A kind of pirfenidone sustained-release granules and its preparation method and application

Abstract

The present invention discloses a pirfenidone sustained-release granule and a preparation method and application thereof. Specifically, the sustained-release granule contains pirfenidone, a sustained-release material and an acrylic resin; wherein the sustained-release material is selected from the following group: glyceryl behenate, glyceryl palmitostearate, agar, glycerol, carnauba wax, or a combination thereof. The sustained-release granule has a good sustained-release effect, so the number of medications is small and the compliance is good.

Description

Technical Field

[0001] The present application relates to the field of pharmaceutical preparations, and in particular, to a pirfenidone sustained-release granule and a preparation method and application thereof. Background Art

[0002] Pirfenidone (PFD) is an anti-fibrotic drug that was first approved for marketing in Japan in 2008 in the form of tablets. The original developer is Shionogi Pharmaceutical Co., Ltd. Pirfenidone is one of the only two drugs approved for the treatment of idiopathic fibrosis and is also the first-line drug of choice and a must-have drug for idiopathic fibrosis.

[0003] The pirfenidone currently on the market are all ordinary immediate-release preparations, and the recommended dosage is three times a day. Patient compliance is poor. Therefore, it is necessary to develop long-acting sustained-release preparations to improve patient compliance.

[0004] CN101972236A discloses a sustained-release preparation containing pirfenidone, which comprises an active ingredient pirfenidone, a sustained-release skeleton material and an additive, wherein the sustained-release skeleton material is one or a combination of a hydrophilic gel skeleton material, an erodible sustained-release skeleton material and a water-insoluble sustained-release skeleton material, and the water-insoluble sustained-release skeleton material is ethyl cellulose or acrylic resin.

[0005] CN107080741A discloses a pirfenidone sustained-release preparation, wherein the pirfenidone is dispersed in a sustained-release skeleton material, and the skeleton material is selected from cellulose derivatives, acrylic resins, vinyl polymers, and the like.

[0006] WO2023 / 208241A1 discloses a sustained-release oral solid preparation of pirfenidone, wherein the preparation has a double-layer structure, and the sustained-release layer contains a swelling material, a shaping material and an adhesive material, and the swelling material is selected from glyceryl behenate, carnauba wax, hydroxypropyl methylcellulose, etc.

[0007] The above-mentioned sustained-release preparations are all tablets, which have disadvantages such as difficulty in swallowing, dissolution and bioavailability, but granules can solve the above disadvantages. Therefore, it is necessary to develop a pirfenidone sustained-release granule with good compliance, less frequency of taking, easy swallowing and high bioavailability. Summary of the invention

[0008] In view of the deficiencies in the prior art, the present invention provides a pirfenidone sustained-release granule, which can reduce the number of medications and improve compliance, and has important clinical significance.

[0009] In the first aspect of the present invention, a pirfenidone sustained-release granule is provided, wherein the sustained-release granule contains pirfenidone, a sustained-release material and an acrylic resin; wherein the sustained-release material is selected from the following group: glyceryl behenate, glyceryl palmitostearate, agar, glycerol, carnauba wax, or a combination thereof.

[0010] In a preferred example, the acrylic resin is a water-insoluble acrylic resin.

[0011] In a preferred example, the acrylic resin is selected from the following group: Eudragit L, Eudragit S, Eudragit RL, Eudragit RS, Eudragit NE, Eudragit FS, or a combination thereof; preferably Eudragit L100, Eudragit L100-55, or a combination thereof.

[0012] In a preferred embodiment, the sustained-release granules contain:

[0013] Pirfenidone 20-55 parts by weight;

[0014] 40-70 parts by weight of sustained-release material;

[0015] 5 to 15 parts by weight of acrylic resin.

[0016] In another preferred embodiment, the sustained-release granules contain:

[0017] Pirfenidone 25-50 parts by weight;

[0018] 45-63 parts by weight of sustained-release material;

[0019] 5 to 12.5 parts by weight of acrylic resin.

