PEPTIDE AMIDE COMPOSITION AND PREPARATION METHOD THEREFOR

Abstract

Disclosed are a peptide amide compound composition, a preparation method therefor and medical use thereof. Specifically, the composition contains a compound of formula (I) and pH regulators, and the pH of the solution thereof is 3-5.5. The composition is stable and requires few excipients, and is stable in clinical use.

##STR00001##

Claims

1. A pharmaceutical composition comprising a compound of formula (I) below or a pharmaceutically acceptable salt thereof and a pH regulator, wherein the composition has a pH value of 3-5.5, ##STR00014## wherein R.sup.1 is selected from ##STR00015## m.sub.1 and m.sub.2 are each independently selected from 1, 2, 3 or 4; m.sub.3 and m.sub.4 are each independently selected from 0, 1, 2, 3 or 4, provided that m.sub.3 and m.sub.4 are not both 0; n.sub.1 and n.sub.2 are each independently selected from 0, 1, 2, 3 or 4; Z is selected from CR.sup.z1R.sup.z2 or NR.sup.z3; R.sup.z1 and R.sup.z2 are each independently selected from H, F, Cl, Br, I, OH, CF.sub.3, nitro, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.2-6alkenyl, C.sub.2-6alkynyl, —C(═O)—C.sub.1-6alkyl, —(CH.sub.2).sub.q—C(═O)O—C.sub.1-6alkyl, —(CH.sub.2).sub.q—NR.sup.1eR.sup.1f, —(CH.sub.2).sub.q—COOH, —(CH.sub.2).sub.q—CONH.sub.2, C.sub.3-8carbocyclyl, or 3- to 8-membered heterocyclyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally further substituted with 0-5 substituents selected from F, Cl, Br, I, OH, CF.sub.3, ═O, carboxyl, nitro, cyano, amino, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8carbocyclyl or 3- to 8-membered heterocyclyl, the heterocyclyl contains 1 to 3 heteroatoms optionally selected from N, O or S, and when the heteroatom is S, the heterocyclyl can optionally contain S, S═O or S(═O).sub.2; R.sup.1e and R.sup.1f are each independently selected from H, C.sub.1-6alkyl, —C(═O)O—C.sub.1-6alkyl, —C(═O)O—(CH.sub.2).sub.q—C.sub.3-8carbocyclyl, or —C(═O)O—(CH.sub.2).sub.q-3- to 8-membered heterocyclyl, wherein the alkyl, carbocyclyl or heterocyclyl is optionally further substituted with 0-5 substituents selected from F, Cl, Br, I, OH, CF.sub.3, cyano, nitro, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8carbocyclyl or 3- to 8-membered heterocyclyl, and the heterocyclyl contains 1 to 3 heteroatoms selected from N, O or S; or R.sup.z1 and R.sup.z2 together with the carbon atoms to which they are attached form a 3- to 10-membered nitrogen-containing heterocyclic ring, wherein the ring is optionally further substituted with a substituent selected from F, Cl, Br, I, OH, CF.sub.3, cyano, nitro, ═O, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8carbocyclyl or 3- to 8-membered heterocyclyl; R.sup.1a and R.sup.1b are each independently selected from F, CF.sub.3, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl or 3- to 8-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl or heterocyclyl is optionally further substituted with 0-5 substituents selected from F, Cl, Br, I, OH, CF.sub.3, nitro, cyano, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8carbocyclyl or 3- to 8-membered heterocyclyl, and the heterocyclyl contains 1 to 3 heteroatoms optionally selected from N, O or S; R.sup.z3 is independently selected from H, —C(═O)—C.sub.1-6alkyl, —C(═O)O—C.sub.1-6alkyl, —C(═O)—C.sub.3-8carbocyclyl, —C(═O)O—C.sub.3-8carbocyclyl, —C(═O)O -(3- to 8-membered heterocyclyl), —S(═O).sub.p—C.sub.1-6alkyl, —S(═O).sub.p—C.sub.3-8carbocyclyl, —S(═O).sub.p-(3- to 8-membered heterocyclyl), —C(═O)NR.sup.1gR.sup.1h, —S(═O).sub.p—NR.sup.1iR.sup.1j or 3- to 8-membered heterocyclyl, wherein the alkyl, carbocyclyl or heterocyclyl is optionally further substituted with 0-5 substituents selected from F, Cl, Br, I, OH, CF.sub.3, nitro, cyano, amino, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8carbocyclyl or 3- to 8-membered heterocyclyl, and the heterocyclyl contains 1 to 3 heteroatoms optionally selected from N, O or S; R.sup.1g, R.sup.1h, R.sup.1i, and R.sup.1j are each independently selected from H or C.sub.1-6alkyl; or R.sup.19 and R.sup.1h together with the nitrogen atoms to which they are attached form a 3- to 10-membered heterocyclic ring, wherein the ring is optionally further substituted with a substituent selected from F, Cl, Br, I, OH, CF.sub.3, cyano, nitro, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.2-6alkenyl, C.sub.2-6alkynyl or —S(═O).sub.p—C.sub.1-6alkyl, and the heterocyclic ring contains 1 to 3 heteroatoms selected from N, O or S; q is selected from 0, 1, 2, 3 or 4; p is selected from 0, 1 or 2; a is selected from 0, 1, 2 or 3; R.sup.4 is independently selected from H, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl or —(CH.sub.2).sub.q—C.sub.3-8carbocyclyl, wherein the alkyl, alkenyl, alkynyl or carbocyclyl is optionally further substituted with 0-5 substituents selected from F, Cl, Br, I, OH, CN, CF.sub.3, NO.sub.2, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8carbocyclyl or 3- to 8-membered heterocyclyl, and the heterocyclyl contains 1 to 3 heteroatoms selected from N, O or S; R.sup.2, R.sup.3, R.sup.7 and R.sup.8 are each independently selected from H, C.sub.1-6alkyl, —C(═O)O—C.sub.1-4alkyl, —C(═O)O—(CH.sub.2).sub.q—C.sub.3-8carbocyclyl, —C(═O)O—(CH.sub.2).sub.q-3- to 8-membered heterocyclyl or ##STR00016## wherein the alkyl, carbocyclyl or heterocyclyl is optionally further substituted with 0-5 substituents selected from F, Cl, Br, I, OH, CF.sub.3, nitro, cyano, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8carbocyclyl or 3- to 8-membered heterocyclyl, and the heterocyclyl contains 1 to 3 heteroatoms optionally selected from N, O or S; b is selected from 0, 1, 2, 3, 4 or 5; c is selected from 0, 1, 2, 3, 4 or 5; R.sup.5 and R.sup.6 are each independently selected from F, Cl, Br, I, CF.sub.3, cyano, nitro, C.sub.1-4alkyl, —OR.sup.5a, —C(O)OR.sup.5b, —SR.sup.5c, —S(O)R.sup.5d, —S(O).sub.2R.sup.5 or —NR.sub.5R.sup.5g; R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, R.sup.5e, R.sup.5f and R.sup.5g are each independently selected from H or C.sub.1-4alkyl; or R.sup.5f and R.sup.5g together with the nitrogen atoms to which they are attached form a 5- to 6-membered heterocyclic ring, wherein the heterocyclic ring contains 1 to 3 heteroatoms optionally selected from N, O or S.

2. The composition according to claim 1, wherein the compound of formula (I) has a structure of formula (II): ##STR00017##

3. The composition according to claim 1, wherein the pH regulator is selected from acetic acid, phosphoric acid, tartaric acid, benzoic acid, or buffer solutions formed from the foregoing acids and corresponding salts thereof.

4. The composition according to claim 3, wherein the pH regulator is selected from an acetic acid-sodium acetate buffer system, a tartaric acid-sodium hydrogen tartarate buffer system or a tartaric acid-sodium hydrogen tartarate-sodium tartrate concomitant buffer system.

