CN115671069A - Ruuggolide tablet and preparation method thereof - Google Patents

Abstract

The invention relates to the technical field of medicines, and provides a Ruugolii tablet and a preparation method thereof. The tablet comprises the following components in percentage by weight: 20 to 40 percent of Ruogeli, 40 to 70 percent of filling agent, 1 to 10 percent of disintegrating agent, 2 to 8 percent of adhesive and 0.1 to 2 percent of lubricant; wherein the Ruuggol is jet milled to a D90 of less than 50 microns. The Ruuggolide tablet provided by the invention has good in-vitro dissolution rate, can be dissolved out in 30min in vitro by more than 85%, has good dissolution effect and high bioavailability, is more beneficial to in-vivo absorption, and has good stability.

Description

Ruuggolide tablet and preparation method thereof

Technical Field

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

Background

Ruogelix (Relugolix) is an oral non-peptide gonadotropin releasing hormone (GnRH) receptor antagonist that competitively binds to the pituitary GnRH receptor and binds to the receptor to reduce luteinizing hormoneRelease of adult hormone (LH) and Follicle Stimulating Hormone (FSH) resulting in a decrease in testosterone release is useful in treating adult patients with advanced prostate cancer. The chemical name of Ruogeli is N- (4- (1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2, 4-dioxo-1, 2,3, 4-tetrahydrothieno [2,3-d ]]Pyrimidin-6-yl) phenyl) -N' -methoxyurea having the molecular formula C ₂₉ H ₂₇ F ₂ N ₇ O ₅ S, molecular weight is 623.63, and chemical structural formula is

The Ruuggolide is an insoluble anhydrous crystal free alkali drug, is not beneficial to the absorption of the drug in vivo, and the existing Ruuggolide tablets still have the problems of low dissolution rate and poor stability. Therefore, there is a need to provide a riluguli tablet with higher dissolution rate and better stability to better meet the clinical and market demands.

Disclosure of Invention

In order to overcome the defects in the prior art, the invention aims to provide a rilogeli tablet and a preparation method thereof, so as to solve the problems of low dissolution rate and poor stability of the existing rilogeli tablet.

The embodiment of the invention provides a Ruuggolide tablet, which comprises the following components in percentage by weight:

20 to 40 percent of Ruogeli,

40 to 70 percent of filling agent,

1 to 10 percent of disintegrating agent,

2 to 8 percent of adhesive,

0.1 to 2 percent of lubricant,

wherein the Ruuggol is comminuted by air flow to a D90 of less than 50 microns.

According to the Ruuggolin tablet provided by the embodiment of the invention, ruuggolin is crushed to D90 smaller than 50 micrometers by a jet milling technology, and then the Ruuggolin crushed to a specific particle size is compounded with other components to prepare the Ruuggolin tablet by a wet granulation process, so that the prepared Ruuggolin tablet has a better in-vitro dissolution rate, the dissolution rate in vitro 30min can reach more than 85%, the dissolution effect is good, the bioavailability is high, the in-vivo absorption is facilitated, and the stability is good.

In a second aspect of embodiments of the present invention, there is provided a method for preparing a rilogeli tablet according to the first aspect, including the following steps:

weighing Ruuggol, and crushing the Ruuggol to D90 of less than 50 microns through airflow;

mixing the crushed Ruugeli, the filler and the disintegrating agent, and then adding the adhesive for wet granulation to obtain granules;

mixing the granules with the lubricant, and tabletting to obtain plain tablets;

and coating the plain tablets to obtain the Ruogeli tablets.

The preparation method provided by the embodiment of the invention has the advantages of simple process, convenience in operation and suitability for large-scale industrial production, the prepared Ruugeli tablet has good dissolution rate which can reach more than 85% after 30min in vitro dissolution, good dissolution effect, high bioavailability, better contribution to in vivo absorption and good stability.

Detailed Description

In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific examples described herein are merely illustrative of the invention and that the embodiments of the invention are not limited thereto.

Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The experimental reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the dosage of the experimental reagent is the dosage of the reagent in the conventional experimental operation if no special description exists; the experimental methods are all conventional methods unless otherwise specified.

