CN108653225B

CN108653225B - Nimesulide preparation and preparation method thereof

Info

Publication number: CN108653225B
Application number: CN201810930075.8A
Authority: CN
Inventors: 黄晶; 杨刚; 李守明; 王洪萍; 马明为
Original assignee: Hubei Wellness Pharmaceutical Co ltd
Current assignee: Hubei Wellness Pharmaceutical Co ltd
Priority date: 2018-08-15
Filing date: 2018-08-15
Publication date: 2021-01-08
Anticipated expiration: 2038-08-15
Also published as: CN108653225A

Abstract

The invention provides a nimesulide preparation and a preparation method thereof. A nimesulide preparation is mainly prepared by wet granulation of the following components: according to weight percentage, nimesulide 19.0-28.0%, surfactant 0.07-0.50%, adhesive 1.0-2.0%, disintegrating agent 4.0-9.0%, filler 30.0-70.0%, lubricant 0.5-1.2%, and water in balance. The invention is obtained by granulating by taking water as a wetting agent, avoids possible crystal form transformation and toxic and side effects, ensures the safety and effectiveness of the preparation, and realizes faster dissolution.

Description

Nimesulide preparation and preparation method thereof

Technical Field

The invention relates to the field of medicines, in particular to a nimesulide preparation and a preparation method thereof.

Background

Nimesulide (Nimesulide) is a proprietary product of Helsinn corporation, switzerland, first marketed in italy in 1985, and is currently used in over 50 countries with market sizes exceeding $ 10 billion, including tablets marketed under the trade names of Aulin and Mesulid in france, portuga, greece, switzerland, russia, thailand and brazil, at a specification of 100mg (rld). Nimesulide was never evaluated by the FDA in the united states and it is not marketed. Nimesulide, available under the trade names of Aulin and Mesulid, is a nonsteroidal anti-inflammatory drug that selectively inhibits cyclooxygenase ii, and thus has significant anti-inflammatory, analgesic, and antipyretic effects. A large amount of clinical literature data at home and abroad show that nimesulide has quicker antipyretic and analgesic effects and equivalent adverse reactions compared with ibuprofen and acetaminophen.

At the end of the 60's 20 th century, nimesulide was invented by 3M Pharmaceuticals, a new chemical entity, and the synthesis process was patented in 1974 as U.S. patent No. u.s.p.3856859. In 1980, Helsinn, Switzerland, received exclusive patent rights for nimesulide worldwide. Nimesulide was first marketed in italy in 1985 and is currently used in over 50 countries, with market sizes exceeding $ 10 billion.

As nimesulide is a drug with extremely strong hydrophobicity, the nimesulide is insoluble in water and has water solubility of about 0.01mg/mL at room temperature. Overcoming the poor water solubility of nimesulide brings significant significance to the application of nimesulide.

Patent application CN102000050 uses ethanol as diluent to prepare nimesulide preparation to improve dissolution rate. The nimesulide can generate crystal form transformation in an ethanol solution, so that the drug effect of the preparation obtained by the scheme is reduced, and the application of the preparation is limited.

In view of the above, the present invention is particularly proposed.

Disclosure of Invention

The first purpose of the invention is to provide a nimesulide preparation which is obtained by granulating by taking water as a wetting agent, avoids possible crystal form transformation and toxic and side effects, ensures the safety and effectiveness of the preparation, and realizes faster dissolution.

The second purpose of the invention is to provide the preparation method of the nimesulide preparation, which adopts a non-organic solvent to carry out wet granulation, thereby ensuring the safety and effectiveness of the preparation and improving the safety in the production process; and the preparation process is simple and is suitable for industrial mass production.

In order to solve the technical problems, the invention provides the following technical scheme:

a nimesulide preparation is mainly prepared by wet granulation of the following components: according to the weight percentage, the weight percentage of the alloy is,

nimesulide 19.0-28.0%,

0.07 percent to 0.50 percent of surfactant,

1.0 to 2.0 percent of adhesive,

4.0 to 9.0 percent of disintegrating agent,

30.0 to 70.0 percent of filling agent,

0.5 to 1.5 percent of lubricant,

the balance of water.

