A kind of meloxicam internal suspension and preparation method thereof

Abstract

The invention discloses a meloxicam internal suspension and a preparation method thereof. The raw materials of the meloxicam internal suspension include, by mass percentage, 0.05% meloxicam, 40-70% glycerol, 0.3% suspending agent, 0.1%-1% citric acid monohydrate, 0.5-5% sodium dihydrogen phosphate, 0.05-0.2% sodium benzoate, 0.5-5% silicon dioxide, and the balance is water; the sum of the mass percentages of all raw materials is 100%. The present invention adopts hydrophilic silicon dioxide as a stabilizer, and through high-pressure homogenization technology, the system is in a flocculated state, the molecules are not easy to aggregate, the system is physically stable, and the dosage is ensured to be accurate.

Description

Technical Field

[0001] The invention belongs to the technical field of veterinary drugs, and particularly relates to a meloxicam internal suspension and a preparation method thereof. Background Art

[0002] The chemical name of meloxicam (MLX) is 2-methyl-4-hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1 dioxide, and its molecular formula is C 14 H 13 N3O4S2, with a molecular weight of 351.4, is a chemical drug synthesized by Boehringer Ingelheim in Germany in 1996. It is a non-steroidal anti-inflammatory drug and the world's first selective cyclooxygenase inhibitor. It is currently commonly used to treat diseases such as rheumatoid arthritis and osteoarthritis. MLX belongs to Class II drugs in biopharmaceutical classification. It is weakly acidic and has the characteristics of low solubility and high permeability. The solubility of MLX in water is only 4.4μg / mL, and the solubility increases with the increase of the pH value of the solution. It is almost insoluble in organic solvents such as methanol and ethanol, and soluble in organic solvents such as dimethyl sulfoxide and N,N-dimethylformamide.

[0003] Suspension refers to a non-uniform liquid preparation formed by poorly soluble solid drugs being dispersed in a dispersion medium in the form of particles. Suspension is a thermodynamically unstable coarse dispersion system, and the main problem is physical stability. The dispersion of drug particles in the suspension is large, which makes the suspended particles have a high surface free energy and is in an unstable state. In order to improve the physical stability of the suspension, stabilizers such as suspending agents, wetting agents, flocculants, deflocculants, etc. need to be added during preparation. Among them, wetting agents are generally surfactants with an HLB range of 7-11, such as polysorbates, polyoxyethylene castor oil, and poloxamers. When using pet medications, pet owners need to convert according to the weight of the animal and prepare a small medicine dispenser for taking the medicine, such as Figure 1 As shown, there are two problems when using the suspension: (1) Drug molecules aggregate during the storage process of the suspension. Shaking after storage is required to ensure uniformity during administration and accuracy of dosing. The addition of surfactants during the shaking process and the drug collection process will cause a large amount of foam, resulting in uneven dosage; (2) Meloxicam is highly hydrophobic, and molecules are prone to aggregation during storage, resulting in large amounts of aggregation at the bottom or surface, making it impossible to disperse.

[0004] The existing technology has conducted many studies on oral preparations of meloxicam. For example, Wang Linlin et al.'s "The Effect of Different Preparation Methods on the Properties of Meloxicam Nanosuspensions" used 0.5% sodium cholate and 0.5% Tween 20 as stabilizers. In this method, traditional surfactants were added to prepare MLX nanosuspensions by medium grinding, anti-solvent precipitation and pH precipitation. The particle size, in vitro release and other aspects were investigated. The results showed that the medium grinding method was more suitable for the preparation of MLX nanosuspensions than the other two methods, and the crystal form consistency and placement stability could be maintained; Yu Yao et al.'s "Preparation, Characterization and In Vitro and In Vitro Behavior of Meloxicam Nanocrystals of Different Particle Sizes" used PVPk17 to prepare MLX with a particle size of 3 μm by high-pressure homogenization to improve bioavailability, but did not describe the stability; Bi Jiawei et al.'s "Preparation of Meloxicam Solid Dispersion Tablets and Study of Their Dissolution" used hot melt extrusion technology and powder direct tableting to prepare meloxicam solid dispersion tablets, which improved the dissolution and bioavailability of meloxicam. However, none of them provide a physically stable system that can facilitate drug administration to pets. Summary of the invention

