CN114699380A

CN114699380A - Etodolac tablet and preparation method thereof

Info

Publication number: CN114699380A
Application number: CN202111617427.2A
Authority: CN
Inventors: 叶飞; 牛犇; 杭夏清
Original assignee: Nanjing Lianzhi Pharmaceutical Technology Co ltd
Current assignee: Nanjing Lianzhi Pharmaceutical Technology Co ltd
Priority date: 2021-12-27
Filing date: 2021-12-27
Publication date: 2022-07-05

Abstract

The invention provides an etodolac tablet, which comprises etodolac, a filler, an adhesive, a disintegrating agent, a lubricant and a coating material, and the etodolac tablet comprises the following components in percentage by mass: 50-75% of etodolac, 10-40% of filler, 3-10% of adhesive, 2-8% of disintegrating agent, 0.5-3% of lubricant and 1-5% of coating material. The etodolac tablet realizes good fitting with a dissolution curve of a commercially available preparation in a medium with the pH of 6.8, and the in vitro dissolution behaviors of the etodolac tablet and the commercially available preparation are similar; after the stability test of the etodolac tablet is accelerated for 6 months and carried out for 18 months for a long time, the characters, the dissolution rates, the contents and related substances have no obvious change, which shows that the stability of the etodolac tablet is good; etodolac tablets are significantly superior to commercially available etodolac tablets in treating pain and inflammation associated with osteoarthritis in pet dogs.

Description

Etodolac tablet and preparation method thereof

Technical Field

The invention relates to an etodolac tablet and a preparation method thereof.

Background

The etodolac tablet has a definite therapeutic effect on pain and inflammation related to osteoarthritis of the pet dog, and can quickly relieve discomfort of the pet dog. Etodolac is an effective non-steroidal anti-inflammatory drug, belongs to indoleacetic acids, has strong analgesic effect, is widely used for treating postoperative pain, relieves the symptoms of rheumatoid arthritis and osteoarthritis, and delays osteopathic change caused by arthritis. The medicine has high safety, and rarely causes gastrointestinal adverse reaction and renal function damage common in common non-steroidal anti-inflammatory drugs.

Etodolac is different from other non-steroidal anti-inflammatory drugs, and has a tetrahydropyran mother ring, so that the good pharmacological effect is maintained, and the side effect is reduced. The mechanism of action of non-steroidal anti-inflammatory drugs is to control inflammation and relieve pain by inhibiting COX activity, reducing prostaglandin E2 production. COX is a key catalytic enzyme for the conversion of arachidonic acid to prostaglandin E2, and it has two isoenzymes (COX-1, COX-2). COX-1 is mainly used for promoting physiological prostaglandin synthesis at gastrointestinal tract, kidney and platelet, and protecting gastrointestinal mucosa; COX-2 is mainly used to promote the synthesis of prostaglandins at arthritis, and has anti-inflammatory and analgesic effects. The gastrointestinal toxicity of non-steroidal anti-inflammatory drugs is associated with COX-2 selectivity. Etodolac has the advantages of higher and proper COX-2 selectivity, little influence on COX-1 in a therapeutic dose, and protection of gastrointestinal mucosa while exerting a strong anti-inflammatory effect; another advantage of this is the protective effect on the chondrocytes.

At present, the pet market has fewer medicines for treating related pain and inflammation caused by osteoarthritis of pet dogs, and most of the products have the defects of low medicine release stability effect, high irritation to gastrointestinal tracts, low bioavailability, inconvenience in packaging, transportation and storage, complex preparation method and the like.

Disclosure of Invention

The invention aims to overcome the defects in the prior art, provides an etodolac tablet and a preparation method thereof, and solves the problems of low drug release stability effect, large irritation to gastrointestinal tracts, low bioavailability, inconvenience in packaging, transportation and storage, complex preparation method and the like of most products.

In order to solve the technical problems, the invention adopts the technical scheme that: an etodolac tablet comprises etodolac, a filling agent, a binder, a disintegrating agent, a lubricant and a coating material, and the etodolac tablet comprises the following components in percentage by mass:

further, the filler is one or a mixture of more of lactose monohydrate, microcrystalline cellulose or corn starch.

