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] This invention relates to pharmaceutical technology, and more particularly to a sustained-release oral solid dosage form of pirfenidone. [Background technology]

[0002] Existing pirfenidone products on the market are immediate-release tablets and capsules, and a once-daily sustained-release formulation is not yet available. However, existing dosage forms have the following drawbacks: 1. Existing products require administration 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, that patient compliance is low, and that if patients forget how to take the medication and take it before meals, it is likely to cause side effects.

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

[0005] All existing products are general immediate-release formulations, and their 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. However, the administration times for this series result in high blood concentrations during the day and 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 only adverse reaction observed in this variety was a peak blood concentration of C max It has been shown that there is a correlation between these two.

[0007] All existing products are immediate-release formulations, meaning that upon ingestion, they undergo a process of rapid disintegration, release, and absorption into the bloodstream. Rapid absorption allows for the time to reach peak blood concentration (T). max Approximately 1-2 hours, half-life T 1 / 2is about 2 hours, and the maximum blood concentration C rapidly reaches in the body max is observed. However, administration three times a day means that the maximum blood concentration C max is observed three times. According to many literature materials, a series of side effects occur when the C max of this drug is too high. However, the pioneer pharmaceutical product recommends an administration method after meals to reduce the side effects caused by the C max being too high. Therefore, a series of side effects caused by the relatively high C max after multiple administrations a day were not reliably improved.

[0008] 4. The ratio of the peak trough value of the existing product (C max / C min ) is large, and the blood concentration is unstable.

[0009] The existing product is administered three times a day. Due to the frequent administration times, there is a large difference in the peak trough blood concentration, and the ratio of the peak trough value (C max / C min ) is large, and the number of fluctuations is also large, so a stable blood concentration cannot be generated. According to the common knowledge in the pharmaceutical field, a large peak trough value ratio is known to easily cause a series of side effects.

Summary of the Invention

Problems to be Solved by the Invention

[0010] From the above, it is necessary to research and develop a new dosage form of pirfenidone product with good compliance, reduced dosing frequency, and stable blood concentration fluctuations.

Means for Solving the Problems

[0011] In response to the problems that the compliance of multiple administrations a day of the existing product is poor and the fluctuations in blood concentration are large and unstable, the present invention develops an oral sustained release preparation that can be taken once a day and can be stably and effectively released in 24 hours. The specific plan is as follows: 1. A sustained-release formulation is included, the sustained-release formulation containing a swelling-dissolving material, a plasticizing material, and an adhesive material. The weight percentage of the swellable dissolving material in the solid formulation is 10-25%, the weight percentage of the plasticizing 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 plasticizing material is in the range of 50 to 60,000 MPa.s. The aforementioned swelling and 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, tragacanth gum, acacia gum, and shellac. The plastic material is one or more selected from the group consisting of sodium carboxymethylcellulose, calcium carboxymethylcellulose, ethylcellulose, carbomer, polylactic acid, polylactic acid-glycolic acid copolymer, sodium alginate, hydrogenated vegetable oil, ethylene vinyl copolymer, polymethacrylic acid, beeswax, glyceryl monostearate, polyethylene, and ethylene vinyl acetate copolymer. The adhesive material is one or more selected from the group consisting of hydroxyethylcellulose, gelatin, polyoxyethylene, carbomer, pectin, chitosan, glucose, alginate, fucosamine, starch, and chitin. When the aforementioned oral sustained-release dosage form is administered to an individual once daily at a daily dose, the blood concentration parameter reached within 24 hours after administration corresponds to the peak blood concentration (C) corresponding to the blood concentration-time curve. max ) and minimum blood concentration (C min A sustained-release solid oral formulation of pirfenidone, characterized in that the ratio of ) is within 2 to 10, preferably within 2 to 5, and more preferably within 2 to 3.5.

[0012] 2. Preferably, the oral sustained-release solid dosage form of pirfenidone is The formulation is characterized in that the proportion of the sustained-release formulation to the total tablet weight is 50-100% or any number within that range, or the proportion of the sustained-release formulation to the total tablet weight is 50%, 60%, 65%, 70%, 73%, 78%, 85%, 73%, 80%, 85%, 90%, or any two of these numbers.

