Helizemibe tablet and preparation method thereof

Abstract

The invention relates to a helizimibe tablet, a helizimibe solid dispersion composition as well as a preparation method and application of the helizimibe solid dispersion composition. The preparation method comprises the following steps: carrying out wet granulation, drying, size stabilization and tabletting on the seaweed and auxiliary materials to obtain the seaweed tablet.

Description

[0001] Cross-references This application claims priority to Chinese Patent Application No. 201711183388.3, ​​filed with the China Patent Office on November 23, 2017, entitled “A Haizemab Tablet and a Method for Preparing the Same”, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] This invention belongs to the pharmaceutical field, specifically relating to Haizemabu tablets and their preparation process. Background Technology

[0003] Haizemib (HS-25) is a cholesterol-lowering drug, disclosed in WO2011017907, and has the following structural formula:

[0004]

[0005] Haizemab reduces plasma cholesterol levels by inhibiting the cholesterol absorption protein NPCILI in intestinal epithelial cells, thereby reducing the absorption of cholesterol, phytosterols, and the reabsorption of cholesterol in bile. Clinically, this product is used for: 1. Primary hypercholesterolemia; 2. Homozygous familial hypercholesterolemia (HoFH); 3. Treatment of homozygous sitosterolemia (or phytosterolemia).

[0006] The active pharmaceutical ingredient (API) of zebucil exhibits high electrostatic adsorption, resulting in poor flowability; it also has poor solubility in water, leading to poor absorption in vivo; furthermore, this compound is sensitive to temperature and humidity. Due to these issues with stability and absorption, a suitable preparation process is needed to develop zebucil into a stable formulation with good in vivo absorption.

[0007] Hazemib is a poorly soluble drug. To improve its bioavailability in vivo, a suitable surfactant, such as Tween or sodium lauryl sulfate, is usually added to the formulation. In the tablet formulation of this invention, sodium lauryl sulfate can be added as a surfactant. Because hazemib is unstable to alkali, the amount of sodium lauryl sulfate is generally controlled to be less than 5% of the tablet weight.

[0008] Micronizing active pharmaceutical ingredients (APIs) is a common method to improve drug dissolution and increase bioavailability. However, due to the high electrostatic adsorption of zebufen API, excessively small particle size after micronization can exacerbate electrostatic adsorption, increasing the contact area with moisture and air, thus leading to product instability. On the other hand, excessively large particle size can result in slow dissolution and low bioavailability in the finished product. This invention provides a suitable particle size range for the API. Within this range, zebufen API exhibits strong processability, and the prepared product demonstrates good bioavailability, stable crystal form and related substances, thus possessing significant commercial production value.

[0009] Solid dispersion technology is another method to improve the bioavailability of poorly soluble drugs. However, this technology carries the risk that the drug may undergo a crystal transformation, changing from a high-energy amorphous state to a stable crystalline form. This could potentially compromise the drug's stability and solubility.

[0010] Hazelmeb tablets prepared by water granulation, without added antioxidants in the formulation, are relatively stable under long-term accelerated storage conditions. However, hazelmeb tablets prepared by ethanol granulation, without added antioxidants in the formulation, show faster impurity growth. This is mainly because amorphous hazelmeb has high energy, a greater probability of contact with moisture and oxidizing substances in the formulation, and is easily degraded under temperature influence. This invention adds an appropriate amount of antioxidant, such as butylated hydroxytoluene (BHT), to the water or organic solvent formulation, which can effectively reduce degradation impurities. Adding an appropriate amount of BHT to hazelmeb tablets contributes to product stability, and the amount added can be adjusted according to the process.

[0011] This patent describes in detail the wet granulation process of Haizemai tablets. Regardless of whether water or ethanol is used for granulation, the resulting tablets have a smooth appearance, rapid in vitro release, qualified content and content uniformity, and all degradation impurities do not exceed the limit requirements. The crystal form is stable, and the production process is simple, effectively addressing related problems in industrial production. Summary of the Invention

[0012] To address the aforementioned technical problems, this invention provides a Haizemab tablet and its preparation process, which has advantages such as high bioavailability, good stability, high yield, and ease of commercial production.

[0013] The Haizemab tablets of the present invention contain excipients such as Haizemab, fillers, binders, disintegrants, and lubricants, wherein Haizemab accounts for 1-20% of the tablet weight. Preferably, the Haizemab tablets also contain stabilizers and / or surfactants.