Further, the adhesive is one or a combination of several of hydroxypropyl cellulose, hydroxypropyl methylcellulose or povidone.

Further, the disintegrating agent is one or a mixture of more of croscarmellose sodium, carboxymethyl starch sodium and carboxymethyl cellulose calcium.

Further, the lubricant is one or a combination of more of talcum powder, magnesium stearate or colloidal silicon dioxide.

Further, the composition comprises, by mass, 75% of etodolac, 13% of microcrystalline cellulose, 5% of hydroxypropyl cellulose, 3% of croscarmellose sodium, 1% of magnesium stearate and 3% of opadry.

Further, the preparation method of the etodolac tablet comprises the following steps: primarily mixing etodolac, a filler and an adhesive for granulation, screening and finishing granules step by step, mixing a disintegrating agent and a lubricant, pressing the mixture into tablets, and finishing a coating process by a coating material to obtain the etodolac tablets.

Further, in the primary mixing process, the stirring speed is set to be 5r/s, the chopping speed is set to be 20r/s, then the mixture is mixed for 10min, and after the mixture is uniformly mixed, purified water is added for granulation for 5 min.

Further, the screening process is specifically as follows, wet and whole granules are taken by a 20-mesh sieve, then the drying process is carried out, and the whole granules are taken by a 24-mesh sieve, and the moisture content is less than 3%.

Further, the hardness of the etodolac tablet is 8-12 kg.

Compared with the prior art, the invention has the beneficial effects that:

1) the etodolac tablet realizes good fitting with a dissolution curve of a commercially available preparation in a medium with the pH of 6.8, and the dissolution curves of the etodolac tablet and the commercially available preparation are similar;

2) after stability investigation of the etodolac tablet accelerated for 6 months and for a long time of 18 months, the characters, the dissolution degree, the content and related substances have no obvious change, which shows that the etodolac tablet has good stability;

3) the etodolac tablet provided by the invention is remarkably superior to a commercially available etodolac tablet group in the effect of treating related pain and inflammation caused by osteoarthritis of pet dogs.

Drawings

The disclosure of the present invention is illustrated with reference to the accompanying drawings. It is to be understood that the drawings are designed solely for the purposes of illustration and not as a definition of the limits of the invention. In the drawings, like reference numerals are used to refer to like parts. Wherein:

FIG. 1 is a dissolution profile of etodolac tablets and commercial formulations prepared according to the methods of examples 1-8 of the present invention.

Detailed Description

It is easily understood that the technical solution according to the present invention can be provided with various alternative structures and implementations by those skilled in the art without changing the spirit of the present invention. Therefore, the following detailed description and the accompanying drawings are merely illustrative of the technical aspects of the present invention, and should not be construed as limiting or restricting the technical aspects of the present invention.

An embodiment according to the present invention is shown in connection with fig. 1. An etodolac tablet comprises etodolac, a filler, a binder, a disintegrant, a lubricant and a coating material, and the etodolac tablet comprises the following components in percentage by mass:

wherein the filler is one or more of lactose monohydrate, microcrystalline cellulose or corn starch; the adhesive is one or the combination of several of hydroxypropyl cellulose, hydroxypropyl methylcellulose or polyvidone; the disintegrant is one or more of croscarmellose sodium, sodium carboxymethyl starch or calcium carboxymethylcellulose; the lubricant is one or more of talcum powder, magnesium stearate or colloidal silica.

A preparation method of etodolac tablets comprises the following steps: the etodolac tablet is prepared by mixing an etodolac filling agent and an adhesive for granulation, sieving the granules step by step, mixing a disintegrating agent and a lubricating agent, pressing the mixture into tablets, and finishing the coating process by a coating material. In the primary mixing process, setting the stirring speed to be 5r/s, setting the chopping speed to be 20r/s, then mixing for 10min, adding purified water after even mixing, and granulating for 5 min. The sieving process comprises drying the wet granules with 20 mesh sieve, and sieving with 24 mesh sieve to obtain granules with water content of less than 3%.

The present invention will be described in further detail with reference to examples.

