Carboxylic amine triazole solid dispersion, tablet and preparation process thereof

Abstract

The application belongs to the field of medicine, and particularly relates to a carboxyamine triazole solid dispersion, a tablet and a preparation process thereof. The carrier material of the solid dispersion is one or more of PVP K30, HP-beta-CD, PVP K60, PVP K90, hydroxypropyl cellulose, polymethacrylate derivative or copolyvidone, and the mass ratio of the carboxyamine triazole to the carrier material is 1:1-5. The preparation method comprises the following steps: firstly, dissolving the carboxyamine triazole in solvent 1 to obtain solution 1, dissolving the carrier material in solvent 2 to obtain solution 2; then, mixing the solution 1 and the solution 2; finally, granulating the mixed solution through a fluidized bed, and sieving to obtain the product. The carboxyamine triazole solid dispersion tablet prepared in the research has reasonable prescription process, good stability, in-vivo bioavailability equivalent to that of a soft capsule, and does not contain a large amount of PEG400 and has high production efficiency, thereby providing a basis for researching oral carboxyamine triazole tablets for treating solid tumors and autoimmune diseases.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a carboxyamine triazole solid dispersion, tablets, and their preparation process. Background Technology

[0002] Carboxytriazole is one of the most representative anticancer drugs. Currently, carboxytriazole has completed Phase III clinical trials, using a soft capsule formulation. Addressing the issue of poor stability of carboxytriazole soft capsules during long-term storage in early clinical trials, which could lead to drug release and excessive levels of related substances, patent CN 112353778 B provides an improved soft capsule formulation and preparation process. This ensures that the drug content does not decrease and the increase in related substances is minimal during long-term storage. The soft capsules are sealed in HDPE plastic bottles, with the caps kept sealed during long-term storage, isolating them from the external environment and ensuring good stability within the bottle. However, patient use requires opening the cap, which breaks the original sealed packaging. Furthermore, since this product is packaged in multi-dose containers, frequent opening can cause the soft capsules to absorb moisture from the environment, increasing the risk of drug release from the contents.

[0003] The earliest research on computer-aided instruction (CAI) formulations appeared in a clinical study evaluating the safety and potential cell-inhibiting effects of CAI in treating refractory cancers. Formulation 1 was an oral liquid formulation of CAI in PEG-400, and formulation 2 was a gelatin capsule containing CAI dissolved in PEG-400. Both formulations exhibited gastrointestinal adverse reactions such as nausea and vomiting. Due to the high viscosity and poor taste of the liquid formulation, Kohn EC et al. prepared a micronized formulation of CAI by pulverizing it into microparticles with an average particle size of less than 5 μm and encapsulating them in gelatin shells. A phase I clinical trial was conducted in patients with refractory solid tumors. Pharmacokinetic analysis showed that the bioavailability of this micronized formulation was reduced by 58% compared to the previously reported PEG-400 liquid formulation.

[0004] Solid dispersions (SDs) are intermediates in which drugs are highly dispersed in suitable carrier materials, thereby improving drug dissolution rate and oral bioavailability. Carrier materials play a crucial role in SDs. Besides improving drug wettability and ensuring high dispersion, in amorphous solid dispersions (ASDs), the carrier material can disrupt the original crystal lattice of the drug, causing the API to transform into a higher-energy amorphous form. Amorphous APIs tend to exhibit a higher level of supersaturation in aqueous media than crystalline APIs, thus possessing higher apparent solubility.

[0005] Currently, research on carboxytriazole solid dispersions is almost nonexistent. Given the poor solubility of carboxytriazole raw materials, the difficulty in swallowing soft capsule formulations, and the side effects of polyethylene glycol as an excipient in soft capsule formulations, which can cause nausea, vomiting, and weight loss in some patients with long-term use, we are committed to developing a carboxytriazole solid dispersion and using this solid dispersion to prepare tablets. Summary of the Invention

[0006] To address the problems in the prior art, this invention provides a carboxytriazole solid dispersion and its preparation method, as well as a tablet formulation and its preparation method. The method is simple and rapid, and the dissolution rate and bioavailability of the specific carboxytriazole solid dispersion and its tablets prepared by this invention are improved. Compared with soft capsule dosage forms, they are bioequivalent; patient compliance is higher, and they have broader market value.

[0007] To achieve the objectives of this invention, the following technical solution is adopted:

[0008] A carboxyamine triazole solid dispersion, wherein the carrier material of the solid dispersion is one or more selected from PVP K30, HP-β-CD, PVPK60, PVP K90, hydroxypropyl cellulose, polymethacrylate derivatives and copovidone.

