Pirfenidone oral sustained release solid dosage form

Abstract

The present invention provides an oral sustained release solid formulation of pirfenidone relating to a formulation technique, comprising a sustained release formulation, the sustained release formulation containing a swelling and dissolving material, a plastic material and an adhesive material, the weight percentage of the swelling and dissolving material in the solid formulation being 10-25%, the weight percentage of the plastic material in the solid formulation being 10-25%, and the weight percentage of the adhesive material in the solid formulation being 1-8%. This solid formulation can be orally administered once a day, without any restriction on whether it can be administered before or after meals, and is effective immediately after administration and is released stably and effectively for 24 hours, thereby providing a pirfenidone product with significantly improved compliance and stable blood concentration.

Description

[Technical field]

[0001] The present invention relates to the pharmaceutical technology, and in particular to an oral sustained release solid formulation of pirfenidone. [Background technology]

[0002] The existing pirfenidone products on the market are immediate-release tablets and capsules, and no once-daily sustained-release formulations have been released. The existing dosage forms have the following disadvantages: 1. Existing products need to be administered three times a day, resulting in poor patient compliance.

[0003] All existing products are general immediate-release formulations, and their clinical data and package inserts clearly indicate that the products must be administered after meals, leading to low patient compliance and the likelihood of side effects occurring if patients forget the dosage instructions and take the drug before meals.

[0004] 2. The dosing method of existing products is affected by mealtimes, resulting in low effective blood concentrations at night.

[0005] All existing products are general immediate release formulations, and the clinical data and package inserts clearly indicate that these products must be administered after meals. Therefore, the daily meal and administration times are fixed at 08:00, 12:00, and 18:00, but the administration times in this series result in high blood concentrations during the day and too low blood concentrations at night, making it difficult to reliably achieve stable and effective blood concentrations within 24 hours.

[0006] 3. Based on existing data, the side effects observed in this variety were at maximum blood concentration C max It has been shown to be correlated with

[0007] All existing products are immediate-release formulations, which, when ingested, undergo a process of rapid disintegration, release, and absorption into the bloodstream. Rapid absorption allows for the T max The half-life is about 1 to 2 hours, T 1 / 2It takes about 2 hours for the blood to reach its maximum concentration C max However, administration three times a day resulted in a higher maximum blood concentration of C max This means that the drug's C max If the concentration is too high, a series of side effects will occur, but the original drug is recommended to be administered after meals, so C max It has been shown that the relatively high C max The series of side effects caused by the drug were not reliably improved.

[0008] 4. Peak-to-trough value ratio of existing products (C max / C min ) is large and blood concentrations are unstable.

[0009] Existing products are administered three times a day, and the frequency of administration increases the difference between the peak and trough blood concentrations, resulting in a large peak-trough ratio (C max / C min ) is large and fluctuates frequently, making it impossible to generate a stable blood concentration. It is commonly known in the pharmaceutical field that a large peak-to-trough ratio is likely to cause a series of side effects. Summary of the Invention [Problem to be solved by the invention]

[0010] For these reasons, there is a need to research and develop new dosage forms of pirfenidone products that improve compliance, reduce the frequency of dosing, and stabilize blood concentration fluctuations. [Means for solving the problem]

[0011] In response to the problems of poor compliance with multiple daily administration of existing products and large fluctuations in blood concentration, the present invention has developed an oral sustained release formulation that can be taken once a day and can release stably and effectively over 24 hours. The specific plan is as follows: 1. A sustained release formulation, comprising a swelling and dissolving material, a plastic material and an adhesive material; The weight percentage of the swellable and soluble material in the solid preparation is 10-25%, the weight percentage of the plastic material in the solid preparation is 10-25%, and the weight percentage of the adhesive material in the solid preparation is 1-8%. The viscosity of the swelling and dissolving material is in the range of 500 mpa.s to 300,000 mpa.s, the viscosity of the adhesive material is in the range of 50 to 100,000 mpa.s, and the viscosity of the plastic material is in the range of 50 to 60,000 mpa.s; The swellable dissolving material is one or more selected from the group consisting of sodium carboxymethylcellulose, glyceryl behenate, sodium alginate, calcium alginate, potassium alginate, hydroxypropyl methylcellulose (HPMC), carbomer, ammonium alginate, carnauba wax, gum tragacanth, gum arabic, and shellac; The plastic material is one or more selected from the group consisting of sodium carboxymethylcellulose, calcium carboxymethylcellulose, ethylcellulose, carbomer, polylactic acid, polylactic-glycolic acid copolymer, sodium alginate, hydrogenated vegetable oil, ethylene-vinyl copolymer, polymethacrylic acid, beeswax, glyceryl monostearate, polyethylene, ethylene-vinyl acetate copolymer; The adhesive material is one or more selected from the group consisting of hydroxyethyl cellulose, gelatin, polyoxyethylene, carbomer, pectin, chitosan, glucose, alginate, fucosamine, starch, chitin; The blood concentration parameters achieved when the oral sustained release dosage form is administered once daily to an individual in a daily dose are the maximum blood concentration (C) corresponding to the blood concentration-time curve within 24 hours after administration. max ) and minimum blood concentration (C min ) is within a range of 2 to 10, preferably within a range of 2 to 5, and more preferably within a range of 2 to 3.5.