In a first aspect, the present embodiment provides a riluguli tablet, which includes the following components in percentage by weight:

20 to 40 percent of Ruogeli,

40 to 70 percent of filling agent,

1 to 10 percent of disintegrating agent,

2 to 8 percent of adhesive,

0.1 to 2 percent of lubricant,

wherein the Ruuggol is comminuted by air flow to a D90 of less than 50 microns.

Further, the D90 of the relogelix is 15 to 47 micrometers, for example, 15 micrometers, 20 micrometers, 25 micrometers, 30 micrometers, 35 micrometers, 40 micrometers, or 47 micrometers, and the like may be used.

The jet milling is that the self-milling action of the material is utilized, and the high-speed air flow or hot steam generated by compressed air is used to impact the material, so that the materials are strongly collided and rubbed with each other, thereby achieving the purpose of fine milling. According to the embodiment of the invention, ruugeli is crushed to D90 of less than 50 microns by adopting a jet milling technology, so that the in-vitro dissolution rate of the prepared tablet can be effectively improved. When the D90 of Ruugeli is greater than 50 microns, the in vitro dissolution of the resulting tablets is low.

In any of the above embodiments, preferably, the filler is at least one of lactose monohydrate, mannitol, calcium hydrogen phosphate, microcrystalline cellulose, and corn starch.

More preferably, the filler is mannitol, and the mannitol has an average particle size of 10 to 50 micrometers.

In any of the above embodiments, preferably, the disintegrant is at least one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and crospovidone.

More preferably, the disintegrant is sodium carboxymethyl starch. A large number of experimental researches show that the dosage of the sodium carboxymethyl starch has great influence on the in-vitro dissolution rate and stability of the tablet. When the dosage of the sodium carboxymethyl starch is less than 1%, the in-vitro dissolution rate of the prepared tablet is low; when the dosage of the sodium carboxymethyl starch exceeds 10%, the prepared tablet has low in-vitro dissolution rate and poor stability.

In any of the above embodiments, preferably, the binder is at least one of hydroxypropyl cellulose, gelatin, and starch slurry.

More preferably, the binder is hydroxypropyl cellulose.

In practical application, the hydroxypropyl cellulose can be prepared into a hydroxypropyl cellulose solution with the concentration of 4% -8% by using purified water as a binder. By controlling the concentration of the hydroxypropyl cellulose solution to be 4-8%, the prepared particles can be ensured to have moderate hardness, the yield of whole particles can be improved, and the compression property of the particles is improved. When the concentration of the hydroxypropylcellulose solution is less than 4%, the adhesiveness is poor, the proportion of fine powder in the granule becomes large, the flowability is poor, the compressibility is poor, the yield is low, and the hardness of the resulting granule is low. When the concentration of the hydroxypropyl cellulose solution is higher than 8%, the viscosity is too high, the granulation and the size stabilization are difficult, the yield of finished products is low, the tabletting is not favorable, and the surfaces of the prepared tablets do not meet the relevant regulations of the tablets.

When the binder is povidone, the adhesiveness is deteriorated, the particles are loose, the compressibility is poor, the hardness is small, and the yield of the finished product is low.

In any of the above embodiments, preferably, the lubricant is at least one of magnesium stearate, calcium stearate, and sodium stearyl fumarate.

More preferably, the lubricant is magnesium stearate.

In a second aspect, the embodiments of the present invention further provide a method for preparing a rilogeli tablet according to the first aspect, including the following steps:

weighing Rugoside, and airflow-pulverizing the Rugoside to D90 of less than 50 microns;

mixing the crushed Ruugeli, the filler and the disintegrating agent, and then adding the adhesive for wet granulation to obtain granules;

mixing the granules with the lubricant, and tabletting to obtain plain tablets;

and coating the plain tablets to obtain the Ruugeli tablets.