5. The composition according to claim 4, wherein the pH regulator is at a concentration of 1 mmol/L-500 mmol/L.

6. The composition according to claim 3, wherein the tartaric acid is selected from D-tartaric acid, L-tartaric acid or a racemate thereof.

7. The composition according to claim 1, wherein the compound of formula (I) has a weight/volume, w/v, of 0.001%-1%.

8. The composition according to claim 1, wherein the composition is a sterile lyophilized powder for injection or a solution for injection.

9. The composition according to claim 1, wherein the composition may further contain a stabilizer.

10. The composition according to claim 9, wherein the stabilizer is selected from mannitol, glucose or trehalose.

11. The composition according to claim 1, wherein the composition may further contain an antioxidant.

12. The composition according to claim 11, wherein the antioxidant is selected from edetate disodium or sodium calcium edetate.

13. The composition according to claim 1, wherein the composition may further contain an isotonic regulator or an antibacterial agent.

14. A method for preparing the composition according to claim 1, the method comprising the following steps: (1) dissolving ingredients, other than an active substance, in water for injection; (2) adding the active substance to the solution obtained in step (1), wherein the active substance is the compound of formula (I) or a pharmaceutically acceptable salt thereof; and (3) adding water to a constant volume, carrying out sterilizing filtration through a 0.22 μm filter, filling and sealing.

15. The method according to claim 14, wherein, the method comprises the following steps: (1) dissolving the pH regulator, the isotonic regulator, the antioxidant, the stabilizer, the antibacterial agent and a filler to water for injection; (2) adding the active substance to the solution obtained in step (1); and (3) adding water to a constant volume, carrying out sterilizing filtration through a 0.22 μm filter, filling and sealing.

16. The method according to claim 15, wherein, the method comprises the following steps: (1) dissolving ingredients, other than an active substance, in water for injection; (2) adding the active substance to the solution obtained in step (1), wherein the active substance is the compound of formula (I) or a pharmaceutically acceptable salt thereof; (3) adjusting the pH value with the pH regulator to a range of 3.0-5.5; and (4) adding water to a constant volume, carrying out sterilizing filtration through a 0.22 μm filter, filling and sealing.

17. The method according to claim 16, wherein, the method comprises the following steps: (1) dissolving the pH regulator, the isotonic regulator, the antioxidant, the stabilizer, the antibacterial agent and a filler to water for injection; (2) adding the active substance to the solution obtained in step (1); (3) adjusting the pH value with the pH regulator to a range of 3.0-5.5; and (4) adding water to a constant volume, carrying out sterilizing filtration through a 0.22 m filter, filling and sealing.

18. The method according to claim 17, further comprising a lyophilizing step.

19. The method according to claim 18, wherein the lyophilizing step comprises: (1) pre-freezing; (2) cooling partition boards to −35° C. or lower and maintaining for 1-2 h; then cooling a chamber to −50° C. or lower and vacuuming to 20 Pa or lower; opening a limited leakage valve; raising the temperature to −5° C. over 3-5 h and maintaining for another 1-3 h; raising the temperature to 10° C. over 2-4 h and maintaining until the temperature of the preparation reaches 0° C. or higher; raising the temperature to 35° C. over 2-3 h and maintaining until the temperature of the preparation reaches 25° C. or higher; and then closing the limited leakage valve and maintaining the temperature for 1-3 h; and (3) vacuuming or charging nitrogen, completely stoppering, and then taking out from the chamber and capping.

20. A method for treating or preventing a disease or condition associated with kappa opioid receptors in a mammal, wherein the method comprises administering the composition according to claim 1.

21. The method according to claim 20, wherein the disease or condition associated with kappa opioid receptors is selected from the group consisting of pain, inflammation, itching, edema, hyponatremia, hypokalemia, intestinal obstruction, cough and glaucoma.

22. The method according to claim 21, wherein the pain is selected from neuropathic pain, somatic pain, visceral pain and skin pain.

23. (canceled)

24. (canceled)

25. The composition according to claim 4, wherein the pH regulator is at a concentration of 10 mmol/L-50 mmol/L.

26. The composition according to claim 1, wherein the compound of formula (I) has a weight/volume, w/v, of 0.002%-0.05%.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0123] FIG. 1 shows curves of glacial acetic acid or tartaric acid-adjusted pH versus total impurity of compound II solution.

[0124] FIG. 2 shows a curve of different pH versus total impurity of compound II solution.

DETAILED DESCRIPTION OF EMBODIMENTS

[0125] The technical solutions of the present disclosure will be described in detail below in conjunction with the drawings and examples, but the protection scope of the present disclosure includes but is not limited thereto.

[0126] Unless otherwise specified, tartaric acid is from Merck, Germany.

Example 1 pH Range

[0127] 750 ml of water for injection was measured and taken; nitrogen was charged beneath the surface of the liquid for about 20 min; and the water temperature was controlled to be 50° C. or less. 37.5 mg of compound II was weighed, added to the above-mentioned water for injection and stirred to dissolution and clarification to obtain solution (1). Solution (1) was adjusted with glacial acetic acid (source: Chengdu Kelong Chemical Co., Ltd.) and tartaric acid to different pH values, respectively, and aqueous solutions containing compound II at different pH values were obtained. The aqueous solutions were placed under the conditions of 40° C.±2° C. for 10 days, and the performance of related substances in the solutions at different pH values was examined (including the solution at a pH value not being adjusted), with data shown in Table 1.

TABLE-US-00001 TABLE 1 Examination results of related substances in solutions containing compound II at different pH values Sample Total storage impurity condition Sample pH value (%) 40° C. ± Compound II 2.94 0.986 2° C., 10 solution (at a pH 3.99 0.490 days value adjusted 4.94 0.742 with glacial 6.01 1.079 acetic acid) 6.97 1.588 7.86 1.450 9.12 (the solution at a pH 1.586 value not being adjusted) Compound II 3.03 0.980 solution (at a pH 3.99 0.486 value adjusted 4.79 0.702 with tartaric 5.95 1.289 acid) 6.97 1.496 7.86 1.580 9.12 (the solution at a pH 1.586 value not being adjusted)

[0128] Curves of pH versus total impurity, which are plotted with the data of the pH values and total impurity of compound II solution (at a pH value adjusted with glacial acetic acid) and compound II solution (at a pH value adjusted with tartaric acid) in Table 1 respectively, are shown in FIG. 1. It can be seen from Table 1 and FIG. 1 that the compound II aqueous solutions prepared thereby have the best stability at a pH value of about 4; and related substances in the compound II solutions at a pH value adjusted with glacial acetic acid and tartaric acid show substantially the same trend of changes.

[0129] Considering the operability of industrial production, we examined the stability of solutions at a pH range of 3-5.5. 750 ml of water for injection was measured and taken; nitrogen was charged beneath the surface of the liquid for about 20 min; and the water temperature was controlled to be 50° C. or less. 37.5 mg of compound II was weighed, added to the above-mentioned water for injection and stirred to dissolution and clarification to obtain solution (1). Solution (1) was adjusted with glacial acetic acid (source: Chengdu Kelong Chemical Co., Ltd.) to different pH values, and aqueous solutions containing compound II at different pH values were obtained. The aqueous solutions were placed under the conditions of 40° C.±2° C. for 10 days, and the performance of related substances in the solutions at different pH values was examined, with data shown in Table 2.