[0009] Preferably, the carrier material of the solid dispersion is one or more of PVP K30, HP-β-CD, PVP K60, PVP K90, hydroxypropyl cellulose, and copovidone.

[0010] Preferably, the mass ratio of the carboxyamine triazole to the carrier material is 1:1-5.

[0011] Preferably, the molar ratio of the carboxyamine triazole to the carrier material is 1:1-3.

[0012] Another object of the present invention is to provide a method for preparing the above-mentioned carboxyamine triazole solid dispersion, comprising the following steps:

[0013] (1) Add carboxytriazole to solvent 1 and dissolve it by ultrasonication to obtain solution 1. Add the carrier material to solvent 2 and dissolve it to obtain solution 2.

[0014] (2) Mix solution 1 and solution 2 and sonicate to obtain a mixed solution;

[0015] (3) The mixed solution is granulated by fluidized bed granulation and then sieved to obtain the final product;

[0016] Solvent 1 is tetrahydrofuran and / or acetone;

[0017] The solvent 2 is one or more of anhydrous ethanol, acetone, methanol, and ethanol:dichloromethane 1:1.

[0018] Preferably, in the fluidized bed granulation process described in step (3), the inlet air temperature is 80-90℃, the material temperature is ≥70℃ when spraying liquid, and the atomization pressure is 1.5-2.0 Bar.

[0019] Preferably, the sieving in step (3) is sieved through a 30-60 mesh sieve; more preferably, it is sieved through a 30 mesh sieve.

[0020] Another object of the present invention is to provide a carboxytriazole solid dispersion tablet, wherein the raw materials include the following components in parts by weight: 40-70 parts of carboxytriazole solid dispersion, 25-50 parts of filler, 3-8 parts of disintegrant and 1-5 parts of lubricant.

[0021] Preferably, the carboxytriazole solid dispersion tablets contain the following components in parts by weight: 40-50 parts of carboxytriazole solid dispersion, 40-50 parts of filler, 3-5 parts of disintegrant, and 1-2 parts of lubricant.

[0022] Preferably, the filler is selected from one or more of microcrystalline cellulose, lactose, and mannitol;

[0023] Preferably, the disintegrant is selected from one or more of PVPP, sodium carboxymethyl starch, and sodium croscarmellose; more preferably, it is selected from one of PVPP and sodium croscarmellose.

[0024] Preferably, the lubricant is selected from one or more of magnesium stearate, glyceryl behenate, and talc.

[0025] Preferably, the filler is selected from microcrystalline cellulose, the disintegrant is selected from PVPP, and the lubricant is selected from magnesium stearate.

[0026] Another object of the present invention is to provide a method for preparing a composition, comprising the following steps:

[0027] (1) Mix the carboxyamine triazole solid dispersion, filler and disintegrant to obtain a mixture;

[0028] (2) The mixture is granulated by dry method to obtain granules;

[0029] (3) Mix the granules with the lubricant and compress them into tablets.

[0030] Preferably, the mixing time in step (1) is 20-40 min; the mixing wheel speed is 3-6 rpm, the roller pressure is 60-70 KN, and the feeding speed is 55-65 rpm during the dry granulation process.

[0031] The final objective of this invention is to provide the use of carboxytriazole solid dispersions or carboxytriazole solid dispersions prepared by the above methods or the above compositions in the preparation of medicaments for treating solid tumors, macular degeneration, retinopathy, chronic myeloid leukemia, and autoimmune diseases, including but not limited to rheumatoid arthritis, psoriasis, inflammatory bowel disease, and Blau syndrome.

[0032] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0033] (1) The carboxytriazole solid dispersion tablets prepared in this study have a reasonable formulation process, good stability, and bioavailability in vivo equivalent to that of soft capsules. Moreover, the tablets of this invention do not contain a large amount of PEG400, have fewer toxic side effects, and have high production efficiency, providing a basis for studying oral carboxytriazole tablets for the treatment of solid tumors and autoimmune diseases.

[0034] (2) The present invention further studies the formulation of carboxytriazole solid dispersion tablets, and its dissolution rate is significantly faster than that of soft capsules. Attached Figure Description

[0035] Figure 1 The solubility of carboxyamine triazole solid dispersion in pure water;

[0036] Figure 2 In vitro release of carboxytriazole solid dispersion (pH 1.0, 2% SDS);

[0037] Figure 3 Cumulative dissolution of carboxytriazole solid dispersion tablets (pH 1.0, 2% SDS);

[0038] Figure 4 The DSC spectrum of the carboxyamine triazole solid dispersion is shown; the curves from top to bottom are PVP K30, carboxyamine triazole, 200219-SD-K30 (1:3), and a physical mixture.