Further, in the wet granulation step: the crushed Ruugeli, the filler and the disintegrating agent can be put into a fluidized bed for mixing, and then the adhesive is added for wet granulation, wherein the parameter conditions of the fluidized bed are as follows: the atomization pressure is 0.2 to 0.4MPa, and may be, for example, 0.2MPa, 0.25MPa, 0.3MPa, 0.35MPa or 0.4MPa; the material temperature is 30-40 deg.C, for example, 30 deg.C, 32 deg.C, 35 deg.C, 38 deg.C or 40 deg.C; the intake air frequency is 20 to 40Hz, and may be, for example, 20Hz, 25Hz, 30Hz, 35Hz, or 40Hz.

The fluidized bed is adopted for wet granulation, granulation and drying can be carried out simultaneously, the granulation efficiency is high, and the particle fluidity is good.

Further, after wet granulation, the wet granulation is dried to a moisture content of 2-3%, e.g., to 2%, 2.5%, or 3%; and then sieving the granules with a 20-mesh sieve for size stabilization to obtain the granules.

Furthermore, in the process of coating the plain tablets, the weight gain of the coating is controlled to be 2-3%. The tablet is coated with film, and has improved stability, moisture resistance and opacity.

The invention is described in further detail with reference to a part of the test results, which are described in detail below with reference to specific examples.

Example 1

The formulation of the rilogeli tablet provided in this example is as follows:

23% of Ruogeli, 67% of a filler (mannitol with the average particle size of 40 microns), 5% of a disintegrating agent (sodium carboxymethyl starch), 4% of a binder (hydroxypropyl cellulose) and 1% of a lubricant (magnesium stearate).

The preparation method of the Ruugeli tablet comprises the following steps:

s1, crushing Ruogeli to obtain Ruogeli powder with the D90 of 47 microns by using a jet mill for later use. S2, weighing Ruugeli powder, mannitol and sodium carboxymethyl starch according to the prescription amount, putting the Ruugeli powder, the mannitol and the sodium carboxymethyl starch into a fluidized bed, mixing for 3-5 min, adding a hydroxypropyl cellulose solution with the concentration of 6% into the fluidized bed, and preparing wet particles by a wet method, wherein the parameter conditions of the fluidized bed are as follows: atomizing under 0.2Mpa, material temperature 30 deg.C, and air inlet frequency 20Hz, drying the obtained wet granules to water content of about 2%, sieving the obtained dry granules with 20 mesh sieve, and grading to obtain granules. And S3, adding the granules prepared in the step S2 and magnesium stearate into a three-dimensional mixer for mixing, wherein the mixing revolution is 10 r/min, mixing for 8min to obtain intermediate granules, and tabletting after the content of the intermediate granules is reduced, wherein the hardness is controlled to be 6-10 kg, so that plain tablets are obtained. And S4, coating the plain tablets prepared in the step S3 by using an efficient coating machine, and controlling the weight of the coating to be increased by 2-3% to obtain the Ruugolii tablets.

Example 2

The formulation of the rilogeli tablet provided in this example is as follows:

31% of Ruuggol, 56.25% of a filler (mannitol with an average particle size of 25 micrometers), 8% of a disintegrating agent (sodium carboxymethyl starch), 4% of a binder (hydroxypropyl cellulose) and 0.75% of a lubricant (magnesium stearate).

The preparation method of the Ruugeli tablet comprises the following steps:

s1, crushing Ruogeli to obtain Ruogeli powder with D90 of 28 micrometers by using a jet mill for later use. S2, weighing Ruugeli powder, mannitol and sodium carboxymethyl starch according to the formula amount, putting the Ruugeli powder, the mannitol and the sodium carboxymethyl starch into a wet granulator, mixing for 8min, adding a 4.5% hydroxypropyl cellulose solution into the wet granulator, preparing wet granules by a wet method, sieving the wet granules with a 24-mesh sieve, drying the prepared wet granules by a hot air circulation air box, controlling the drying temperature to be 50 ℃, drying the prepared wet granules until the moisture content is about 2%, sieving the obtained dry granules with a 20-mesh sieve, and grading to obtain granules. And S3, adding the granules prepared in the step S2 and magnesium stearate into a three-dimensional mixer for mixing, wherein the mixing revolution is 12 r/min, mixing for 10min to obtain intermediate granules, and tabletting after the content of the intermediate granules is reduced, wherein the hardness is controlled to be 6-10 kg, so that plain tablets are obtained. And S4, coating the plain tablets prepared in the step S3 by using an efficient coating machine, and controlling the weight of the coating to be increased by 2-3% to obtain the Ruugolii tablets.

