Flufenidone capsule preparation as well as preparation method and application thereof

Abstract

The invention provides a flufenidone capsule preparation as well as a preparation method and application thereof. The florfenidone capsule preparation comprises florfenidone serving as an active ingredient and a pharmaceutically acceptable capsule preparation carrier serving as an inactive ingredient, and the florfenidone serving as the active ingredient is prepared by crushing the florfenidone and then sieving the crushed florfenidone through a 60-100-mesh sieve, preferably a 70-90-mesh sieve and most preferably a 80-mesh sieve; the pharmaceutically acceptable capsule preparation carrier comprises a filler, a disintegrating agent, an adhesive and a lubricant. The flufenidone capsule provided by the invention has better in-vitro dissolution rate, can be dissolved out for 30 minutes in vitro to reach 85% or more, and is good in dissolution effect, high in bioavailability, more beneficial to in-vivo absorption and good in stability.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to a flufenidone capsule preparation, a preparation method and application thereof. Background Art

[0002] Fluorofenidone, chemically named 1-(3-fluorophenyl)-5-methyl-1H-pyridone, belongs to the pyridone class of compounds. Pharmacological studies have shown that the drug has a good therapeutic effect on a variety of organ fibrosis diseases such as liver cirrhosis, liver fibrosis, renal fibrosis, including diabetic nephropathy, chronic tubulointerstitial nephritis, etc., and its effect is stronger than similar compounds.

[0003] The commonly used solid dispersion technology requires a large amount of organic solvents as solvents during the preparation process, and organic solvents are not easy to completely remove, and residual solvents may cause adverse reactions. Because the samples prepared by solid dispersion technology may not be stable in the dispersed state of the drug, and the drug crystal form may change during the storage of the drug, the drug may undergo physical or chemical changes, thereby affecting its efficacy and stability, and the solubility and bioavailability of the preparation will tend to decrease. Summary of the invention

[0004] Therefore, the purpose of the present invention is to overcome the defects in the prior art and provide a fluorofenidone capsule preparation, a preparation method and application thereof. The fluorofenidone capsule preparation of the present invention can be used to treat various organ fibrosis diseases such as liver cirrhosis, liver fibrosis, renal fibrosis, including diabetic nephropathy and chronic tubulointerstitial nephritis.

[0005] To achieve the above object, the first aspect of the present invention provides a fluorofenidone capsule preparation, which comprises fluorofenidone as an active ingredient and a pharmaceutically acceptable capsule preparation carrier as an inactive ingredient, wherein:

[0006] The flufenidone as the active ingredient is obtained by pulverizing and passing through a 60-100 mesh sieve, preferably a 70-90 mesh sieve, and most preferably an 80 mesh sieve;

[0007] The pharmaceutically acceptable capsule preparation carrier comprises: a filler, a disintegrant, a binder and a lubricant;

[0008] And the mass ratio of each component is:

[0009] Flufenidone: 60-80 parts;

[0010] Filler: 10-30 parts;

[0011] Disintegrant: 1-5 parts;

[0012] Adhesive: 1-3 parts;

[0013] Lubricant: 0.1 to 2 parts.

[0014] According to the first aspect of the present invention, the flufenidone capsule preparation, wherein the mass fraction ratio of each component is:

[0015] Flufenidone: 65-75 parts, preferably 68-72 parts;

[0016] Filler: 20-30 parts, preferably 25-30 parts;

[0017] Disintegrant: 1 to 4 parts, preferably 2 to 4 parts;

[0018] Binder: 1.5-2.5 parts, preferably 1.5-2 parts;

[0019] Lubricant: 0.1 to 1 part, preferably 0.2 to 0.6 part.

[0020] According to the flufenidone capsule preparation of the first aspect of the present invention, the filler is selected from one or more of the following: anhydrous lactose, pregelatinized starch, sucrose, mannitol, sorbitol, microcrystalline cellulose, corn starch, cellulose-lactose, preferably selected from one or more of the following: anhydrous lactose, pregelatinized starch, sucrose, mannitol, corn starch, cellulose-lactose, more preferably selected from one or more of the following: anhydrous lactose, pregelatinized starch, corn starch, cellulose-lactose.