TABLE-US-00002 TABLE 2 Examination results of related substances in solutions containing compound II at different pH values Sample storage pH Total impurity condition Sample value (%) 40° C. ± Compound II 2.98 1.005 2° C., 10 solution (at a pH 3.22 0.842 days value adjusted with 3.49 0.624 glacial acetic acid) 3.74 0.537 3.99 0.498 4.25 0.506 4.48 0.602 4.77 0.695 5.00 0.755 5.24 0.866 5.51 0.921

[0130] A curve of pH versus total impurity, which is plotted with the data of the pH values and total impurity of compound II solution in Table 2, is shown in FIG. 2. It can be seen from Table 2 and FIG. 2 that this product is stable at a pH range of 3-5.5.

Example 2 Formulation 1

[0131] The prescription is as follows:

TABLE-US-00003 Substances Content Compound II  0.10 g Glacial acetic acid 0.525 g Sodium acetate 0.207 g Water for injection, making up  1000 ml the volume to

[0132] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Glacial acetic acid (source: Chengdu Kelong Chemical Co., Ltd.) and sodium acetate (source: Chengdu Jinshan Chemical Test Co., Ltd.) were added to the above-mentioned water for injection under stirring and then stirred to dissolution and clarification to obtain solution (1). Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing, and formulation 1 solution for injection was obtained.

[0133] The sample of Formulation 1 solution for injection was placed under the conditions of 40° C.±2° C. for 5 days; compound II raw material (stored under refrigerated conditions of 2° C.-8° C.) was used as a control; and changes of related substances in the sample were examined, with data shown in Table 3.

TABLE-US-00004 TABLE 3 Examination results of related substances of formulation 1 solution for injection Sample storage Total impurity Sample condition (%) Compound II 0 days 1.098 Formulation 1 solution for 40° C. ± 1.164 injection 2° C., 5 days

[0134] After the sample prepared according to Example 2 was placed at 40° C. 2° C. for high temperature acceleration for 5 days, the total impurity level was not significantly different from that of the raw material at day 0, indicating that formulation 1 has a good stability.

Example 3 Formulation 2

[0135] The prescription is as follows:

TABLE-US-00005 Substances Content Compound II  0.10 g Glacial acetic acid 1.050 g Sodium acetate 0.415 g Water for injection, making up  1000 ml the volume to

[0136] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Glacial acetic acid (source: Chengdu Kelong Chemical Co., Ltd.) and sodium acetate (source: Chengdu Jinshan Chemical Test Co., Ltd.) were added to the above-mentioned water for injection under stirring and then stirred to dissolution and clarification to obtain solution (1). Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing, and formulation 2 solution for injection was obtained.

[0137] Formulation 2 solution for injection was placed under the conditions of 40° C. 2° C. for 5 days; compound II raw material (stored under refrigerated conditions of 2° C.-8° C.) was used as a control; and changes of related substances in the sample were examined, with data shown in Table 4.

TABLE-US-00006 TABLE 4 Examination results of related substances of formulation 2 solution for injection Sample storage Total impurity Sample condition (%) Compound II 0 days 1.098 Formulation 2 solution 40° C. ± 1.132 for injection 2° C., 5 days

[0138] After the sample of formulation 2 solution for injection was placed at 40° C. 2° C. for high temperature acceleration for 5 days, the total impurity level was not significantly different from that of the raw material at day 0, indicating that formulation 2 solution for injection has a good stability.

Example 4 Formulation 3

[0139] The prescription is as follows:

TABLE-US-00007 Substances Content Compound II  0.10 g Glacial acetic acid 1.260 g Sodium acetate 0.518 g Water for injection, 1000 ml making up the volume to

[0140] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Glacial acetic acid (source: Chengdu Kelong Chemical Co., Ltd.) and sodium acetate (source: Chengdu Jinshan Chemical Test Co., Ltd.) were added to the above-mentioned water for injection under stirring and then stirred to dissolution and clarification to obtain solution (1). Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing, and formulation 3 solution for injection was obtained.

[0141] Formulation 3 solution for injection was placed under the conditions of 40° C. 2° C. for 5 days; compound II raw material (stored under refrigerated conditions of 2° C.-8° C.) was used as a control; and changes of related substances in the sample were examined, with data shown in Table 5.

TABLE-US-00008 TABLE 5 Examination results of related substances of formulation 3 solution for injection Sample storage Total Sample condition impurity (%) Compound II 0 days 1.098 Formulation 3 40° C. ± 2° C., 1.119 solution for 5 days injection

[0142] After formulation 3 solution for injection was placed at 40° C.±2° C. for high temperature acceleration for 5 days, the total impurity level was not significantly different from that of the raw material at day 0, indicating that formulation 3 solution for injection has a good stability.

Example 5 Formulation 4

[0143] The prescription is as follows:

TABLE-US-00009 Substances Content Compound II  0.10 g Glacial acetic acid 0.525 g Sodium acetate 0.207 g Mannitol  1.0 g Water for injection, 1000 ml making up the volume to

[0144] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Glacial acetic acid (source: Chengdu Kelong Chemical Co., Ltd.) and sodium acetate (source: Chengdu Jinshan Chemical Test Co., Ltd.) were added to the above-mentioned water for injection under stirring and then stirred to dissolution and clarification to obtain solution (1). Mannitol (source: Merck, Germany) was weighed, added to solution (1) and stirred to clarification to afford solution (2). Compound II was weighed, added to solution (2) and stirred to clarification, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing, and formulation 4 solution for injection was obtained.

[0145] Formulation 4 solution for injection was placed under the conditions of 40° C. 2° C. for 9 days; compound II raw material (stored under refrigerated conditions of 2° C.-8° C.) was used as a control; and changes of related substances in the sample were examined, with data shown in Table 6.

TABLE-US-00010 TABLE 6 Examination results of related substances of formulation 4 solution for injection Sample storage Total Sample condition impurity (%) Compound II 0 days 1.238 Formulation 4 40° C. ± 2° C., 1.281 solution for 9 days injection

[0146] After formulation 4 solution for injection was placed at 40° C.±2° C. for high temperature acceleration for 9 days, the total impurity level was not significantly different from that of the raw material at day 0, indicating that formulation 4 solution for injection has a good stability.

Example 6 Formulation 5

[0147] The prescription was as follows:

TABLE-US-00011 Substances Content Compound II  0.10 g Glacial acetic acid 0.525 g Anhydrous sodium acetate 0.207 g Mannitol  10.0 g Water for injection, 1000 ml making up the volume to

[0148] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Glacial acetic acid (source: Chengdu Kelong Chemical Co., Ltd.) and sodium acetate (source: Chengdu Jinshan Chemical Test Co., Ltd.) were added to the above-mentioned water for injection under stirring and then stirred to dissolution and clarification to obtain solution (1). Mannitol (source: Merck, Germany) was weighed, added to solution (1) and stirred to clarification to afford solution (2). Compound II was weighed, added to solution (2) and stirred to clarification, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing, and formulation 5 solution for injection was obtained.

[0149] Formulation 5 solution for injection was placed under the conditions of 40° C. 2° C. for 9 days; compound II raw material (stored under refrigerated conditions of 2° C.-8° C.) was used as a control; and changes of related substances in the sample were examined, with data shown in Table 7.

TABLE-US-00012 TABLE 7 Examination results of related substances of formulation 5 solution for injection Sample storage Total Sample condition impurity (%) Compound II 0 days 1.238 Formulation 5 40° C. ± 2° C., 1.279 solution for 9 days injection

[0150] After formulation 5 solution for injection was placed at 40° C.±2° C. for high temperature acceleration for 9 days, the total impurity level was not significantly different from that of the raw material at day 0, indicating that formulation 5 solution for injection has a good stability.

