WO2019169531A1 - Meloxicam tablet for pets - Google Patents

Abstract

The present invention relates to a meloxicam tablet for pets, comprising 0.15 to 0.25% of micronized meloxicam. The meloxicam pharmaceutical tablet for pets comprises the following weight percentages of raw materials: 0.15 to 0.25% of micronized meloxicam, 75 to 85% of a filler, 5 to 10% of a flocculant, 5 to 15% of a flavouring agent, 0.5 to 1.5% of a lubricant, and 0.5 to 1.5% of a toner. The pharmaceutical composition of micronized meloxicam obtained by the method of the present invention not only maintains all effective constituent of the active pharmaceutical ingredient, but also achieves maximum blood concentration rapidly after oral administration of the medicament and improves bioavailability due to micronization and addition of the flocculant.

Description

A meloxicam tablet for pets Technical field

The invention belongs to the technical field of veterinary medicine, and particularly relates to a meloxicam tablet for pets.

Background technique

Meloxicam (C ₁₄ H ₁₃ N ₃ O ₄ S ₂ ) is a non-steroidal anti-inflammatory drug mainly used in animal husbandry and pet breeding. At present, meloxicam has been widely used in the treatment of inflammation and pain diseases at home and abroad. In particular, meloxicam is superior to other drugs of the same type in gastrointestinal and renal tolerance, and is effective in the treatment of rheumatoid arthritis, osteoarthritis and other inflammatory diseases.

However, since meloxicam is insoluble in water, it is impossible to use drugs in a mixed manner. Although there are meloxicam oral liquids and water-soluble granules, the water solubility is improved to some extent or can be taken internally or mixed. However, the preparation cost of the water-soluble granules and the oral liquid is high, and the oral liquid transportation and packaging are inconvenient, and the bioavailability thereof is not high. Accordingly, the object of the present invention is to improve the absorption of a drug by oral administration to solve the low bioavailability of poor solubility of meloxicam.

Summary of the invention

In order to overcome the problem of poor solubility of meloxicam in the prior art, the present invention provides a micronized meloxicam tablet having suitable solubility and a process for the preparation thereof.

In order to solve the above technical problems, the present invention provides a meloxicam pharmaceutical tablet for pets, which comprises 0.15 to 0.25% of micronized meloxicam.

Preferably, a meloxicam pharmaceutical tablet for pets comprises the following raw materials by weight: micronized meloxicam 0.15 to 0.25%, filler 75-85%, flocculant 5 to 10%, fragrance 5 ～15%, lubricant 0.5 to 1.5%, toner 0.5 to 1.5%.

Preferably, the meloxicam pharmaceutical tablet for pets has a particle size at a 95% cumulative volume of micronized meloxicam below 60 μm. It is preferable that the particle diameter at the 95% cumulative volume thereof is 30 μm or less; more preferably, the particle diameter at the 90% cumulative volume thereof is 20 μm or less.

The meloxicam pharmaceutical tablet of the present invention further comprises a pharmaceutical excipient including, but not limited to, a flocculating agent, a disintegrating agent, a filler, a binder, a wetting agent, a lubricant, a sweetener, etc. Wherein the flocculating agent is selected from one or more of sodium citrate, sodium carboxymethyl starch, and croscarmellose sodium; the filler is selected from the group consisting of microcrystalline cellulose, starch, lactose, sucrose, pregelatinization One or more of starch, calcium hydrogen phosphate dihydrate, mannitol, sorbitol; lubricant selected from magnesium stearate, silica, talc, sodium lauryl sulfate, stearyl fumarate One or more of sodium and PEG6000; the flavoring agent is selected from one or more of beef flavor, stevioside, sucralose, sodium saccharin and aspartame; the toner is selected from yellow iron oxide, brown oxide One or several combinations of iron and red iron oxide; the binder is selected from one or more of hypromellose, povidone K30, sodium carboxymethylcellulose, starch slurry; wetting agent Selected from ethanol or water.

The pharmaceutically acceptable carrier is widely used in the field of pharmaceutical technology, and can be suitably selected by those skilled in the art, and may further include a stabilizer, an emulsifier, a glidant, and a coating agent in addition to the foregoing types. Etc., or other carriers or excipients that may be appreciated by those skilled in the art.

A method for preparing micronized meloxicam, which is to pre-pulse meloxicam to prepare particles having a particle size of 50-100 μm, and then micronized by ultrafine pulverization technology to prepare a particle size of 5-15 μm. powder.

Pre-crushing is carried out using conventional comminution techniques in the art including, but not limited to, grinding, extrusion, impact, cutting, and the pulverizing apparatus used includes, but is not limited to, mortars, ball mills, fluid energy mills, preferably streams using collision techniques. Can grind.