[0021] According to the first aspect of the present invention, the flufenidone capsule preparation, wherein:

[0022] The disintegrant is selected from one or more of the following: sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone, preferably sodium carboxymethyl starch or cross-linked sodium carboxymethyl cellulose, and most preferably cross-linked sodium carboxymethyl cellulose.

[0023] According to the first aspect of the present invention, the flufenidone capsule preparation, wherein:

[0024] The binder is selected from one or more of the following: methylcellulose, hydroxyethylcellulose, hypromellose, hydroxypropyl cellulose, povidone, preferably selected from one or more of the following: methylcellulose, hydroxyethylcellulose, hypromellose, hydroxypropyl cellulose, more preferably hypromellose or hydroxypropyl cellulose.

[0025] According to the flufenidone capsule preparation of the first aspect of the present invention, the lubricant is magnesium stearate or calcium stearate, and magnesium stearate is most preferred.

[0026] The second aspect of the present invention provides a method for preparing the flufenidone capsule preparation according to the first aspect, the method comprising the following steps:

[0027] 1) Weigh the raw material compound flufenidone, crush and sieve;

[0028] 2) mixing the sieved flufenidone in step 1) with the filler and the disintegrant, adding the binder to granulate, drying and sieving to obtain flufenidone granules; and

[0029] 3) mixing the fluorofenidone particles obtained in step 2) with the lubricant to obtain contents, and filling the contents into capsule shells to obtain the fluorofenidone capsule preparation.

[0030] According to the method of the second aspect of the present invention, in said step 2):

[0031] The granulation method is selected from one or more of the following: wet granulation, fluidized bed granulation, dry granulation, powder mixing granulation, preferably selected from one or more of the following: wet granulation, fluidized bed granulation, powder mixing granulation, and most preferably wet granulation;

[0032] The mixing time is 3 to 10 minutes, preferably 4 to 6 minutes, and most preferably 5 minutes;

[0033] The binder is added in the form of an aqueous solution, and the mass percentage concentration of the solute of the binder in water is preferably 2% to 10%, more preferably 3% to 8%, and further preferably 4% to 5%; and / or

[0034] The mesh number of the sieve after drying is 10-40 meshes, preferably 20-30 meshes, and most preferably 20 meshes.

[0035] According to the method of the second aspect of the present invention, in said step 3):

[0036] The mixing time is 5 to 20 minutes, preferably 10 to 15 minutes, most preferably 10 minutes; and / or

[0037] The mixing speed is 5 to 30 rpm, preferably 10 to 20 rpm, and most preferably 15 rpm.

[0038] The third aspect of the present invention provides the use of the flufenidone capsule preparation described in the first aspect in the preparation of a medicament for treating organ fibrosis diseases;

[0039] Preferably, the organ fibrosis disease is selected from one or more of the following: cirrhosis, liver fibrosis, and kidney fibrosis;

[0040] More preferably, the renal fibrosis disease is selected from one or more of the following: diabetic nephropathy, chronic tubulointerstitial nephritis, and renal fibrosis.

[0041] According to a preferred embodiment of the present invention, the flufenidone capsules of the present invention comprise the following components in percentage by mass:

[0042] Flufenidone: 65% to 75%

[0043] Filler: 20%~30%

[0044] Disintegrant: 2% to 5%

[0045] Adhesive: 1%~3%

[0046] Lubricant: 0.1%~1%

[0047] Wherein, the flufenidone is crushed by a crusher and then passed through an 80-mesh sieve.