Example 1

Prescription:

the preparation method comprises the following steps:

placing etodolac, lactose monohydrate, corn starch and hydroxypropyl cellulose in a wet granulator, setting a stirring speed of 5r/s and a chopping speed of 20r/s, mixing for 10min, adding purified water for granulation for 5min, performing wet granulation by using a 20-mesh sieve, drying in an oven until the water content is less than 3%, performing granulation by using a 24-mesh sieve, adding additional auxiliary materials of croscarmellose sodium and magnesium stearate, mixing for 10min, tabletting, controlling the hardness to be 8.0-12.0kg, coating by using an opadry aqueous solution (with the solid content of 10%) and increasing the weight by 3.0%.

Example 2

Prescription:

the preparation method comprises the following steps:

placing etodolac, lactose monohydrate and hydroxypropyl methylcellulose into a wet granulator, setting a stirring rotation speed of 5r/s, a chopping rotation speed of 20r/s, mixing for 10min, adding purified water for granulation for 5min, sieving with a 20-mesh sieve for wet granulation, drying in an oven until the water content is less than 3%, sieving with a 24-mesh sieve for granulation, adding additional auxiliary materials of carboxymethyl starch sodium and talcum powder, mixing for 10min, tabletting, controlling the hardness to be 8.0-12.0kg, and coating by using an opadry solution (with the solid content of 10%) to increase the weight by 4.0%.

Example 3

Prescription:

the preparation method comprises the following steps:

placing etodolac, corn starch and hypromellose in a wet granulator, setting stirring speed at 5r/s, chopping speed at 20r/s, mixing for 10min, adding purified water, granulating for 5min, wet granulating with 20 mesh sieve, oven drying until water content is less than 3%, granulating with 24 mesh sieve, adding additional adjuvants of carboxymethylcellulose calcium and magnesium stearate, mixing for 10min, tabletting, controlling hardness to 8.0-12.0kg, coating with Opadry water solution (solid content is 10%), and increasing weight by 2.0%.

Example 4

Prescription:

the preparation method comprises the following steps:

placing etodolac, microcrystalline cellulose and hydroxypropyl cellulose in a wet granulator, setting a stirring speed of 5r/s and a chopping speed of 20r/s, mixing for 10min, adding purified water for granulation for 5min, carrying out wet granulation by using a 20-mesh sieve, drying in an oven until the water content is less than 3%, carrying out granulation by using a 24-mesh sieve, adding additional auxiliary materials of croscarmellose sodium and magnesium stearate, mixing for 10min, tabletting, controlling the hardness to be 8.0-12.0kg, coating by using an opadry aqueous solution (with the solid content of 10%) and increasing the weight by 3.0%.

Example 5

Prescription:

the preparation method comprises the following steps:

placing etodolac, microcrystalline cellulose and hydroxypropyl cellulose in a wet granulator, setting a stirring speed of 5r/s and a chopping speed of 20r/s, mixing for 10min, adding purified water for granulation for 5min, carrying out wet granulation by using a 20-mesh sieve, drying in an oven until the water content is less than 3%, carrying out granulation by using a 24-mesh sieve, adding additional auxiliary materials of croscarmellose sodium and magnesium stearate, mixing for 10min, tabletting, controlling the hardness to be 8.0-12.0kg, coating by using an opadry aqueous solution (with the solid content of 10%) and increasing the weight by 3.5%.

Example 6

Prescription:

the preparation method comprises the following steps:

placing etodolac, microcrystalline cellulose and hydroxypropyl cellulose in a wet granulator, setting a stirring speed of 5r/s and a chopping speed of 20r/s, mixing for 10min, adding purified water for granulation for 5min, carrying out wet granulation by using a 20-mesh sieve, drying in an oven until the water content is less than 3%, carrying out granulation by using a 24-mesh sieve, adding additional auxiliary materials of croscarmellose sodium and magnesium stearate, mixing for 10min, tabletting, controlling the hardness to be 8.0-12.0kg, coating by using an opadry aqueous solution (with the solid content of 10%) and increasing the weight by 2.4%.