Example 7 Formulation 6

[0151] The prescription is as follows:

TABLE-US-00013 Substances Prescription Compound II  0.10 g Glacial acetic acid 0.466 g Sodium acetate 0.302 g Mannitol  50.0 g Water for injection, 1000 ml making up the volume to

[0152] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Glacial acetic acid (source: Chengdu Kelong Chemical Co., Ltd.) and sodium acetate (source: Chengdu Jinshan Chemical Test Co., Ltd.) were added to the above-mentioned water for injection under stirring and then stirred to dissolution and clarification to obtain solution (1). Compound II was weighed, added to solution (1) and stirred to clarification to afford solution (2). Mannitol (source: Qingdao Bright Moon Seaweed Group Co., Ltd.) was weighed, added to solution (2) and stirred to clarification, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing, and formulation 6 solution for injection was obtained.

[0153] Formulation 6 solution for injection was placed under the conditions of 2° C.-8° C. and 25° C.±2° C., respectively, and changes of pH values and related substances of each sample were examined, with data shown in Table 8.

TABLE-US-00014 TABLE 8 Examination results of pH values and related substances of formulation 6 solution for injection Sample storage pH Total condition value impurity (%) 2° C.-8° C., 4.22 0.651 81 days 25° C. ± 2° C., 4.22 0.686 81 days

[0154] Conclusion: Under storage conditions of different temperatures, the pH values and total impurity levels were substantially the same, and the content of the total impurity was low, indicating that formulation 6 has a good stability.

Example 8 Formulation 7

[0155] The prescription is as follows:

TABLE-US-00015 Substances Content Compound II  0.10 g Glacial acetic acid 0.466 g Sodium acetate 0.302 g Glucose  50.0 g Water for injection, 1000 ml making up the volume to

[0156] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Glacial acetic acid (source: Chengdu Kelong Chemical Co., Ltd.) and sodium acetate (source: Chengdu Jinshan Chemical Test Co., Ltd.) were added to the above-mentioned water for injection under stirring and then stirred to dissolution and clarification to obtain solution (1). Compound II was weighed, added to solution (1) and stirred to clarification to afford solution (2). Glucose (source: Weifang Shengtai Medicine Co., Ltd.) was weighed, added to solution (2) and stirred to clarification, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing, and formulation 7 solution for injection was obtained.

Example 9 Formulation 8

[0157] The prescription is as follows:

TABLE-US-00016 Substances Content Compound II  0.2 g Glacial acetic acid 4.66 g Anhydrous sodium acetate 1.82 g Water for injection, 1000 ml making up the volume to

[0158] Water for injection in a volume of 95% of the constant volume was measured and taken, and the water temperature was controlled to be 30° C. or less. Glacial acetic acid (source: Duksan Pure Chemicals Co., Ltd. of Republic of Korea) and sodium acetate trihydrate (source: Duksan Pure Chemicals Co., Ltd. of Republic of Korea) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (1). Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing; a leak detection was carried out; and after passing the detection, formulation 8 solution for injection was obtained.

Example 10 Formulation 9

[0159] The prescription is as follows:

TABLE-US-00017 Substances Content Compound II 1.00 g Glacial acetic acid 4.66 g Anhydrous sodium acetate 1.82 g Water for injection, 1000 ml making up the volume to

[0160] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Glacial acetic acid (source: Taishan Xinning Pharmaceutical Co., Ltd.) and sodium acetate (source: Taishan Xinning Pharmaceutical Co., Ltd.) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (1). Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing; a leak detection was carried out; and after passing the detection, formulation 9 solution for injection was obtained.

Example 11 Formulation 10

[0161] The prescription is as follows:

TABLE-US-00018 Substances Content Compound II 5.00 g Glacial acetic acid 4.66 g Anhydrous sodium acetate 1.82 g Water for injection, 1000 ml making up the volume to

[0162] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Glacial acetic acid (source: Taishan Xinning Pharmaceutical Co., Ltd.) and sodium acetate (source: Taishan Xinning Pharmaceutical Co., Ltd.) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (1). Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing; a leak detection was carried out; and formulation 10 solution for injection was obtained.

[0163] Formulation 8 solution for injection obtained in Example 9 was placed under the conditions of 25° C.±2° C. and RH 60%±5%, and 2° C.-8° C.; the quality indicators of the preparation were measured 3 months later; and the results are shown in Table 9.

TABLE-US-00019 TABLE 9 Stability of formulation 8 solution for injection Condition 2° C.-8° C. 25° C. Time 3 months 3 months Character Colorless Colorless clear liquid clear liquid pH value  4.23  4.28 Total  0.291  0.317 impurity (%)

[0164] Conclusion: Compared with the sample under the conditions of 2° C.-8° C. for 3 months, the sample under the conditions of 25° C. for 3 months showed no significant difference in various quality indicators, indicating that the stability of formulation 8 solution for injection was good within 3 months.

[0165] Formulation 9 solution for injection obtained in Example 10 was placed under the conditions of 25° C.±2° C. and RH 60%±5%; the quality indicators of the preparation were measured 6 months later; and the results are shown in Table 10.

TABLE-US-00020 TABLE 10 Stability of formulation 9 solution for injection Time 0 months 6 months Character Colorless Colorless clear liquid clear liquid pH value 4.3 4.3 Color Colorless Colorless Related Maximum  0.28  0.29 substances individual impurity (%) Total  0.90  1.05 impurity (%) Content (%) 102.2  102.5 

[0166] Conclusion: Compared with the sample at month 0, the sample at month 6 showed no significant change in various quality indicators, indicating that formulation 9 solution for injection has a good stability.

[0167] Formulation 10 solution for injection prepared in Example 11 was placed under the conditions of 25° C.±2° C. and RH 60%±5%; the quality indicators of the preparation were measured 6 months later; and the results are shown in Table 11.

TABLE-US-00021 TABLE 11 Stability of formulation 10 solution for injection Time 0 months 6 months Character Colorless Colorless clear liquid clear liquid pH value 4.5 4.5 Color Colorless Colorless Related Maximum  0.20  0.21 substances individual impurity (%) Total  0.91  0.99 impurity (%) Content (%) 99.9  100.2 

[0168] Conclusion: Compared with the sample at month 0, the sample at month 6 showed no significant change in various quality indicators, indicating that the sample obtained in the present disclosure has a good stability.

Example 12 Formulation 11

[0169] The prescription is as follows:

TABLE-US-00022 Substances Content Compound II 0.10 g Glacial acetic acid 4.66 g Anhydrous sodium acetate 1.82 g Water for injection, making up 10000 ml the volume to

[0170] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Glacial acetic acid (source: Taishan Xinning Pharmaceutical Co., Ltd.) and sodium acetate (source: Taishan Xinning Pharmaceutical Co., Ltd.) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (1). Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing; a leak detection was carried out; and formulation 11 solution for injection was obtained.

Example 13 Formulation 12

[0171] The prescription is as follows:

TABLE-US-00023 Substances Content Compound II 10.00 g Glacial acetic acid 13.98 g Anhydrous sodium acetate 5.46 g Water for injection, making up 10000 ml the volume to

[0172] Water for injection in a volume of 90% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Glacial acetic acid (source: Taishan Xinning Pharmaceutical Co., Ltd.) and sodium acetate (source: Taishan Xinning Pharmaceutical Co., Ltd.) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (1). Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing; a leak detection was carried out; and formulation 12 solution for injection was obtained.

Example 14 Formulation 13

[0173] The prescription is as follows:

TABLE-US-00024 Substances Content Compound II 50.00 g Glacial acetic acid 46.6 g Anhydrous sodium acetate 18.2 g Water for injection, making up 10000 ml the volume to

[0174] Water for injection in a volume of 90% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Glacial acetic acid (source: Taishan Xinning Pharmaceutical Co., Ltd.) and sodium acetate (source: Taishan Xinning Pharmaceutical Co., Ltd.) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (1). Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing; a leak detection was carried out; and formulation 13 solution for injection was obtained.