[0048] The filler is selected from at least one or more of anhydrous lactose, cellulose-lactose, sucrose, mannitol, sorbitol, pregelatinized starch, microcrystalline cellulose, and corn starch, preferably cellulose-lactose. The present invention has found through a large number of experiments that when cellulose-lactose is used as a filler, it can effectively reduce the fine powder rate after granulation, increase the fluidity of the particles, reduce the difficulty of particle filling, and improve the feasibility and fluency of the preparation process.

[0049] The disintegrant is selected from at least one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone, wherein cross-linked sodium carboxymethyl cellulose is preferred. The present invention has found through experiments that the amount of cross-linked sodium carboxymethyl starch has a great influence on the in vitro dissolution and stability of the capsule. Generally speaking, the more the amount of disintegrant increases, the more obvious the particle disintegration effect is, and the faster the dissolution is, and vice versa. It was found through experiments that when the amount of cross-linked sodium carboxymethyl starch is 2% to 5%, the dissolution meets the requirements.

[0050] The binder is selected from at least one or more of methylcellulose, hydroxyethylcellulose, hypromellose, hydroxypropylcellulose, and povidone, wherein hypromellose is preferred. The present invention has found through a large number of experiments that the granulation effect of hypromellose prepared as an aqueous solution to participate in granulation is better, while the granulation effect is poor when the powder is used for granulation, so the capsule is preferably prepared as an aqueous solution to participate in granulation.

[0051] The lubricant is magnesium stearate and / or calcium stearate, preferably magnesium stearate.

[0052] The fluorofenidone capsules of the present invention are crushed by a pulverizer until they pass through an 80-mesh sieve, and then the crushed fluorofenidone is mixed with other components, and then the fluorofenidone capsules are prepared by wet granulation process, fluidized bed granulation, dry granulation, powder mixing and other processes. The prepared fluorofenidone capsules have good in vitro dissolution, and the in vitro dissolution can reach more than 85% in 30 minutes, the dissolution effect is good, and the chemical stability is good. The present invention conducts a large number of experiments on the method of wet granulation, and investigates the difference between fluidized bed granulation and wet granulation. According to the granulation state of the particles and the dissolution results, it can be known that both wet granulation and fluidized bed granulation meet the requirements. In the present invention, wet granulation is preferentially used to prepare the capsules.

[0053] The preparation method of the flufenidone capsule of the present invention mainly comprises the following steps:

[0054] (1) grinding flufenidone until it passes through an 80-mesh sieve, mixing the ground flufenidone, a filler, and a disintegrant, and then adding the binder to perform wet granulation to obtain granules;

[0055] (2) The wet granules are granulated and then dried, and then dry granulated, and then a lubricant is added and mixed to obtain contents, and the contents are filled into corresponding capsules to obtain the flufenidone capsules.

[0056] The fluorofenidone capsules of the present invention include the following components in percentage by mass: 65% to 75% fluorofenidone, 20% to 30% filler, 1% to 5% disintegrant, 1% to 3% binder, and 0.1% to 1% lubricant; wherein the fluorofenidone is crushed by a pulverizer until it passes through an 80-mesh screen. The fluorofenidone capsules provided by the present invention have good in vitro dissolution, and the dissolution rate can reach more than 85% in vitro within 30 minutes, with good dissolution effect, high bioavailability, more conducive to in vivo absorption, and good stability.

[0057] The present invention adopts wet granulation, fluidized bed granulation, powder filling and the like to prepare the flufenidone capsules. The process operation is simple, the technology is mature, and the energy consumption is low. If the wet granulation process is adopted in the preparation process, purified water is used as a solvent or a wetting agent, and no organic solvent needs to be introduced. In contrast, the commonly used solid dispersion technology needs to use a large amount of organic solvent as a solvent in the preparation process, and the organic solvent is not easy to be completely removed. The residual solvent may cause adverse reactions. Therefore, from the perspectives of drug residual solvent control, environmental protection and explosion prevention, the technology adopted in the present invention has obvious technical advantages.