[0014] Preferably, the filler is at least one of lactose, microcrystalline cellulose, and pregelatinized starch; more preferably, it is at least one of lactose and microcrystalline cellulose; more preferably, it is at least one of 30-60% by weight lactose and 20-60% by weight microcrystalline cellulose.

[0015] Preferably, the adhesive is at least one of hydroxypropyl cellulose and polyvinyl ketone; more preferably, it is polyvinyl ketone; more preferably, it is 1-5% by weight of polyvinyl ketone; most preferably, it is 1-5% by weight of polyvinyl ketone K30.

[0016] Preferably, the disintegrant is at least one of crospovidone and crospovidone sodium carboxymethyl cellulose; preferably, it is 1-10% by weight of crospovidone or 1-10% by weight of crospovidone sodium carboxymethyl cellulose.

[0017] Preferably, the stabilizer is at least one of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT); more preferably, it is BHT; more preferably, it is 0.005-0.1% by weight of BHT.

[0018] Preferably, the surfactant is at least one of sodium dodecyl sulfate and polysorbate; more preferably, it is sodium dodecyl sulfate; more preferably, it is 1-5% by weight of sodium dodecyl sulfate.

[0019] Preferably, the lubricant is at least one of magnesium stearate and talc; more preferably, it is magnesium stearate; more preferably, it is 0.5 to 2% by weight of magnesium stearate.

[0020] The Haizemabu tablets can be granulated using water, alcohol, acetone, or similar solvents, or mixtures thereof, and then compressed into tablets.

[0021] Through extensive experimentation, the inventors unexpectedly discovered that dissolving Hezemib in an organic solvent containing povidone, and then pouring or spraying it into excipients, yields a solid dispersion. This method can solve the problem of electrostatic adsorption of the active pharmaceutical ingredient and also inhibit crystal transformation.

[0022] Based on this discovery, the present invention provides, in one aspect, a zemab solid dispersion composition comprising zemab and povidone.

[0023] In another aspect, the present invention provides a Hazemabu tablet comprising the Hazemabu solid dispersion composition described herein.

[0024] In another aspect, the present invention also provides the use of the haizemab solid dispersion composition described herein in the preparation of haizemab solid dosage forms. The solid dosage forms are preferably selected from tablets, capsules, granules, and powders.

[0025] This invention also provides a method for preparing the haizemab solid dispersion composition described herein, comprising the following steps: dissolving haizemab in an organic solvent containing povidone. In some specific embodiments, the method for preparing the haizemab solid dispersion composition optionally further comprises pouring or spraying the haizemab solution obtained in the above steps into an excipient, and optionally performing granulation and / or drying steps. The organic solvent may be selected from organic solvents such as alcohols, ethers, ketones, and esters, including but not limited to methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, n-pentanol, isopentanol, n-hexanol, cyclohexanol, tetrahydrofuran, diethyl ether, methyl ethyl ether, ethyl acetate, ethyl formate, or mixtures thereof; preferably, the organic solvent is selected from ethanol, isopropanol, and mixtures thereof with water.

[0026] The Haizemabu tablets of the present invention can be prepared by wet granulation followed by tableting with water. More preferably, the Haizemabu tablets can be prepared by the following method:

[0027] (1) Mix Haizemab with lactose, microcrystalline cellulose, sodium dodecyl sulfate and croscarmellose sodium evenly;

[0028] (2) Dissolve povidone in water;

[0029] (3) Add the povidone solution obtained in step (2) to the mixture obtained in step (1) for granulation, drying and granulation;

[0030] (4) Mix the granules after granulation in step (3) with magnesium stearate evenly and compress into tablets.

[0031] Preferably, the hezemab used in the above preparation process is hezemab crystal form I.

[0032] Preferably, the particle size range of Haizemab used in the above preparation process is 1μm≤D90≤100μm, and more preferably 1μm≤D90≤50μm.