[0013] 3. Preferably, the oral sustained-release solid dosage form of pirfenidone is A formulation characterized in that the API in the sustained-release formulation is 50-100% of the total API or any value within that range, or the ratio of the total API is 50%, 60%, 65%, 70%, 73%, 78%, 85%, 73%, 80%, 85%, 90%, or any two of these values.

[0014] 4. Preferably, the oral sustained-release solid dosage form of pirfenidone is The formulation is characterized in that the specific gravity of the swelling-dissolving material to the adhesive material is 1-9:1, 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 plasticizing material is 0.2-1:1, 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 dosage form of pirfenidone is: A formulation characterized by being a single-layer tablet in which the sustained-release formulation constitutes 100% of the tablet weight.

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

[0017] 7. Preferably, the oral sustained-release solid dosage form of pirfenidone is The ratio of the API in the immediate-release preparation to the API in the sustained-release preparation is 0.1 to 0.6, and the preparation is characterized by this.

[0018] 8. Preferably, the oral sustained-release solid preparation of the pirfenidone The viscosity of the swelling and dissolving material is selected from any of the ranges 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 any of the ranges of 55 to 60000 mPa·s, 55 to 10000 mPa·s, 55 to 1000 mPa·s or 60 to 200 mPa·s. The viscosity of the adhesive material is selected from any of the ranges of 55 to 100000 mPa·s, 60 to 200 mPa·s, 65 to 10000 mPa·s, 4000 to 10000 mPa·s, 5000 to 10000 mPa·s, 5500 to 7500 mPa·s or 7000 to 10000 mPa·s, and the preparation is characterized by this.

[0019] 9. Preferably, the oral sustained-release solid preparation of the pirfenidone The type number of hydroxypropyl methylcellulose used as the swelling and dissolving material is one or more selected from the group consisting of K100LV, K4M, K750, K100, K200M, E5LV. The molecular weight of the polyoxyethylene is 10 to 7 million, and the preparation is characterized by this.

[0020] 10. Preferably, the oral sustained-release solid preparation of any of the above pirfenidones is a tablet, and the minimum size in the three dimensions of its length, width and height is 8.0 mm or more. The dimension having the minimum size needs to satisfy the following conditions in terms of the expansion growth rate. The formulation is characterized by a growth rate of 4.5% or more within 1 hour, 12% or more after 2 hours, 25% or more after 4 hours, 20% or more after 6 hours, and 40% or more after 10 hours in a test solution at 37°C, 900 ml, and pH 4.5 with a rotation speed of 75 rpm.

[0021] 11. Preferably, the oral sustained-release solid dosage form of pirfenidone is One of the following specifications is available: (1) The amount of pirfenidone is 500-700 mg. (2) The amount of pirfenidone is 600 mg. (3) The amount of pirfenidone is 700-1000 mg. (4) A preparation characterized by containing 801 mg of pirfenidone.

[0022] 12. Preferably, any of the above-mentioned oral sustained-release solid dosage forms of pirfenidone is The aforementioned dosage form is characterized by eluting more than 15% of the active substance within 0.5 hours, more than 25% within 2 hours, 50-70% within 10 hours, and more than 80% within 20 hours in a test solution at 37°C, 900 ml, and pH 4.5, using USP Standard Method 2, at a rotation speed of 75 rpm.

[0023] 13. Preferably, the oral sustained-release solid dosage form of pirfenidone is A formulation characterized by having the following parameter characteristics when used for individual administration: it remains in the stomach for at least 12 hours, the continuous duration of a blood concentration higher than 300 ng / ml is 15 hours or more within a 24-hour single-dose interval, and the peak blood concentration is 3500 ng / ml or less, preferably 2500 ng / ml or less.

[0024] 14. Preferably, the oral sustained-release solid dosage form of pirfenidone is The formulation is characterized in that, when used for individual administration, the expressed blood concentration parameters 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 dosage form of pirfenidone is A pharmaceutical preparation characterized in that the dosage form is a tablet or a capsule, and the tablet within it may be a single-layer tablet, a double-layer tablet, a triple-layer tablet, a core tablet, or a ring tablet.