[0012] 2. Preferably, the oral sustained release solid formulation of pirfenidone comprises: Here, the ratio of the sustained release formulation to the total tablet weight is 50 to 100% or any numerical value within that range, or the ratio of the sustained release formulation to the total tablet weight is 50%, 60%, 65%, 70%, 73%, 78%, 85%, 73%, 80%, 85%, 90%, or a range in which any two of these numerical values ​​are formed.

[0013] 3. Preferably, the oral sustained release solid formulation of pirfenidone comprises: The sustained release formulation is characterized in that the API in the sustained release formulation is 50 to 100% of the total API or any value within that range, or the ratio to the total API is 50%, 60%, 65%, 70%, 73%, 78%, 85%, 73%, 80%, 85%, 90%, or a range in which any two of these values ​​are formed.

[0014] 4. Preferably, the oral sustained release solid formulation of pirfenidone comprises: The preparation is characterized in that the specific gravity of the swellable / soluble material to the adhesive material is 1 to 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1, and the specific gravity of the adhesive material to the plastic material is 0.2 to 1:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1 or 0.9:1.

[0015] 5. The oral sustained release solid formulation of pirfenidone comprises A monolayer tablet, wherein the sustained release formulation accounts for 100% of the tablet weight.

[0016] 6. Preferably, the oral sustained release solid formulation of pirfenidone comprises: A formulation further comprising an immediate release formulation, wherein the specific gravity of said immediate release formulation to said sustained release formulation is 1-10, preferably 2-8.

[0017] 7. Preferably, the oral sustained release solid formulation of pirfenidone comprises: A formulation, wherein the ratio of API in the immediate release formulation to API in the sustained release formulation is 0.1 to 0.6.

[0018] 8. Preferably, the oral sustained release solid formulation of pirfenidone comprises: The viscosity of the swelling and dissolving material is selected from the range of 500 to 5000 mpa.s, 500 to 1000 mpa.s, 2000 to 5000 mpa.s, 50000 to 150000 mpa.s, or 150000 to 300000 mpa.s. The viscosity of the plastic material is selected from the range of 55 to 60,000 mpa.s, 55 to 10,000 mpa.s, 55 to 1,000 mpa.s, or 60 to 200 mpa.s. A formulation characterized in that the viscosity of the adhesive material is selected from the ranges of 55 to 100,000 mpa.s, 60 to 200 mpa.s, 65 to 10,000 mpa.s, 4,000 to 10,000 mpa.s, 5,000 to 10,000 mpa.s, 5,500 to 7,500 mpa.s or 7,000 to 10,000 mpa.s.

[0019] 9. Preferably, the oral sustained release solid formulation of pirfenidone comprises: The model number of the hydroxypropyl methylcellulose used in the swelling and dissolving material is one or more selected from the group consisting of K100LV, K4M, K750, K100, K200M, and E5LV; A preparation characterized in that the molecular weight of the polyoxyethylene is 100,000 to 7,000,000.

[0020] 10. Preferably, any of the above-mentioned oral sustained release solid formulations of pirfenidone include A tablet, the minimum dimensions of which in the three dimensions of length, width, and height are 8.0 mm or more; The dimension with the smallest size must satisfy the following condition in the expansion growth rate: A formulation characterized in that the growth rate is 4.5% or more within 1 hour, 12% or more within 2 hours, 25% or more within 4 hours, 20% or more within 6 hours, and 40% or more within 10 hours in a test solution of 37°C, 900 ml, and pH 4.5 at a rotation speed of 75 rpm.

[0021] 11. Preferably, the oral sustained release solid formulation of pirfenidone comprises: It has one of the following specifications: (1) The pirfenidone content is 500-700 mg. (2) The pirfenidone content is 600 mg. (3) The pirfenidone content is 700-1000 mg. (4) A formulation containing 801 mg of pirfenidone.

[0022] 12. Preferably, any of the above oral sustained release solid formulations of pirfenidone include The dosage form is characterized in that, when measured in a test solution of 37°C, 900 ml, pH 4.5 and at a rotation speed of 75 rpm according to USP Standard 2 method, more than 15% of the active substance is dissolved within 0.5 hours, more than 25% of the active substance is dissolved within 2 hours, 50-70% of the active substance is dissolved within 10 hours, and more than 80% of the active substance is dissolved within 20 hours.

[0023] 13. Preferably, the oral sustained release solid formulation of pirfenidone comprises: A formulation characterized by having the following parameter characteristics when administered to an individual: retention in the stomach for at least 12 hours; continuous time during a 24-hour single administration interval during which the blood concentration is higher than 300 ng / ml is 15 hours or more; and a maximum blood concentration of 3500 ng / ml or less, preferably a maximum blood concentration of 2500 ng / ml or less.