[0020] In a preferred example, the sustained-release granules do not contain hydroxypropyl cellulose.

[0021] In another preferred embodiment, the hydroxypropyl cellulose is hydroxypropyl cellulose EXF.

[0022] In a preferred example, the weight ratio of the acrylic resin to the sustained-release material is 1:(3.5-10); preferably 1:(4-10); more preferably 1:(5-9).

[0023] In another preferred embodiment, the particle size of the sustained-release granules is 0.45 mm to 2 mm; preferably 0.45 mm to 1 mm; more preferably 0.8 mm to 1 mm.

[0024] The second aspect of the present invention provides a method for preparing the pirfenidone sustained-release granules according to the first aspect of the present invention, wherein the method is wet granulation or melt granulation.

[0025] In a preferred example, the wet granulation method comprises the following steps: adding pirfenidone, molten sustained-release material and acrylic resin into a granulator, and wet granulating to obtain granules.

[0026] In another preferred embodiment, the wet granulation method comprises the following steps: adding pirfenidone and acrylic resin into a granulator, adding molten sustained-release material after mixing, and wet granulating to obtain granules.

[0027] In a preferred embodiment, the melt granulation method comprises the following steps: mixing pirfenidone, sustained-release material and acrylic resin, hot-melt extruding at 120-180° C., and then pulverizing and sieving after cooling to obtain granules.

[0028] In another preferred embodiment, the melt granulation method comprises the following steps: mixing pirfenidone, sustained-release material and acrylic resin, hot-melt extruding at 120-180°C, crushing after cooling, granulating with a 10-mesh sieve, and then passing through 18-mesh and 24-mesh sieves respectively to obtain the granules.

[0029] The third aspect of the present invention provides a use of the pirfenidone sustained-release granules as described in the first aspect of the present invention or the pirfenidone sustained-release granules prepared by the preparation method described in the second aspect of the present invention in the preparation of a drug for treating idiopathic pulmonary fibrosis.

[0030] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0031] After long and in-depth research, the inventors have found that the present invention discloses a pirfenidone sustained-release granule and its preparation method and application. Specifically, the sustained-release granule contains pirfenidone, a sustained-release material and an acrylic resin; wherein the sustained-release material is selected from the following group: glyceryl behenate, glyceryl palmitostearate, agar, glycerol, carnauba wax, or a combination thereof. The sustained-release granule has a good sustained-release effect, so the number of medications is small and the compliance is good.

[0032] the term

[0033] As used herein, the term "pirfenidone" refers to a compound as shown in the following formula, or a derivative drug substance thereof:

[0034]

[0035] Since the preparation of the present invention can be applicable to various solid forms, the pirfenidone raw material applicable to the present invention can be pirfenidone raw salt, or it can be or its pharmaceutically acceptable derivatives, including cocrystals, salts, free acids, prodrugs (such as esters), polymorphs and solvates of pirfenidone.

[0036] Screen mesh aperture

[0037] As used herein, "40 mesh" corresponds to a sieve aperture of 0.45 mm.

[0038] As used herein, "24 mesh" corresponds to a sieve aperture of 0.80 mm.

[0039] As used herein, "18 mesh" corresponds to a sieve aperture of 1 mm.

[0040] As used herein, "10 mesh" corresponds to a sieve aperture of 2 mm.

[0041] In vitro dissolution test

[0042] According to the dissolution and release determination method of Method 2 of Part IV General Chapter 0931 of the "Chinese Pharmacopoeia" (2020 edition), 900 ml of phosphate buffer (pH 6.8) was used as the dissolution medium, and the paddle method (75 rpm) was used.

[0043] The main advantages of the present invention are:

[0044] 1. In the present invention, by selecting the types of sustained-release materials and acrylic resins and adjusting the corresponding ratios, the pirfenidone sustained-release particles prepared have good sustained-release effects.

