INJECTABLE PHARMACEUTICAL COMPOSITION CONTAINING MELOXICAM, AND PREPARATION METHOD THEREFOR

Abstract

An injectable pharmaceutical composition containing meloxicam, and a preparation method therefor. The pharmaceutical composition includes meloxicam nanoparticles, a surface stabilizer, and a sedimentation inhibiting agent. The pharmaceutical composition has good stability, is not easy to settle, and is applicable to industrial large-scale production.

Claims

1.-13. (canceled)

14. An injectable pharmaceutical composition, comprising meloxicam nanoparticles and a surface stabilizer, wherein the pharmaceutical composition further comprises a sedimentation inhibitor, wherein the sedimentation inhibitor is one or more selected from the group consisting of glycerol, propylene glycol, polyethylene glycol, albumin, hydroxyethyl starch, sodium carboxymethyl cellulose and hydroxypropyl--cyclodextrin.

15. The pharmaceutical composition according to claim 14, wherein the sedimentation inhibitor is glycerol.

16. The pharmaceutical composition according to claim 14, wherein the weight ratio of meloxicam to the sedimentation inhibitor is 1:0.1-1:100.

17. The pharmaceutical composition according to claim 14, wherein the weight ratio of meloxicam to the sedimentation inhibitor is 1:0.1-1:50.

18. The pharmaceutical composition according to claim 14, wherein the weight ratio of meloxicam to the sedimentation inhibitor is 1:0.5-1:20.

19. The pharmaceutical composition according to claim 14, wherein the weight ratio of meloxicam to the sedimentation inhibitor is 1:0.5-1:10.

20. The pharmaceutical composition according to claim 14, wherein the surface stabilizer is one or more selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl methylcellulose, Tween 80, poloxamer, polyethylene glycol 15-hydroxystearate, lecithin, sodium deoxycholate, sodium cholate, sodium dodecyl sulfonate and sodium dodecyl sulfate.

21. The pharmaceutical composition according to claim 14, wherein the weight ratio of meloxicam to the surface stabilizer is 1:0.01-1:100.

22. The pharmaceutical composition according to claim 14, wherein the surface stabilizer does not comprise glycerol.

23. The pharmaceutical composition according to claim 14, wherein the surface stabilizer comprises a first surface stabilizer and a second surface stabilizer, wherein the first surface stabilizer is selected from the group consisting of non-ionic surface stabilizers and zwitterionic surface stabilizers; and the second surface stabilizer is an anionic surface stabilizer.

24. The pharmaceutical composition according to claim 23, wherein the first surface stabilizer is selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl methylcellulose, Tween 80, poloxamer, polyethylene glycol 15-hydroxystearate or lecithin.

25. The pharmaceutical composition according to claim 23, wherein the second surface stabilizer is selected from the group consisting of sodium deoxycholate, sodium cholate, sodium dodecyl sulfonate or sodium dodecyl sulfate, and more preferably sodium deoxycholate or sodium cholate.

26. The pharmaceutical composition according to claim 23, wherein the weight ratio of meloxicam to the first surface stabilizer is 1:0.01-1:100; and the weight ratio of meloxicam to the second surface stabilizer is 1:0.01-1:100.

27. The pharmaceutical composition according to claim 14, wherein the average particle size of the meloxicam nanoparticles is less than 2000 nm.

28. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition further comprises a liquid medium selected from the group consisting of water, saline solution, safflower seed oil, ethanol, t-butanol, hexane and ethylene glycol.

29. The pharmaceutical composition according to claim 14, wherein meloxicam is present in an amount of 10-100 mg/mL, based on the weight-to-volume ratio of the active ingredient to the pharmaceutical composition.

30. An injectable pharmaceutical composition, comprising: (1) meloxicam nanoparticles, (2) polyvinylpyrrolidone, (3) sodium deoxycholate, (4) a sedimentation inhibitor and (5) water, wherein, the sedimentation inhibitor is one or more selected from the group consisting of glycerol, polyethylene glycol and hydroxyethyl starch; and the average particle size of the meloxicam nanoparticles is less than 500 nm.