Example 15 Formulation 14

[0175] The prescription is as follows:

TABLE-US-00025 Substances Content Compound II 1.00 g Mannitol 500 g Edetate disodium 0.5 g Glacial acetic acid 4.66 g Anhydrous sodium acetate 1.82 g Water for injection, making up 10000 ml the volume to

[0176] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Mannitol (source: Qingdao Bright Moon Seaweed Group Co., LTD.), glacial acetic acid (source: Taishan Xinning Pharmaceutical Co., Ltd.), sodium acetate (source: Taishan Xinning Pharmaceutical Co., Ltd.) and edetate disodium (source: Hunan Er-kang Pharmaceutical Co., Ltd.) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (1). Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing; a leak detection was carried out; and formulation 14 solution for injection was obtained.

Example 16 Formulation 15

[0177] The prescription is as follows:

TABLE-US-00026 Substances Content Compound II 10.00 g Mannitol 500 g Edetate disodium 0.5 g Glacial acetic acid 23.3 g Anhydrous sodium acetate 9.1 g Water for injection, making up 10000 ml the volume to

[0178] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Mannitol (source: Qingdao Bright Moon Seaweed Group Co., LTD.), glacial acetic acid (source: Taishan Xinning Pharmaceutical Co., Ltd.), sodium acetate (source: Taishan Xinning Pharmaceutical Co., Ltd.) and edetate disodium (source: Hunan Er-kang Pharmaceutical Co., Ltd.) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (1). Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing; a leak detection was carried out; and formulation 15 solution for injection was obtained.

Example 17 Formulation 16

[0179] The prescription is as follows:

TABLE-US-00027 Substances Content Compound II 0.10 g Mannitol 500 g Edetate disodium 0.5 g Glacial acetic acid 4.66 g Anhydrous sodium acetate 1.82 g Water for injection, making up 10000 ml the volume to

[0180] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Mannitol (source: Qingdao Bright Moon Seaweed Group Co., LTD.), glacial acetic acid (source: Taishan Xinning Pharmaceutical Co., Ltd.), sodium acetate (source: Taishan Xinning Pharmaceutical Co., Ltd.) and edetate disodium (source: Hunan Er-kang Pharmaceutical Co., Ltd.) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (1). Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing; a leak detection was carried out; and formulation 16 solution for injection was obtained.

Example 18 Formulation 17

[0181] The prescription is as follows:

TABLE-US-00028 Substances Content Compound II 2.00 g Mannitol 100 g Edetate disodium 0.5 g Glacial acetic acid 9.32 g Anhydrous sodium acetate 3.64 g Water for injection, making up 10000 ml the volume to

[0182] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Mannitol (source: Qingdao Bright Moon Seaweed Group Co., LTD.), glacial acetic acid (source: Taishan Xinning Pharmaceutical Co., Ltd.), sodium acetate (source: Taishan Xinning Pharmaceutical Co., Ltd.) and edetate disodium (source: Hunan Er-kang Pharmaceutical Co., Ltd.) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (1). Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing; a leak detection was carried out; and formulation 17 solution for injection was obtained.

Example 19 Formulation 18

[0183] The prescription is as follows:

TABLE-US-00029 Substances Content Compound II 1.00 g Edetate disodium 0.5 g Glacial acetic acid 4.66 g Anhydrous sodium acetate 1.82 g Water for injection, making up 10000 ml the volume to

[0184] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Glacial acetic acid (source: Taishan Xinning Pharmaceutical Co., Ltd.), sodium acetate (source: Taishan Xinning Pharmaceutical Co., Ltd.) and edetate disodium (source: Hunan Er-kang Pharmaceutical Co., Ltd.) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (1). Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing; a leak detection was carried out; and formulation 18 solution for injection was obtained.

Example 20 Formulation 19

[0185] The prescription is as follows:

TABLE-US-00030 Substances Content Compound II 1.00 g Edetate disodium 1.00 g Glacial acetic acid 4.66 g Anhydrous sodium acetate 1.82 g Water for injection, making up 10000 ml the volume to

[0186] Water for injection in a volume of 95% of the constant volume was measured and taken, and the water temperature was controlled to be 30° C. or less. Glacial acetic acid (source: Taishan Xinning Pharmaceutical Co., Ltd.), sodium acetate (source: Taishan Xinning Pharmaceutical Co., Ltd.) and edetate disodium (source: Hunan Er-kang Pharmaceutical Co., Ltd.) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (1). Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing; a leak detection was carried out; and formulation 19 solution for injection was obtained.

Example 21 Formulation 20

[0187] The prescription is as follows:

TABLE-US-00031 Substances Content Compound II 1.00 g Trehalose 200 g Glacial acetic acid 4.66 g Anhydrous sodium acetate 1.82 g Water for injection, making up 10000 ml the volume to

[0188] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Trehalose (source: Ron Pharm), glacial acetic acid (source: Taishan Xinning Pharmaceutical Co., Ltd.) and sodium acetate (source: Taishan Xinning Pharmaceutical Co., Ltd.) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (1). Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing; a leak detection was carried out; and formulation 20 solution for injection was obtained.

Example 22 Formulation 21

[0189] The prescription is as follows:

TABLE-US-00032 Substances Content Compound II 5.00 g Sodium chloride 90.00 g Sodium phosphate 31.20 g Phosphoric acid Adjusting the pH value to 3-5.5 Water for injection, making up 10000 ml the volume to

[0190] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Sodium chloride (source: Tianjin Haiguang Pharmaceutical Co., Ltd.) and sodium phosphate (source: Sichuan Xilong Chemical Co., Ltd.) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification and adjusted with phosphoric acid (source: Chengdu Kelong Chemical Co., Ltd.) to a pH value of 3-5.5 to obtain solution (1). Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing; a leak detection was carried out; and formulation 21 solution for injection was obtained.

Example 23 Formulation 22

[0191] The prescription is as follows:

TABLE-US-00033 Substances Content Compound II 5.00 g Sodium chloride 90.00 g Sodium benzoate 10.00 g Tartaric acid Adjusting the pH to 3-5.5 Water for injection, making up 10000 ml the volume to

[0192] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Sodium benzoate (source: Chengdu Huayi Pharmaceutical Excipient Manufacturing Co., Ltd.) and sodium chloride (source: Tianjin Haiguang Pharmaceutical Co., Ltd.) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (1). Compound II was weighed, added to solution (1) and stirred until complete dissolution. An appropriate amount of tartaric acid was added to adjust the pH to 3-5.5, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing; a leak detection was carried out; and formulation 22 solution for injection was obtained.

Example 24 Formulation 23

[0193] The prescription is as follows:

TABLE-US-00034 Substances Content Compound II 1.00 g Tartaric acid 15 g Sodium hydroxide Adjusting the pH to 3-5.5 Trehalose 1000 g Water for injection, 10000 ml making up the volume to

[0194] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Trehalose (source: Ron Pharm) and tartaric acid (source: Chengdu Kelong Chemical Reagent Factory) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification; an appropriate amount of sodium hydroxide (Sichuan Xilong Chemical Co., Ltd.) was added to adjust the pH to 3-5.5; and solution (1) was obtained. Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing; a leak detection was carried out; and formulation 23 solution for injection was obtained.

[0195] Formulation 23 solution for injection obtained in Example 24 was placed under the conditions of 25° C.±2° C. and RH 60%±5%; the quality indicators of the preparation were measured 1 month later; and the results are shown in Table 12.

TABLE-US-00035 TABLE 12 Stability of formulation 23 solution for injection 0 months 25° C. 1 month Character Colorless Colorless clear liquid clear liquid pH value 4.22 4.53 Total impurity (%) 0.565 0.608

[0196] Conclusion: Compared with the sample at month 0, the sample at month 1 showed no significant change in various quality indicators, indicating that formulation 23 solution for injection has a good stability.