[0045] 2. Existing pirfenidone preparations are all common immediate-release preparations with poor patient compliance. The preparation of the present invention is a sustained-release granule, which has the advantages of high bioavailability and less frequency of administration, and can significantly improve patient compliance.

[0046] 3. Most of the existing sustained-release granule preparations are coated preparations, which have complex production processes and high production costs. The sustained-release granules of the present invention omit complex steps such as coating, have a simple production process, and are more conducive to large-scale commercial production.

[0047] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for the unrecorded specific conditions in the following examples are usually carried out under normal conditions or under the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0048] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0049] During the research, the applicant found that when the size of the prepared pirfenidone sustained-release particles is less than 0.45 mm, its solubility reaches 80% or more in 4 hours, and the sustained-release effect cannot be obtained. Therefore, the size of the particles in the examples of this application is greater than 0.45 mm (ie, greater than 40 mesh).

[0050] Example 1: Preparation of pirfenidone sustained-release granules

[0051] Weigh the amounts of pirfenidone, glyceryl behenate and Eudragit L100 in Table 1 respectively, heat and melt glyceryl behenate for later use, add pirfenidone and Eudragit L100 to a wet granulator, fully mix at a stirring speed of 600 rpm and a shear speed of 1500 rpm, then add the molten glyceryl behenate for granulation, and after granulation, use a 10-mesh sieve to granulate, and then pass through 18-mesh and 24-mesh sieves respectively to obtain the product.

[0052] Table 1. Preparation of pirfenidone sustained-release granules according to the components in the following table

[0053] Material Name Proportion Dosage / g Pirfenidone 25.00％ 60.00 Glyceryl Behenate 62.50％ 150.00 Eudragit L100 12.50％ 30.00 total 100.00％ 240.00

[0054] Example 2: Preparation of pirfenidone sustained-release granules

[0055] Weigh the amounts of pirfenidone, glyceryl behenate and Eudragit L100 in Table 2 respectively, heat and melt glyceryl behenate for later use, add pirfenidone and Eudragit L100 to a wet granulator, fully mix at a stirring speed of 600 rpm and a shear speed of 1500 rpm, then add the molten glyceryl behenate for granulation, and after granulation, use a 10-mesh sieve to granulate, and then pass through 18-mesh and 24-mesh sieves respectively to obtain the product.

[0056] Table 2. Preparation of pirfenidone sustained-release granules according to the components in the following table

[0057] Material Name Proportion Dosage / g Pirfenidone 30.00％ 20.00 Glyceryl Behenate 60.00％ 40.00 Eudragit L100 10.00％ 6.67 total 100.00％ 66.67

[0058] Example 3: Preparation of Pirfenidone Sustained-Release Granules

[0059] Weigh the amounts of pirfenidone, carnauba wax, behenic acid glyceryl and Eudragit L100-55 shown in Table 3, mix them thoroughly, add them to a hot melt extruder and extrude them at a temperature of 150° C. After the extrudate is cooled, it is crushed using a pulverizer, granulated using a 10-mesh sieve, and then sieved through 18-mesh and 24-mesh sieves respectively.

[0060] Table 3. Preparation of pirfenidone sustained-release granules according to the components in the following table

[0061]

[0062]

[0063] Example 4: Preparation of Pirfenidone Sustained-Release Granules

[0064] Weigh the amounts of pirfenidone, carnauba wax, behenic acid glyceryl and Eudragit L100-55 shown in Table 4, mix them thoroughly, add them to a hot melt extruder and extrude them at a temperature of 150° C. After the extrudate is cooled, it is crushed using a pulverizer, granulated using a 10-mesh sieve, and then sieved through 18-mesh and 24-mesh sieves respectively.