[0058] Because samples prepared using solid dispersion technology may not be stable in the drug dispersion state, and the drug crystal form may change during storage, the drug may undergo physical or chemical changes, thereby affecting its efficacy and stability. At the same time, the solubility and bioavailability of the preparation will tend to decrease. The preparation process used in the present invention has a lower risk of changes in crystal form and stability.

[0059] Compared with the prior art, the flufenidone capsule preparation and preparation method thereof of the present invention may have but are not limited to the following beneficial effects:

[0060] 1. The preparation method of the present invention has simple process, convenient operation and is suitable for large-scale industrial production.

[0061] 2. The flufenidone capsules prepared by the preparation method of the present invention have good solubility, and the dissolution rate can reach more than 85% in 30 minutes in vitro. The dissolution effect is good, the bioavailability is high, it is more conducive to in vivo absorption, and the stability is good. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] The embodiments of the present invention are described in detail below with reference to the accompanying drawings, wherein:

[0063] Figure 1 The dissolution curves of the flufenidone capsule preparations prepared in Examples 1 to 2 of the present invention in a 0.1 M hydrochloric acid medium are shown.

[0064] Figure 2 The dissolution curves of the flufenidone capsule preparations prepared in Examples 3 to 4 of the present invention in a 0.1 M hydrochloric acid medium are shown.

[0065] Figure 3 The dissolution curves of the flufenidone capsule preparations prepared in Examples 5 to 6 of the present invention in a 0.1 M hydrochloric acid medium are shown. DETAILED DESCRIPTION

[0066] The present invention is further described below by means of specific examples. However, it should be understood that these examples are only used for more detailed and specific description and should not be understood as limiting the present invention in any form.

[0067] This section generally describes the materials and test methods used in the experiments of the present invention. Although many materials and operating methods used to achieve the purpose of the present invention are well known in the art, the present invention is still described as detailed as possible. It is clear to those skilled in the art that in the context, if not specifically stated, the materials and operating methods used in the present invention are well known in the art.

[0068] The reagents and instruments used in the following examples are as follows:

[0069] Reagents:

[0070] Hydrochloric acid was purchased from Guangzhou Chemical Reagent Factory.

[0071] Flufenidone was purchased from Chongqing Tiandi Pharmaceutical Co., Ltd.

[0072] Anhydrous lactose was purchased from Metz-Levosberg Dairy House GmbH & Co. KG, Germany.

[0073] Microcrystalline cellulose was purchased from Shandong Liaocheng Ahua Pharmaceutical Co., Ltd.

[0074] Croscarmellose sodium was purchased from DuPunc Nutrition USA.

[0075] Hydroxypropyl methylcellulose and pregelatinized starch were purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd.

[0076] Magnesium stearate and corn starch were purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.

[0077] Cellulose-lactose was purchased from Metz-Levosberg Dairy House GmbH & Co. KG, Germany.

[0078] Hydroxypropyl cellulose was purchased from Ashland Specialty Ingredients GP.

[0079] instrument:

[0080] Analytical balance, model XS205DU, purchased from Mettler Toledo;

[0081] Analytical balance, model CP213, purchased from Ohaus Instruments Co., Ltd.;

[0082] Vacuum degasser, model ZKT-18F, purchased from Tianda Tianfa Technology Co., Ltd.;

[0083] Dissolution apparatus, model RC1207DP, purchased from Tianda Tianfa Technology Co., Ltd.

[0084] Ultraviolet spectrophotometer, model UV-2700, purchased from Shimadzu Laboratory Equipment Co., Ltd.;

[0085] The pH meter, model S220, was purchased from Mettler Toledo.

[0086] Example 1

[0087] This example is an exemplary description of the flufenidone capsule preparation and its preparation method of the present invention.

[0088] The flufenidone capsule formulation provided in this embodiment is as follows:

[0089] Flufenidone 70%;

[0090] Anhydrous lactose 12% (filler);

[0091] Microcrystalline cellulose 11% (filler);

[0092] Croscarmellose sodium 4% (disintegrant);

[0093] Hydroxypropyl methylcellulose 2.5% (binder);

[0094] Magnesium stearate 0.5% (lubricant).