Example 25 Formulation 24

[0197] The prescription is as follows:

TABLE-US-00036 Substances Content Compound II 1.00 g Tartaric acid 15 g Sodium hydroxide Adjusting the pH to 3-5.5 Trehalose 400 g Water for injection, 10000 ml making up the volume to

[0198] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Trehalose (source: Ron Pharm) and tartaric acid (source: Chengdu Kelong Chemical Reagent Factory) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification; an appropriate amount of sodium hydroxide (Sichuan Xilong Chemical Co., Ltd.) was added to adjust the pH to 3-5.5; and solution (1) was obtained. Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing; a leak detection was carried out; and formulation 24 solution for injection was obtained.

[0199] Formulation 24 solution for injection obtained in Example 25 was placed under the conditions of 40° C.±2° C. and RH 75%±5%; the quality indicators of the preparation were measured 15 d later; and the results are shown in Table 13.

TABLE-US-00037 TABLE 13 Stability of formulation 24 solution for injection Time 0 months 40° C. 15 d Character Colorless Colorless clear liquid clear liquid pH value  4.20  4.20 Total impurity (%)  0.560  0.628

[0200] Conclusion: Compared with the sample at month 0, the sample under the conditions of 40° C. for 15 d showed no significant change in various quality indicators, indicating that formulation 24 solution for injection has a good stability.

Example 26 Formulation 25

[0201]

TABLE-US-00038 Substances Content Compound II 1.00 g Tartaric acid   15 g Sodium hydroxide Adjusting the pH to 3-5.5 Water for injection, 10000 ml making up the volume to

[0202] Water for injection in a volume of 95% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for 20 min or longer; and the water temperature was controlled to be 30° C. or less. Tartaric acid (source: Chengdu Kelong Chemical Reagent Factory) was weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification; an appropriate amount of sodium hydroxide (source: Chengdu Kelong Chemical Co., Ltd.) was added to adjust the pH to 3-5.5; and solution (1) was obtained. Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a 0.22 μm filter and then subjected to filling and sealing; a leak detection was carried out; and formulation 25 solution for injection was obtained.

[0203] Formulation 25 solution for injection obtained in Example 26 was placed under the conditions of 25° C.±2° C. and RH 60%±5%; the quality indicators of the preparation were measured 13 d later; and the results are shown in Table 14.

TABLE-US-00039 TABLE 14 Stability of formulation 25 solution for injection 0 months 25° C. 13 d Character Colorless Colorless clear liquid clear liquid pH value  4.18  4.20 Total impurity (%)  0.518  0.487

[0204] Conclusion: Compared with the sample at month 0, the sample under the conditions of 25° C. for 13 d showed no significant change in various quality indicators, indicating that formulation 25 solution for injection has a good stability.

[0205] Sterile Lyophilized Powder for Injection:

Example 27 Formulation 26

[0206]

TABLE-US-00040 Substances Content Compound II 1.00 g Trehalose  400 g Tartaric acid   15 g Sodium hydroxide Adjusting the pH to 3-5.5 Water for injection, 10000 ml making up the volume to

[0207] Water for injection in a volume of 95% of the constant volume was measured and taken, and the water temperature was controlled to be 30° C. or less. Trehalose (source: Ron Pharm) and tartaric acid (source: Chengdu Kelong Chemical Reagent Factory) were weighed and added to the above-mentioned water for injection under stirring; sodium hydroxide (source: Chengdu Kelong Chemical Co., Ltd.) was used to adjust the pH value to 3-5.5; and the mixture was stirred to dissolution and clarification to obtain solution (1).

[0208] Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water.

[0209] Following sterilizing filtration through a 0.22 μm filter, filling and sealing were carried out, wherein the resulting solution was filled into 3 ml penicillin vials in a loading amount of 1 ml/vial, and the vials were partially stoppered and placed in a lyophilizer for pre-freezing.

[0210] Partition boards were cooled to −35° C. or lower which was maintained for 1-2 h; then a chamber was cooled to −50° C. or lower and vacuumed to 20 Pa or lower; a limited leakage valve was opened and the temperature was raised to −5° C. over 5 h which was maintained for another 2 h; the temperature was raised to 10° C. over 4 h which was maintained until the temperature of the preparation reached 0° C. or higher; the temperature was risen to 35° C. over 3 h which was maintained until the temperature of the preparation reached 25° C. or higher; and then the limited leakage valve was closed, and the temperature was maintained for 2 h.

[0211] Vacuuming or charging nitrogen was performed, and the vials were completely stoppered, taken out from the chamber and capped.

[0212] Formulation 26 lyophilized sample prepared in Example 27 was placed under the conditions of 25° C.±2° C. and RH 60%±5%; the quality indicators of the preparation were measured 6 months later; and the results are shown in Table 15.

TABLE-US-00041 TABLE 15 Stability of formulation 26 lyophilized sample 0 months 10 days 3 months 6 months Character White loose White loose White loose White loose solid solid solid solid Appearance of Colorless Colorless Colorless Colorless reconstituted clear solution clear solution clear solution clear solution solution pH of  4.15  4.17 \  4.20 reconstituted solution Total impurity  0.614  0.577  0.621  0.629

[0213] Conclusion: Compared with the sample at month 0, the sample within 6 months showed no significant change in various quality indicators, indicating that the sample obtained in the present disclosure has a good stability.

Example 28 Formulation 27

[0214]

TABLE-US-00042 Substances Content Compound II  0.2 g Trehalose  400 g Tartaric acid   15 g Sodium hydroxide Adjusting the pH to 3-5.5 Water for injection, 10000 ml making up the volume to

[0215] Water for injection in a volume of 95% of the constant volume was measured and taken, and the water temperature was controlled to be 30° C. or less. Trehalose (source: Ron Pharm) and tartaric acid (source: Hunan Er-kang Pharmaceutical Co., Ltd.) were weighed and added to the above-mentioned water for injection under stirring; sodium hydroxide (source: Hunan Er-kang Pharmaceutical Co., Ltd.) was used to adjust the pH value to 3-5.5; and the mixture was stirred to dissolution and clarification to obtain solution (1).

[0216] Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water.

[0217] Following sterilizing filtration through a 0.22 μm filter, filling and sealing were carried out, wherein the resulting solution was filled into 3 ml penicillin vials in a loading amount of 1 ml/vial, and the vials were partially stoppered and placed in a lyophilizer for pre-freezing.

[0218] Partition boards were cooled to −35° C. or lower which was maintained for 1-2 h; then a chamber was cooled to −50° C. or lower and vacuumed to 20 Pa or lower; a limited leakage valve was opened and the temperature was raised to −5° C. over 5 h which was maintained for another 2 h; the temperature was raised to 10° C. over 4 h which was maintained until the temperature of the preparation reached 0° C. or higher; the temperature was risen to 35° C. over 3 h which was maintained until the temperature of the preparation reached 25° C. or higher; and then the limited leakage valve was closed, and the temperature was maintained for 2 h.

[0219] Vacuuming or charging nitrogen was performed, and the vials were completely stoppered, taken out from the chamber and capped.

Example 29 Formulation 28

[0220]

TABLE-US-00043 Substances Content Compound II  5 g Trehalose 400 g Tartaric acid  15 g Sodium hydroxide Adjusting the pH to 3-5.5 Water for injection, 10000 ml making up the volume to

[0221] Water for injection in a volume of 95% of the constant volume was measured and taken, and the water temperature was controlled to be 30° C. or less. Trehalose (source: Ron Pharm) and tartaric acid (source: Hunan Er-kang Pharmaceutical Co., Ltd.) were weighed and added to the above-mentioned water for injection under stirring; sodium hydroxide (source: Hunan Er-kang Pharmaceutical Co., Ltd.) was used to adjust the pH value to 3-5.5; and the mixture was stirred to dissolution and clarification to obtain solution (1).