[0033] The Haizemab tablets of the present invention can also be prepared by wet granulation followed by tableting using organic solvents and their solutions. The organic solvents and their solutions are preferably alcohol solvents and their solutions, more preferably ethanol and its solutions, and even more preferably ethanol solutions. The Haizemab tablets can be prepared by the following methods:

[0034] (1) Mix lactose, microcrystalline cellulose, sodium lauryl sulfate and crospovidone evenly, or mix lactose, microcrystalline cellulose and crospovidone evenly;

[0035] (2) Dissolve Hazemab, Povidone, and Butylated Hydroxytoluene (BHT) in an alcohol solvent, or dissolve Hazemab and Povidone in an alcohol solvent;

[0036] (3) Add the solution obtained in step (2) to the mixture obtained in step (1) for granulation, drying and granulation;

[0037] (4) Mix the granules obtained in step (3) with magnesium stearate evenly and compress into tablets.

[0038] Preferably, the ethanol solution is an aqueous ethanol solution; more preferably, the concentration of the aqueous ethanol solution is ≥60% (w / w); even more preferably, the concentration of the aqueous ethanol solution is ≥75% (w / w); and most preferably, the concentration of the aqueous ethanol solution is 80-90% (w / w).

[0039] Preferably, the amount of ethanol solution used is 30% to 50% (w / w) of the prescription amount; more preferably, the amount of ethanol solution used is 35% to 45% (w / w) of the prescription amount.

[0040] Preferably, in the preparation method of the present invention, the weight ratio of Hezemib to povidone ranges from 10:1 to 1:1; more preferably, the weight ratio ranges from 5:1 to 5:3.

[0041] Preferably, in the preparation method of the present invention, the granulation method includes high-speed stirring granulation or fluidized bed granulation.

[0042] Preferably, in the preparation method of the present invention, the Haizemabu tablets prepared by the method of the present invention contain more than 90% Haizemabu in an amorphous form.

[0043] The zemab tablets of the present invention preferably contain 5 to 20 mg of zemab per drug dose unit; more preferably, the dose of zemab contained in each drug dose unit is 5 mg, 10 mg or 20 mg.

[0044] Preferably, each dose unit of the Haizemabu tablets further contains 20-250 mg of lactose, 20-200 mg of microcrystalline cellulose, 1-10 mg of croscarmellose sodium or 5-30 mg of croscarmellose, 1-15 mg of povidone K30, 0-0.2 mg of butylated hydroxytoluene, 0-15 mg of sodium dodecyl sulfate, and 0.5-10 mg of magnesium stearate.

[0045] Haizemab active pharmaceutical ingredient (API) exhibits high electrostatic adsorption and poor flowability; it also has poor solubility in water and poor absorption in vivo. This invention provides two methods for preparing Haizemab tablets. One method involves micronizing the Haizemab API and then directly mixing it with excipients, followed by wet granulation with water to obtain Haizemab tablets, with a suitable API particle size range optimized. The other method includes the following steps: dissolving the Haizemab API in an organic solvent, preferably in an organic solvent containing povidone, and then optionally pouring or spraying the resulting solution onto the excipients for granulation. These methods address the electrostatic adsorption problem and, as a simple solid dispersion technique, improve bioavailability. The optimal amount of povidone used is also optimized, effectively solving the electrostatic adsorption problem of Haizemab API, mitigating the risk of crystal transformation, and ensuring that the resulting Haizemab tablets remain amorphous during stable storage. The preparation method provided by this invention improves the bioavailability of zemab, is easy to commercialize, and has high economic value. Attached Figure Description

[0046] Figure 1 XRD pattern of placebo Haizemib

[0047] Figure 2 XRD pattern of Hezemib API (Crystal Form I)

[0048] Figure 3 XRD pattern of a mixture of placebo and active pharmaceutical ingredient (Crystal Form I) of zebufenib

[0049] Figure 4 XRD pattern of 20% API concentration Haizemab tablets in October

[0050] Figure 5 XRD patterns of 20% API concentration Haizemab tablets in March

[0051] Figure 6 XRD patterns of 20% API concentration Haizemab tablets in September Detailed Implementation

[0052] The present invention will be described in detail below with reference to the embodiments. It should be noted that the following embodiments are for illustrative purposes only and are not intended to limit the invention. Experimental methods in the following embodiments that do not specify specific conditions are performed according to conventional methods and conditions, or as selected according to the product instructions.

[0053] The active pharmaceutical ingredient (API) of Haizemab described in this invention is provided by Zhejiang Hisun Pharmaceutical Co., Ltd. The crystal form of Haizemab API is crystal form I, and its preparation is described in WO2014036956.