[0095] The preparation method of flufenidone capsules is as follows:

[0096] (1) First, grind flufenidone and pass it through an 80-mesh sieve for later use.

[0097] (2) Weigh 15g of hydroxypropyl methylcellulose and dissolve it in 300ml of purified water to prepare a 5% hydroxypropyl methylcellulose solution. Weigh 350g of flufenidone (pure and dry), 60g of anhydrous lactose, 55g of microcrystalline cellulose, and 20g of cross-linked sodium carboxymethyl cellulose and put them into a wet granulator for mixing for 5 minutes. Then add 250ml of 5% hydroxypropyl methylcellulose solution to the wet granulator for wet granulation to prepare wet granules. Then, the wet granules are dried in a fluidized bed, and the material temperature is controlled to 40°C. The obtained wet granules are dried to a moisture content of ≤3.0%. The dried granules are sieved through a 20-mesh sieve to obtain granules.

[0098] (3) The above granules and 2.5 g of magnesium stearate were added to a mixer and mixed at a mixing speed of 10 rpm for 10 min to obtain a total mixed granule.

[0099] (4) Filling the capsules with a filling machine to obtain flufenidone capsules.

[0100] Example 2

[0101] This example is another exemplary description of the flufenidone capsule preparation and preparation method thereof of the present invention.

[0102] The flufenidone capsule formulation provided in this embodiment is as follows:

[0103] Flufenidone 70%;

[0104] Pregelatinized starch 13% (filler);

[0105] Microcrystalline cellulose 10% (filler);

[0106] Croscarmellose sodium 4% (disintegrant);

[0107] Hydroxypropyl methylcellulose 2.5% (binder);

[0108] Magnesium stearate 0.5% (lubricant).

[0109] The preparation method of flufenidone capsules is as follows:

[0110] (1) First, grind flufenidone and pass it through an 80-mesh sieve for later use.

[0111] (2) Weigh 20g of hydroxypropyl methylcellulose and dissolve it in 500ml of purified water to prepare a 4% hydroxypropyl methylcellulose solution. Weigh 350g of flufenidone (pure and dry), 65g of pregelatinized starch, 50g of microcrystalline cellulose, and 20g of cross-linked sodium carboxymethyl cellulose and add them into a ziplock bag for manual mixing for 5 minutes. Then add the mixed materials into the fluidized bed, and after the material is heated to 50°C, start spraying, add 312.5ml of 4% hydroxypropyl methylcellulose solution for wet granulation to prepare granules, dry the obtained wet granules to a moisture content of ≤3.0%, and pass the dried granules through a 20-mesh sieve for granulation to obtain granules.

[0112] (3) The above granules and 2.5 g of magnesium stearate were added to a mixer and mixed at a mixing speed of 10 rpm for 10 min to obtain a total mixed granule.

[0113] (4) Filling the capsules with a filling machine to obtain flufenidone capsules.

[0114] Example 3

[0115] This example is another exemplary description of the flufenidone capsule preparation and the preparation method thereof of the present invention.

[0116] The flufenidone capsule formulation provided in this embodiment is as follows:

[0117] Flufenidone 70%;

[0118] Cellulose-Lactose 23% (filler);

[0119] Croscarmellose sodium 4% (disintegrant);

[0120] Hydroxypropyl methylcellulose 2.5% (binder);

[0121] Magnesium stearate 0.5% (lubricant).

[0122] The preparation method of flufenidone capsules is as follows:

[0123] (1) Grind flufenidone and pass it through an 80-mesh sieve for later use.