[0024] 14. Preferably, the oral sustained release solid formulation of pirfenidone comprises: A formulation characterized in that the blood concentration parameters expressed when used for individual administration are a maximum blood concentration (Cmax) of 800 ng / ml to 3500 ng / ml, preferably 1000 ng / ml to 2500 ng / ml, and a maximum blood concentration (Cmin) of 300 ng / ml or more, preferably 400 ng / ml or more.

[0025] 15. Preferably, the oral sustained release solid formulation of pirfenidone comprises: A preparation characterized in that the dosage form is a tablet or capsule, and the tablet therein may be a single-layer tablet, a double-layer tablet, a triple-layer tablet, a dry-coated tablet, or a ring-shaped tablet.

[0026] 16. Preferably, the oral sustained release solid formulation of pirfenidone comprises: The dosage form is a three-layer tablet, the middle layer being 10% or more of the total tablet weight, and the third layer being 15% or more of the total tablet weight. Effect of the Invention

[0027] In view of the poor compliance of conventional oral pirfenidone products with multiple daily doses, the problem of only taking it after meals and the large fluctuation of blood concentration, the present invention has developed an oral sustained release formulation that can be taken once a day before or after meals. After entering the human body, the formulation developed by the present invention realizes the control of sustained release of the drug by the tablet-shaped structure in which some of the drug is rapidly released and then reaches a peak, and the other part of the drug is expanded, so that the maximum blood concentration Cmax does not drop suddenly and is released stably and effectively within 24 hours, and the blood concentration is stable and the peak-to-trough ratio is close to 2 and less than 3, thereby reducing the side effects caused by unstable blood concentration and high peak-to-trough ratio.

[0028] Term definition Maximum blood concentration Cmax: refers to the maximum concentration of a drug reached in the blood after administration of the drug.

[0029] Minimum blood concentration Cmin: refers to the minimum concentration of a drug reached in the blood after administration of the drug. [Brief description of the drawings]

[0030] [Figure 1] FIG. 1. The length expansion growth rate curves of the pirfenidone bilayer tablets of Example 1 of the present invention and Comparative Examples 1, 2, and 3. [Diagram 2] FIG. 2. Width expansion growth rate curves of pirfenidone bilayer tablets of Example 1 of the present invention and Comparative Examples 1, 2, and 3. [Diagram 3] FIG. 3. Height expansion growth rate curves of pirfenidone bilayer tablets of Example 1 of the present invention and Comparative Examples 1, 2, and 3. [Figure 4] FIG. 4. The length expansion growth rate curves of the pirfenidone bilayer tablets of Example 2 of the present invention and Comparative Examples 4, 5, and 6. [Diagram 5] FIG. 5. Width expansion growth rate curves of pirfenidone bilayer tablets of Example 2 of the present invention and Comparative Examples 4, 5, and 6. [Figure 6] FIG. 6. Height expansion growth rate curves of pirfenidone bilayer tablets of Example 2 of the present invention and Comparative Examples 4, 5, and 6. [Figure 7] FIG. 7. The length expansion growth rate curves of the pirfenidone bilayer tablets of Example 3 of the present invention and Comparative Examples 7 and 8. [Figure 8] FIG. 8. Width expansion growth rate curves of pirfenidone bilayer tablets of Example 3 of the present invention and Comparative Examples 7 and 8. [Figure 9] FIG. 9. Height expansion growth rate curves of pirfenidone bilayer tablets of Example 3 of the present invention and Comparative Examples 7 and 8. [Figure 10] FIG. 10. The length expansion growth rate curves of the pirfenidone bilayer tablets of Example 4 of the present invention and Comparative Examples 9 and 10. [Figure 11] FIG. 11. Width expansion growth rate curves of pirfenidone bilayer tablets of Example 5 of the present invention and Comparative Examples 9 and 10. [Figure 12] FIG. 12. Height expansion growth rate curves of pirfenidone bilayer tablets of Example 6 of the present invention and Comparative Examples 9 and 10. [Figure 13] Figure 13. Cumulative dissolution rate curves of Example 1 and Comparative Examples 1, 2, and 3. [Figure 14]Figure 14. Cumulative dissolution rate curves of Example 2 and Comparative Examples 4, 5, and 6. [Figure 15] Figure 15. Cumulative dissolution rate curves of Example 3 and Comparative Examples 7 and 8. [Figure 16] Figure 16. Cumulative dissolution rate curves of Example 4 and Comparative Examples 9 and 10. [Figure 17] FIG. 17. Comparative blood concentration curves of the pirfenidone bilayer tablet of the present invention when orally administered once a day and the existing pirfenidone tablet when orally administered three times a day. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS I. Formulations of Examples and Controls Example 1. Preparation of 1000 pirfenidone bilayer tablets [Table 1] The manufacturing method of Example 1 specifically includes the following steps: A. Preparation of drug-containing immediate-release layered granules: 150 g of pirfenidone, 30 g of pregelatinized starch, 60 g of crystalline cellulose, and 8 g of crospovidone were weighed and mixed uniformly, granulated, wet-granulated, and dried. 2 g of sodium stearyl fumarate was then added and mixed to obtain immediate-release layered blended granules.