[0039] Figure 5 The XRD patterns of carboxyamine triazole solid dispersions are shown below; the curves from top to bottom are PVP K30, carboxyamine triazole, 200219-SD-K30 (1:3), and a physical mixture.

[0040] Figure 6 The cumulative dissolution rate of SDP-K3013-220306 solid dispersion tablets in medium 1 (pH 1.0, 2% SDS);

[0041] Figure 7 The cumulative dissolution rate of SDP-K3013-220306 solid dispersion tablets in medium 2 (pH 6.8, 2% SDS);

[0042] Figure 8 Blood concentration-time curves after oral administration of 4.45 mg / kg to Beagle dogs;

[0043] Figure 9 This represents the cumulative dissolution rate of carboxytriazole solid dosage form in FaSSIF-V2. Detailed Implementation

[0044] The present invention will be further described below with reference to specific embodiments. The carboxytriazole soft capsules used below are manufactured by Beijing Great Wall Pharmaceutical Co., Ltd., and the batch number is 201201.

[0045] Preparation of carboxyamine triazole solid dispersions in Examples 1-8

[0046] The formulations for Examples 1-8 are shown in Table 1. Examples 1-2 are solid dispersions SD-K30 (1:2) and SD-K30 (1:3) prepared using PVP K30 as the carrier material, with mass ratios of carboxyamine triazole to carrier PVP K30 of 1:2 and 1:3, respectively. Examples 3-4 are solid dispersions SD-CD (1:2) and SD-CD (1:3) prepared using HPβCD as the carrier material, with molar ratios of carboxyamine triazole to HPβCD of 1:2 and 1:3, respectively. The remaining examples are shown in Table 1. The solid dispersions of carboxyamine triazole were prepared using a top-spray granulation method with a Chongqing Yingge FL 200 fluidized bed granulator and dryer.

[0047] The specific preparation process is as follows:

[0048] (1) Solution preparation: Prepare solutions of carboxytriazole and carrier material according to Table 1. Weigh the prescribed amount of carboxytriazole and add it to the prescribed amount of solvent 1, and dissolve it by sonication to obtain solution 1. Weigh the prescribed amount of carrier material and add it to solvent 2 to obtain solution 2. Add solution 1 to solution 2, stir evenly, and then sonicate until the solution is clear and ready for use.

[0049] (2) Preparation of solid dispersion: The inlet air temperature of the fluidized bed was set to 85℃. When the material temperature exceeded 70℃, the spraying of the drug-containing solution began. The atomization pressure was set to 1.8 Bar, and the speed of the liquid supply pump was gradually increased from the lowest value to keep the material temperature at 75℃ throughout the preparation process. After spraying, drying continued at an inlet air temperature of 85℃. During this period, samples were taken and the moisture content was measured using a rapid moisture analyzer until the moisture content was below 1.5%.

[0050] (3) Sieving: Collect the solid dispersion and pass it through a 30-mesh sieve to obtain particles smaller than 30 mesh.

[0051] Table 1 Formulation of carboxytriazole solid dispersion

[0052]

[0053] In the above tablets, the carboxyamine triazole solid dispersions prepared in Examples 1-4 are respectively designated as: 211204-SD-K30 (1:2), 211205-SD-K30 (1:3), 211211-SD-CD (1:2) and 211212-SD-CD (1:3).

[0054] Comparative Examples 1-3

[0055] The formulation of the solid dispersion in the control group is as follows:

[0056] Table 2 Formulation of carboxytriazole solid dispersion

[0057]

[0058] The preparation method is the same as in Example 2.

[0059] Experiment 1: Study on the properties of carboxyamine triazole solid dispersion

[0060] 1.1 Determination of the content of carboxyamine triazole solid dispersion

[0061] A solid dispersion containing approximately 50 mg of carboxytriazole was weighed into a 100 mL volumetric flask, dissolved in a solvent, and its content was determined. The solvent was a mixture of potassium dihydrogen phosphate buffer (1.4 g of potassium dihydrogen phosphate was dissolved in 1000 mL of water, and the pH was adjusted to 3.2 with phosphoric acid) and acetonitrile (30:70). The content of the solid dispersion was determined in triplicate, and the average value was taken. The actual content of the solid dispersion was basically the same as the theoretical content, as shown in Table 3.

[0062] Table 3 Formulation of carboxytriazole solid dispersion

[0063]

[0064] 1.2 In vitro release and dissolution of carboxyamine triazole solid dispersions

[0065] 1.2.1 In vitro release

[0066] (1) Solubility in pure water

[0067] Experiment: Take a vial, add 10 mL of purified water to each vial, and then add excess carboxytriazole and the solid dispersions of Examples 1-4 sequentially. Perform three replicates for each sample. Seal the vials with plastic wrap and place them in a shaker set to 25°C and 100 rpm. Take samples at 1.5 h, 12 h, and 24 h. For each sample, take 1000 μL of the supernatant from each vial and place it in a 1.5 mL centrifuge tube. Centrifuge at 11000 rpm for 15 min. After centrifugation, take 100 μL of the supernatant for content analysis.