The ultrafine pulverization technique is selected from the group consisting of mechanical pulverization, vibration pulverization, jet pulverization, and ultrasonic pulverization; The device used for ultrafine grinding is selected from the group consisting of QWJ-5 airflow vortex mill, CWM-80 super vortex mill, CWM-120 super vortex mill, CWJ-30 superfine pulverizer.

The preparation method of the meloxicam tablet for pets of the invention comprises the following steps:

(1) meloxicam is subjected to micronization treatment to obtain meloxicam powder having a particle diameter of 3 to 10 μm;

(2) The micronized meloxicam having a particle size of 3-10 μm and a flocculating agent, a filler, a flavoring agent, a toner, etc., respectively, are passed through a 60 mesh sieve to remove agglomerates, and then uniformly mixed;

(3) Adding a lubricant to the uniformly mixed raw material powder in a 300,000-level environment, preparing a soft material, placing it in a high-speed wet mixing granulator, opening shearing and stirring, mixing for 10 minutes;

(4) Total mixing: In the environment of 300,000-level area, add lubricant for 3-15 minutes and mix evenly;

(5) Tableting, sheet weight control ± 2%, hardness 120 ~ 180N, that is.

Preferably, the present invention uses a superfine pulverization technique to prepare a compound of meloxicam having a particle size of 5-15 μm, which improves the water solubility of meloxicam, improves the bioavailability, and increases the clinical efficacy of the pharmaceutical preparation.

A pharmaceutical composition of micronized meloxicam, wherein the micronized meloxicam has a particle size at a cumulative volume of 95% below 60 μm; preferably the micronized meloxicam 95% cumulative volume The particle size at the place is 30 μm or less.

The pharmaceutical composition of the micronized meloxicam prepared by the method of the invention not only maintains all the active ingredients of the raw material medicine, but also can rapidly reach the maximum blood concentration and can improve after oral administration of the medicine due to micronization and addition of flocculating agent. Bioabsorbability.

Detailed ways

The above scheme will be further described below in conjunction with specific embodiments. It is to be understood that the examples are intended to illustrate the invention and not to limit the scope of the invention. The implementation conditions employed in the examples can be further adjusted according to the conditions of the specific manufacturer, and the unspecified implementation conditions are usually the conditions in the conventional experiment.

Example 1 Preparation method of meloxicam tablet

1, ingredients

(1) Meloxicam micronization treatment: Ultrafine pulverization of meloxicam raw materials was carried out using a mechanical pulverizer, and the pulverized raw material particles were collected, and the particle size of the fine powder was measured by a Malvern laser particle size analyzer at a cumulative volume of 90%. The particle size is below 30μm.

(2) Screening: In the environment of 300,000-level area, the original and auxiliary materials are respectively passed through a 60-mesh sieve to remove agglomerates to obtain a uniform particle group.

(3) Pre-mixing: Microcrystalline cellulose, sodium citrate, meloxicam, yellow iron oxide, brown iron oxide, red iron oxide, beef flavor, and dioxide are sequentially weighed in a 300,000-level environment. Silicon, pre-gelatinized starch, placed in a high-speed wet mixing granulator, opened shearing and stirring, mixed for 10min

(4) Total mixing: In the environment of 300,000-level area, weigh the prescribed amount of magnesium stearate in the above wet mixing granulator, open shearing and stirring, mix for 3 minutes, take 10 samples at different positions. The intermediate product is tested, and after the test is passed, the tablet is pressed.

2, tablet

In the environment of 300,000-level area, the weight of the piece is calculated according to the content of the intermediate product, and the tablet weight is controlled by ±2%, and the hardness is 120-180N;

3, packaging

The pressed piece, double aluminum blister machine, 7 pieces / plate, 1 plate / box.

[identification]

(1) Take the appropriate amount of fine powder (about equivalent to meloxicam 15mg), add 10ml of chloroform, shake to dissolve meloxicam, 4000 rpm, centrifugation for 5 minutes, take the supernatant and add three 3 drops of ferric chloride test solution, shaken, and placed pale purple after placement.

(2) In the chromatogram recorded under the content determination, the retention time of the main peak of the test solution should be consistent with the retention time of the main peak of the reference solution.