[0054] Example 1: Haizemab tablets (water-granulated), specification: 10mg, each tablet weighing 100mg. The prescription composition (unit: g) is as follows:

[0055]

[0056] Preparation method:

[0057] 1. After passing the raw material of Haizemab (unmicronized), 200-mesh monohydrate lactose, 101 microcrystalline cellulose, sodium dodecyl sulfate, and sodium croscarmellose through a 40-mesh sieve, premix them.

[0058] 2. Dissolve povidone K30 in purified water (30% of the prescription amount) and set aside.

[0059] 3. Add the povidone K30 solution from step 2 to the mixture from step 1, granulate, and granulate the wet granules using a 1.0 mm sieve.

[0060] 4. Place the wet granules in a fluidized bed, set the fluidized bed inlet air temperature to 55-65℃, and begin drying.

[0061] Granulation using a 5.1.0mm sieve.

[0062] 6. Add magnesium stearate and mix.

[0063] 7. Tableting.

[0064] Example 2: Haizemab tablets (water-granulated), specification: 10mg, each tablet weighing 100mg. The prescription composition (unit: g) is as follows:

[0065]

[0066] Preparation method:

[0067] The raw material of Haizemab was pulverized using an air jet mill, and the preparation method was the same as in Example 1.

[0068] Example 3: Haizemab tablets (alcohol-granulated formula), 10mg, 200mg per tablet. The formula composition (unit: g) is as follows:

[0069]

[0070] Preparation method:

[0071] 1. Premix 200-mesh monohydrate lactose, 101-mesh microcrystalline cellulose, and 40-mesh crospovidone XL.

[0072] 2. Dissolve butylated hydroxytoluene, povidone K30, and zebufen in an 85% (w / w) aqueous ethanol solution (35% of the prescription amount) to prepare an adhesive solution for later use.

[0073] 3. Add the binder solution from step 2 to the mixture from step 1, granulate, and granulate the wet granules using a 1.0 mm sieve.

[0074] 4. Place the wet granules in an oven, set the temperature to 40-50℃, and begin drying.

[0075] Granulation using a 5.1.0mm sieve.

[0076] 6. Add magnesium stearate and mix.

[0077] 7. Tableting.

[0078] Example 4: Haizemab tablets, specification: 5mg, each tablet weighing 100mg. The prescription composition (unit: g) is as follows:

[0079]

[0080] Preparation method: Same as in Example 3

[0081] Example 5: Haizemab tablets, specification: 5mg, each tablet weighing 100mg. The prescription composition (unit: g) is as follows:

[0082]

[0083] Preparation method: Same as in Example 3.

[0084] Example 6: Haizemab tablets, specification: 5mg, 100mg per tablet. The prescription composition (unit: g) is as follows:

[0085]

[0086] Preparation method: Same as in Example 3.

[0087] Example 7: Haizemab tablets, specification: 5mg, 100mg per tablet. The prescription composition (unit: g) is as follows:

[0088]

[0089] Preparation method:

[0090] 1. Premix 200-mesh monohydrate lactose, 101 microcrystalline cellulose, XL crospovidone, and sodium dodecyl sulfate through a 40-mesh sieve.

[0091] 2. Dissolve butylated hydroxytoluene, povidone K30, and zebufen in an 85% (w / w) aqueous ethanol solution (35% of the prescription amount) to prepare an adhesive solution for later use.

[0092] 3. Add the binder solution from step 2 to the mixture from step 1, granulate, and granulate the wet granules using a 1.0 mm sieve.

[0093] 4. Place the wet granules in an oven, set the temperature to 40-50℃, and begin drying.

[0094] Granulation using a 5.1.0mm sieve.

[0095] 6. Add magnesium stearate and mix.

[0096] 7. Tableting.

[0097] Example 8: Haizemab tablets, specification: 10mg, 200mg per tablet. The prescription composition (unit: g) is as follows:

[0098]

[0099] Preparation method: Same as in Example 7.

[0100] Example 9: Haizemab tablets, specification: 20mg, 400mg per tablet. The prescription composition (unit: g) is as follows:

[0101]

[0102] Preparation method: Same as in Example 7.