[0068] Results: Within 24 hours, compared with the carboxytriazole raw material, 211204-SD-K30 (1:2) in Example 1 and 211205-SD-K30 (1:3) in Example 2 both increased the solubility of carboxytriazole by approximately 150 times. 211211-SD-CD (1:2) in Example 3 and 211212-SD-CD (1:3) in Example 4 increased the solubility of carboxytriazole by more than 300 times. Results for Examples 1-4 are as follows: Figure 1 As shown.

[0069] Solid dispersions of carboxytriazole can effectively increase the solubility of carboxytriazole in pure water.

[0070] (2) In vitro release

[0071] Experiment: The in vitro release of the solid dispersion and the in vitro dissolution behavior of the carboxytriazole soft capsules were investigated in 1000 mL of hydrochloric acid medium containing SDS at pH 1.0.

[0072] Results: Within 15 minutes, all solid dispersions released more than 85% of the drug, and the final cumulative release rate was all above 90%. The cumulative release rate of Example 2 (211205-SD-K30 (1:3)) was slightly higher. Specific results for the in vitro release rates of the carboxytriazole soft capsules and Examples 1-4 are as follows... Figure 2 As shown.

[0073] The in vitro release rates of Examples 5-8 and Comparative Examples 1-3 are shown in Table 4 below:

[0074] Table 4 Results of in vitro release rate

[0075]

[0076] Conclusion: The above experimental results show that the in vitro release rate and release degree of the solid dispersions in Examples 1 to 8 are better than those in the comparative examples.

[0077] 1.3 Stability Study of Carboxyamine Triazole Solid Dispersion

[0078] Influencing Factors Experiment

[0079] The influence factors of four batches of solid dispersions were investigated for 0 days, 5 days, 10 days and 30 days under illumination conditions of 4500±500 Lux, high temperature conditions of 60℃, high humidity conditions of 25℃ and relative humidity of 75±5%RH.

[0080] The results of the experiment on the influencing factors of carboxyamine triazole solid dispersion are shown in Table 5.

[0081] Properties: After being laid out under light conditions, the surface of the solid dispersion changes from white to slightly yellow. After being laid out under high temperature conditions, the properties remain almost unchanged. Under high humidity conditions, it becomes moist and clumps together.

[0082] Content: Under high temperature conditions, the content of carboxytriazole solid dispersions remained almost unchanged after sample release. Under light conditions, from day 0 to day 30, the content of carboxytriazole solid dispersions gradually decreased, with the content of 211204-SD-K30 (1:2) decreasing by more than 10%, and the content of other solid dispersions decreasing by about 7%. Under high humidity conditions, the content of carboxytriazole solid dispersions decreased slightly.

[0083] Related substances: Under high temperature and high humidity conditions, the contents of known impurities G and total impurities in the solid dispersions did not increase significantly compared to day 0, and there were no significant differences in the contents of known impurities G and total impurities between solid dispersions.

[0084] Conclusion: The experimental results of the influencing factors suggest that solid dispersions should be protected from light and moisture during storage and transportation. Packaging materials that can protect from light and moisture should be selected, and attention should be paid to moisture protection when storing solid dispersions.

[0085] Table 5. Influencing Factors and Experimental Results of Carboxytriazole Solid Dispersions

[0086]

[0087]

[0088] Examples 9-14: Preparation of carboxyamine triazole solid dispersion tablets

[0089] The tablet prescription is shown in Table 6-11 below;

[0090] Table 6. Formulation of carboxytriazole solid dispersion tablets

[0091]

[0092] Table 7. Formulation of carboxytriazole solid dispersion tablets

[0093]

[0094] Table 8. Formulation of carboxytriazole solid dispersion tablets

[0095]

[0096]

[0097] Table 9. Formulation of carboxytriazole solid dispersion tablets

[0098]

[0099] Table 10 Formulation of carboxytriazole solid dispersion tablets

[0100]

[0101] Table 11 Formulation of Carboxytriazole Solid Dispersion Tablets

[0102]

[0103] Preparation process

[0104] Based on the formulation in Table 6-11, 600 tablets of each type of solid dispersion were initially prepared. The specific preparation process is as follows:

[0105] (1) Initial mixing: Weigh the materials for each formulation, and put the solid dispersion, filler and disintegrant into a three-dimensional mixer and mix for 30 minutes.

