Neomycin-lactulose eutectic and preparation method thereof

Abstract

The present invention provides a neomycin-lactulose cocrystal and a preparation method thereof. The cocrystal is prepared from neomycin and lactulose. The powder X-ray diffraction pattern of the neomycin-lactulose cocrystal has diffraction angles 2θ=12.3°±0.2°, 13.9°±0.2°, 14.9°±0.2°, 16.2°±0.2°, 17.3°±0.2°, 18.1°±0.2°, 18.8° The neomycin-lactulose cocrystal of the present invention has characteristic peaks at 14.5°±0.2°, 19.5°±0.2°, 22.1°±0.2°, 23.2°±0.2°, 24.7°±0.2°, 25.4°±0.2°, 27.4°±0.2°, 28.0°±0.2°, 29.2°±0.2°, 29.8°±0.2°, 31.7°±0.2°, and 33.3°±0.2°. Compared with existing neomycin, the neomycin-lactulose cocrystal of the present invention has more stable physical properties and significantly improved bioavailability under the same conditions.

Description

Technical Field

[0001] The invention belongs to the field of chemical pharmacy, and particularly relates to a neomycin-lactulose cocrystal and a preparation method thereof. Background Art

[0002] Neomycin is an aminoglycoside antibiotic produced by Streptomyces freundii. It is active against both Gram-positive and Gram-negative bacteria. It has complete cross-resistance with kanamycin and partial cross-resistance with streptomycin. Similar to other antibiotics of its class, neomycin is also active against many Gram-negative bacteria, such as Escherichia coli, Klebsiella, Proteus, Enterobacter, Salmonella, Shigella, Brucella, and Pasteurella. Neisseria meningitidis and Neisseria gonorrhoeae are also sensitive to neomycin. Neomycin is a white or off-white powder that is highly hygroscopic.

[0003] The efficacy of oral solid dosage forms depends significantly on the solid form of the active pharmaceutical ingredient (API). Different solid forms of the active pharmaceutical ingredient (API) exhibit varying physicochemical properties, such as solubility, stability, and in vivo bioavailability. Data show that over 40% of marketed drugs and 90% of compounds under development exhibit a range of inherent defects. Consequently, addressing these inherent defects has become a research hotspot. Pharmaceutical cocrystals are formed by non-covalently bonding the active pharmaceutical ingredient (API) to a cocrystal former in a specific stoichiometric ratio. The resulting cocrystal improves the stability and bioavailability of the original drug. Summary of the Invention

[0004] The purpose of the present invention is to provide a neomycin-lactulose cocrystal and a preparation method thereof to solve the problems existing in the above-mentioned prior art, so that the neomycin-lactulose cocrystal can effectively avoid the introduction of harmful substances, increase the stability of neomycin, and effectively improve the bioavailability of neomycin.

[0005] The technical solution adopted by the present invention is: a neomycin-lactulose eutectic is prepared from neomycin and lactulose; the molar ratio of the neomycin to the lactulose is (1-2):(1-2).

[0006] Furthermore, the powder X-ray diffraction pattern of the neomycin-lactulose cocrystal has characteristic peaks at diffraction angles 2θ=12.3°±0.2°, 13.9°±0.2°, 14.9°±0.2°, 16.2°±0.2°, 17.3°±0.2°, 18.1°±0.2°, 18.8°±0.2°, 19.5°±0.2°, 22.1°±0.2°, 23.2°±0.2°, 24.7°±0.2°, 25.4°±0.2°, 27.4°±0.2°, 28.0°±0.2°, 29.2°±0.2°, 29.8°±0.2°, 31.7°±0.2°, and 33.3°±0.2°.

[0007] The preparation method of neomycin-lactulose cocrystal comprises the following steps:

[0008] 1) Place neomycin and lactulose in a flask and add an organic solvent to completely mix and dissolve them;

[0009] 2) The mixture obtained in step 1) is subjected to rotary evaporation and drying to remove the solvent, and the mixture is ground and sieved to obtain neomycin-lactulose cocrystal.

[0010] Furthermore, in step 1), the organic solvent is one or more of methanol, ethanol, acetone, acetonitrile and ethyl acetate.

[0011] Furthermore, in step 1), the ratio of the total mass of neomycin and lactulose to the organic solvent is 1 g:(10-25 mL).

[0012] Furthermore, in step 1), the temperature of the rotary evaporation is 25-50° C., and the rotation speed is 30-60 rpm.

[0013] The beneficial effects obtained by the present invention are: 1. Compared with the existing neomycin, the neomycin-lactulose cocrystal of the present invention has more stable physical properties and its bioavailability is significantly improved under the same conditions.

[0014] 2. The preparation method of the present invention has mild conditions, simple operation, good reproducibility and low production cost; and the bioavailability of the obtained neomycin-lactulose cocrystal is effectively improved, and the stability of neomycin is increased. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 The measured powder X-ray diffraction pattern of Example 1 of the present invention;

[0016] Figure 2 is the measured powder X-ray diffraction pattern of neomycin;

[0017] Figure 3 is the measured powder X-ray diffraction pattern of lactulose;

[0018] Figure 4 It is the dynamic water adsorption diagram of neomycin and Example 1 of the present invention;

[0019] Figure 5 The drug-time curve of neomycin and Example 1 of the present invention is shown in FIG. DETAILED DESCRIPTION

[0020] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.

[0021] Example 1

[0022] 614.6 mg of neomycin and 342.3 mg of lactulose were placed in a flask, 20 mL of acetone was added, the solvent was removed by rotary evaporation at 40° C. and 40 rpm, the mixture was dried at 60° C., ground and sieved to obtain neomycin-lactulose cocrystal.