Example 3

The formulation of the rilogeli tablet provided in this example is as follows:

36% of Ruugeli, 55.5% of a filler (mannitol with an average particle size of 25 micrometers), 5% of a disintegrating agent (sodium carboxymethyl starch), 3% of a binder (hydroxypropyl cellulose) and 0.5% of a lubricant (magnesium stearate).

The preparation method of the Ruugeli tablet comprises the following steps:

s1, crushing Ruogeli to D90 of 15 microns by using a jet mill to obtain Ruogeli powder for later use. S2, weighing Ruugeli powder, mannitol and sodium carboxymethyl starch according to the prescription amount, putting the Ruugeli powder, the mannitol and the sodium carboxymethyl starch into a wet granulator, mixing for 5min, adding a 7.5% hydroxypropyl cellulose solution into the wet granulator, performing wet preparation on wet granules, sieving the wet granules with a 24-mesh sieve, drying the wet granules by using a fluidized bed, controlling the temperature of the material to be 40 ℃, drying the prepared wet granules until the moisture content is about 2%, and sieving the obtained dry granules with a 20-mesh sieve to obtain granules. And S3, adding the granules prepared in the step S2 and magnesium stearate into a three-dimensional mixer for mixing, wherein the mixing revolution is 10 r/min, mixing for 8min to obtain intermediate granules, and tabletting after the content of the intermediate granules is reduced, wherein the hardness is controlled to be 6-10 kg, so that plain tablets are obtained. And S4, coating the plain tablets prepared in the step S3 by using an efficient coating machine, and controlling the weight of the coating to be increased by 2-3% to obtain the Ruugolii tablets.

Example 4

The formulation of the rilogeli tablet provided in this example is as follows:

40% of Ruogeli, 45.5% of a filling agent (lactose monohydrate), 7% of a disintegrating agent (sodium carboxymethyl starch), 5.5% of a binding agent (hydroxypropyl cellulose) and 2% of a lubricating agent (magnesium stearate).

The preparation method of the Ruugeli tablet comprises the following steps:

s1, crushing Ruogeli to D90 of 20 microns by using a jet mill to obtain Ruogeli powder for later use. S2, weighing Ruugeli powder, lactose monohydrate and sodium carboxymethyl starch according to the formula amount, putting the Ruugeli powder, the lactose monohydrate and the sodium carboxymethyl starch into a wet granulator, mixing for 5min, adding a hydroxypropyl cellulose solution with the concentration of 8% into the wet granulator, preparing wet granules by a wet method, sieving the wet granules with a 24-mesh sieve, drying the wet granules by a fluidized bed, controlling the temperature of the material to be 30 ℃, drying the prepared wet granules until the moisture content is about 2%, and sieving the obtained dry granules with a 20-mesh sieve for finishing to obtain the granules. And S3, adding the granules prepared in the step S2 and magnesium stearate into a three-dimensional mixer for mixing, wherein the mixing revolution is 10 r/min, mixing for 8min to obtain intermediate granules, and tabletting after the content of the intermediate granules is reduced, wherein the hardness is controlled to be 6-10 kg, so that plain tablets are obtained. And S4, coating the plain tablets prepared in the step S3 by using an efficient coating machine, and controlling the coating weight to be increased by 2-3% to obtain the Ruugolii tablets.

Example 5

The formulation of the rilogeli tablet provided in this example is as follows:

28% of Ruogeli, 55.5% of a filling agent (calcium hydrophosphate), 9.3% of a disintegrating agent (sodium carboxymethyl starch), 7% of a binding agent (hydroxypropyl cellulose) and 0.2% of a lubricating agent (magnesium stearate).