[0106] (2) Dry granulation: The mixed materials are added to the Shenzhen Xinyite Mini-DC dry granulator to prepare granules, improving the flowability of the materials. The parameters are set as follows: roller speed 5 rpm, roller pressure 66.34 KN, and feeding speed 60 rpm.

[0107] (3) Final mixing: Weigh the prescribed amount of magnesium stearate and add it to the prepared granules, and mix for 5 minutes.

[0108] (4) Content determination: Determine the content of the final mixed particles and calculate the tablet weight.

[0109] (5) Tableting: The final mixed material is compressed into tablets in a tableting machine. The batch numbers of the tablets in Examples 9-12 are designated as SDP-K3012-22011401, SDP-K3013-22011402, SDP-CD12-22011701 and SDP-CD13-22011701, respectively.

[0110] Comparative Examples 4-8

[0111] The formulations for Comparative Examples 4-8 are shown in Tables 12-16. The preparation methods are the same as in Example 10.

[0112] Table 12 Formulation of Carboxytriazole Solid Dispersion Tablets

[0113]

[0114] Table 13 Formulation of carboxytriazole solid dispersion tablets

[0115]

[0116] Formulation of 14-carboxyamine triazole solid dispersion tablets

[0117]

[0118] Table 15 Formulation of Carboxytriazole Solid Dispersion Tablets

[0119]

[0120] Table 16 Formulation of Carboxytriazole Solid Dispersion Tablets

[0121]

[0122] Experiment 2: Detection of Carboxytriazole Solid Dispersion Tablets

[0123] The tablet weight, hardness, content, and cumulative dissolution rate at pH 1.0 and 2% SDS were determined.

[0124] Tablet weight: Randomly select 10 tablets from each batch to measure the total weight, and calculate the average tablet weight. Perform the measurement 3 times in parallel for each batch and take the average value.

[0125] Hardness: Randomly select 10 tablets from each group and measure their hardness. Calculate the average value.

[0126] Content: Randomly select 3 tablets from each of the tablets, place each tablet in a 100 mL volumetric flask, dissolve in a solvent, and then determine the content. The solvent is 0.01 mol / L potassium dihydrogen phosphate buffer solution (pH 3.2): acetonitrile (3:7).

[0127] The tablet compression parameters and test results are shown in Table 17.

[0128] Table 17. Compression parameters and test results of carboxytriazole solid dispersion tablets.

[0129]

[0130]

[0131] Conclusion: Based on the above results, the carboxytriazole solid dispersion tablets prepared using the formulation of this invention meet the requirements for pharmaceutical tablets in terms of hardness, tablet weight, content, dissolution, and other indicators.

[0132] Dissolution: The paddle method was used. Dissolution tests of tablets were conducted at 100 rpm and 37°C in 1000 mL of pH 1.0, 2% SDS dissolution medium. Three tablets from each batch were tested in parallel. Dissolution results for soft capsules and tablets from Examples 9-12 are shown below. Figure 3 The dissolution results of the tablets in Examples 13-14 and Comparative Examples 4-8 are shown in Table 18.

[0133] Table 18 shows the dissolution results:

[0134]

[0135] Results and Discussion: Based on the dissolution results, the cumulative dissolution rate of the tablets in each example reached over 85% within 45 minutes, which was significantly better than that of the carboxytriazole soft capsules and the comparative example, with higher dissolution rate and better dissolution behavior.

[0136] Example 15: Small-scale preparation of carboxyamine triazole solid dispersion tablets

[0137] (1) Preparation of carboxyamine triazole solid dispersion

[0138] According to the formulation in Example 2 of Table 1, a solid dispersion of carboxytriazole and PVP K30 with a mass ratio of 1:3 was prepared. The batch number of the solid dispersion was: 200219-SD-K30(1:3).

[0139] Characterization of carboxyamine triazole solid dispersions

[0140] A. The prepared solid dispersion 200219-SD-K30 (1:3) was characterized by DSC as follows.

[0141] Experiment: Scan range 25–500℃, heating rate 10.0℃·min -1 A blank aluminum crucible was used as a reference, and the atmosphere was nitrogen. DSC spectra of PVP K30, carboxytriazole, 200219-SD-K30 (1:3), and a physical mixture of carboxytriazole and PVP K30 at a mass ratio of 1:3 were recorded. (See attached table). Figure 4 .

[0142] Results: The DSC spectrum showed that, compared with the physical mixture, the characteristic peak of carboxytriazole disappeared in the spectrum of 200219-SD-K30(1:3), indicating that carboxytriazole exists in an amorphous state in the carrier material PVP K30.