[0032] B. Preparation of drug-containing sustained-release layer granules: 450 g of pirfenidone, 160 g of sodium alginate, 100 g of HPMC K100M, 200 g of HPMC K200M, 60 g of PEO, and 53 g of crystalline cellulose were weighed and mixed for 3 to 5 minutes, 52 g of PVP K30 was added, kneaded, wet-granulated, and dried, and 10 g of talc and 24 g of colloidal silica were further added and mixed to obtain blended granules for the sustained-release layer.

[0033] C. Compression of bilayer tablets: An appropriate amount of drug-containing sustained-release layer granules was weighed and placed in the die of a tablet press, pre-pressurized, and then an appropriate amount of drug-containing immediate-release layer granules was weighed and placed in the die of a tablet press, and compressed into bilayer tablets.

[0034] Comparative Example 1. Preparation of 1000 Pirfenidone Bilayer Tablets [Table 2] The manufacturing method of Comparative Example 1 was the same as that of Example 1, and bilayer tablets of the same shape and size were produced.

[0035] The difference between the formulations of Comparative Example 1 and Example 1 was that the unit formulation amount of HPMC K 100 M in the sustained release layer in Comparative Example 1 was 200 mg, and the unit formulation amount of crystalline cellulose PH 101 was 93 mg. The rest of the formulation was the same as that in Example 1.

[0036] The ratio of the swelling and dissolving material to the total tablet weight in Comparative Example 1 was 26.68%, and the ratio of the swelling and dissolving material to the total tablet weight in Example 1 was 22.08%.

[0037] Comparative Example 2. Preparation of 1000 Pirfenidone Bilayer Tablets [Table 3] The manufacturing method of Comparative Example 2 was the same as that of Example 1, and bilayer tablets of the same shape and size were produced.

[0038] The difference in the formulation between Comparative Example 2 and Example 1 was that the unit formulation amount of sodium alginate in the sustained release layer in Comparative Example 1 was 100 mg, and the unit formulation amount of crystalline cellulose PH 101 was 153 mg, while the rest were the same as in Example 1.

[0039] The ratio of the plastic material to the total tablet weight in Comparative Example 2 was 7.15%, and the ratio of the plastic material to the total tablet weight in Example 1 was 11.77%.

[0040] Comparative Example 3. Preparation of 1000 Pirfenidone Bilayer Tablets [Table 4] The manufacturing method of Comparative Example 3 was the same as that of Example 1, and bilayer tablets of the same shape and size were produced.

[0041] The difference between the formulations of Comparative Example 3 and Example 1 was that the unit formulation amount of PEO (N80) in the sustained release layer in Comparative Example 1 was 150 mg, and the rest was the same as in Example 1.

[0042] The ratio of the adhesive material to the total tablet weight in Comparative Example 3 was 10.35%, and the ratio of the adhesive material to the total tablet weight in Example 1 was 4.42%.

[0043] Example 2. Preparation of 1000 pirfenidone bilayer tablets [Table 5] The manufacturing method of Example 2 was the same as that of Example 1, and bilayer tablets of the same shape and size were produced.

[0044] The specific manufacturing method is as follows: A. Preparation of drug-containing immediate-release layer granules: 80 g of pirfenidone, 50 g of pregelatinized starch, 50 g of crystalline cellulose, and 8 g of croscarmellose sodium were weighed and mixed uniformly, granulated, wet-granulated, and dried, and then 2 g of magnesium stearate was added and mixed to obtain blended granules for the immediate-release layer.

[0045] B. Preparation of drug-containing sustained-release layer granules: 520 g of pirfenidone, 280 g of sodium alginate, 100 g of HPMC K750, 200 g of HPMC K100M, 100 g of PEO, and 53 g of crystalline cellulose were weighed and mixed for 3 to 5 minutes, 52 g of PVP K30 was added, kneaded, wet-granulated, and dried, and 10 g of talc and 24 g of colloidal silica were further added and mixed to obtain blended granules for the sustained-release layer.

[0046] C. Compression of bilayer tablets: An appropriate amount of drug-containing sustained-release layer granules was weighed and placed in the die of a tablet press, pre-pressurized, and then an appropriate amount of drug-containing immediate-release layer granules was weighed and placed in the die of a tablet press, and compressed into bilayer tablets.

[0047] Comparative Example 4. Preparation of 1000 Pirfenidone Bilayer Tablets [Table 6] The manufacturing method of Comparative Example 4 was the same as that of Example 2, and bilayer tablets of the same shape and size were produced.

[0048] The main difference between Comparative Example 4 and Example 2 was the viscosity of the swellable dissolving material. The viscosity range of HPMC K 100 LV used in Comparative Example 4 was 80-120 mpa.s, while the viscosity range of HPMC K 750 used in Example 2 was 562-1050 mpa.s and the viscosity range of HPMC K 100 M was 75000-140000 mpa.s.

[0049] Comparative Example 5. Preparation of 1000 Pirfenidone Bilayer Tablets [Table 7] The manufacturing method of Comparative Example 5 was the same as that of Example 2, and bilayer tablets of the same shape and size were produced.