[Check] The test solution under the determination of the relevant substance is used as the test solution. Precisely measure 2 ml, place it in a 100 ml volumetric flask, dilute to the mark with alkaline methanol solution, shake well, and use as a control solution. Take the appropriate amount of 2-amino-5-methylthiazole reference substance, dilute with alkaline methanol solution to make a solution containing about 0.5μg per 1ml, as the impurity reference solution, take the appropriate amount of the test solution and the impurity reference solution. Mix in a ratio of 1:1 and shake well as a system suitability test solution. According to the chromatographic conditions under the content determination, accurately measure the system suitability test solution 20μl, inject into the liquid chromatograph, adjust the flow rate and other chromatographic conditions, so that the retention time of meloxicam peak is about 8.5 to 10 minutes, 2-amino The separation of the -5-methylthiazole peak from the meloxicam peak should be greater than 1.5. Precisely measure 20 μl of each of the test solution, the control solution and the impurity reference solution, and inject them into the liquid chromatograph separately, and record the chromatogram to twice the retention time of the main component peak. If there is impurity peak in the chromatogram of the test solution, the peak of 2-amino-5-methylthiazole should not be larger than 1.5 times (0.3%) of the main peak area of the impurity reference solution, except for the peak before the relative retention time is less than 0.5. The area of other single impurity peaks shall not be greater than 0.25 times (0.5%) of the main peak area of the control solution, and the sum of the impurity peak areas shall not be greater than 0.5 times (1.0%) of the main peak area of the control solution. Any chromatographic peak in the chromatogram of the test solution that is less than 0.025 times the main peak area of the control solution is negligible.

The content uniformity is taken from a piece of this product, placed in a stopper bottle, and 10 ml of an alkaline methanol solution is precisely added. According to the method under the content determination, it is determined according to the law according to the method of "ultrasound for 10 minutes to dissolve meloxicam" (Appendix) 0941), should comply with the regulations.

Dissolution of this product, according to the dissolution test (Appendix 0931, second method), with phosphate buffer (take 6.81 g of potassium dihydrogen phosphate, dissolved in 800 ml of water, adjust the pH to 7.5 with 0.5 mol / L sodium hydroxide, Add water to dissolve into 1000ml) 500ml as dissolution medium, the rotation speed is 50 rpm, operate according to law, after 45 minutes, take the solution, filter, discard about 3ml of the initial filtrate, take the filtrate as the test solution; The reference substance of Xikang is about 12.5mg, accurately weighed, placed in a 50ml volumetric flask, add 2.5ml of methanol and 0.5ml of 0.1mol/L sodium hydroxide solution, dissolve in the ultrasonic solution, dilute to the mark with the dissolution medium, shake well, accurately measure 1 ml, placed in a 50 ml volumetric flask, diluted to the mark with the dissolution medium, shaken, as a reference solution; according to the method of content determination, calculate the dissolution amount of meloxicam in each tablet. The limit is 75% of the marked amount and should be in accordance with the regulations.

Microbial limit aerobic bacteria, total number of molds and yeasts Take this product fine powder, add sterile sodium chloride-peptone buffer (pH 7.0) to make a 1:100 test solution. The test solution, microbiological counting method (Appendix 1105 plate method) and non-sterile veterinary drug microbial limit standard (Appendix 1107) should be inspected.

Escherichia coli should be taken from the fine powder of this product, the control bacteria inspection method (Appendix 1106) and the non-sterile veterinary drug microbial limit standard (Appendix 1107) should be in compliance with the regulations.

Others should comply with the relevant provisions under the tablet (Appendix 0101).

[Content determination] Measured by high performance liquid chromatography (Appendix 0512).

Chromatographic conditions and system suitability test using octadecylsilane bonded silica as a filler (Agilent ZORBAX SB-C18, 5μm, 4.6 × 250mm or equivalent performance column); with 0.2% diammonium phosphate solution (phosphoric acid adjustment) The pH was 7.0)-methanol-isopropyl alcohol (640:320:40) as the mobile phase; the detection wavelength was 270 nm, and the column temperature was 30 °C. The number of theoretical plates is not less than 1500 according to the peak of meloxicam.

Determination method Take 20 pieces of this product, accurately weighed, finely ground, accurately weighed the appropriate amount (about 12.5mg equivalent to meloxicam), placed in a stopper bottle, precision added 50ml of alkaline methanol solution, sonicated for 10 minutes, so that Meloxicam was dissolved, allowed to cool, shaken, 4000 rpm, centrifuged for 5 minutes, filtered, as a test solution, accurately weighed 20 μl into the liquid chromatograph, and recorded the chromatogram. Another appropriate amount of meloxicam reference substance, accurately weighed, dissolved in alkaline methanol solution and diluted to make a solution containing about 250μg per 1ml, the same method, according to the external standard method to calculate the peak area, that is.

[Function and use] Non-steroidal anti-inflammatory drugs. It is used to relieve inflammation and pain caused by acute and chronic bone and muscle diseases in dogs.

[Usage and Dosage] in terms of meloxicam. Oral: 1kg body weight, dog 0.1mg, once a day, doubled for the first time, used for 3 to 4 days.