[0143] B. The prepared solid dispersion 200219-SD-K30 (1:3) was characterized by XRD as follows.

[0144] Experiment: Cu-Ka target (high voltage 40 kV, tube current 100 mA), step scan 0.02° / step, scan range 5°–50°, scan speed 20° / min, test conditions room temperature. XRD patterns of PVP K30, carboxytriazole, 200219-SD-K30 (1:3), and a physical mixture of carboxytriazole and PVP K30 at a mass ratio of 1:3 were recorded. See [link to XRD pattern]. Figure 5 .

[0145] Results: XRD patterns showed that the characteristic peaks of carboxytriazole disappeared in the spectrum of 200219-SD-K30(1:3) compared with the physical mixture, indicating that carboxytriazole exists in an amorphous state in the carrier material PVP K30.

[0146] Conclusion: The DSC and XRD characterization results of the solid dispersion of carboxytriazole 200219-SD-K30 (1:3) showed that carboxytriazole existed in an amorphous state within the carrier material PVP K30, thus the solid dispersion of carboxytriazole was successfully prepared. (2) Preparation of solid dispersion tablets of carboxytriazole

[0147] 10,000 tablets of a carboxytriazole to carrier solid dispersion with a mass ratio of 1:3 were prepared according to the formulation and preparation process of Example 10 in Table 7. The batch number of the tablets is: SDP-K3013-220306. The hardness, content, and dissolution of the tablets were tested according to the methods for testing carboxytriazole solid dispersion tablets. Dissolution was investigated using two dissolution media: medium 1 was a pH 1.0, 2% SDS hydrochloride medium, and medium 2 was a pH 6.8, 2% SDS phosphate medium.

[0148] The test results of SDP-K3013-220306 tablets are shown in Table 19:

[0149] Table 19 Test Results of SDP-K3013-220306 Tablets

[0150]

[0151] The dissolution results of soft capsules and SDP-K3013-220306 tablets in media 1 and media 2 are as follows: Figure 6-7 As shown.

[0152] in conclusion

[0153] Based on the formulation process, the characterization results of the solid dispersion 200219-SD-K30 (1:3) of carboxytriazole, and the quality attribute results of the tablet SDP-K3013-220306, it is believed that the formulation of SDP-K3013-220306 tablets is simple, the preparation process is relatively easy, and the dissolution behavior is good in the dissolution medium of pH 6.8 and 2% SDS.

[0154] Experiment 4: In vivo bioavailability study of carboxytriazole solid dosage form

[0155] Using the soft capsule-2011201 as a control, the bioavailability of the solid dispersion tablet SDP-K3013-220306 in Beagle dogs after a single oral dose of 4.45 mg / kg was investigated. Soft capsule manufacturer: Beijing Great Wall Pharmaceutical Co., Ltd., batch number 201201.

[0156] 1.1.1 1 Examination of the formulation

[0157] Both are 50mg carboxytriazole soft capsules-2011201 and carboxytriazole solid dispersion tablets SDP-K3013-220306.

[0158] 1.1.2 2 Experimental Animals

[0159] Animal grouping: Eight Beagle dogs (half male and half female) were randomly divided into two groups: Group A (soft capsule-20120) and Group C (SDP-K3013-220306), with four dogs in each group (half male and half female). Specific grouping details are shown in Table 20. Water intake was not restricted for the animals after administration.

[0160] Table 20 Grouping of animal experiments with carboxytriazole tablets

[0161]

[0162] Blood collection time points: before oral administration and 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 36 h, 48 h, 72 h, 96 h, 120 h, and 144 h after administration.

[0163] Blood collection tube information: Blood collection tubes containing the anticoagulant sodium heparin.

[0164] Blood collection method and volume: Fast overnight for one day before administration of the drug. For the forelimb vein, collect approximately 2 mL of blood at the designated sampling time point.

[0165] Sample processing: After gently tapping several times to ensure thorough mixing, place the sample in wet ice and centrifuge at 4℃, 2000g for 10 minutes. Separate the plasma, aliquot the plasma samples after centrifugation, and store them in a refrigerator at -70℃ to -90℃.

[0166] 4.1 Liquid Chromatography and Mass Spectrometry Conditions

[0167] The LC-MS analysis conditions are shown in Table 21:

[0168] Table 21 Liquid Chromatography and Mass Spectrometry Conditions

[0169]

[0170]

[0171] 1.1.3 4 Methods for Determining Drug Concentration

[0172] 4.2 Preparation of Standard Curve Samples and Quality Control Samples

[0173] Using an acetonitrile-water (50:50) mixture as solvent and diluent, a series of standard curve solutions and quality control concentration solutions for carboxytriazole reference standards were prepared. The concentration of the carboxytriazole stock solution was 2000 ng / mL, and solutions of other concentrations were obtained by diluting the stock solution with diluent. The standard curve concentrations and quality control concentrations are shown below:

[0174] Standard curve concentrations: 10, 20, 50, 100, 200, 500, 1000, 2000 ng / mL;

[0175] Quality control concentrations: 20, 200, 1600 ng / mL.