[0050] The main difference between Comparative Example 5 and Example 2 was the viscosity of the plastic material.

[0051] The viscosity range of the sodium alginate used in Example 4 was 60 to 170 mpa.s, and the viscosity range of the polyvinyl alcohol used in Comparative Example 2 was 20 to 30 mpa.s.

[0052] Comparative Example 6. Preparation of 1000 Pirfenidone Bilayer Tablets [Table 8] The manufacturing method of Comparative Example 6 was the same as that of Example 2, and bilayer tablets of the same shape and size were produced.

[0053] The main difference between Comparative Example 6 and Example 2 was the viscosity of the adhesive material. The viscosity range of chitosan used in Comparative Example 6 was 1 to 40 mpa.s, and the viscosity range of PEO (N80) used in Example 2 was 65 to 90 mpa.s.

[0054] Example 3. Preparation of 1000 pirfenidone bilayer tablets [Table 9] The manufacturing method of Example 3 was the same as that of Example 1, and bilayer tablets of the same shape and size were produced.

[0055] Comparative Example 7. Preparation of 1000 Pirfenidone Bilayer Tablets [Table 10] The manufacturing method of Comparative Example 7 was the same as that of Example 3, and bilayer tablets of the same shape and size were produced.

[0056] The main difference between Comparative Example 7 and Example 3 was that the ratio of the sustained-release layer to the total tablet weight in Comparative Example 7 was 49.6%, while the ratio of the sustained-release layer to the total tablet weight in Example 3 was 76.8%.

[0057] Comparative Example 8. Preparation of 1000 Pirfenidone Bilayer Tablets [Table 11] The manufacturing method of Comparative Example 8 was the same as that of Example 3, and bilayer tablets of the same shape and size were produced.

[0058] The main difference between Comparative Example 8 and Example 3 is that in Comparative Example 8, the unit dosage amount of pirfenidone in the immediate-release layer was 50 mg, and the unit dosage amount of pirfenidone in the sustained-release layer was 550 mg, whereas in Example 3, the unit dosage amount of pirfenidone in the immediate-release layer was 220 mg, and the unit dosage amount of pirfenidone in the sustained-release layer was 380 mg.

[0059] Example 4. Preparation of 1000 pirfenidone bilayer tablets [Table 12] The manufacturing method of Example 4 was the same as that of Example 1, and bilayer tablets of the same shape and size were produced.

[0060] The specific manufacturing method is as follows: A. Preparation of drug-containing immediate-release layer granules: 100 g of pirfenidone, 30 g of pregelatinized starch, 60 g of crystalline cellulose, and 8 g of croscarmellose sodium were weighed and mixed uniformly, granulated, wet-granulated, and dried, and then 2 g of magnesium stearate was added and mixed to obtain blended granules for the immediate-release layer.

[0061] B. Preparation of drug-containing sustained-release layer granules: 500 g of pirfenidone, 210 g of sodium alginate, 250 g of HPMC K100M, 100 g of PEO, and 52 g of microcrystalline cellulose were weighed and mixed for 3 to 5 minutes, 52 g of PVP K30 was added, kneaded, wet-granulated, and dried, and 10 g of magnesium stearate and 24 g of colloidal silica were further added and mixed to obtain blended granules for the sustained-release layer.

[0062] C. Compression of bilayer tablets: An appropriate amount of drug-containing sustained-release layer granules was weighed and placed in the die of a tablet press, pre-pressurized, and then an appropriate amount of drug-containing immediate-release layer granules was weighed and placed in the die of a tablet press, and compressed into bilayer tablets.

[0063] Comparative Example 9. Preparation of 1000 pirfenidone bilayer tablets [Table 13] The manufacturing method of Comparative Example 9 was the same as that of Example 4, and bilayer tablets of the same shape and size were produced.

[0064] The main difference between Comparative Example 9 and Example 4 is that the HPMC in the sustained release layer in Comparative Example 9 The unit dosage of K100M was 500 mg, the unit dosage of PEO(303) was 50 mg, and the swelling and dissolving material:adhesive material ratio was 10:1. In Example 4, the unit formulation amount of HPMC / K100M in the sustained-release layer was 250 mg, the unit formulation amount of PEO(303) was 100 mg, and the swelling and dissolving material:adhesive material=5:2.

[0065] Comparative Example 10. Preparation of 1000 Pirfenidone Bilayer Tablets [Table 14] The manufacturing method of Comparative Example 10 was the same as that of Example 4, and bilayer tablets of the same shape and size were produced.

[0066] The main differences between Comparative Example 10 and Example 4 are that the unit formulation amount of sodium alginate in the sustained-release layer in Comparative Example 10 was 400 mg, the unit formulation amount of PEO (303) was 70 mg, and the adhesive material:plastic material=7:40, while the unit formulation amount of HPMCK100M in the sustained-release layer in Example 4 was 210 mg, the unit formulation amount of PEO (303) was 100 mg, and the adhesive material:plastic material=10:21.