Example 7

Prescription:

the preparation method comprises the following steps:

placing etodolac, microcrystalline cellulose and hydroxypropyl cellulose in a wet granulator, setting a stirring speed of 5r/s and a chopping speed of 20r/s, mixing for 10min, adding purified water for granulation for 5min, carrying out wet granulation by using a 20-mesh sieve, drying in an oven until the water content is less than 3%, carrying out granulation by using a 24-mesh sieve, adding additional auxiliary materials of croscarmellose sodium and magnesium stearate, mixing for 10min, tabletting, controlling the hardness to be 8.0-12.0kg, coating by using an opadry aqueous solution (with the solid content of 10%) and increasing the weight by 3.1%.

Example 8

Prescription:

the preparation method comprises the following steps:

placing etodolac, microcrystalline cellulose and hydroxypropyl cellulose in a wet granulator, setting a stirring speed of 5r/s and a chopping speed of 20r/s, mixing for 10min, adding purified water for granulation for 5min, carrying out wet granulation by using a 20-mesh sieve, drying in an oven until the water content is less than 3%, carrying out granulation by using a 24-mesh sieve, adding additional auxiliary materials of croscarmellose sodium and magnesium stearate, mixing for 10min, tabletting, controlling the hardness to be 8.0-12.0kg, coating by using an opadry aqueous solution (with the solid content of 10%) and increasing the weight by 2.9%.

Example 9: determination of dissolution curve of etodolac tablets

According to a dissolution and release determination method (0931 second method of the general rule of the four departments in 2020 edition) of etodolac tablets prepared by the method of the embodiment 1-8 of the invention, dissolution curves of self-made samples and commercially available samples of the etodolac tablets are determined, 900ml of phosphate buffer solution (pH 6.8) is used as a solvent, the rotating speed is 50 revolutions per minute, the operation is carried out according to the method, at the 5 th, 10 th, 15 th and 30 th minutes, a proper amount of solution is taken for filtering, after primary filtrate is discarded, a proper amount of subsequent filtrate is precisely taken, and a dissolution medium is added for dilution to prepare a solution containing 22 mug in each 1ml, and the solution is used as a test sample solution; further, 0.02g of a control sample dried under reduced pressure at 60 ℃ for 4 hours was precisely weighed, placed in a 100ml measuring flask, dissolved with 10ml of methanol, diluted with a dissolution medium to a predetermined scale, shaken, and precisely measured in an appropriate amount, diluted with a dissolution medium to give a solution containing 20. mu.g per 1ml, and used as a control solution, and the above solutions were measured for absorbance at a wavelength of 279nm by UV-visible spectrophotometry, and a dissolution curve was plotted as shown in FIG. 1 below.

The dissolution curve detection result shows that the etodolac tablet prepared by the method of the embodiment 4 realizes good fitting with the dissolution curve of a commercial preparation in a medium with pH6.8, and the in-vitro dissolution behaviors of the etodolac tablet and the commercial preparation are most similar, so that the small sample of the embodiment 4 is taken as a main research object in subsequent research.

Example 10: etodolac tablet stability test

And (3) accelerated test: etodolac tablets prepared by the method of embodiment 4 of the invention are placed in a constant temperature and humidity box under the condition of commercial package, placed under the conditions of 40 ℃ plus or minus 2 ℃ and 75% plus or minus 5% of relative humidity, sampled at 1 st, 2 nd, 3 th and 6 th months in time respectively, and detected according to a quality standard draft, and the results are shown in Table 1.

Table 1: accelerated test detection data summary table

And (3) long-term test: etodolac tablets prepared by the method of embodiment 4 of the invention are placed in a constant temperature and humidity box under the condition of commercial package, placed under the conditions of 25 ℃ plus or minus 2 ℃ and 60% plus or minus 5% of relative humidity, sampled at 3 rd, 6 th, 9 th, 12 th and 18 th months in time respectively, and measured according to a quality standard draft. The results of the measurement were compared with the results of the measurement at 0 month, and the results are shown in Table 2.

Table 2: long-term test detection data summary table

The stability examination result shows that after the stability examination of 6 months and 18 months for a long time, the characters, dissolution rates, contents and related substances of the etodolac tablet have no obvious change, which indicates that the stability of the etodolac tablet is good.