[0005] One of the purposes of the present invention is to provide a meloxicam internal suspension, which comprises, by mass percentage, 0.05% meloxicam, 40-70% glycerol, 0.3% suspending agent, 0.1%-1% citric acid monohydrate, 0.5-5% sodium dihydrogen phosphate, 0.05-0.2% sodium benzoate, 0.5-5% silicon dioxide, and the balance is water; the sum of the mass percentages of all the raw materials is 100%.

[0006] Furthermore, the suspending agent is selected from hydroxyethyl cellulose, sodium carboxymethyl cellulose, and PVP.

[0007] Furthermore, the viscosity of the hydroxyethyl cellulose is 25-150 cp, 250-450 cp, 1000-1500 cp or 1500-2500 cp.

[0008] Furthermore, the PVP is PVP k25 or PVP k30.

[0009] The second object of the present invention is to provide a method for preparing the above-mentioned meloxicam oral suspension, comprising the following steps:

[0010] Step 1, weighing the prescribed amount of meloxicam, glycerin and silicon dioxide, and stirring and mixing;

[0011] Step 2, weigh the prescribed amount of hydroxyethyl cellulose and add it to 1 / 3 of the prescribed amount of water, wait for it to swell, then add the prescribed amount of sodium dihydrogen phosphate and citric acid monohydrate, and stir to completely dissolve it;

[0012] Step 3, adding the solution in step 2 to the mixture in step 1 and stirring to mix;

[0013] Step 4, weigh the prescribed amount of sodium benzoate and dissolve it in 1 / 3 of the prescribed amount of water, then add it to the mixed solution in step 3 and stir to mix, then add the remaining prescribed amount of water to 100% under stirring, and homogenize under high pressure to obtain the meloxicam oral suspension.

[0014] Furthermore, in step 1, the stirring conditions are 20-30° C. and 800-1200 rpm.

[0015] Furthermore, in step 2, the stirring conditions are 20-30° C. and 800-1200 rpm.

[0016] Furthermore, in step 3, the stirring conditions are 20-30° C., 800-1200 rpm, and 2-20 min.

[0017] Furthermore, in step 4, the stirring conditions are 20-30° C. and 800-1200 rpm.

[0018] Furthermore, in step 4, the high pressure homogenization condition is 1000-1500 bar high pressure homogenization for 5 times.

[0019] Meloxicam belongs to Class II drugs in biopharmaceutics classification, with low solubility, high permeability and strong hydrophobicity. Meloxicam oral suspension is easy to settle and agglomerate during placement, so a large amount of stabilizer needs to be added during the preparation process to ensure the physical stability of the product during placement, the uniformity when taking and the accuracy of the divided dose. In particular, it is necessary to add a surfactant as a wetting agent, adsorb on the surface of the particles, increase its hydrophilicity, and produce a better dispersion effect. However, the large amount of surfactant added leads to a large amount of foam generated during the shaking and drug dispensing process during use, which cannot be accurately quantified. Therefore, the present invention is designed to use hydrophilic silica as a stabilizer, combined with high-pressure homogenization technology, to prepare a uniform meloxicam suspension.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] (1) Silica can increase the stability of the solution and form a uniform emulsion. At the same time, silica is a hydrophilic insoluble particle with amphiphilicity. It acts as an emulsifier to stabilize the emulsion system. It undergoes emulsification through a high-pressure homogenization process and forms a uniform substance with the hydrophobic drug and solution system. Using hydrophilic silica as a stabilizer and high-pressure homogenization technology, the system is in a flocculated state, the molecules are not easy to aggregate, the system is physically stable, and the dosage is accurate.