[0176] 4.3 Sample Pretreatment

[0177] (1) Add 50 μL each of the mixed standard curve sample, quality control sample, blank sample, QC0 and test sample to a 96-well plate.

[0178] (2) For standard curve samples, quality control samples, test samples, and QC0, add 20 μL of internal standard working solution (50 ng / mL). For blank samples, add the corresponding volume of solvent (without internal standard). Then add 200 μL of MPB to all samples.

[0179] (3) For all samples, vortex for about 5 minutes to mix thoroughly.

[0180] (4) Centrifugation: 4℃, 3000rpm, 5 minutes.

[0181] (5) Transfer the supernatant: Transfer 100 μL of supernatant into a new 96-well plate.

[0182] (6) Add 100 μL of MPA and shake well.

[0183] 4.4 Calculation and Statistical Analysis of Pharmacokinetic Parameters

[0184] Pharmacokinetic parameters of two formulations administered orally to Beagle dogs were calculated using Excel in conjunction with the PKsolver add-in.

[0185] Statistical analysis was performed using GraphPad Prism 8 software. Multiple comparisons of relevant data among groups were conducted using a combination of t-tests and one-way ANOVA. A p-value less than 0.05 was considered statistically significant.

[0186] 4.5 Bioavailability of the formulation

[0187] Beagle dogs were used as test animals. They were orally administered carboxytriazole at a dose of 4.45 mg / kg in two formulations: soft capsules (201201) and solid dispersion tablets (SDP-K3013-220306). The plasma concentration-time curves of the two formulations in dogs are shown below. Figure 8 As shown in Table 22, the pharmacokinetic parameters of plasma are as follows. The experimental results indicate that, compared to carboxytriazole soft capsules-201201, the relative bioavailability of carboxytriazole solid dispersion tablets SDP-K3013-220306 was 121.67%. Both formulations had relatively long half-lives of 23.73 h and 24.05 h, respectively. The soft capsules reached peak plasma concentration faster than the formulation of this invention, with a Tmax (h) of 4.22 h for soft capsules-201201 and 11.56 h for SDP-K3013-220306. In previous in vitro dissolution studies, in two dissolution media (pH 1.0, 2% SDS solution and pH 6.8, 2% SDS solution), SDP-K3013-220306 exhibited better dissolution characteristics than soft capsules-201201. The bioavailability results of the two formulations in dogs showed that the main absorption site of the two formulations was in the intestine. By reviewing the literature, we found a dissolution medium that is more representative of the in vivo situation, a second-generation simulated intestinal fluid specifically developed for poorly soluble drugs, and re-measured the in vitro dissolution of the two formulations in this dissolution medium.

[0188] Table 22 Pharmacokinetic parameters of carboxytriazole solid dosage form in Beagle dogs (n=4)

[0189]

[0190] Conclusion: Statistical analysis showed no statistically significant difference in Cmax (ng / mL) and AUC 0-144h (ng / mL*h) between the two formulations, demonstrating that the carboxytriazole solid dispersion tablet SDP-K3013-220306 is bioequivalent to the carboxytriazole soft capsules.

[0191] 4.6 In vivo-in vitro correlation study

[0192] Because the dissolution of carboxytriazole solid formulations in pH 1.0, 2% SDS and pH 6.8, 2% SDS showed low correlation with in vivo performance, a biorelevant dissolution medium, FaSSIF-V2, was simulated under fasting conditions. This is a fasting intestinal fluid simulation based on the conventional fasting intestinal fluid (FaSSIF) formulation, using maleic acid buffer instead of sodium dihydrogen phosphate buffer, maintaining the sodium taurocholate concentration in FaSSIF while reducing the lecithin concentration. Maleic acid has an appropriate buffering capacity within the pH range of 5.4-6.5 and is closer to the physiological osmotic pressure of the human body. The specific preparation method of FaSSIF-V2 is shown in Table 23.

[0193] Table 23 Intestinal fluid under simulated fasting conditions

[0194]

[0195] 5.1 Determination of dissolution in biologically relevant dissolution media

[0196] Dissolution conditions: The dissolution conditions for carboxytriazole solid dosage forms are as follows. Dissolution medium: FaSSIF-V2; Medium volume: 1000 mL; Apparatus: Slurry method; Rotation speed: 100 rpm; Temperature: 37℃; Sampling time: 48 h.