Example 11: test of clinical application effect of etodolac tablets

To examine the effect of the present invention in clinical application, we selected 60 naturally occurring pet dogs as experimental animals in a pet hospital, and each dog was randomly divided into 3 groups of 20 dogs each exhibiting associated pain and inflammation caused by osteoarthritis within 7 days. One group was left untreated as a blank control; one group used commercially available etodolac tablets as a treatment control group; the final group used the product of the invention made in example 4 as the test group.

1. Test protocol

The product and the commercial etodolac tablet are both mixed in food of sick dogs for oral administration once a day, the administration dose is 10mg/kg body weight, and the administration lasts for 5 days. The change condition of the disease part of the dog and the physical signs such as the movement behavior are observed before and after the test. The disease condition is judged according to the sign observation results of the sick dog before, on the same day as, 3 days after and 5 days after the administration. The method is divided into a plurality of grades of curing (no disease manifestation), improving (the red and swollen condition of a disease part is relieved, the exercise condition becomes better), no change and more serious (the red and swollen condition of the disease part is aggravated, and the exercise condition is worse).

2. Test results

2.1 blank control group

After the 5 th day, 2 dogs with the blank control group showed some improvement in symptoms, 3 dogs showed no obvious change, and the rest 15 dogs showed more serious symptoms such as aggravated red swelling and worse movement status of the affected parts.

2.2 commercial Etodolac tablet test treatment group

After 3 days of administration, 4 dogs were substantially cured, 6 dogs were improved in symptoms, 9 dogs were not significantly changed, and 1 dog was more severe. After 5 days of administration, 11 dogs were substantially cured, 4 dogs were improved in symptoms, and 5 dogs were not significantly changed.

2.3 test treatment group of products of the invention

After 3 days of administration, 6 dogs were substantially cured, 9 dogs had improved symptoms, and 5 dogs had no significant change. After 5 days of administration, 17 dogs healed and 3 dogs improved symptoms significantly.

The test data were collated and the results are shown in the following table

Test results show that the etodolac tablet provided by the invention is remarkably superior to a commercially available etodolac tablet set in the effects of treating related pain and inflammation caused by osteoarthritis of pet dogs.

The technical scope of the present invention is not limited to the above description, and those skilled in the art can make various changes and modifications to the above-described embodiments without departing from the technical spirit of the present invention, and these changes and modifications should fall within the protective scope of the present invention.

Claims

1. The etodolac tablet is characterized by comprising etodolac, a filler, a binder, a disintegrant, a lubricant and a coating material, wherein the etodolac tablet comprises the following components in percentage by mass:

2. the etodolac tablet of claim 1, wherein the filler is one or a combination of lactose monohydrate, microcrystalline cellulose, or corn starch.

3. The etodolac tablet of claim 1, wherein the binder is one or a combination of hydroxypropyl cellulose, hypromellose, or povidone.

4. An etodolac tablet according to claim 1, wherein the disintegrant is one or a mixture of croscarmellose sodium, sodium carboxymethyl starch or calcium carboxymethylcellulose.

5. The etodolac tablet of claim 1, wherein the lubricant is one or a combination of talc, magnesium stearate, or colloidal silicon dioxide.

6. Etodolac tablets according to claims 1-5, comprising, in mass fraction, 75% Etodolac, 13% microcrystalline cellulose, 5% hydroxypropyl cellulose, 3% croscarmellose sodium, 1% magnesium stearate and 3% Opadry.

7. A method for preparing an etodolac tablet according to claim 6, comprising the steps of: primarily mixing etodolac, a filling agent and an adhesive for granulation, screening the granules step by step, mixing a disintegrating agent and a lubricating agent, pressing the mixture into tablets, and finishing a coating process by using a coating material to obtain the etodolac tablets.

8. A preparation method of etodolac tablets according to claim 7, wherein in the primary mixing process, the stirring speed is set to be 5r/s, the chopping speed is set to be 20r/s, then the mixture is mixed for 10min, and after the uniform mixing, purified water is added for granulation for 5 min.

9. A process for preparing etodolac tablet according to claim 8, wherein the sieving process is specifically as follows, the drying process is carried out after wet and whole granules are sieved with a 20 mesh sieve, and the whole granules are sieved with a 24 mesh sieve, and the moisture content is less than 3%.

10. The method for preparing an etodolac tablet according to claim 9, wherein the etodolac tablet has a hardness of 8-12 kg.