The preparation method of the Ruugeli tablet comprises the following steps:

s1, crushing Ruogeli to D90 of 20 microns by using a jet mill to obtain Ruogeli powder for later use. S2, weighing Ruogeli powder, calcium hydrophosphate and sodium carboxymethyl starch according to the prescription amount, putting the Ruogeli powder, the calcium hydrophosphate and the sodium carboxymethyl starch into a wet granulator, mixing for 5min, adding a 5% hydroxypropyl cellulose solution into the wet granulator, carrying out wet preparation on wet granules, sieving the wet granules with a 24-mesh sieve, drying the wet granules by using a fluidized bed, controlling the temperature of the material to be 35 ℃, drying the prepared wet granules until the moisture content is about 2%, and sieving the obtained dry granules with a 20-mesh sieve to complete granules, thereby obtaining the granules. And S3, adding the granules prepared in the step S2 and magnesium stearate into a three-dimensional mixer for mixing, wherein the mixing revolution is 10 r/min, mixing for 8min to obtain intermediate granules, and tabletting after the content of the intermediate granules is reduced, wherein the hardness is controlled to be 6-10 kg, so that plain tablets are obtained. And S4, coating the plain tablets prepared in the step S3 by using an efficient coating machine, and controlling the weight of the coating to be increased by 2-3% to obtain the Ruugolii tablets.

Comparative example 1

Compared with example 3, the comparative example has the same components, content and preparation method as example 3 except that hydroxypropyl cellulose is replaced by povidone in the same amount.

Comparative example 2

In this comparative example, the components and the contents and the preparation method were the same as those of example 3 except that the content of hydroxypropylcellulose was adjusted to 1% as compared with example 3.

Comparative example 3

In this comparative example, the components and the contents and the preparation method were the same as those of example 3, except that the content of hydroxypropylcellulose was adjusted to 9% as compared with example 3.

Comparative example 4

In this comparative example, the components and contents and preparation method were the same as those of example 3, except that the concentration of the hydroxypropylcellulose solution was adjusted to 3% as compared with example 3.

Comparative example 5

In this comparative example, the components and contents and preparation method were the same as those of example 3, except that the concentration of the hydroxypropylcellulose solution was adjusted to 9% as compared with example 3.

Comparative example 6

Compared with example 3, the components and the content and the preparation method of the comparative example are the same as those of example 3, except that sodium carboxymethyl starch is replaced by croscarmellose sodium in the same amount.

Comparative example 7

In this comparative example, the components and the contents and the preparation method were the same as those of example 3, except that the content of sodium carboxymethyl starch was adjusted to 0.5% as compared with example 3.

Comparative example 8

In this comparative example, the components and the contents and the preparation method were the same as those of example 3, except that the content of sodium carboxymethyl starch was adjusted to 11% as compared with example 3.

Comparative example 9

This comparative example is similar to example 3 in composition and content and preparation method, except that Ruugeli was pulverized to D90 of 52 μm using a jet mill.

And (3) product performance testing:

(1) Dissolution test

Dissolution rate test tests were performed on the rilogeli tablets prepared in the above examples 1 to 5 and comparative examples 1 to 9. Dissolution is determined by reference to dissolution and release determination methods (second method of 0931, the four general rules of the 2020 edition of Chinese pharmacopoeia).

Testing the instrument: high performance liquid chromatography and dissolution rate tester; dissolution medium: citrate buffer at pH 5.5; volume of dissolution medium: 900mL, rotation speed: 50 revolutions per minute; sampling time: 5min, 10min, 15min, 30min, 45min, 60min.

Taking each sample, according to a dissolution and release determination method (0931 second method of the general rule of the four parts of the 2020 edition of Chinese pharmacopoeia), taking 900mL of citrate buffer solution with pH of 5.5 as a dissolution medium, performing a paddle method at 50 revolutions per minute, operating according to the method, and taking solutions at different time points for 60 minutes for determination. The dissolution profile test results for each set of samples are shown in table 1 below.

TABLE 1

As can be seen from table 1, the rilogeli tablets prepared in examples 1 to 5 of the present invention have good dissolution rate, and the dissolution rate in vitro for 30min can reach 85%, and the dissolution effect is good, and the bioavailability is high, which is more favorable for in vivo absorption, while the rilogeli tablets prepared in comparative examples 1 to 9 have poor dissolution rate, and the dissolution rate in 30min is lower than 85%.