The invention takes water as wetting agent, and adds the preparation auxiliary materials of the surfactant, the adhesive, the filling agent, the disintegrating agent, the lubricant and the like in specific proportion, and the formed preparation has the following effects:

the nimesulide does not generate crystal form transformation in water, so that the problems of drug effect reduction, toxic and side effects increase and the like caused by crystal form transformation are avoided, and the production safety is improved;

secondly, the dissolution speed is high, and the used auxiliary materials can accelerate the dissolution of nimesulide.

In addition, the raw materials used in the above formulations can be further optimized, as detailed below.

The proportion of each component in the preparation is preferably, by weight percentage,

nimesulide 23.0% -28.0%, preferably 19% -25.0%, preferably 19% -23.0%, or 19% -22.0%, or 19% -21.0% etc.;

0.20 to 0.50 percent of surfactant, preferably 0.2 to 0.23 percent, preferably 0.20 to 0.40 percent, 0.20 to 0.30 percent, or 0.20 to 0.25 percent, or 0.20 to 0.22 percent, and the like,

1.3% -2.0%, preferably 1.3% -1.5%, preferably 1.3% -1.45%, or 1.3% -1.4% of adhesive;

4.5 to 9.0 percent of disintegrant, preferably 4.6 to 7 percent, preferably 4.6 to 6 percent, or 4.6 to 5 percent,

30.0 to 70.0 percent of filler, preferably 48 to 50 percent, preferably 48 to 49 percent,

0.5 to 1.2%, preferably 0.5 to 0.7%, preferably 0.5 to 0.6%,

the water is preferably 24% to 35%, preferably 24% to 28%, or 24% to 27%, or 24% to 28%, or 24% to 25%.

For the selection of the auxiliary materials, the combination effect of different types of auxiliary materials is different, and the dissolution rate, the particle dispersion degree, the safety, the components and the like are mainly influenced. After screening, the following types are preferred.

Preferably, the binder is one or more of sodium carboxymethylcellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, gelatin, polyvinylpyrrolidone, and the like, preferably hydroxypropyl cellulose.

Preferably, the lubricant is one or more of magnesium stearate, aerosil, talcum powder, hydrogenated vegetable oil, polyethylene glycol and magnesium lauryl sulfate, preferably magnesium stearate;

preferably, the disintegrant is one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl cellulose, preferably sodium carboxymethyl starch;

preferably, the filler is one or more of microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate for medical use, mannitol and lactose, preferably one or more of microcrystalline cellulose and lactose; preferably, the microcrystalline cellulose is PH101, PH102, PH103, PH 105, PH301 or PH302, etc., and the lactose is 200M, and the lactose and the microcrystalline cellulose are added to generate a synergistic effect, so that the drug dissolution rate is greatly improved.

Preferably, the surfactant is one or more of sodium lauryl sulfate, sodium dodecylbenzene sulfonate, amino acid type surfactant, betaine type surfactant and docusate sodium, preferably sodium lauryl sulfate.

In addition, the particle size of nimesulide itself also affects the dissolution rate, and the particle size distribution is preferably selected as follows: the particle size of 5-20 μm is more than 90 wt%.

The production process of the preparation of the invention is wet granulation, and the following sequence can be adopted when mixing the raw materials so as to improve the dispersion degree of the raw materials:

step A: according to the formula amount, firstly mixing the adhesive with water to prepare an adhesive solution;

and B: mixing nimesulide, the surfactant, the filler and a part of the disintegrant with the binder solution, carrying out wet granulation, and drying to obtain drug-containing granules;

and C: mixing the drug-containing particles with the lubricant and the remaining disintegrant.

The adhesive is dissolved firstly, so that the dispersity of the raw materials can be improved, the bonding among particles is more uniform, and the granulation is facilitated.

