.max h 0.617 0.407 Group B 0.868 0.181 Group A CLz/F L/h/kg 7406.228 1188.233 Group B 5664.876 1071.185 Group A Vz/F L/kg 21319.791 3196.406 Group B 43816.086 8037.842 Group A C.sub.max ng/L 276.249 56.868 Group B 449.186 34.668
(89) 7. Result and Discussion
(90) By comparing the main pharmacokinetic parameters and their ratios of the same molar dose of memantine paroxetine cocrystal salt and memantine hydrochloride, it can be found that the main pharmacokinetic parameters such as T.sub.1/2, T.sub.max, C.sub.max and AUC.sub.(0-∞) were significantly different; The results show that: T.sub.1/2 time is significantly longer, which is 2.79 times; T.sub.max time is longer, which is 1.41 times; C.sub.max value is significantly increased, which is 1.62 times; AUC.sub.(0-∞) is significantly strengthened, which is 4.10 times.
(91) The above is only a better embodiment of the invention and does not limit the invention. Any modification, equivalent replacement and improvement made within the spirit and principles of the invention shall be included in the protection scope of the invention.