[0067] II. In vitro testing of formulations To ensure rapid efficacy (with partial rapid release) and sustained efficacy within 24 hours after once-daily dosing, the formulation must have a swelling rate that ensures a sufficiently long retention time in the stomach and that drug release is stable during that time. Therefore, the specifications are met simultaneously in the swelling rate test and in vitro dissolution test.

[0068] 2.1 In vitro expansion test Conditions for in vitro dissolution experiments: Test solution: pH 4.5, paddle method + rotating basket, 37°C, rotation speed 75 rpm, test solution volume: 900 ml.

[0069] According to multiple laboratory-scale experiments in the present invention, for a tablet of 600-800 mg, if the tablet manufactured according to the formulation of the present invention has a minimum size of 8.0 mm or more in three dimensions of length, width, and height, and the expansion growth rate of the dimension with the minimum size reaches the following specifications, the formulation can be ensured to be retained in the stomach due to expansion for at least 12 hours, and a slow sustained release of the API can be realized: Growth rates were confirmed to be over 4.5% within 1 hour, over 12% within 2 hours, over 25% within 4 hours, over 20% within 6 hours, and over 40% within 10 hours.

[0070] The minimum three-dimensional size of the tablet in the examples of the present invention is 18.0-19.0 mm in length, 10-11 mm in width, and 8.0-9.5 mm in height. It has been confirmed through testing that if the in vitro swelling growth rate of the tablet of the minimum size meets the specifications listed in Table 15, the formulation will be retained in the stomach due to swelling for at least 12 hours, thereby realizing a slow sustained release of the API.

[0071] [Table 15] [Table 16] The expansion growth rate curves of the length, width and height of the pirfenidone bilayer tablets of Example 1 and Comparative Examples 1, 2 and 3 are shown in Figs.

[0072] As seen from Table 16 and Figures 1 to 3, when the specific gravity of the swelling and dissolving material was higher than 25% (Comparative Example 1), the specific gravity of the plastic material was lower than 10% (Comparative Example 2), and the specific gravity of the adhesive material (Comparative Example 3) was higher than 8%, the swelling growth rate of at least one of the three dimensions of the tablet length, width, and height became incompatible from the second hour, resulting in failure to control the slow sustained release of the API depending on the swelling of the tablet.

[0073] [Table 17] The expansion growth rate curves of the length, width and height of the pirfenidone bilayer tablets of Example 2 and Comparative Examples 4, 5 and 6 are shown in Figs.

[0074] As can be seen from Table 17 and Figures 4 to 6, even if the specific gravities of the swelling and dissolving material, the plastic material, and the adhesive material are within the appropriate ranges, when the viscosity of the swelling and dissolving material in the formulation is less than 500 mpa.s (Comparative Example 4), the viscosity of the plastic material is less than 50 mpa.s (Comparative Example 5), and the viscosity of the adhesive material is less than 50 mpa.s (Comparative Example 6), the swelling growth rate of at least one dimension among the three dimensions of the length, width, and height of the tablet, especially the higher dimension having the minimum size, becomes significantly incompatible from the beginning, which results in failure to control the slow sustained release of the API by relying on the swelling of the tablet.

[0075] [Table 18] The expansion growth rate curves of the length, width, and height of the pirfenidone bilayer tablets of Example 3 and Comparative Examples 7 and 8 are shown in FIGS.

[0076] 7, 8, and 9, when the ratio of the sustained-release layer to the total tablet weight was less than 50% (Comparative Example 7), it affected the swelling growth rate of the tablet.

[0077] The swelling and dissolving materials, plastic materials and adhesive materials in the tablet are all contained in the sustained-release layer. In order to guarantee the expansion rate and thickness of the sustained-release layer, the sustained-release layer must reach a certain proportion in the total tablet weight to ensure that the tablet contains sufficient swelling and dissolving materials, plastic materials and adhesive materials, so that the tablet can expand to a certain and sufficient volume in the stomach, delay its uptake into the intestinal tract, and guarantee a stable sustained release.

[0078] [Table 19] The expansion growth rate curves of the length, width, and height of the pirfenidone bilayer tablets of Example 4 and Comparative Examples 9 and 10 are shown in FIGS.

[0079] 10 to 12, varying the ratio of swelling-dissolving material:adhesive material (Comparative Example 9) or varying the ratio of adhesive material:plastic material (Comparative Example 9) had almost no effect on the expansion growth rate.

[0080] 2.2 In vitro dissolution test Conditions for in vitro dissolution experiments: Test solution: pH 4.5, paddle method + rotating basket, 37°C, rotation speed 75 rpm, test solution volume: 900 ml.

[0081] Multiple laboratory-scale tests have confirmed that if the in vitro dissolution rate meets the specifications in Table 20, it can ensure that the blood concentration reaches its peak quickly after administration, is completely released within 24 hours, maintains the effective concentration range, and has a peak-to-trough ratio of less than 3.

[0082] [Table 20] The cumulative dissolution rates are shown in the table below and in FIG.