[0026] 16. Preferably, the oral sustained-release solid dosage form of pirfenidone is A formulation characterized in that the dosage form is a three-layer tablet, the middle layer accounts for 10% or more of the total tablet weight, and the third layer accounts for 15% or more of the total tablet weight. [Effects of the Invention]

[0027] This invention addresses the problems of conventional oral pirfenidone products, such as poor compliance with multiple daily doses, inability to take the drug only after meals, and significant fluctuations in blood concentration. Therefore, it develops an oral sustained-release formulation that can be taken once daily before or after meals. The formulation developed by this invention ensures that, after entering the body, some of the drug is rapidly released to reach its peak, while other parts are controlled by an expanded tablet structure. This prevents a rapid decrease in the maximum blood concentration (Cmax), guaranteeing stable and effective release within 24 hours. The stable blood concentration and peak-to-trough ratio, approaching 2 and less than 3, reduce side effects associated with unstable blood concentrations and a high peak-to-trough ratio.

[0028] Term definition Maximum blood concentration (Cmax): This refers to the highest concentration of a drug that can be reached in the blood after administration.

[0029] Minimum blood concentration (Cmin): This refers to the lowest concentration of a drug that can be reached in the blood after administration. [Brief explanation of the drawing]

[0030] [Figure 1] Figure 1. Curves of expansion growth rates in length for pirfenidone bilayer tablets of Example 1 and Comparative Examples 1, 2, and 3 of the present invention. [Figure 2] Figure 2. Expansion growth rate curves in width of pirfenidone bilayer tablets for Example 1 and Comparative Examples 1, 2, and 3 of the present invention. [Figure 3] Figure 3. Expansion growth rate curves in height for pirfenidone bilayer tablets of Example 1 and Comparative Examples 1, 2, and 3 of the present invention. [Figure 4] Figure 4. Expansion growth rate curves in length for pirfenidone bilayer tablets of Example 2 and Comparative Examples 4, 5, and 6 of the present invention. [Figure 5] Figure 5. Expansion growth rate curves in width of pirfenidone bilayer tablets for Example 2 and Comparative Examples 4, 5, and 6 of the present invention. [Figure 6] Figure 6. Expansion growth rate curves in height for pirfenidone bilayer tablets of Example 2 and Comparative Examples 4, 5, and 6 of the present invention. [Figure 7] Figure 7. Expansion growth rate curves in length of pirfenidone bilayer tablets for Example 3 of the present invention and Comparative Examples 7 and 8. [Figure 8] Figure 8. Expansion growth rate curves in width of pirfenidone bilayer tablets for Example 3 of the present invention and Comparative Examples 7 and 8. [Figure 9] Figure 9. Expansion growth rate curves in height for pirfenidone bilayer tablets of Example 3 and Comparative Examples 7 and 8 of the present invention. [Figure 10] Figure 10. Expansion growth rate curves in length of pirfenidone bilayer tablets for Example 4 of the present invention and Comparative Examples 9 and 10. [Figure 11] Figure 11. Expansion growth rate curves in width of pirfenidone bilayer tablets for Example 5 of the present invention and Comparative Examples 9 and 10. [Figure 12] Figure 12. Expansion growth rate curves in height for pirfenidone bilayer tablets of Example 6 and Comparative Examples 9 and 10 of the present invention. [Figure 13] Figure 13. Cumulative dissolution rate curves for Example 1 and Comparative Examples 1, 2, and 3. [Figure 14]Figure 14. Cumulative dissolution rate curves for Example 2 and Comparative Examples 4, 5, and 6. [Figure 15] Figure 15. Cumulative dissolution rate curves for Example 3 and Comparative Examples 7 and 8. [Figure 16] Figure 16. Cumulative dissolution rate curves for Example 4 and Comparative Examples 9 and 10. [Figure 17] Figure 17. Comparison curve of blood concentration when the pirfenidone bilayer tablet of the present invention is administered orally once daily and when an existing pirfenidone tablet is administered orally three times daily. [Modes for carrying out the invention]

[0031] Modes for carrying out the invention I. Formulations of the Examples and Controls Example 1. Manufacturing of 1000 bilayer pirfenidone tablets. [Table 1] The manufacturing method of Example 1 specifically includes the following steps: A. Production of drug-containing immediate-release granules: Weigh 150g of pirfenidone, 30g of pregelatinized starch, 60g of crystalline cellulose, and 8g of crospovidone, mix them uniformly, and then granulate, wet granulation, and drying. Furthermore, 2g of sodium stearyl fumarate was added and mixed to obtain an immediate-release blend granule.