[0023] Example 2

[0024] 307.3 mg of neomycin and 171.1 mg of lactulose were placed in a flask, and 18 mL of a mixed solution of acetonitrile and ethyl acetate was added. The solvent was removed by rotary evaporation at 30°C and 60 rpm, and the mixture was dried at 60°C, ground and sieved to obtain neomycin-lactulose cocrystals.

[0025] Example 3

[0026] 184.4 mg of neomycin and 171.1 mg of lactulose were placed in a flask, 15 mL of methanol was added, and the solvent was removed by rotary evaporation at 50° C., 30 rpm, and the mixture was dried at 60° C., ground and sieved to obtain neomycin-lactulose cocrystals.

[0027] Example 4

[0028] 122.9 mg of neomycin and 136.9 mg of lactulose were placed in a flask, 10 mL of ethanol was added, and the solvent was removed by rotary evaporation at 25°C and 60 rpm. The mixture was dried at 60°C, ground and sieved to obtain neomycin-lactulose cocrystals.

[0029] Test example

[0030] 1. Sample determination and structural characterization

[0031] The neomycin-lactulose cocrystal prepared in Example 1 was measured and characterized as follows: Powder X-ray diffraction was performed using a TD-3700 diffractometer. A silicon sample was used for calibration before measuring the sample, and the sample was measured after meeting the requirements. Measurement conditions: Radiation, tube voltage 30kV, tube current 20mA, scanning range 5-35°, scanning step spacing 0.015°, scanning speed 9° / min. The powder X-ray diffraction of the neomycin-lactulose cocrystal obtained in Example 1 is as follows: Figure 1 shown. Figure 2 This is the powder X-ray diffraction pattern of neomycin tested under the same conditions. Figure 3 This is the powder X-ray diffraction pattern of lactulose tested under the same conditions. Figure 1 、 Figure 2 、 Figure 3 It can be concluded that the product obtained in Example 1 is a new crystalline substance, namely, neomycin-lactulose cocrystal.

[0032] exist Figure 1 The X-ray powder diffraction of neomycin-lactulose cocrystal has characteristic peaks at diffraction angles 2θ = 12.3°±0.2°, 13.9°±0.2°, 14.9°±0.2°, 16.2°±0.2°, 17.3°±0.2°, 18.1°±0.2°, 18.8°±0.2°, 19.5°±0.2°, 22.1°±0.2°, 23.2°±0.2°, 24.7°±0.2°, 25.4°±0.2°, 27.4°±0.2°, 28.0°±0.2°, 29.2°±0.2°, 29.8°±0.2°, 31.7°±0.2°, and 33.3°±0.2°.

[0033] 2. Hygroscopicity study

[0034] A dynamic vapor sorption instrument was used to evaluate the hygroscopicity and deliquescent properties of chlortetracycline and its cocrystals. Approximately 10 mg of crystalline powder was placed in an aluminum pan, which was placed in the instrument and the relative humidity (RH) was increased from 0% to 95% in 5% increments at 25°C under nitrogen. Figure 4 The results show that the critical relative humidity of neomycin-lactulose reaches 80%, which is much higher than that of neomycin, thus improving the defect of neomycin that it is easy to absorb moisture.

[0035] 3. Pharmacokinetic studies

[0036] Ten male Sprague-Dawley rats were selected for oral pharmacokinetic testing. The rats were divided into two groups (n=5): one receiving neomycin and the other receiving neomycin-lactulose cocrystal. The rats were fasted for 12 hours prior to the experiment and had free access to water. Neomycin and neomycin-lactulose cocrystals were administered orally by gavage at a dose of 50 mg / kg (calculated as neomycin). Blood samples were collected at different time points to determine relevant pharmacokinetic parameters and plot drug-time curves. As shown in Table 1, the bioavailability of neomycin-lactulose cocrystals was 35% higher than that of neomycin.

[0037] Table 1 Pharmacokinetic parameters of neomycin and neomycin-lactulose cocrystal

[0038]

[0039] The embodiments described above are merely descriptions of preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Without departing from the spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by persons skilled in the art should fall within the scope of protection defined by the claims of the present invention.

[0040] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.

Claims

1. A neomycin-lactulose cocrystal, characterized by: Made from neomycin and lactulose; the molar ratio of neomycin to lactulose is 1:1; The powder X-ray diffraction pattern of the neomycin-lactulose cocrystal has characteristic peaks at diffraction angles 2θ=12.3°±0.2°, 13.9°±0.2°, 14.9°±0.2°, 16.2°±0.2°, 17.3°±0.2°, 18.1°±0.2°, 18.8°±0.2°, 19.5°±0.2°, 22.1°±0.2°, 23.2°±0.2°, 24.7°±0.2°, 25.4°±0.2°, 27.4°±0.2°, 28.0°±0.2°, 29.2°±0.2°, 29.8°±0.2°, 31.7°±0.2°, and 33.3°±0.2°.

2. The method for preparing the neomycin-lactulose cocrystal according to claim 1, wherein: The steps include: 1) Place neomycin and lactulose in a flask and add an organic solvent to mix and dissolve them completely; 2) The mixture obtained in step 1) is subjected to rotary evaporation and drying to remove the solvent, and the mixture is ground and sieved to obtain neomycin-lactulose cocrystals.

3. The method for preparing the neomycin-lactulose cocrystal according to claim 2, wherein: In step 1), the organic solvent is one or more of methanol, ethanol, acetone, acetonitrile and ethyl acetate.

4. The method for preparing the neomycin-lactulose cocrystal according to claim 2, wherein: In step 1), the ratio of the total mass of neomycin and lactulose to the organic solvent is 1 g: (10-25 mL).

5. The method for preparing neomycin-lactulose cocrystal according to claim 2, characterized in that: In step 1), the temperature of the rotary evaporation is 25-50° C., and the rotation speed is 30-60 rpm.

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