[0197] Dissolution Method: The dissolution method for carboxytriazole solid dosage forms is as follows. Under the above conditions, the dissolution curves of carboxytriazole soft capsules-2011201 and carboxytriazole solid dispersion tablets SDP-K3013-220306 were investigated in FaSSIF-V2 medium, with six tablets from each batch investigated in parallel. Sampling points were 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, and 24 h. 10 mL of sample was taken at each sampling point, and 10 mL of dissolution medium at the same temperature was added simultaneously. The 10 mL sample was filtered through a 0.45 μm microporous membrane, 5 mL of the initial filtrate was discarded, and the subsequent filtrate was used as the test solution. 10 μL of this solution was accurately injected into the liquid phase for content analysis.

[0198] Dissolution results: The dissolution profiles of two solid dosage forms of carboxytriazole, soft capsule-201201 and solid dispersion tablet SDP-K3013-220306, in FaSSIF-V2 are shown below. Figure 9As shown in the figure. The experimental results showed that the dissolution of the two formulations in simulated intestinal fluid basically matched the drug-time curves of the two formulations in dogs. In the dissolution curves, the release of soft capsule-201201 was higher than that of SDP-K3013-220306 in the first hour; between 1 and 5 hours, the cumulative release of SDP-K3013-220306 was higher; after 10 hours, there was no significant difference in the cumulative dissolution of the two formulations. Based on the results of the in vivo experiments, it is believed that the dissolution and bioavailability of the two formulations in FaSSIF-V2 are similar.

[0199] The above detailed description is a specific description of one of the feasible embodiments of the present invention. This embodiment is not intended to limit the patent scope of the present invention. All equivalent implementations or modifications that do not depart from the present invention should be included within the scope of the technical solution of the present invention.

Claims

1. A carboxyamine triazole solid dispersion tablet, characterized in that, The raw materials of the tablets include the following components in parts by weight: 40-70 parts of carboxyamine triazole solid dispersion, 25-50 parts of filler, 3-8 parts of disintegrant and 1-5 parts of lubricant; The filler is selected from one or more of microcrystalline cellulose, lactose and mannitol; the disintegrant is selected from one or two of PVPP and croscarmellose sodium; and the lubricant is selected from one or two of magnesium stearate and behenate glyceride. The carrier material of the solid dispersion is one or more of PVP K30, HP-β-CD, PVP K60, PVP K90, hydroxypropyl cellulose, and copovidone; The mass ratio of the carboxyamine triazole to the carrier material is 1:1-5; or the molar ratio is 1:1-3. The preparation method of carboxyamine triazole solid dispersion includes the following steps: (1) Dissolve carboxyamine triazole in solvent 1 to obtain solution 1, and dissolve the carrier material in solvent 2 to obtain solution 2; (2) Mix solution 1 and solution 2 to obtain a mixed solution; (3) The mixed solution is granulated by fluidized bed granulation and then sieved to obtain the final product; Solvent 1 is tetrahydrofuran and / or acetone; Solvent 2 is one or more of anhydrous ethanol, acetone, and methanol.

2. The carboxyamine triazole solid dispersion tablet according to claim 1, characterized in that, In the fluidized bed granulation process described in step (3), the inlet air temperature is 80-90℃, the material temperature is ≥70℃ when spraying liquid, and the atomization pressure is 1.5-2.0 Bar; the sieving is 30-60 mesh.

3. The carboxyamine triazole solid dispersion tablet according to claim 1, characterized in that, The filler is selected from microcrystalline cellulose, the disintegrant is selected from PVPP, and the lubricant is selected from magnesium stearate.

4. A method for preparing a carboxyamine triazole solid dispersion tablet according to any one of claims 1-3, characterized in that, The steps include the following: (1) Mix the carboxyamine triazole solid dispersion, filler and disintegrant to obtain a mixture; (2) The mixture is granulated by dry method to obtain granules; (3) Mix the granules with the lubricant and compress them into tablets.

5. The preparation method according to claim 4, characterized in that, The mixing time in step (1) is 20-40 min; the mixing wheel speed is 3-6 rpm, the roller pressure is 60-70 KN, and the feeding speed is 55-65 rpm during the dry granulation process.

6. The use of a carboxytriazole solid dispersion tablet according to any one of claims 1-3 in the preparation of a medicament for treating solid tumors, macular degeneration, retinopathy, chronic myeloid leukemia, and autoimmune diseases, wherein the autoimmune diseases are selected from rheumatoid arthritis, psoriasis, inflammatory bowel disease, or Blau syndrome.

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