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

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

[0034] Comparative Example 1: Manufacturing of 1000 Pirfenidone Bilayer Tablets [Table 2] The manufacturing method for Comparative Example 1 was the same as that for Example 1, and a two-layer tablet with the same shape and size was produced.

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

[0036] In Comparative Example 1, the ratio of the swollen dissolving material to the total tablet weight was 26.68%, while in Example 1, the ratio was 22.08%.

[0037] Comparative Example 2: Manufacturing of 1000 Pirfenidone Bilayer Tablets [Table 3] The manufacturing method for Comparative Example 2 was the same as that for Example 1, and a two-layer tablet with the same shape and size was produced.

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

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

[0040] Comparative Example 3: Manufacturing of 1000 Pirfenidone Bilayer Tablets [Table 4] The manufacturing method for Comparative Example 3 was the same as that for Example 1, and a two-layer tablet with the same shape and size was produced.

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

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

[0043] Example 2. Manufacturing of 1000 bilayer pirfenidone tablets. [Table 5] The manufacturing method for Example 2 was the same as that for Example 1, and a two-layer tablet with the same shape and size was produced.

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

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

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

[0047] Comparative Example 4. Manufacturing of 1000 Pirfenidone Bilayer Tablets [Table 6] The manufacturing method for Comparative Example 4 was the same as that for Example 2, and a two-layer tablet with the same shape and size was produced.

[0048] The main difference between Comparative Example 4 and Example 2 was the viscosity of the swelling and dissolving materials. 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 75,000-140,000 MPa.s.

[0049] Comparative Example 5. Manufacturing of 1000 Pirfenidone Bilayer Tablets [Table 7] The manufacturing method for Comparative Example 5 was the same as that for Example 2, and a two-layer tablet with the same shape and size was produced.

[0050] The main difference between Comparative Example 5 and Example 2 was the viscosity of the plasticizing 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. Manufacturing of 1000 Pirfenidone Bilayer Tablets [Table 8] The manufacturing method for Comparative Example 6 was the same as that for Example 2, and a two-layer tablet with the same shape and size was produced.

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

[0054] Example 3. Manufacturing of 1000 bilayer pirfenidone tablets. [Table 9] The manufacturing method for Example 3 was the same as that for Example 1, and a two-layer tablet with the same shape and size was produced.

[0055] Comparative Example 7. Manufacturing of 1000 Pirfenidone Bilayer Tablets [Table 10] The manufacturing method for Comparative Example 7 was the same as that for Example 3, and a two-layer tablet with the same shape and size was 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 in Example 3 was 76.8%.

[0057] Comparative Example 8. Manufacturing of 1000 Pirfenidone Bilayer Tablets [Table 11] The manufacturing method for Comparative Example 8 was the same as that for Example 3, and a two-layer tablet with the same shape and size was produced.

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

[0059] Example 4. Manufacturing of 1000 bilayer pirfenidone tablets [Table 12] The manufacturing method for Example 4 was the same as that for Example 1, and a two-layer tablet with the same shape and size was produced.

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

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

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

[0063] Comparative Example 9. Manufacturing of 1000 Pirfenidone Bilayer Tablets [Table 13] The manufacturing method for Comparative Example 9 was the same as that for Example 4, and a two-layer tablet with the same shape and size was produced.

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

[0065] Comparative Example 10. Manufacturing of 1000 Pirfenidone Bilayer Tablets [Table 14] The manufacturing method for Comparative Example 10 was the same as that for Example 4, and a two-layer tablet with the same shape and size was produced.

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

[0067] 2. In vitro testing of the formulation To ensure that the drug takes effect rapidly (with partial rapid release) after being taken once daily and maintains its effect within 24 hours, the formulation needs to have a sufficient expansion and growth rate to remain in the stomach for a sufficiently long time, ensuring stable drug release during that period. Therefore, the specifications must be met simultaneously in both the expansion and growth rate test and the in vitro dissolution test.

[0068] 2.1 In vitro expansion test In vitro elution experiment conditions: Test solution: pH 4.5, paddle method + rotating basket, 37°C, rotation speed 75 rpm, test solution volume: 900 ml.