31. The pharmaceutical composition according to claim 30, wherein the weight ratio of meloxicam to the sedimentation inhibitor is 1:0.5-1:20; the weight ratio of meloxicam to polyvinylpyrrolidone is 1:0.05-1:5; and the weight ratio of meloxicam to sodium deoxycholate is 1:0.05-1:5.

32. A method for preparing the injectable pharmaceutical composition according to claim 14, comprising the steps of: 1) mixing a surface stabilizer, meloxicam and an optional sedimentation inhibitor; 2) grinding the above mixed system to prepare a dispersion; and optionally 3) mixing a sedimentation inhibitor with the above dispersion.

33. A method for preparing the injectable pharmaceutical composition according to claim 30, comprising the steps of: 1) mixing a surface stabilizer, meloxicam and an optional sedimentation inhibitor; 2) grinding the above mixed system to prepare a dispersion; and optionally 3) mixing a sedimentation inhibitor with the above dispersion.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0045] The present invention is further described in detail by the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only, and are not intended to limit the scope of the present invention.

[0046] In the following examples, the insoluble particles in the nanoparticle injection were determined with reference to the microscopic method under the general rule of United States Pharmacopeia (USP) <788>. Each test sample container contained no more than 3,000 particles with a particle size of 10 m or more, and no more than 300 particles with a particle size of 25 m or more.

[0047] The impurity amount of the nanoparticle injection was determined by HPLC. Detection condition: ODS-2 column (5 m, 4.6150 mm), mobile phase: methanol/water, detection wavelengths: 260 nm and 350 nm.

EXAMPLE 1

[0048] Polyvinylpyrrolidone was used as the first surface stabilizer, sodium deoxycholate was used as the second surface stabilizer, and glycerol was used as the sedimentation inhibitor to prepare the nanoparticle injection. The specific prescription ingredients and their dosages are as follows:

TABLE-US-00001 TABLE 1 Prescription ingredients and dosages Prescription Dosage ingredients of Prescription Name (weight-to-volume ratio) each injection amount Meloxicam 2.5% 30 mg 150 g PVP-K17 0.5% 6 mg 30 g Sodium 0.25% 3 mg 15 g deoxycholate Glycerol 2.5% 30 mg 150 g Water qs qs qs

[0049] Preparation method:

[0050] 1) a prescription amount of PVP-K17 and sodium deoxycholate were dissolved in 50% of the total weight of water;

[0051] 2) the above system was added with the API meloxicam, and mixed well;

[0052] 3) the above mixed system was added to the cavity of a mill filled with grinding beads, and grinded for 6 hours; and

[0053] 4) the above grinded solution was added with the sedimentation inhibitor, and set to the target weight.

[0054] The indicators such as particle size, pH, osmotic pressure, insoluble particles and related substances of the above nanoparticle injection were determined. The test results are as follows:

TABLE-US-00002 TABLE 2 Results of particle size, pH, osmotic pressure and insoluble particles Average particle Insoluble particles (number) Osmotic pressure Time pH size (nm) PdI 10 m 25 m 302 mOsm/kg Initial point 7.02 86.80 0.264 17 10 40 C. 10 d 6.84 93.10 0.244 16 9

TABLE-US-00003 TABLE 3 Results of related substances Time Maximum single impurity Total impurities Initial point 0.132% 0.324% 40 d_10 D 0.164% 0.367%

[0055] The results showed that the injection prepared with 2.5% glycerol as the sedimentation inhibitor had a qualified osmotic pressure, and there were no significant changes in pH, particle size, insoluble particles and related substances after the injection was stored under an accelerated condition of 40 C. for a period of time, indicating that the sample had a good stability.

EXAMPLE 2

[0056] PVP-K17 was used as the first surface stabilizer, sodium cholate was used as the second surface stabilizer, and glycerol was used as the sedimentation inhibitor to prepare the nanoparticle injection. The specific prescription ingredients and their dosages are as follows:

TABLE-US-00004 TABLE 4 Prescription ingredients and dosages Prescription Dosage ingredients of Prescription Name (weight-to-volume ratio) each injection amount Meloxicam 2.5% 30 mg 150 g PVP-K17 0.5% 6 mg 30 g Sodium 0.25% 3 mg 15 g deoxycholate Glycerol .sup.5% 60 mg 300 g Water qs qs qs

[0057] Preparation method:

[0058] 1) a prescription amount of PVP-K17 and sodium cholate were dissolved in 50% of the total weight of water;

[0059] 2) the above system was added with the API meloxicam, and mixed well;

[0060] 3) the above mixed system was added to the cavity of a mill filled with grinding beads, and grinded for 8 hours; and

[0061] 4) the above grinded solution was added with the sedimentation inhibitor, and set to the target weight.