[0022] (2) The suspension system does not contain surfactants as wetting agents. During the process of drug absorption in clinical use, no foam is generated, the volume is accurately determined, and clinical convenience is improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is a picture of a small medicine dispenser.

[0024] Figure 2 This is a picture of the appearance of the sample obtained in Example 1.

[0025] Figure 3 This is a picture of the appearance of the sample prepared in Comparative Example 1.

[0026] Figure 4 This is a picture of the appearance of the sample prepared in Comparative Example 2.

[0027] Figure 5 This is a picture of the appearance of the sample prepared in Comparative Example 3.

[0028] Figure 6 This is a picture of the appearance of the sample prepared in Comparative Example 4.

[0029] Figure 7 The particle appearance of the samples prepared in the examples and comparative examples under a microscope, wherein: A is comparative example 1, B is example 1, C is comparative example 2, D is comparative example 3, and E is comparative example 4. DETAILED DESCRIPTION

[0030] The preferred embodiments of the present invention will be described in detail below in conjunction with examples. It should be understood that the following examples are provided only for the purpose of illustration and are not intended to limit the scope of the present invention. Those skilled in the art may make various modifications and substitutions to the present invention without departing from the purpose and spirit of the present invention.

[0031] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0032] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0033] The prescription adopted in the following examples is as follows:

[0034] prescription Dosage effect Meloxicam 0.05％ API glycerin 60％ Solvents Hydroxyethyl cellulose (25-150cp) 0.3％ Suspending Agents Citric acid monohydrate 0.8％ Coagulant-1 Sodium dihydrogen phosphate 3％ Coagulant-2 Sodium Benzoate 0.15％ Antioxidants Silicon dioxide 2％ Stabilizer water to 100%

[0035] Example 1

[0036] Weigh the prescribed amount of meloxicam, glycerin and silicon dioxide, stir and mix, place in a magnetic stirrer and stir at 1000 rpm for 5 minutes until the meloxicam is evenly distributed in the glycerin; weigh the prescribed amount of hydroxyethyl cellulose and add it to 1 / 3 of the prescribed amount of water, wait for it to swell naturally, add the prescribed amount of sodium dihydrogen phosphate and citric acid monohydrate, stir at 1000 rpm for 5 minutes to completely dissolve it; slowly add it to the meloxicam-glycerin-silicon dioxide mixture and stir at 1000 rpm for 5 minutes; weigh the prescribed amount of sodium benzoate and dissolve it in 1 / 3 of the prescribed amount of water, slowly add it to the preparation and stir at 1000 rpm for 5 minutes, add water to make the volume to 100%, slowly add water when adding water and stir at 1000 rpm for 5 minutes; high-pressure homogenization at 1200 bar for 5 times, add silicon dioxide after homogenization, and obtain the final preparation.

[0037] Comparative Example 1

[0038] The difference between this embodiment and embodiment 1 is that silicon dioxide is added but not homogenized.

[0039] Weigh the prescribed amount of meloxicam, glycerin and silicon dioxide, stir at 1000rpm for 5min to mix, place in a magnetic stirrer and stir until the meloxicam is evenly distributed in the glycerin; weigh the prescribed amount of hydroxyethyl cellulose and add it to 1 / 3 of the prescribed amount of water, wait for it to swell naturally, add the prescribed amount of sodium dihydrogen phosphate and citric acid monohydrate, stir at 1000rpm to completely dissolve them; slowly add them to the meloxicam-glycerin-silicon dioxide mixture and stir at 1000rpm; weigh the prescribed amount of sodium benzoate and dissolve it in 1 / 3 of the prescribed amount of water, slowly add it to the preparation and stir at 1000rpm, add water to make up to 100%, slowly add water and stir at 1000rpm when adding water, add silicon dioxide and stir for 2h to obtain the final preparation.

[0040] Comparative Example 2

[0041] The difference between this embodiment and embodiment 1 is that silicon dioxide is not added and homogenization is not performed.