[0124] (2) Weigh 15g of hydroxypropyl methylcellulose and dissolve it in 300ml of purified water to prepare a 5% hydroxypropyl methylcellulose solution. Weigh 350g of flufenidone (pure and dry), 115g of cellulose-lactose, and 20g of cross-linked carboxymethyl cellulose sodium and put them into a wet granulator for mixing for 5 minutes. Then, add 250ml of 5% hydroxypropyl methylcellulose solution to the wet granulator for wet granulation to prepare wet granules. Then, the wet granules are dried in a fluidized bed, and the material temperature is controlled to 40°C. The obtained wet granules are dried to a moisture content of ≤3.0%. The dried granules are sieved through a 20-mesh sieve to obtain granules.

[0125] (3) The above granules and 2.5 g of magnesium stearate were added to a mixer and mixed at a mixing speed of 10 rpm for 10 min to obtain a total mixed granule.

[0126] (4) Filling the capsules with a filling machine to obtain flufenidone capsules.

[0127] Example 4

[0128] This embodiment is another exemplary description of the flufenidone capsule preparation and the preparation method thereof of the present invention.

[0129] The flufenidone capsule formulation provided in this embodiment is as follows:

[0130] Flufenidone 70%;

[0131] Corn starch 10% (filler);

[0132] Microcrystalline cellulose 13% (filler);

[0133] Croscarmellose sodium 4% (disintegrant);

[0134] Hydroxypropyl cellulose 2.5% (binder);

[0135] Magnesium stearate 0.5% (lubricant).

[0136] The preparation method of flufenidone capsules is as follows:

[0137] (1) First, grind flufenidone and pass it through an 80-mesh sieve for later use.

[0138] (2) Weigh 20g of hydroxypropyl methylcellulose and dissolve it in 500ml of purified water to prepare a 4% hydroxypropyl methylcellulose solution. Weigh 350g of flufenidone (pure and dry), 50g of corn starch, 65g of microcrystalline cellulose, and 20g of cross-linked sodium carboxymethyl cellulose and add them into a ziplock bag for manual mixing for 5 minutes. Then, add the mixed materials into the fluidized bed. After the materials are heated to 50°C, start spraying, add 312.5ml of 4% hydroxypropyl cellulose solution for wet granulation to prepare granules. Dry the obtained wet granules to a moisture content of ≤3.0%, and pass the dried granules through a 20-mesh sieve to obtain granules.

[0139] (3) The above granules and 2.5 g of magnesium stearate were added to a mixer and mixed at a mixing speed of 10 rpm for 10 min to obtain a total mixed granule.

[0140] (4) Filling the capsules with a filling machine to obtain flufenidone capsules.

[0141] Example 5

[0142] This example is another exemplary description of the flufenidone capsule preparation and preparation method thereof of the present invention.

[0143] The flufenidone capsule formulation provided in this embodiment is as follows:

[0144] Flufenidone 70%;

[0145] Cellulose-Lactose 23.5% (filler);

[0146] Croscarmellose sodium 4% (disintegrant);

[0147] Hydroxypropyl cellulose 2% (binder);

[0148] Magnesium stearate 0.5% (lubricant).

[0149] The preparation method of flufenidone capsules is as follows:

[0150] (1) Grind flufenidone and pass it through an 80-mesh sieve for later use.

[0151] (2) 350 g of flufenidone (on a dry basis), 117.5 g of cellulose-lactose, 20 g of cross-linked sodium carboxymethyl cellulose, and 10 g of hydroxypropyl cellulose were weighed and added to a mixer for mixing at a mixing speed of 15 rpm for 30 min to obtain a total mixed granule.

[0152] (3) Add 2.5 g of magnesium stearate and the total mixed granules into a mixer and mix at a mixing speed of 10 rpm for 10 min.

[0153] (4) Filling the capsules with a filling machine to obtain flufenidone capsules.

[0154] Example 6

[0155] This example is another exemplary description of the flufenidone capsule preparation and preparation method thereof of the present invention.