[0083] [Table 21] 13, when the specific gravity of the swelling and dissolving material is higher than 25% (Comparative Example 1), the specific gravity of the plastic material is lower than 10% (Comparative Example 2), and the specific gravity of the adhesive material (Comparative Example 3) is higher than 8%, the specific gravity of the swelling and dissolving material has a slight effect on the dissolution characteristics, but the characteristics are not sensitive to changes in the specific gravity of the plastic material and the adhesive material. In general, the swelling and dissolving material, the plastic material, and the adhesive material mainly affect the expansion characteristics.

[0084] The cumulative dissolution rates are shown in the table below and in FIG.

[0085] [Table 22] 14, the viscosity of the swelling and dissolving material (Comparative Example 4), the viscosity of the plastic material (Comparative Example 5), and the viscosity of the adhesive material (Comparative Example 6) had no significant effect on the dissolution of the tablets. They mainly affected the swelling characteristics.

[0086] The cumulative dissolution rates are shown in the table below and in FIG.

[0087] [Table 23] As can be seen from Table 23 and FIG. 15, the variation in the ratio of the sustained-release layer to the total tablet weight (Comparative Example 7) did not have a clear effect on the dissolution characteristics. However, when the API ratio of the immediate-release layer to the sustained-release layer was too low (Comparative Example 8), the dissolution characteristics in the early phase did not meet the standard, and it was presumed that this would affect the exertion of efficacy by preventing the blood concentration from reaching a peak promptly.

[0088] The cumulative dissolution rates are shown in the table below and in FIG.

[0089] [Table 24] As shown in Table 24 and FIG. 16, when the ratio of swelling-dissolving material:adhesive material was higher than 9 (Comparative Example 9) or when the ratio of adhesive material:plastic material was lower than 0.2 (Comparative Example 9), the dissolution did not reach the standard after 10 hours, and the drug did not exhibit stable and effective efficacy within 24 hours.

[0090] 3. Comparison of in vivo blood concentrations Experiment: Pirfenidone bilayer tablet prepared in Example 1 of the present invention, 600 mg per tablet, 1 tablet per 24 hours, Comparison: Pirfenidone tablets, 200 mg, taken in the morning, afternoon and evening, 3 times a day, 1 tablet each time, Subjects: Healthy subjects aged 19-45 years. The results of blood concentration measurements within 24 hours are shown in Figure 17. The bilayer tablet of the present invention reached a peak of 1500-1750 ng / mL about 1 hour after administration, and within the next 23 hours, the blood concentration was maintained at a level of 750-1500 ng / mL in most cases, with a peak-to-trough ratio of 2.33.

[0091] In contrast, the control tablet produced three peaks in the range of 3500-3800 ng / mL after three doses, but fell to below 1000 ng / mL within 2-6 hours after administration, with a minimum blood concentration of only about 200 ng / mL at 24 hours, resulting in a peak-to-trough ratio of 19:1.

[0092] The diphenyl ketone bilayer tablet developed by the present invention, when taken once a day, quickly reaches a maximum blood concentration and stabilizes in blood concentration within 24 hours, thereby realizing stable and effective action within 24 hours and eliminating the need to administer after meals, which further proves that it effectively reduces side effects caused by large fluctuations in blood concentration and improves drug compliance.

Claims

1. The sustained release formulation includes a swelling and dissolving material, a plastic material, and an adhesive material. The weight percentage of the swellable and soluble material in the solid formulation is 10-25%, the weight percentage of the plastic material in the solid formulation is 10-25%, and the weight percentage of the adhesive material in the solid formulation is 1-8%. The viscosity of the swelling and dissolving material is in the range of 500 mpa.s to 300,000 mpa.s, the viscosity of the adhesive material is in the range of 50 to 100,000 mpa.s, and the viscosity of the plastic material is in the range of 50 to 60,000 mpa.s; The swellable dissolving material is one or more selected from the group consisting of sodium carboxymethylcellulose, glyceryl behenate, sodium alginate, calcium alginate, potassium alginate, hydroxypropyl methylcellulose (HPMC), carbomer, ammonium alginate, carnauba wax, gum tragacanth, gum arabic, and shellac; The plastic material is one or more selected from the group consisting of sodium carboxymethylcellulose, calcium carboxymethylcellulose, ethylcellulose, carbomer, polylactic acid, polylactic-glycolic acid copolymer, sodium alginate, hydrogenated vegetable oil, polymethacrylic acid, beeswax, glyceryl monostearate, polyethylene, ethylene vinyl acetate copolymer; The adhesive material is one or more selected from the group consisting of hydroxyethyl cellulose, gelatin, polyoxyethylene, carbomer, pectin, chitosan, glucose, alginate, fucosamine, starch, chitin; The blood concentration parameters achieved when the oral sustained release dosage form is administered once daily to an individual in a daily dose are the maximum blood concentration (C) corresponding to the blood concentration-time curve within 24 hours after administration. max ) and minimum blood concentration (C min ) is within 2 to 10, preferably within 2 to 5, more preferably within 2 to 3.

5.

2. The oral sustained release solid formulation of pirfenidone according to claim 1, characterized in that the ratio of the sustained release formulation to the total tablet weight is 50-100% or any value within that range, or the ratio of the sustained release formulation to the total tablet weight is 50%, 60%, 65%, 70%, 73%, 78%, 85%, 73%, 80%, 85%, 90%, or a range that forms any two of these values.