Example 2 Preparation method of meloxicam tablet

Preparation method 2. (1) Meloxicam micronization treatment: ultrafine pulverization of meloxicam raw materials using a jet mill, collecting the pulverized raw material particles, and measuring the particle size of the fine powder using a Malvern laser particle size analyzer, 90 The particle size at the % cumulative volume is below 20 μm. The other parts are the same as in the first embodiment.

Example 3 Preparation method of meloxicam tablet

Preparation method 2. (1) meloxicam micronization treatment: (A) meloxicam was pre-pulverized by a fluid energy mill using a collision technique to prepare particles having a particle diameter of 80 μm.

(B) The coarse particles are ultra-finely pulverized by a CWJ-30 type ultrafine pulverizer, and pulverized into fine powder of 5-10 μm.

Crushing conditions: the air temperature after lyophilization is 6 ° C, the water content is 0.5%, the pressure is 0.8 MPa when injected into the ultrafine pulverizer, the working pressure of the ultrafine pulverizer is 0.8 MPa, the internal working temperature is 6 ° C, and the pulverization time is 50min.

Example 4 Meloxicam Tablets

The formulation of the meloxicam tablet was prepared according to the method of Example 1 as shown in Table 1.

Table 1 Formulation of meloxicam tablets

Component	Prescription amount (g/1000 tablets)
Meloxicam	2.5
Microcrystalline cellulose	650.0
Sodium citrate	75.0
Yellow iron oxide	5.9
Brown iron oxide	6.4
Red iron oxide	2.7
Beef flavor	92.5
Silica	9.9
Pregelatinized starch	150.0
Magnesium stearate	5.1
total	1000.0

Example 5 Meloxicam Tablets

The formulation of the meloxicam tablet was prepared according to the method of Example 2 as shown in Table 1.

Example 6 Meloxicam Tablets

The formulation of the meloxicam tablet was prepared according to the method of Example 3 as shown in Table 1.

Comparative Example 1

Tablets were prepared according to the formulation of Table 1 using conventional meloxicam, without micronization.

Determination of the solubility of meloxicam of different particle sizes

According to Preparation Examples 3, 4, and 5, meloxicam having a specific particle diameter was prepared to prepare a supersaturated solution, and the solubility of meloxicam in water was calculated by detecting the content, and the results were as follows:

Conclusion: From the above experimental data, the solubility of meloxicam decreases with increasing particle size.

Test Example 3 Determination of bioavailability of meloxicam of different particle sizes

According to the preparation methods of Examples 1-5 and Comparative Example 1, the corresponding preparations were prepared by using meloxicam of a specific particle diameter and a conventional particle diameter, respectively, and then the blood concentration was determined by oral administration to determine the bioavailability result:

* The bioavailability of Comparative Example 1 was 35%.

Conclusion: According to the above data, the preparation of meloxicam with a particle size of 5-10 μm has the best bioavailability, followed by 95% meloxicam with a particle size of less than 20 μm, and the beauty with a particle size of <5 μm. The bioavailability of the formulation prepared by roxicon, followed by the bioavailability of the formulation of meloxicam having a particle size of less than 30 μm, and much higher than the formulation of the conventional particle size of meloxicam of Comparative Examples 1 and 2; Meloxicam having a diameter of 5-10 μm or 95% particle size of less than 20 μm not only ensures bioavailability, but also makes the production process feasible, fully illustrating the benefits and innovations of the present invention.

The above examples are only intended to illustrate the technical concept and the features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the present invention and to implement the present invention, and the scope of the present invention is not limited thereto. Equivalent transformations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims (6)

1. A meloxicam tablet for pets containing 0.15 to 0.25% of micronized meloxicam.
2. The meloxicam tablet according to claim 1, wherein the meloxicam pharmaceutical tablet for pets comprises the following raw materials by weight: micronized meloxicam 0.15 to 0.25%, a filler 75 to 85%, flocculant 5 to 10%, fragrance 5 to 15%, lubricant 0.5 to 1.5%, and toner 0.5 to 1.5%.
3. The meloxicam tablet according to claim 1, wherein the particle size at the 95% cumulative volume of the micronized meloxicam is 60 μm or less.
4. The meloxicam tablet according to claim 1, wherein the particle size at the 95% cumulative volume of the micronized meloxicam is 30 μm or less.
5. The meloxicam tablet according to claim 1, wherein the particle size at the 90% cumulative volume of the micronized meloxicam is 20 μm or less.
6. The meloxicam tablet according to claim 1, wherein the meloxicam pharmaceutical tablet further comprises a medicinal adjuvant selected from the group consisting of a flocculating agent, a disintegrating agent, a filler, and a viscous agent. Mixture, wetting agent, lubricant, sweetener.