The disintegrant is added in two steps to improve the dissolution rate and disintegration of the medicine, and the whole amount of the disintegrant can be added in the step B during actual production.

In addition, the preparation type of the present invention is not limited to granules, but can be made into tablets, capsules, and the like. Preferably, after step C, the tablets are formed by compression. Tablets are easier to store and transport.

The method has simple process and is easy to be industrially popularized.

Among them, the physical and chemical characteristics of the particle such as size, porosity and friability are affected by the stirring and shearing conditions, so the shearing conditions are also important for the preparation, and the following conditions are adopted after screening.

Preferably, the wet granulation method in step B is: stirring and shearing for 3-5 min at 20-30 HZ.

Preferably, the drying may be followed by size stabilization.

Preferably, the drying method comprises the following steps: drying by a fluidized bed, wherein the drying temperature is 60-95 ℃, preferably 60-65 ℃, and preferably 80-95 ℃; preferably dried to a water content of 4wt% or less.

The invention adopts a drying mode of a fluidized bed, and can achieve the following technical effects:

firstly, the drying efficiency is high;

secondly, the particle size is more uniform;

thirdly, energy loss is reduced;

fourthly, the quality change of the preparation caused by too long drying time is reduced.

Preferably, a tabletting is further included after the step C.

Preferably, in the step B, the method of mixing nimesulide, a surfactant, a filler and a part amount of a disintegrant with the binder solution is: nimesulide, surfactant, filler and a portion of the amount of disintegrant are first dry blended and then mixed with the binder solution.

In summary, compared with the prior art, the invention achieves the following technical effects:

(1) the crystal form transformation of the medicine and possible quality risks are avoided;

(2) the dissolution rate of the medicine is improved;

(3) the production safety is improved;

(4) the production efficiency is improved;

(5) the preparation auxiliary materials of the conventional type are adopted, so that the safety is improved, and the production cost is reduced.

Detailed Description

The technical solutions of the present invention will be described clearly and completely with reference to the following detailed description, but those skilled in the art will understand that the following described examples are some, not all, of the examples of the present invention, and are only used for illustrating the present invention, and should not be construed as limiting the scope of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

The nimesulide particle size distributions used in the following examples are: the particle size of 5-20 μm is more than 90 wt%.

Example 1

The preparation process comprises the following steps: mixing nimesulide as raw material with lactose, microcrystalline cellulose, sodium lauryl sulfate and internally added carboxymethyl starch sodium, adding into a wet granulator, stirring for 4min to mix uniformly, adding hydroxypropyl cellulose water solution, stirring, shearing at 25HZ for granulating for 4min, granulating with 24-mesh sieve, drying at 60-65 deg.C until the water content is less than 4.0%, granulating with 40-mesh sieve, mixing with lubricant and external disintegrating agent, and tabletting according to theoretical content. And (5) detecting the uniformity of the content of the plain tablets and the friability to be qualified.

The dissolution results of this formulation are shown in table 1 below.

TABLE 1 EXAMPLE 1 dissolution Profile results in various media for nimesulide dispersible tablets

Dissolution media	5min	10min	15min	20min	45min
						pH7.4+0.5％tween80	59.60	75.01	80.86	84.12	-
pH6.8+1.0％tween80	45.81	67.82	76.33	-	88.09

Example 2

The dissolution results of this formulation are shown in table 2 below.

Table 2 example 2 dissolution profile results in nimesulide dispersible tablets in each media

Dissolution media	5min	10min	15min	45min
					pH6.8+1.0％tween80	51.75	75.60	79.72	86.31

Example 3

The preparation process comprises the following steps: mixing nimesulide as raw material with lactose, microcrystalline cellulose, sodium lauryl sulfate and internally added carboxymethyl starch sodium, adding into a wet granulator, stirring for 4min to mix uniformly, adding hydroxypropyl cellulose water solution, stirring, shearing at 25HZ for granulating for 4min, granulating with 24-mesh sieve, drying at 80-95 deg.C until the water content is less than 4.0%, granulating with 40-mesh sieve, mixing with lubricant and external disintegrating agent, and tabletting according to the theoretical content. And (5) detecting the uniformity of the content of the plain tablets and the friability to be qualified.