[0222] Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water.

[0223] Following sterilizing filtration through a 0.22 μm filter, filling and sealing were carried out, wherein the resulting solution was filled into 3 ml penicillin vials in a loading amount of 1 ml/vial, and the vials were partially stoppered and placed in a lyophilizer for pre-freezing.

[0224] Partition boards were cooled to −35° C. or lower which was maintained for 1-2 h; then a chamber was cooled to −50° C. or lower and vacuumed to 20 Pa or lower; a limited leakage valve was opened and the temperature was raised to −5° C. over 5 h which was maintained for another 2 h; the temperature was raised to 10° C. over 4 h which was maintained until the temperature of the preparation reached 0° C. or higher; the temperature was risen to 35° C. over 3 h which was maintained until the temperature of the preparation reached 25° C. or higher; and then the limited leakage valve was closed, and the temperature was maintained for 2 h.

[0225] Vacuuming or charging nitrogen was performed, and the vials were completely stoppered, taken out from the chamber and capped.

Example 30 Formulation 29

[0226]

TABLE-US-00044 Substances Content Compound II  1.00 g Trehalose  1000 g Tartaric acid   15 g Sodium hydroxide Adjusting the pH to 3-5.5 Water for injection, 10000 ml making up the volume to

[0227] Water for injection in a volume of 95% of the constant volume was measured and taken, and the water temperature was controlled to be 30° C. or less. Trehalose (source: Ron Pharm) and tartaric acid (source: Hunan Er-kang Pharmaceutical Co., Ltd.) were weighed and added to the above-mentioned water for injection under stirring; sodium hydroxide (source: Hunan Er-kang Pharmaceutical Co., Ltd.) was used to adjust the pH value to 3-5.5; and the mixture was stirred to dissolution and clarification to obtain solution (1).

[0228] Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water.

[0229] Following sterilizing filtration through a 0.22 μm filter, filling and sealing were carried out, wherein the resulting solution was filled into 3 ml penicillin vials in a loading amount of 1 ml/vial, and the vials were partially stoppered and placed in a lyophilizer for pre-freezing.

[0230] Partition boards were cooled to −35° C. or lower which was maintained for 1-2 h; then a chamber was cooled to −50° C. or lower and vacuumed to 20 Pa or lower; a limited leakage valve was opened and the temperature was raised to −5° C. over 5 h which was maintained for another 2 h; the temperature was raised to 10° C. over 4 h which was maintained until the temperature of the preparation reached 0° C. or higher; the temperature was risen to 35° C. over 3 h which was maintained until the temperature of the preparation reached 25° C. or higher; and then the limited leakage valve was closed, and the temperature was maintained for 2 h.

[0231] Vacuuming or charging nitrogen was performed, and the vials were completely stoppered, taken out from the chamber and capped.

Example 31 Formulation 30

[0232]

TABLE-US-00045 Substances Content Compound II 1.00 g Lactose  400 g Tartaric acid   15 g Sodium hydroxide Adjusting the pH to 3-5.5 Water for injection, 10000 ml making up the volume to

[0233] Water for injection in a volume of 95% of the constant volume was measured and taken, and the water temperature was controlled to be 30° C. or less. Lactose (source: MEGGLE GmbH & Co. KG, Germany) and tartaric acid (source: Hunan Er-kang Pharmaceutical Co., Ltd.) were weighed and added to the above-mentioned water for injection under stirring; sodium hydroxide (source: Hunan Er-kang Pharmaceutical Co., Ltd.) was used to adjust the pH value to 3-5.5; and the mixture was stirred to dissolution and clarification to obtain solution (1).

[0234] Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water.

[0235] Following sterilizing filtration through a 0.22 μm filter, filling and sealing were carried out, wherein the resulting solution was filled into 3 ml penicillin vials in a loading amount of 1 ml/vial, and the vials were partially stoppered and placed in a lyophilizer for pre-freezing.

[0236] Partition boards were cooled to −35° C. or lower which was maintained for 1-2 h; then a chamber was cooled to −50° C. or lower and vacuumed to 20 Pa or lower; a limited leakage valve was opened and the temperature was raised to −5° C. over 5 h which was maintained for another 2 h; the temperature was raised to 10° C. over 4 h which was maintained until the temperature of the preparation reached 0° C. or higher; the temperature was risen to 35° C. over 3 h which was maintained until the temperature of the preparation reached 25° C. or higher; and then the limited leakage valve was closed, and the temperature was maintained for 2 h.

[0237] Vacuuming or charging nitrogen was performed, and the vials were completely stoppered, taken out from the chamber and capped.

Example 32 Formulation 31

[0238]

TABLE-US-00046 Substances Content Compound II 1.00 g Sucrose  400 g Tartaric acid   15 g Sodium hydroxide Adjusting the pH to 3-5.5 Water for injection, 10000 ml making up the volume to

[0239] Water for injection in a volume of 95% of the constant volume was measured and taken, and the water temperature was controlled to be 30° C. or less. Sucrose (source: Merck, Germany) and tartaric acid (source: Hunan Er-kang Pharmaceutical Co., Ltd.) were weighed and added to the above-mentioned water for injection under stirring; sodium hydroxide (source: Hunan Er-kang Pharmaceutical Co., Ltd.) was used to adjust the pH value to 3-5.5; and the mixture was stirred to dissolution and clarification to obtain solution (1).

[0240] Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water.

[0241] Following sterilizing filtration through a 0.22 μm filter, filling and sealing were carried out, wherein the resulting solution was filled into 3 ml penicillin vials in a loading amount of 1 ml/vial, and the vials were partially stoppered and placed in a lyophilizer for pre-freezing.

[0242] Partition boards were cooled to −35° C. or lower which was maintained for 1-2 h; then a chamber was cooled to −50° C. or lower and vacuumed to 20 Pa or lower; a limited leakage valve was opened and the temperature was raised to −5° C. over 5 h which was maintained for another 2 h; the temperature was raised to 10° C. over 4 h which was maintained until the temperature of the preparation reached 0° C. or higher; the temperature was risen to 35° C. over 3 h which was maintained until the temperature of the preparation reached 25° C. or higher; and then the limited leakage valve was closed, and the temperature was maintained for 2 h.

[0243] Vacuuming or charging nitrogen was performed, and the vials were completely stoppered, taken out from the chamber and capped.

Example 33 Formulation 32

[0244]

TABLE-US-00047 Substances Content Compound II 1.00 g Hydroxypropyl-  400 g β-cyclodextrin Tartaric acid   15 g Sodium hydroxide Adjusting the pH to 3-5.5 Water for injection, 10000 ml making up the volume to

[0245] Water for injection in a volume of 95% of the constant volume was measured and taken, and the water temperature was controlled to be 30° C. or less. Hydroxypropyl-β-cyclodextrin (source: Roquette, France) and tartaric acid (source: Hunan Er-kang Pharmaceutical Co., Ltd.) were weighed and added to the above-mentioned water for injection under stirring; sodium hydroxide (source: Hunan Er-kang Pharmaceutical Co., Ltd.) was used to adjust the pH value to 3-5.5; and the mixture was stirred to dissolution and clarification to obtain solution (1).

[0246] Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water.

[0247] Following sterilizing filtration through a 0.22 μm filter, filling and sealing were carried out, wherein the resulting solution was filled into 3 ml penicillin vials in a loading amount of 1 ml/vial, and the vials were partially stoppered and placed in a lyophilizer for pre-freezing.

[0248] Partition boards were cooled to −35° C. or lower which was maintained for 1-2 h; then a chamber was cooled to −50° C. or lower and vacuumed to 20 Pa or lower; a limited leakage valve was opened and the temperature was raised to −5° C. over 5 h which was maintained for another 2 h; the temperature was raised to 10° C. over 4 h which was maintained until the temperature of the preparation reached 0° C. or higher; the temperature was risen to 35° C. over 3 h which was maintained until the temperature of the preparation reached 25° C. or higher; and then the limited leakage valve was closed, and the temperature was maintained for 2 h.