[0065] Table 4. Preparation of pirfenidone sustained-release granules according to the components in the following table

[0066] Material Name Proportion Dosage / g Pirfenidone 41.67％ 12.00 Carnauba wax 33.33％ 9.60 Glyceryl Behenate 12.50％ 3.60 Eutectic L100-55 12.50％ 3.60 total 100.00％ 28.80

[0067] Comparative Example 1: Preparation of Pirfenidone Sustained-Release Granules

[0068] Weigh the amounts of pirfenidone, talc, hydroxypropyl methylcellulose K4M CR, Eudragit L100 and hydroxypropyl cellulose EXF shown in Table 5, place all the materials in a wet granulator, and fully mix them at a stirring speed of 600 pm and a shear speed of 1500 rpm. After mixing, add water for granulation to obtain a soft material, place the soft material in an extrusion spheronizer for extrusion and spheronization, respectively, and sieve with 10 mesh and 24 mesh sieves to obtain the soft material.

[0069] Table 5. Preparation of pirfenidone sustained-release granules according to the components in the following table

[0070] Material Name Proportion Dosage / g Pirfenidone 25.00％ 40.00 talcum powder 0.63％ 1.00 Hydroxypropyl methylcellulose K4M CR 56.25％ 90.00 Eudragit L100 11.88％ 19.00 Hydroxypropylcellulose EXF 6.25％ 10.00 total 100.00％ 160.00

[0071] Different from the examples, Comparative Example 1 does not contain glyceryl behenate.

[0072] Comparative Example 2: Preparation of Pirfenidone Sustained-Release Granules

[0073] Weigh the amounts of pirfenidone, behenic acid glyceryl, hydroxypropyl methylcellulose K4M CR and hydroxypropyl cellulose EXF in Table 6 respectively, heat and melt the behenic acid glyceryl for use, add pirfenidone, hydroxypropyl methylcellulose K4M CR and hydroxypropyl cellulose EXF into a wet granulator, mix them thoroughly at a stirring speed of 600 rpm and a shear speed of 1500 rpm, then add the molten behenic acid glyceryl for granulation, and after granulation, use a 10-mesh sieve to granulate, and then pass through an 18-mesh sieve to obtain the product.

[0074] Table 6 Preparation of pirfenidone sustained-release granules according to the components in the following table

[0075] Material Name Proportion Dosage / g Pirfenidone 25.00％ 60.00 Glyceryl Behenate 50.00％ 120.00 Hydroxypropyl methylcellulose K4M CR 18.75％ 45.00 Hydroxypropylcellulose EXF 6.25％ 15.00 total 100.00％ 240.00

[0076] Different from Example 1, Comparative Example 2 does not contain acrylic resin.

[0077] Comparative Example 3: Preparation of Pirfenidone Sustained-Release Granules

[0078] Weigh the amounts of pirfenidone, glyceryl behenate, Eudragit L100 and hydroxypropylcellulose EXF shown in Table 7 respectively, heat and melt glyceryl behenate for standby use, add pirfenidone and Eudragit L100 to a wet granulator, mix thoroughly at a stirring speed of 600 rpm and a shear speed of 1500 rpm, and then quickly add the molten glyceryl behenate to the wet granulator, crush after granulation and pass through a 40-mesh sieve. Add the particles <40 mesh and hydroxypropylcellulose to a wet granulator, add water and granulate at a stirring speed of 600 rpm and a shear speed of 1500 rpm to obtain a soft material, place the soft material in an extrusion spheronizer for extrusion and spheronization, and sieve through 10-mesh and 18-mesh sieves to obtain the soft material.

[0079] Table 7. Preparation of pirfenidone sustained-release granules according to the components in the following table

[0080] Material Name Proportion Dosage / g Pirfenidone 30.00％ 30.00 Glyceryl Behenate 58.00％ 58.00 Eudragit L100 10.00％ 10.00 Hydroxypropylcellulose EXF 2.00％ 2.00 total 100.00％ 100.00

[0081] Different from Examples 4 and 5, Comparative Example 3 contains hydroxypropyl cellulose.

[0082] The results showed that it was difficult to obtain particles with appropriate wetness using this prescription, and strips could not be squeezed out when the particles were too dry; when the particles were too wet, they were rolled and stuck together, and the strength of the rounded particles was low, making it impossible to prepare particles that met the requirements.