[0042] Weigh the prescribed amount of meloxicam and glycerin, stir and mix, place in a magnetic stirrer and stir at 1000 rpm for 5 minutes until the meloxicam is evenly distributed in the glycerin; weigh the prescribed amount of hydroxyethyl cellulose and add it to 1 / 3 of the prescribed amount of water, wait for it to swell naturally, add the prescribed amount of sodium dihydrogen phosphate and citric acid monohydrate, stir at 1000 rpm for 5 minutes to completely dissolve them; slowly add them to the meloxicam-glycerin mixture and stir at 1000 rpm for 5 minutes; weigh the prescribed amount of sodium benzoate and dissolve it in 1 / 3 of the prescribed amount of water, slowly add it to the preparation and stir at 1000 rpm for 5 minutes, add water to make the volume to 100%, slowly add water when adding water and stir at 1000 rpm for 5 minutes; obtain the final preparation.

[0043] Comparative Example 3

[0044] The difference between this embodiment and embodiment 1 is that no silicon dioxide is added but homogenization is used.

[0045] Weigh the prescribed amount of meloxicam and glycerin, stir and mix, place in a magnetic stirrer and stir at 1000 rpm for 5 minutes until the meloxicam is evenly distributed in the glycerin; weigh the prescribed amount of hydroxyethyl cellulose and add it to 1 / 3 of the prescribed amount of water, wait for it to swell naturally, add the prescribed amount of sodium dihydrogen phosphate and citric acid monohydrate, stir at 1000 rpm for 5 minutes to completely dissolve it; slowly add it to the meloxicam-glycerin mixture and stir at 1000 rpm for 5 minutes; weigh the prescribed amount of sodium benzoate and dissolve it in 1 / 3 of the prescribed amount of water, slowly add it to the preparation and stir at 1000 rpm for 5 minutes, add water to make up to 100%, slowly add water when adding water and stir at 1000 rpm for 5 minutes, and homogenize at 1200 bar high pressure for 5 times to obtain the final preparation.

[0046] Comparative Example 4

[0047] The difference between this embodiment and embodiment 1 is that the silicon dioxide is added after homogenization.

[0048] Weigh the prescribed amount of meloxicam and glycerin, stir and mix, place in a magnetic stirrer and stir at 1000 rpm for 5 minutes to evenly distribute the meloxicam in the glycerin; weigh the prescribed amount of hydroxyethyl cellulose and add it to 1 / 3 of the prescribed amount of water, wait for it to swell naturally, add the prescribed amount of sodium dihydrogen phosphate and citric acid monohydrate, stir to completely dissolve; slowly add to the meloxicam-glycerin mixture and stir rapidly; weigh the prescribed amount of sodium benzoate and dissolve it in 1 / 3 of the prescribed amount of water, slowly add to the preparation and stir at 1000 rpm for 5 minutes; add water to make up to 100%, slowly add water while adding and stir at 1000 rpm for 5 minutes; high-pressure homogenization at 1200 bar for 5 times, and then add silicon dioxide to obtain the final preparation.

[0049] The samples prepared in the above examples and comparative examples were tested for viscosity, particle size, relative density and redispersibility.

[0050] 1. Viscosity

[0051] Detection method: Place the product at 20℃ for 10 minutes, shake vigorously for 1 minute, transfer the sample to a measuring cup and place for 2 minutes, and measure with a rotational viscometer (current Chinese veterinary drug 0633 third method) at a shear rate of 75 / s, and measure immediately.

[0052] 2. Granularity

[0053] Detection method: Take about 10 mg of this product and determine the particle size and particle size distribution according to the method (Appendix 0982 Method 1 of the current Chinese Pharmacopoeia of Veterinary Medicine).

[0054] 3. Relative density

[0055] Test method: Take a clean, dry and accurately weighed pycnometer, fill it with the test sample (temperature should be below 20℃), install a thermometer (there should be no bubbles in the bottle), place it in a 20℃ water bath for several minutes to make the temperature of the contents reach 20℃, remove the liquid overflowing the side tube with filter paper, and immediately cover it. Then take the pycnometer out of the water bath, wipe the outside of the pycnometer with filter paper, accurately weigh and subtract the weight of the pycnometer, and after obtaining the weight of the test sample, pour out the test sample, wash the pycnometer, fill it with freshly boiled cold water, and then measure the weight of water at the same temperature according to the above method, and calculate according to the following formula:

[0056] The relative density of the test sample weight = test sample weight / water weight.