(2) Stability test

The rilogeli tablets prepared in the above examples 1 to 5 and comparative examples 1 to 9 were stored for 3 months at a temperature of 40 ℃ and a relative humidity of 75% according to the requirements of the guidelines of the stability tests of the raw drugs and the preparations (9001 pharmaceutical preparations of the guidelines of stability tests of the raw drugs and the preparations in the four parts of the chinese pharmacopoeia 2020 edition), and the dissolution rates and the test results of the related substances of the respective groups of samples were as shown in the following table 2.

TABLE 2

As can be seen from table 2, after the rilogeli tablets prepared in examples 1 to 5 of the present invention are placed at 40 ℃ and 75% relative humidity for 3 months, the changes of the dissolution rate and the related substance level are not large compared with the dissolution rate and the related substance level at month 0, which indicates that the stability is good and meets the related requirements. After accelerated tests for 3 months, the contents of related substances in the Ruugolii tablets prepared in comparative examples 1, 6 and 8 have obvious increasing tendency and poor stability. Therefore, the replacement of the binder by povidone, the replacement of the disintegrant by croscarmellose sodium, or the increase of the amount of the disintegrant both increases the level of substances related to the product and decreases the stability.

In addition, a large number of experimental researches show that the mean particle size of mannitol has a remarkable influence on the dissolution rate and stability of the Ruugolii tablet. Specifically, on the basis of example 3, each group of rilugolith tablets was prepared by adjusting the mean particle sizes of mannitol to 5 μm, 15 μm, 25 μm, 35 μm, 45 μm and 55 μm, respectively, while the remaining components and contents and preparation method were kept unchanged. According to the test method for the dissolution rate and stability test, the dissolution rate and stability test is performed on each prepared group of riluguli tablets, and the test results are shown in table 3 below.

TABLE 3

As can be seen from table 3, when the mean particle size of mannitol is less than 10 microns or more than 50 microns, the dissolution rate and stability of the produced rilogeli tablet are poor.

The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it should be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; such modifications and substitutions do not depart from the spirit and scope of the embodiments of the present invention, and they should be construed as being included therein.

Claims (9)

1. The Ruuggolide tablet is characterized by comprising the following components in percentage by weight:

20 to 40 percent of Ruogeli,

40 to 70 percent of filling agent,

1 to 10 percent of disintegrating agent,

2 to 8 percent of adhesive,

0.1 to 2 percent of lubricant,

wherein the Ruuggol is jet milled to a D90 of less than 50 microns.

2. A rilogeli tablet according to claim 1, wherein the rilogeli has a D90 of 15-47 microns.

3. A Ruugeli tablet according to claim 1, wherein the filler is at least one of lactose monohydrate, mannitol, dibasic calcium phosphate, microcrystalline cellulose, corn starch.

4. A Ruugeli tablet according to claim 3, wherein the filler is mannitol, the mannitol having an average particle size of 10 to 50 microns.

5. A Ruugeli tablet according to claim 1, wherein the disintegrant is at least one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone.

6. A Ruugeli tablet according to claim 1, wherein the binder is at least one of hydroxypropyl cellulose, gelatin, starch slurry.

7. A Ruugeli tablet according to claim 1, wherein the lubricant is at least one of magnesium stearate, calcium stearate, sodium stearyl fumarate.

8. A process for the preparation of a Ruugeli tablet according to any one of claims 1 to 7, comprising the steps of:

weighing Ruuggol, and crushing the Ruuggol to D90 of less than 50 microns through airflow;

mixing the crushed Ruugeli, the filler and the disintegrating agent, and then adding the adhesive for wet granulation to obtain granules;

mixing the granules with the lubricant, and tabletting to obtain plain tablets;

and coating the plain tablets to obtain the Ruogeli tablets.

9. A method of manufacturing a rilogeli tablet according to claim 8, wherein the coating is weighted by 2% to 3%.