The dissolution results of this formulation are shown in table 3 below.

Table 3 example 3 dissolution profile results in various media for nimesulide dispersible tablets

Dissolution media	5min	10min	15min	20min	45min
						pH7.4+0.5％tween80	65.31	79.38	84.72	87.54	-
pH6.8+1.0％tween80	49.42	69.88	76.45	-	88.99

Example 4

The preparation process comprises the following steps: mixing nimesulide as raw material with lactose, microcrystalline cellulose, sodium lauryl sulfate and internally added carboxymethyl starch sodium, adding into a wet granulator, stirring for 4min to mix uniformly, adding hydroxypropyl cellulose water solution, stirring, shearing at 30HZ for granulating for 4min, granulating with 24-mesh sieve, drying at 80-95 deg.C until the water content is less than 4.0%, granulating with 40-mesh sieve, mixing with lubricant and external disintegrating agent, and tabletting according to the theoretical content. And (5) detecting the uniformity of the content of the plain tablets and the friability to be qualified.

The dissolution results of this formulation are shown in table 4 below.

Table 4 example 4 nimesulide dispersible tablet dissolution profile results

Dissolution media	5min	10min	15min	45min
					pH6.8+1.0％tween80	51.78	77.69	86.03	96.36

Example 5

The preparation process comprises the following steps: mixing nimesulide as raw material with lactose, microcrystalline cellulose, sodium dodecyl sulfate and sodium carboxymethyl starch, adding into a wet granulator, stirring for 4min to mix uniformly, adding hydroxypropyl cellulose water solution, stirring, shearing at 20HZ for 3min, drying at 80-95 deg.C until the water content is less than 4.0%, granulating with a 40 mesh shaking screen, mixing with lubricant and external disintegrating agent, and tabletting according to the theoretical content. And (5) detecting the uniformity of the content of the plain tablets and the friability to be qualified.

The dissolution results of this formulation are shown in table 5 below.

TABLE 5 example 5 dissolution Profile results in various media for nimesulide dispersible tablets

Example 6

The preparation process comprises the following steps: mixing nimesulide as raw material with lactose, microcrystalline cellulose, sodium dodecyl sulfate and sodium carboxymethyl starch, adding into a wet granulator, stirring for 4min to mix uniformly, adding hydroxypropyl cellulose water solution, stirring, shearing, granulating for 3min, drying at 80-95 deg.C until the water content is less than 4.0%, sieving with a 40 mesh shaking sieve, mixing with lubricant and external disintegrating agent, and tabletting according to the theoretical tablet weight. And (5) detecting the uniformity of the content of the plain tablets and the friability to be qualified.

The dissolution results of this formulation are shown in table 6 below.

TABLE 6 dissolution Curve results in various media of example 6 Nimesulide dispersible tablets

Dissolution media	5min	10min	15min	20min
					pH7.4+0.5％tween80	60.20	75.22	81.34	85.25

Example 7

The dissolution results of this formulation are shown in table 7 below.

TABLE 7 dissolution Curve results in each media of example 7 Nimesulli dispersible tablets

Dissolution media	5min	10min	15min	20min
					pH7.4+0.5％tween80	61.25	76.58	83.24	86.25

Example 8

The difference from example 5 is that the formulation auxiliary materials used are different:

the preparation process comprises the following steps: mixing nimesulide as raw material with lactose, microcrystalline cellulose, sodium dodecyl sulfate and internally added carboxymethyl starch sodium, adding into a wet granulator, stirring for 4min to mix uniformly, adding hydroxypropyl methylcellulose water solution, stirring, shearing, granulating for 3min, drying at 80-95 ℃ until the water content is less than 4.0%, granulating with a 40-mesh vibrating screen, mixing with lubricant and externally added disintegrating agent, and tabletting according to the theoretical content. And (5) detecting the uniformity of the content of the plain tablets and the friability to be qualified.