[0069] Multiple laboratory-scale experiments in this invention have shown that, for 600-800 mg tablets, tablets manufactured according to the formulation of this invention have a minimum size of 8.0 mm or more in the three dimensions of length, width, and height, and the expansion growth rate of the dimension having the minimum size meets the following specifications, ensuring that the formulation remains in the stomach for at least 12 hours due to expansion, thereby achieving slow, sustained release of the API. Regarding the growth rate, it was confirmed that it was 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] In the embodiments of the present invention, the minimum three-dimensional size of the tablet is 18.0-19.0 mm in length, 10-11 mm in width, and 8.0-9.5 mm in height. Tests confirmed that if the in vitro expansion growth rate of the smallest size tablet conforms to the specifications listed in Table 15, the formulation will remain in the stomach for at least 12 hours due to expansion, thereby achieving a slow, sustained release of the API.

[0071] [Table 15] [Table 16] Figures 1 to 3 show the expansion growth rate curves in length, width, and height for the pirfenidone bilayer tablets of Example 1 and Comparative Examples 1, 2, and 3.

[0072] As can be seen from Table 16 and Figures 1-3, when the specific gravity of the swollen dissolving material was higher than 25% (Comparative Example 1), the specific gravity of the plasticizing material was lower than 10% (Comparative Example 2), and the specific gravity of the adhesive material (Comparative Example 3) was higher than 8%, a mismatch in the expansion growth rate of at least one of the three dimensions of the tablet (length, width, and height) occurred from the second hour onward, resulting in a failure to control the slow, sustained release of the API dependent on the expansion of the tablet.

[0073] [Table 17] Figures 4 to 6 show the expansion growth rate curves in length, width, and height for the pirfenidone bilayer tablets of Example 2 and Comparative Examples 4, 5, and 6.

[0074] As can be seen from Table 17 and Figures 4-6, even when the specific gravities of the swelling-dissolving material, plasticizer, and adhesive material are within an appropriate range, if the viscosity of the swelling-dissolving material in the formulation is less than 500 MPa·s (proportional ratio 4), the viscosity of the plasticizer is less than 50 MPa·s (proportional ratio 5), and the viscosity of the adhesive material is less than 50 MPa·s (proportional ratio 6), the expansion growth rate becomes significantly unsuitable from the start in at least one dimension among the three dimensions of the tablet (length, width, and height), particularly in the higher dimension with the smallest size. This results in a failure to control the slow, sustained release of the API, which depends on the expansion of the tablet.

[0075] [Table 18] Figures 7 to 9 show the expansion growth rate curves in length, width, and height for the pirfenidone bilayer tablets of Example 3 and Comparative Examples 7 and 8.

[0076] Table 18 and Figures 7, 8, and 9 show that when the ratio of the sustained-release layer to the total tablet weight was less than 50% (Comparative Example 7), it affected the expansion growth rate of the tablet.

[0077] In tablets, the swelling-dissolving material, plasticizing material, and adhesive material are all located within the sustained-release layer. To ensure the expansion rate and thickness of the sustained-release layer, the sustained-release layer must reach a certain ratio to the total tablet weight. Only then can the tablet be ensured to contain sufficient swelling-dissolving material, plasticizing material, and adhesive material, thereby allowing the tablet to expand to a certain sufficient volume in the stomach, delaying its uptake into the intestinal tract and ensuring stable sustained release.

[0078] [Table 19] Figures 10 to 12 show the expansion growth rate curves in length, width, and height for the pirfenidone bilayer tablets of Example 4 and Comparative Examples 9 and 10.

[0079] Table 19 and Figures 10-12 show that variations in the ratio of swelling-dissolving material to adhesive material (Comparative Example 9) or variations in the ratio of adhesive material to plasticizer (Comparative Example 9) had little effect on the expansion growth rate.

[0080] 2.2 In vitro elution test In vitro elution experiment conditions: Test solution: pH 4.5, paddle method + rotating basket, 37°C, rotation speed 75 rpm, test solution volume: 900 ml.

[0081] Multiple lab-scale studies have confirmed that, if the in vitro elution rate meets the specifications in Table 20, it is possible to ensure that the blood concentration reaches a peak rapidly after administration, is completely released within 24 hours, the blood concentration remains within the effective concentration range, and the peak-to-trough ratio is 3 or less.

[0082] [Table 20] The cumulative dissolution rates are shown in the table below and in Figure 13.