[0249] Vacuuming or charging nitrogen was performed, and the vials were completely stoppered, taken out from the chamber and capped.

Example 34 Formulation 33

[0250]

TABLE-US-00048 Substances Content Compound II 1.00 g Trehalose  400 g Tartaric acid   45 g Sodium hydroxide Adjusting the pH to 3-5.5 Water for injection, 10000 ml making up the volume to

[0251] Water for injection in a volume of 95% of the constant volume was measured and taken, and the water temperature was controlled to be 30° C. or less. Trehalose (source: Ron Pharm) and tartaric acid (source: Hunan Er-kang Pharmaceutical Co., Ltd.) were weighed and added to the above-mentioned water for injection under stirring; sodium hydroxide (source: Hunan Er-kang Pharmaceutical Co., Ltd.) was used to adjust the pH value to 3-5.5; and the mixture was stirred to dissolution and clarification to obtain solution (1).

[0252] Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water.

[0253] Following sterilizing filtration through a 0.22 μm filter, filling and sealing were carried out, wherein the resulting solution was filled into 3 ml penicillin vials in a loading amount of 1 ml/vial, and the vials were partially stoppered and placed in a lyophilizer for pre-freezing.

[0254] Partition boards were cooled to −35° C. or lower which was maintained for 1-2 h; then a chamber was cooled to −50° C. or lower and vacuumed to 20 Pa or lower; a limited leakage valve was opened and the temperature was raised to −5° C. over 5 h which was maintained for another 2 h; the temperature was raised to 10° C. over 4 h which was maintained until the temperature of the preparation reached 0° C. or higher; the temperature was risen to 35° C. over 3 h which was maintained until the temperature of the preparation reached 25° C. or higher; and then the limited leakage valve was closed, and the temperature was maintained for 2 h.

[0255] Vacuuming or charging nitrogen was performed, and the vials were completely stoppered, taken out from the chamber and capped.

Example 35 Formulation 34

[0256]

TABLE-US-00049 Substances Content Compound II 1.00 g Trehalose  400 g Tartaric acid  7.5 g Sodium hydroxide Adjusting the pH to 3-5.5 Water for injection, 10000 ml making up the volume to

[0257] Water for injection in a volume of 95% of the constant volume was measured and taken, and the water temperature was controlled to be 30° C. or less. Trehalose (source: Ron Pharm) and tartaric acid (source: Hunan Er-kang Pharmaceutical Co., Ltd.) were weighed and added to the above-mentioned water for injection under stirring; sodium hydroxide (source: Hunan Er-kang Pharmaceutical Co., Ltd.) was used to adjust the pH value to 3-5.5; and the mixture was stirred to dissolution and clarification to obtain solution (1).

[0258] Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water.

[0259] Following sterilizing filtration through a 0.22 μm filter, filling and sealing were carried out, wherein the resulting solution was filled into 3 ml penicillin vials in a loading amount of 1 ml/vial, and the vials were partially stoppered and placed in a lyophilizer for pre-freezing.

[0260] Partition boards were cooled to −35° C. or lower which was maintained for 1-2 h; then a chamber was cooled to −50° C. or lower and vacuumed to 20 Pa or lower; a limited leakage valve was opened and the temperature was raised to −5° C. over 5 h which was maintained for another 2 h; the temperature was raised to 10° C. over 4 h which was maintained until the temperature of the preparation reached 0° C. or higher; the temperature was risen to 35° C. over 3 h which was maintained until the temperature of the preparation reached 25° C. or higher; and then the limited leakage valve was closed, and the temperature was maintained for 2 h.

[0261] Vacuuming or charging nitrogen was performed, and the vials were completely stoppered, taken out from the chamber and capped.

Example 36 Formulation 35

[0262]

TABLE-US-00050 Substances Content Compound II 10.00 g Trehalose   500 g Sodium phosphate 78.01 g Phosphoric acid Adjusting the pH to 3-5.5 Water for injection, 10000 ml making up the volume to

[0263] Water for injection in a volume of 95% of the constant volume was measured and taken, and the water temperature was controlled to be 30° C. or less. Trehalose (source: Ron Pharm) and sodium phosphate (source: Sichuan Xilong Chemical Co., Ltd.) were weighed and added to the above-mentioned water for injection under stirring; phosphoric acid (source: Chengdu Kelong Chemical Co., Ltd.) was used to adjust the pH value to 3-5.5; and the mixture was stirred to dissolution and clarification to obtain solution (1).

[0264] Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water.

[0265] Following sterilizing filtration through a 0.22 μm filter, filling and sealing were carried out, wherein the resulting solution was filled into 3 ml penicillin vials in a loading amount of 1 ml/vial, and the vials were partially stoppered and placed in a lyophilizer for pre-freezing.

[0266] Partition boards were cooled to −35° C. or lower which was maintained for 1-2 h; then a chamber was cooled to −50° C. or lower and vacuumed to 20 Pa or lower; a limited leakage valve was opened and the temperature was raised to −5° C. over 5 h which was maintained for another 2 h; the temperature was raised to 10° C. over 4 h which was maintained until the temperature of the preparation reached 0° C. or higher; the temperature was risen to 35° C. over 3 h which was maintained until the temperature of the preparation reached 25° C. or higher; and then the limited leakage valve was closed, and the temperature was maintained for 2 h.

[0267] Vacuuming or charging nitrogen was performed, and the vials were completely stoppered, taken out from the chamber and capped.

Example 37 Formulation 36

[0268]

TABLE-US-00051 Substances Content Compound II  0.1 g Trehalose  400 g Tartaric acid   15 g Sodium hydroxide Adjusting the pH to 3-5.5 Water for injection, 10000 ml making up the volume to

[0269] Water for injection in a volume of 95% of the constant volume was measured and taken, and the water temperature was controlled to be 30° C. or less. Trehalose (source: Ron Pharm) and tartaric acid (source: Hunan Er-kang Pharmaceutical Co., Ltd.) were weighed and added to the above-mentioned water for injection under stirring; sodium hydroxide (source: Hunan Er-kang Pharmaceutical Co., Ltd.) was used to adjust the pH value to 3-5.5; and the mixture was stirred to dissolution and clarification to obtain solution (1).

[0270] Compound II was weighed, added to solution (1) and stirred until complete dissolution, and a constant volume was achieved by adding water.

[0271] Following sterilizing filtration through a 0.22 μm filter, filling and sealing were carried out, wherein the resulting solution was filled into 3 ml penicillin vials in a loading amount of 1 ml/vial, and the vials were partially stoppered and placed in a lyophilizer for pre-freezing.

[0272] Partition boards were cooled to −35° C. or lower which was maintained for 1-2 h; then a chamber was cooled to −50° C. or lower and vacuumed to 20 Pa or lower; a limited leakage valve was opened and the temperature was raised to −5° C. over 5 h which was maintained for another 2 h; the temperature was raised to 10° C. over 4 h which was maintained until the temperature of the preparation reached 0° C. or higher; the temperature was risen to 35° C. over 3 h which was maintained until the temperature of the preparation reached 25° C. or higher; and then the limited leakage valve was closed, and the temperature was maintained for 2 h.

[0273] Vacuuming or charging nitrogen was performed, and the vials were completely stoppered, taken out from the chamber and capped.

[0274] The above embodiments are only preferred embodiments of the present disclosure and are not intended to limit the present disclosure. For those skilled in the art, several improvements, modifications, and equivalent replacements may also be made without departing from the principle of the present disclosure, and these improvements, modifications, and equivalent replacements shall be contained within the scope of protection of the present disclosure.