[0156] The flufenidone capsule formulation provided in this embodiment is as follows:

[0157] Flufenidone 70%;

[0158] Anhydrous lactose 10% (filler);

[0159] Microcrystalline cellulose 13% (filler);

[0160] Croscarmellose sodium 4% (disintegrant);

[0161] Hydroxypropyl cellulose 2.5% (binder);

[0162] Magnesium stearate 0.5% (lubricant).

[0163] The preparation method of flufenidone capsules is as follows:

[0164] (1) First, grind flufenidone and pass it through an 80-mesh sieve for later use.

[0165] (2) Weigh 20g of hydroxypropyl cellulose and dissolve it in 500ml of purified water to prepare a 4% hydroxypropyl cellulose solution. Weigh 350g of flufenidone (pure and dry), 50g of anhydrous lactose, 65g of microcrystalline cellulose, and 20g of cross-linked sodium carboxymethyl cellulose and add them into a ziplock bag for manual mixing for 5 minutes. Then add the mixed materials into the fluidized bed, and after the material is heated to 50°C, start spraying, add 312.5ml of 4% hydroxypropyl cellulose solution for wet granulation to prepare granules, dry the obtained wet granules to a moisture content of ≤3.0%, and pass the dried granules through a 20-mesh sieve for granulation to obtain granules.

[0166] (3) The above granules and 2.5 g of magnesium stearate were added to a mixer and mixed at a mixing speed of 10 rpm for 10 min to obtain a total mixed granule.

[0167] (4) Filling the capsules with a filling machine to obtain flufenidone capsules.

[0168] Example 7

[0169] This example is used to illustrate the dissolution curve data of the flufenidone capsule preparations prepared in Examples 1-6 of the present invention.

[0170] Dissolution method:

[0171] Medium volume: 900ml

[0172] Method: Basket method (General Chapter 0931 Method 1 of the Chinese Pharmacopoeia 2020 Edition)

[0173] Speed ​​100r / min

[0174] Medium: 0.1M hydrochloric acid

[0175] Detection method: UV (311mm)

[0176] Sampling points: 5min, 10min, 15min, 30min, 45min, 60min

[0177] Table 1 Dissolution curve data of flufenidone capsule preparations of Examples 1-6 in 0.1M

[0178]

[0179]

[0180] As shown in Table 1 and Figure 1 , Figure 2 , Figure 3 As shown, the samples prepared according to the above examples can be dissolved quickly in 0.1 M hydrochloric acid medium with a dissolution amount greater than 60% in 5 minutes and a dissolution amount greater than 85% in 15 minutes.

[0181] Although the effects of some embodiments are shown above, those skilled in the art should understand that according to the concept of the present invention, the aforementioned other embodiments without specific effects or other technical solutions of the present invention not shown in the embodiments can also achieve the following technical effects stated in the invention content section that are equivalent to the embodiments:

[0182] 1. The preparation method of the present invention has simple process, convenient operation and is suitable for large-scale industrial production.

[0183] 2. The flufenidone capsules prepared by the preparation method of the present invention have good solubility, and the dissolution rate can reach more than 85% in 30 minutes in vitro. The dissolution effect is good, the bioavailability is high, it is more conducive to in vivo absorption, and the stability is good.

[0184] Although the present invention has been described to a certain extent, it is obvious that appropriate changes in various conditions can be made without departing from the spirit and scope of the present invention. It is understood that the present invention is not limited to the embodiments described, but belongs to the scope of the claims, which includes equivalent replacements of each factor described.

Claims

1. A flufenidone capsule preparation, characterized in that: The flufenidone capsule preparation comprises flufenidone as an active ingredient and a pharmaceutically acceptable capsule preparation carrier as an inactive ingredient, wherein: The flufenidone as the active ingredient is obtained by pulverizing and passing through a 60-100 mesh sieve, preferably a 70-90 mesh sieve, and most preferably an 80 mesh sieve; The pharmaceutically acceptable capsule preparation carrier comprises: a filler, a disintegrant, a binder and a lubricant; And the mass ratio of each component is: Flufenidone: 60-80 parts; Filler: 10-30 parts; Disintegrant: 1-5 parts; Adhesive: 1-3 parts; Lubricant: 0.1 to 2 parts.