[0083] Comparative Example 4: Preparation of Pirfenidone Sustained-Release Granules

[0084] The pirfenidone sustained-release granules shown in Table 8 were prepared by a method similar to that of Example 4.

[0085] Table 8. Preparation of pirfenidone sustained-release granules according to the components in the following table

[0086] Material Name Proportion Dosage / g Pirfenidone 41.67％ 20.00 Carnauba wax 27.08％ 13.00 Glyceryl Behenate 12.50％ 6.00 Eutectic L100-55 18.75％ 9.00 total 100.00％ 48.00

[0087] Different from the examples, the weight ratio of the acrylic resin material (i.e., Eudragit L100-55) to the sustained-release material is relatively large in Comparative Example 4. Specifically, in Examples 1-4, the weight ratios of the acrylic resin to the sustained-release material (i.e., glyceryl behenate and carnauba wax) are 1:5, 1:6, 1:9, and 1:3.7, respectively, while in Comparative Example 4, the weight ratio of the acrylic resin to the sustained-release material is increased to 1:2.

[0088] Test Example 1: In vitro dissolution test

[0089] According to the dissolution and release determination method of the second method of Part IV General Rules 0931 of the "Chinese Pharmacopoeia" (2020 edition), 900 ml of phosphate buffer (pH 6.8) was used as the dissolution medium and the slurry method (75 rpm) was used to detect the in vitro release of the pirfenidone sustained-release granules of the present invention at 1 h, 2 h, 4 h, 8 h, 12 h, and 16 h. The results are shown in Table 9.

[0090] Table 9 In vitro release of pirfenidone sustained-release granules prepared by the present invention

[0091]

[0092] The experimental results show that the sustained-release granules prepared in the examples of the present invention can all be sustained-released, while the sustained-release granules prepared in the comparative examples are dissolved faster, reaching more than 80% in 4 hours, indicating that the granules of the present application have a good sustained-release effect.

[0093] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A pirfenidone sustained-release granule, characterized in that: The sustained-release granules are composed of pirfenidone, sustained-release material and acrylic resin; Wherein, the sustained-release material is selected from the group consisting of glyceryl behenate, carnauba wax, or a combination thereof; The acrylic resin is Eudragit L; And the sustained-release granules contain: Pirfenidone 20-55 parts by weight; 40-70 parts by weight of sustained-release material; 5-15 parts by weight of acrylic resin.

2. The sustained-release granules according to claim 1, characterized in that The acrylic resin is selected from the group consisting of Eudragit L100, Eudragit L100-55, or a combination thereof.

3. The sustained-release granules according to claim 1, characterized in that The sustained-release granules do not contain hydroxypropylcellulose.

4. The sustained-release granules according to claim 1, characterized in that The weight ratio of the acrylic resin to the sustained-release material is 1: (3.5-10).

5. The sustained-release granules according to claim 1, characterized in that The weight ratio of the acrylic resin to the sustained-release material is 1: (4-10).

6. The sustained-release granules according to claim 1, characterized in that The weight ratio of the acrylic resin to the sustained-release material is 1: (5-9).

7. A method for preparing the pirfenidone sustained-release granules according to any one of claims 1 to 6, characterized in that: The method is wet granulation or melt granulation.

8. A preparation method according to claim 7, characterized in that: The wet granulation method comprises the following steps: adding pirfenidone, melted sustained-release material and acrylic resin into a granulator, and wet granulating to obtain granules.

9. A preparation method according to claim 7, characterized in that: The melt granulation method comprises the following steps: mixing pirfenidone, sustained-release material and acrylic resin, hot-melt extruding at 120-180° C., and crushing and sieving after cooling to obtain granules.

10. Use of the pirfenidone sustained-release granules according to any one of claims 1 to 6 or the pirfenidone sustained-release granules prepared by the preparation method according to claims 7 to 9 in preparing a medicament for treating idiopathic pulmonary fibrosis.

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