[0083] [Table 21] Table 21 and Figure 13 show that when the specific gravity of the swelling-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-dissolving material has a slight effect on the dissolution characteristics, but it is not sensitive to changes in the specific gravity of the plastic material and the adhesive material. Generally, the swelling-dissolving material, plastic material, and adhesive material mainly affected the expansion characteristics.

[0084] The cumulative dissolution rates are shown in the table below and in Figure 14.

[0085] [Table 22] Table 22 and Figure 14 show that the viscosity of the swelling dissolution material (Comparative Example 4), the viscosity of the plasticizing material (Comparative Example 5), and the viscosity of the adhesive material (Comparative Example 6) did not have a 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 Figure 15.

[0087] [Table 23] Table 23 and Figure 15 show that variations in the ratio of the sustained-release layer to the total tablet weight (Comparative Example 7) do not have a clear effect on the dissolution characteristics. However, when the API ratio between the immediate-release layer and the sustained-release layer is too low (Comparative Example 8), the dissolution performance in the initial stage does not meet the standard, which is presumed to affect the efficacy as the blood concentration does not reach its peak rapidly.

[0088] The cumulative dissolution rates are shown in the table below and in Figure 16.

[0089] [Table 24] As shown in Table 24 and Figure 16, when the ratio of swelling dissolving material to adhesive material was higher than 9 (Comparative Example 9) or when the ratio of adhesive material to plasticizer was lower than 0.2 (Comparative Example 9), the dissolution rate did not reach the standard after 10 hours, and the product did not exhibit stable and effective efficacy after 24 hours.

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

[0091] On the other hand, the control tablet produced three peaks in the range of 3500-3800 ng / mL after three doses, but the concentration fell 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 biphenylketone bilayer tablets developed in this invention, when taken once daily, rapidly reach peak blood concentration and stabilize within 24 hours. This demonstrates stable and effective action within 24 hours, eliminating the need for post-meal administration. This further proves that it effectively reduces side effects caused by large fluctuations in blood concentration and improves drug compliance.

Claims

1. A sustained-release solid oral preparation of pirfenidone, comprising a sustained-release preparation, wherein the sustained-release preparation contains a swelling-dissolving material, a plasticizing material, and an adhesive material, In the oral sustained-release solid dosage form, the weight percentage of the swelling-dissolving material is 10-25%, the weight percentage of the plasticizing material is 10-25%, and the weight percentage of the adhesive material is 1-8%. The viscosity of the swelling dissolution 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 plasticizing material is in the range of 50 to 60,000 MPa.s. The aforementioned swelling and dissolving material is one or more selected from the group consisting of sodium carboxymethylcellulose, glyceryl behenate, calcium alginate, potassium alginate, hydroxypropyl methylcellulose (HPMC), ammonium alginate, carnauba wax, tragacanth gum, acacia gum, and shellac. The plastic material is one or more selected from the group consisting of carboxymethylcellulose calcium, ethylcellulose, carbomer, polylactic acid, polylactic acid-glycolic acid copolymer, sodium alginate, hydrogenated vegetable oil, polymethacrylic acid, beeswax, glyceryl monostearate, polyethylene, and ethylene vinyl acetate copolymer. The adhesive material is one or more selected from the group consisting of hydroxyethylcellulose, gelatin, polyoxyethylene, pectin, chitosan, glucose, fucosamine, starch, and chitin. When the oral sustained-release solid dosage form is administered to an individual once daily at a daily dose, the blood concentration parameter reached within 24 hours after administration corresponds to the peak blood concentration (C) corresponding to the blood concentration-time curve. max ) and minimum blood concentration (C min A sustained-release solid oral dosage form of pirfenidone, characterized in that the ratio of ) is within 2 to 10.

2. Here, the ratio of the sustained-release formulation to the total tablet weight is 50-100% or any number within that range, or the ratio of the sustained-release formulation to the total tablet weight is 50%, 60%, 65%, 70%, 73%, 78%, 85%, 90%, or any two of these numbers. The oral sustained-release solid formulation of pirfenidone according to claim 1, characterized in that it is within the range in which a pyramidone is formed.

3. The oral sustained-release solid dosage form of pirfenidone according to claim 2, 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%, 90%, or any two of these values.