[0062] The indicators such as particle size, pH, osmotic pressure, insoluble particles and related substances of the above nanoparticle injection were determined. The test results are as follows:

TABLE-US-00005 TABLE 5 Results of particle size, pH, osmotic pressure and insoluble particles Osmotic Average particle Insoluble particles (number) pressure Time pH size (nm) PdI 10 m 25 m 621 mOsm/kg Initial point 7.01 86.03 0.256 14 7 40 C. 10 days 6.79 92.10 0.243 17 11

TABLE-US-00006 TABLE 6 Results of related substances Time Maximum single impurity Total impurities Initial point 0.138% 0.343% 40 C. 10 days 0.152% 0.328%

[0063] The results showed that the injection prepared with 5% glycerol as the sedimentation inhibitor had a qualified osmotic pressure, and there were no significant changes in pH, particle size, insoluble particles and related substances after the injection was stored under an accelerated condition of 40 C. for a period of time, indicating that the sample had a good stability.

EXAMPLE 3

[0064] The ability of different sedimentation inhibitors to inhibit the sedimentation of nanoparticle composition was determined by observing the appearance. The tested nanoparticle compositions comprised 2.5% of meloxicam, 0.5% of PVP-K17 and 0.25% of sodium deoxycholate by weight-to-volume ratio, as well as different types and dosages of sedimentation inhibitors (see Table 7). The nanoparticle injection was prepared by the same preparation method as in Example 1. The test results are shown in Table 7 below.

TABLE-US-00007 TABLE 7 Inhibition of sedimentation by different sedimentation inhibitors Type and dosage of sedimentation Appearance under different storage conditions inhibitor 40 C. 1 M 25 C. 1 M 2-8 C. 1 M 5% of mannitol Small amount of Small amount of Good precipitation precipitation 10% of mannitol Small amount of Small amount of Good precipitation precipitation 5% of sucrose Good Small amount of Good precipitation 10% of sucrose Small amount of Small amount of Good precipitation precipitation 30% of sucrose Precipitation Precipitation Good 10% of dextran 40 Precipitation Precipitation Good 10% of glycerol Good Good Good 20% of glycerol Good Good Good

[0065] The results showed that temperature had a certain affect on the stability of the product. The higher the temperature, the more unstable the system. In addition, glycerol had a better inhibition effect on precipitation than other sedimentation inhibitors.

EXAMPLE 4

[0066] The effect of different types of sedimentation inhibitors was determined by detecting insoluble particles in the samples. The tested nanoparticle compositions comprised 2.5% of meloxicam, 0.5% of PVP-K17 and 0.25% of sodium deoxycholate by weight-to-volume ratio, as well as different types and dosages of sedimentation inhibitors (see Table 8). The test results of insoluble particles after the samples were stored at 40 C. for 15d and 1M are shown in Table 8 below.

TABLE-US-00008 TABLE 8 Effect of different sedimentation inhibitors on insoluble particles of the product 40 C. 15 d 40 C. 1 M Type and dosage insoluble particles insoluble particles of sedimentation (number) (number) inhibitor 10 m 25 m 10 m 25 m 10% of sucrose 121 18 197 30 30% of sucrose 110 14 Obvious Obvious sedimentation sedimentation 10% of dextran 40 123 48 97 (yellow 10 (yellow solid on the solid on the filter filter membrane) membrane) 5% of hydroxyethyl 59 16 57 20 starch 10% of glycerol 75 7 70 7 20% of glycerol 64 4 53 13 100 mM disodium 107 25 Obvious Obvious hydrogen phosphate sedimentation sedimentation 10% of sucrose + 171 28 Obvious Obvious 100 mM disodium sedimentation sedimentation hydrogen phosphate

[0067] The results showed that when sucrose, dextran 40 or phosphate buffer was used as the sedimentation inhibitor, the product showed an increase in insoluble particles and sedimentation after being stored under an accelerated condition for 1M. When glycerol was used as the sedimentation inhibitor, the number of insoluble particles was small, and the nanoparticle system had a good stability.