The dissolution results of this formulation are shown in table 8 below.

TABLE 8 dissolution Curve results in various media for nimesulide dispersible tablets in example 8

Dissolution media	5min	10min	20min
				pH7.4+0.5％tween80	60.21	79.64	88.45

Example 9

The preparation process comprises the following steps: mixing nimesulide raw material, microcrystalline cellulose, sodium dodecyl sulfate and internally added carboxymethyl starch sodium, adding into a wet granulator, stirring for 4min to mix uniformly, adding hydroxypropyl cellulose aqueous solution, stirring, shearing, granulating for 3min, drying at 80-95 ℃ until the moisture is less than 4.0%, granulating with a 40-mesh vibrating screen, mixing with a lubricant and an externally added disintegrating agent, and tabletting according to the theoretical content. And (5) detecting the uniformity of the content of the plain tablets and the friability to be qualified.

The dissolution results of this formulation are shown in table 9 below.

TABLE 9 dissolution Curve results in various media of example 9 Nimesulli dispersible tablets

Example 10

The preparation process comprises the following steps: mixing nimesulide as raw material with lactose, sodium dodecyl sulfate and sodium carboxymethyl starch, adding into wet granulator, stirring for 4min to mix well, adding hydroxypropyl cellulose water solution, stirring, shearing, granulating for 3min, drying at 80-95 deg.C until water content is less than 4.0%, sieving with 40 mesh vibrating sieve, mixing with lubricant and external disintegrating agent, and tabletting according to theoretical content. And (5) detecting the uniformity of the content of the plain tablets and the friability to be qualified.

The dissolution results of this formulation are shown in table 10 below.

TABLE 10 dissolution Curve results in each media of example 10 Nimesulli dispersible tablets

Dissolution media	5min	10min	20min
				pH7.4+0.5％tween80	63.21	79.45	87.46

Comparing example 5 with examples 9 and 10, it can be seen that lactose and microcrystalline cellulose in the formulation have a synergistic effect, and the dissolution rate of the drug is faster when both are used simultaneously.

Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. The nimesulide preparation is characterized by being prepared by wet granulation of the following components: according to the weight percentage, the weight percentage of the alloy is,

nimesulide 19% -25.0%,

0.07 percent to 0.50 percent of surfactant,

1.3 to 1.5 percent of adhesive,

4.6 to 7 percent of disintegrating agent,

48.0 to 50.0 percent of filler,

0.5 to 1.5 percent of lubricant,

the balance of water;

the filler is lactose and microcrystalline cellulose;

the adhesive is hydroxypropyl cellulose;

the lubricant is magnesium stearate;

the disintegrating agent is sodium carboxymethyl starch;

the surfactant is sodium dodecyl sulfate;

the particle size distribution of nimesulide is as follows: the grain diameter is 5-20 mu m, and accounts for more than 90 wt%;

the preparation method of the nimesulide preparation comprises the following steps:

and C: mixing the drug-containing particles with the lubricant and the remaining disintegrant;

the wet granulation method in the step B comprises the following steps: stirring and shearing for 3-5 min at 20-30 HZ; the drying method comprises the following steps: drying by a fluidized bed at the drying temperature of 60-95 ℃.

2. The nimesulide formulation according to claim 1, wherein the drying temperature is 60-65 ℃.

3. The nimesulide formulation according to claim 1, wherein the drying temperature is 80-95 ℃.

4. A nimesulide formulation according to claim 1 wherein said drying is carried out to a moisture content of less than 4 wt%.

5. The nimesulide formulation according to claim 1, further comprising tableting after said step C.

6. A nimesulide formulation as claimed in claim 1, wherein in said step B, nimesulide, a surfactant, a filler and a partial amount of disintegrant are mixed with said binder solution by: nimesulide, surfactant, filler and a portion of the amount of disintegrant are first dry blended and then mixed with the binder solution.