3. The oral sustained release solid formulation of pirfenidone according to claim 2, wherein the API in the sustained release formulation is 50-100% of the total API or any value within that range, or the percentage of the total API is 50%, 60%, 65%, 70%, 73%, 78%, 85%, 73%, 80%, 85%, 90%, or a range that forms any two of these values.

4. The oral sustained release solid formulation of pirfenidone according to claim 1, characterized in that the specific gravity of the swellable and soluble material to the adhesive material is 1 to 9:1 or any numerical value within that range, or 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1, and the specific gravity of the adhesive material to the plastic material is 0.2 to 1:1 or any numerical value within that range, or 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1 or 0.9:

1.

5. 3. The oral sustained release solid formulation of pirfenidone according to claim 2, characterized in that it is a single-layer tablet, and the sustained release formulation accounts for 100% of the tablet weight.

6. The oral sustained release solid formulation of pirfenidone according to claim 2, further comprising an immediate release formulation, wherein the relative gravity of the immediate release formulation to the sustained release formulation is 1-10, preferably 2-8.

7. 7. The oral sustained release solid formulation of pirfenidone according to claim 6, wherein the ratio of API in the immediate release formulation to API in the sustained release formulation is 0.1-0.

6.

8. The viscosity of the swelling dissolving material is selected from the range of 500 to 5000 mpa.s, 500 to 1000 mpa.s, 2000 to 5000 mpa.s, 50000 to 150000 mpa.s, or 150000 to 300000 mpa.s; The viscosity of the plastic material is selected from the range of 55 to 60,000 mpa.s, 55 to 10,000 mpa.s, 55 to 1,000 mpa.s, or 60 to 200 mpa.s; The oral sustained release solid formulation of pirfenidone according to claim 1, characterized in that the viscosity of the adhesive material is selected from the ranges of 55 to 100,000 mpa.s, 60 to 200 mpa.s, 65 to 10,000 mpa.s, 4,000 to 10,000 mpa.s, 5,000 to 10,000 mpa.s, 5,500 to 7,500 mpa.s or 7,000 to 10,000 mpa.s.

9. The hydroxypropyl methylcellulose used in the swelling and dissolving material has a model number selected from the group consisting of K100LV, K4M, K750, K100, K200M, and E5LV.

2. The oral sustained release solid formulation of pirfenidone according to claim 1, wherein the molecular weight of the polyoxyethylene is 100,000 to 7,000,000.

10. A tablet, the minimum dimensions of which in the three dimensions of length, width, and height are 8.0 mm or more; The dimension with the smallest size must satisfy the following condition in the expansion growth rate: The oral sustained release solid formulation of pirfenidone according to any one of claims 1 to 9, characterized in that the growth rate is 4.5% or more within 1 hour, 12% or more within 2 hours, 25% or more within 4 hours, 20% or more within 6 hours, and 40% or more within 10 hours in a test solution of 37°C, 900 mL, and pH 4.5 at a rotation speed of 75 rpm.

11. It has one of the following specifications: (1) The pirfenidone content is 500-700 mg. (2) The pirfenidone content is 600 mg. (3) The pirfenidone content is 700-1000 mg. (4) The oral sustained release solid formulation of pirfenidone described in claim 10, characterized in that the content of pirfenidone is 801 mg.

12. 10. The oral sustained release solid formulation of pirfenidone according to any one of claims 1 to 9, characterized in that the dosage form dissolves more than 15% of the active substance within 0.5 hours, more than 25% within 2 hours, 50-70% of the active substance within 10 hours, and more than 80% of the active substance within 20 hours in a test solution of 37°C, 900 ml, pH 4.5 and a rotation speed of 75 rpm according to USP Standard 2 method.

13. The oral sustained release solid formulation of pirfenidone according to claim 11, characterized in that, when administered to an individual, it has the following parameter characteristics: retention in the stomach for at least 12 hours, the continuous time during which the blood concentration is higher than 300 ng / ml is 15 hours or more during a 24-hour single administration interval, and the maximum blood concentration is 3500 ng / ml or less, preferably 2500 ng / ml or less.

14. The blood concentration parameter expressed when used for individual administration is the maximum blood concentration (C max ) is 800ng / ml to 3500ng / ml, preferably 1000ng / ml to 2500ng / ml, and the maximum blood concentration (C min 12. The oral sustained release solid formulation of pirfenidone according to claim 11, characterized in that the .alpha.-tocopherol concentration is 300 ng / ml or more, preferably 400 ng / ml or more.

15. The oral sustained release solid formulation of pirfenidone according to claim 11, characterized in that the dosage form is a tablet or capsule, in which the tablet may be a single-layer tablet, a double-layer tablet, a triple-layer tablet, a dry-coated tablet, or a ring-shaped tablet.

16. 2. The oral sustained release solid formulation of pirfenidone according to claim 1, characterized in that the dosage form is a three-layer tablet, the middle layer being 10% or more of the total tablet weight and the third layer being 15% or more of the total tablet weight.

Images