EXAMPLE 5

[0068] The effect of different sedimentation inhibitors on the stability of the products was determined. The tested nanoparticle compositions comprised 2.5% of meloxicam, 0.5% of PVP-K17 and 0.25% of sodium deoxycholate by weight-to-volume ratio, as well as different types and dosages of sedimentation inhibitors (see Table 9). The test results of pH, particle size and insoluble particles after the samples were stored at 40 C. or 60 C. for 10d are shown in Table 9 below. The appearance results after the samples were stored at room temperature (25 C.) for 1M are shown in Table 10.

TABLE-US-00009 TABLE 9 Results of pH, particle size and insoluble particles Average Insoluble particles Sedimentation particle (number) inhibitor Time pH size PdI 10 m 25 m 5% of glycerol Initial point 7.01 (23.4 C.) 86.03 nm 0.256 14 7 40 C. 10 d 6.79 (26.2 C.) 92.10 nm 0.243 17 11 60 C. 10 d 6.85 (25.0 C.) 98.56 nm 0.235 28 16 2.5% of glycerol Initial point 7.02 (23.5 C.) 86.80 nm 0.264 17 10 40 C. 10 d 6.84 (26.4 C.) 93.10 nm 0.244 16 9 60 C. 10 d 6.86 (25.7 C.) 99.98 nm 0.232 13 8 2.5% of mannitol Initial point 7.03 (24.0 C.) 86.44 nm 0.267 11 6 40 C. 10 d 6.93 (26.6 C.) 93.58 nm 0.252 17 10 60 C. 10 d 6.88 (26.1 C.) 98.81 nm 0.239 21 13

TABLE-US-00010 TABLE 10 Appearance of the samples comprising different sedimentation inhibitors after being stored at room temperature for 1 M Sedimentation inhibitor Time Appearance 5% of glycerol Room temperature, 1 M Light yellow emulsion, no sedimentation and good appearance 2.5% of glycerol Room temperature, 1 M Light yellow emulsion, no sedimentation and good appearance 2.5% of mannitol Room temperature, 1 M Light yellow emulsion with sedimentation and yellow flaky solid at the bottom

[0069] The results showed that 1) when 5% of glycerol, 2.5% of glycerol or 2.5% of mannitol was used as the sedimentation inhibitor, there was little change in pH after the samples were stored at 40 C. or 60 C. for 10d; 2) for the sample comprising 5% of glycerol, 2.5% of glycerol or 2.5% of mannitol, there was little change in insoluble particles after the samples were stored at 40 C. for 10d; for the sample comprising 5% of glycerol or 2.5% of mannitol, there was a slightly increase in insoluble particles after the samples were stored at 60 C. for 10d, but there was no significant change for the sample comprising 2.5% of glycerol; and 3) after the samples were stored at room temperature for 1M, there were flaky crystals at the bottom of the sample with 2.5% of mannitol as the sedimentation inhibitor, but the appearance of the sample with glycerol as the sedimentation inhibitor was good. The product with glycerol as the sedimentation inhibitor has a better stability than the product with 2.5% of mannitol as the sedimentation inhibitor.

EXAMPLE 6

[0070] The nanoparticle injection obtained in Example 1 was stored respectively at (25 C.2 C., RH605%) and (2-8 C.) for 6 months to determine its stability. The results are shown in Tables 11 and 12.

TABLE-US-00011 TABLE 11 Results of the accelerated test Time (month) 0 3 6 Impurity 0.21 0.26 0.28 amount (%) pH 7.0 7.1 7.0 Particle size 100.4 110.7 112.6 Amount (%) 102.9 103.7 104.5

TABLE-US-00012 TABLE 12 Results of the long-term test Time (month) Tested factor 0 3 6 Impurity 0.21 0.22 0.24 amount (%) pH 7.0 7.1 7.0 Particle size 100.4 134.0 103.5 Amount (%) 102.9 103.5 104.1

[0071] The results showed that there was no significant change in the property, pH, particle size and impurity amount of the sample after long-term storage under each condition, and the stability of the sample was good.