[0057] 4. Redispersibility

[0058] Detection method: Take 15mL of solution and place it in a centrifuge tube. Centrifuge it at 4000 rpm for 10 minutes. Then invert it upside down 10 times to observe whether the precipitate at the bottom is easy to disperse.

[0059] The test results are as follows:

[0060]

[0061]

[0062] According to the above table and Figure 2-7 It can be seen that the particle size of the preparation obtained by adding silicon dioxide first and then homogenizing is smaller, and the particle size is less than 25μm, and its viscosity is larger, which can effectively improve the sedimentation of the suspension and significantly improve the redispersibility of the preparation; according to Figure 3 It can be seen that after the preparation is placed with silica added but without high pressure homogenization, the silica will aggregate into lumps at the bottom and is not easy to disperse again; Figure 4 and Figure 5 It can be seen that the preparation without silicon dioxide will form cakes at the bottom after being placed, and the dispersion of the preparation is poor; Figure 6 It can be seen that although the redispersibility of the preparation can be improved after high-pressure homogenization and then adding silicon dioxide, there will still be a small amount of preparation cake at the bottom of the preparation.

Claims

1. A meloxicam internal suspension, characterized in that: The raw materials include, by mass percentage, 0.05% of meloxicam, 40-70% of glycerol, 0.3% of suspending agent, 0.1%-1% of citric acid monohydrate, 0.5-5% of sodium dihydrogen phosphate, 0.05-0.2% of sodium benzoate, 0.5-5% of silicon dioxide, and the balance is water; the sum of the mass percentages of all the raw materials is 100%.

2. The meloxicam internal suspension according to claim 1, characterized in that: The suspending agent is selected from hydroxyethyl cellulose, sodium carboxymethyl cellulose and PVP.

3. The meloxicam internal suspension according to claim 2, characterized in that: The viscosity of the hydroxyethyl cellulose is 25-150 cp, 250-450 cp, 1000-1500 cp or 1500-2500 cp.

4. The meloxicam internal suspension according to claim 2, characterized in that: The PVP is PVP k25 or PVPk30.

5. The method for preparing the meloxicam internal suspension according to any one of claims 1 to 4, characterized in that: The following steps are involved: Step 1, weighing the prescribed amount of meloxicam, glycerin and silicon dioxide, and stirring and mixing; Step 2, weigh the prescribed amount of hydroxyethyl cellulose and add it to 1 / 3 of the prescribed amount of water, wait for it to swell, then add the prescribed amount of sodium dihydrogen phosphate and citric acid monohydrate, and stir to completely dissolve it; Step 3, adding the solution in step 2 to the mixture in step 1 and stirring to mix; Step 4, weigh the prescribed amount of sodium benzoate and dissolve it in 1 / 3 of the prescribed amount of water, then add it to the mixed solution of step 3 and stir to mix, then add the remaining prescribed amount of water to 100% under stirring, and homogenize under high pressure to obtain the meloxicam oral suspension.

6. The preparation method according to claim 5, characterized in that The stirring conditions in step 1 are 20-30° C. and 800-1200 rpm.

7. The preparation method according to claim 5, characterized in that The stirring conditions in step 2 are 20-30° C. and 800-1200 rpm.

8. The preparation method according to claim 5, characterized in that The stirring conditions in step 3 are 20-30° C., 800-1200 rpm, and 2-20 min.

9. The preparation method according to claim 5, characterized in that The stirring conditions in step 4 are 20-30° C. and 800-1200 rpm.

10. The preparation method according to claim 5, characterized in that In step 4, the high pressure homogenization condition is 1000-1500 bar high pressure homogenization 5 times.

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