4. The oral sustained-release solid formulation of pirfenidone according to claim 1, characterized in that the mass ratio of the swelling-dissolving material to the adhesive material is 1 to 9:1 or any number within that range, or 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1, and the mass ratio of the adhesive material to the plasticizing material is 0.2 to 1:1 or any number 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. The oral sustained-release solid dosage form of pirfenidone according to claim 2, characterized in that it is a single-layer tablet and the sustained-release formulation constitutes 100% of the tablet weight.

6. The oral sustained-release solid dosage form of pirfenidone according to claim 2, further comprising an immediate-release formulation, wherein the mass ratio of the sustained-release formulation to the immediate-release formulation is 1 to 10.

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

6.

8. The viscosity of the swelling dissolution material is selected from one of the following ranges: 500-5000 MPa.s, 500-1000 MPa.s, 2000-5000 MPa.s, 50000-150000 MPa.s, or 150000-300000 MPa.s. The viscosity of the plastic material is 55 to 60,000 MPa.s, 55 to 10,000 MPa.s, 55 to 1,000 MPa.s, or 60 Selected from a range of up 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 any of the following ranges: 55 to 100,000 MPa, 60 to 200 MPa, 65 to 10,000 MPa, 4,000 to 10,000 MPa, 5,000 to 10,000 MPa, 5,500 to 7,500 MPa, or 7,000 to 10,000 MPa.

9. The hydroxypropyl methylcellulose used in the swelling and dissolution material is one or more selected from the group consisting of K100LV, K4M, K750, K100, K200M, and E5LV, The polyoxyethylene has a molecular weight of 10 to 7 million, as described in paragraph 1. This is an oral, sustained-release solid dosage form of pirfenidone.

10. It is a tablet, and its minimum size in the three dimensions of length, width, and height is 8.0 mm or more. The dimension having the minimum size must satisfy the following conditions in terms of expansion growth rate: The oral sustained-release solid dosage form of pirfenidone according to any one of claims 1 to 9, characterized in that, regarding the growth rate, in a test solution at 37°C, 900 ml, pH 4.5, at a rotation speed of 75 rpm, 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.

11. One of the following specifications is available: (1) The pirfenidone content is 500-700 mg, (2) The amount of pirfenidone is 600 mg. (3) The pirfenidone content is 700-1000 mg. (4) The oral sustained-release solid dosage form of pirfenidone according to claim 10, characterized in that the pirfenidone content is 801 mg.

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

13. The oral sustained-release solid formulation of pirfenidone according to claim 11, characterized in that, when used for individual administration, it remains in the stomach for at least 12 hours, and within a 24-hour single-dose interval, the continuous duration of a blood concentration higher than 300 ng / ml is 15 hours or more, and the peak blood concentration is 3500 ng / ml or less.

14. The blood concentration parameter expressed when used for individual administration is the peak blood concentration (C max The ) ranges from 800 ng / ml to 3500 ng / ml, and the lowest blood concentration (C min The oral sustained-release solid formulation of pirfenidone according to claim 11, characterized in that the ) is 300 ng / ml or more.

15. The oral sustained-release solid dosage form of pirfenidone according to claim 11, characterized in that the dosage form is a tablet or capsule, and the tablet is a single-layer tablet, a double-layer tablet, a triple-layer tablet, a core tablet, or a ring tablet.

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

17. The oral sustained-release solid formulation of pirfenidone according to claim 11, characterized in that when used for individual administration, it remains in the stomach for at least 12 hours, and within a 24-hour single-dose interval, the continuous time during which the blood concentration is higher than 300 ng / mL is 15 hours or more, and the peak blood concentration is 2500 ng / mL or less.

18. The oral sustained-release solid formulation of pirfenidone according to claim 11, characterized in that the blood concentration parameters expressed when used for individual administration are a maximum blood concentration (C max) of 1000 ng / mL to 2500 ng / mL and a minimum blood concentration (C min) of 400 ng / mL or more.

19. The oral sustained-release solid formulation of pirfenidone according to Claim 1, characterized in that the ratio of the maximum blood concentration (C max) to the minimum blood concentration (C min) corresponding to the blood concentration-time curve (C max / C min) is 2 to 5.

20. The oral sustained-release solid formulation of pirfenidone according to Claim 1, characterized in that the ratio of the maximum blood concentration (C max) to the minimum blood concentration (C min) corresponding to the blood concentration-time curve (C max / C min) is 2 to 3.5.

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