2. The flufenidone capsule preparation according to claim 1, characterized in that: The mass ratio of each component is as follows: Flufenidone: 65-75 parts, preferably 68-72 parts; Filler: 20-30 parts, preferably 25-30 parts; Disintegrant: 1 to 4 parts, preferably 2 to 4 parts; Binder: 1.5-2.5 parts, preferably 1.5-2 parts; Lubricant: 0.1 to 1 part, preferably 0.2 to 0.6 part.

3. The flufenidone capsule preparation according to claim 1 or 2, characterized in that: The filler is selected from one or more of the following: anhydrous lactose, pregelatinized starch, sucrose, mannitol, sorbitol, microcrystalline cellulose, corn starch, cellulose-lactose, preferably selected from one or more of the following: anhydrous lactose, pregelatinized starch, sucrose, mannitol, corn starch, cellulose-lactose, more preferably selected from one or more of the following: anhydrous lactose, pregelatinized starch, corn starch, cellulose-lactose.

4. The flufenidone capsule preparation according to any one of claims 1 to 3, characterized in that The disintegrant is selected from one or more of the following: sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone, preferably sodium carboxymethyl starch or cross-linked sodium carboxymethyl cellulose, and most preferably cross-linked sodium carboxymethyl cellulose.

5. The flufenidone capsule preparation according to any one of claims 1 to 4, characterized in that: The binder is selected from one or more of the following: methylcellulose, hydroxyethylcellulose, hypromellose, hydroxypropyl cellulose, povidone, preferably selected from one or more of the following: methylcellulose, hydroxyethylcellulose, hypromellose, hydroxypropyl cellulose, more preferably hypromellose or hydroxypropyl cellulose.

6. The flufenidone capsule preparation according to any one of claims 1 to 5, characterized in that: The lubricant is magnesium stearate or calcium stearate, and magnesium stearate is most preferred.

7. A method for preparing the flufenidone capsule preparation according to any one of claims 1 to 6, characterized in that: The method comprises the following steps: 1) Weigh the raw material compound flufenidone, crush and sieve; 2) mixing the sieved flufenidone in step 1) with the filler and the disintegrant, adding the binder to granulate, drying and sieving to obtain flufenidone granules; and 3) mixing the fluorofenidone particles obtained in step 2) with the lubricant to obtain contents, and filling the contents into capsule shells to obtain the fluorofenidone capsule preparation.

8. The method according to claim 7, characterized in that In the step 2): The granulation method is selected from one or more of the following: wet granulation, fluidized bed granulation, dry granulation, powder mixing granulation, preferably selected from one or more of the following: wet granulation, fluidized bed granulation, powder mixing granulation, and most preferably wet granulation; The mixing time is 3 to 10 minutes, preferably 4 to 6 minutes, and most preferably 5 minutes; The binder is added in the form of an aqueous solution, and the mass percentage concentration of the solute of the binder in water is preferably 2% to 10%, more preferably 3% to 8%, and further preferably 4% to 5%; and / or The mesh number of the sieve after drying is 10-40 meshes, preferably 20-30 meshes, and most preferably 20 meshes.

9. The method according to claim 7 or 8, characterized in that: In the step 3): The mixing time is 5 to 20 minutes, preferably 10 to 15 minutes, most preferably 10 minutes; and / or The mixing speed is 5 to 30 rpm, preferably 10 to 20 rpm, and most preferably 15 rpm.

10. Use of the flufenidone capsule preparation according to any one of claims 1 to 6 in the preparation of a medicament for treating organ fibrosis; Preferably, the organ fibrosis disease is selected from one or more of the following: cirrhosis, liver fibrosis, and kidney fibrosis; More preferably, the renal fibrosis disease is selected from one or more of the following: diabetic nephropathy, chronic tubulointerstitial nephritis, and renal fibrosis.

Images