[0103] Example 10: Haizemab tablets, specification: 20mg, 400mg per tablet. The prescription composition (unit: g) is as follows:

[0104]

[0105] Preparation method:

[0106] 1. Premix 200-mesh monohydrate lactose, 101 microcrystalline cellulose, XL crospovidone, and sodium dodecyl sulfate through a 40-mesh sieve.

[0107] 2. Dissolve povidone K30 and zebufen in 85% (w / w) ethanol aqueous solution (35% of the prescription amount) for use as an adhesive solution.

[0108] 3. Add the binder solution from step 2 to the mixture from step 1, granulate, and granulate the wet granules using a 1.0 mm sieve.

[0109] 4. Place the wet granules in an oven, set the temperature to 40-50℃, and begin drying.

[0110] Granulation using a 5.1.0mm sieve.

[0111] 6. Add magnesium stearate and mix.

[0112] 7. Tableting.

[0113] Example 11: Haizemab tablets, specification: 20mg, 100mg per tablet. The prescription composition (unit: g) is as follows:

[0114]

[0115] Preparation method:

[0116] 1. Premix 200-mesh monohydrate lactose, 101-mesh microcrystalline cellulose, and 40-mesh crospovidone XL.

[0117] 2. Dissolve butylated hydroxytoluene, povidone K30, and zebufen in an 85% (w / w) aqueous ethanol solution to prepare an adhesive solution.

[0118] 3. Add the binder solution from step 2 to the mixture from step 1, granulate, and granulate the wet granules using a 1.0 mm sieve.

[0119] 4. Place the wet granules in an oven, set the temperature to 40-50℃, and begin drying.

[0120] Granulation using a 5.1.0mm sieve.

[0121] 6. Add magnesium stearate and mix.

[0122] 7. Tableting.

[0123] Example 12: Hazemib placebo, 400 mg per tablet. The prescription composition (unit: g) is as follows:

[0124]

[0125] Preparation method:

[0126] 1. Premix 200-mesh monohydrate lactose, 101 microcrystalline cellulose, XL crospovidone, and sodium dodecyl sulfate through a 40-mesh sieve.

[0127] 2. Dissolve butylated hydroxytoluene and povidone K30 in an 85% (w / w) aqueous ethanol solution (35% of the prescription amount) for use as an adhesive solution.

[0128] 3. Add the binder solution from step 2 to the mixture from step 1, granulate, and granulate the wet granules using a 1.0 mm sieve.

[0129] 4. Place the wet granules in an oven, set the temperature to 40-50℃, and begin drying.

[0130] Granulation using a 5.1.0mm sieve.

[0131] 6. Add magnesium stearate and mix.

[0132] 7. Tableting.

[0133] Experimental Example 1:

[0134] The tablets prepared in Examples 1 and 2 were administered orally to male beagle dogs, and the pharmacokinetic characteristics in the dogs were investigated. The animal experimental data are shown in Tables 1 and 2.

[0135] Table 1. Pharmacokinetic parameters of HS-25 after oral administration of 10 mg / kg HS-25 tablets (water-granulated) in male beagle dogs (Example 1).

[0136]

[0137] Table 2. Pharmacokinetic parameters of HS-25 after oral administration of 10 mg / kg of HS-25 tablets (micronized water-granulated formulation) in male beagle dogs according to Example 2.

[0138]

[0139] Conclusion: The tablets of Example 2 (which were made by micronizing HS-25 active pharmaceutical ingredient) can significantly improve the bioavailability of HS-25 in vivo.

[0140] Experimental Example 2:

[0141] The tablets prepared in Example 3 were administered orally to male beagle dogs, and the pharmacokinetic characteristics in the dogs were investigated. The animal experimental data are shown in Table 3.

[0142] Table 3. Pharmacokinetic parameters of HS-25 after oral administration of 10 mg / kg HS-25 tablets (ethanol granulation formulation) of Example 3 in male beagle dogs.

[0143]

[0144] Compared with the tablets of Examples 1 and 2 (both of which are water-granulated formulations of Hazemib), the tablets of Example 3 (alcohol-granulated formulation) can achieve higher bioavailability of HS-25 in vivo.

[0145] Experimental Example 3: Stability Study of Haizemib Tablets (10mg specification)

[0146] The tablets prepared in Example 3 were aluminum-plasticized and packaged in blank sealed bags (containing 2g of desiccant). Stability studies were conducted under conditions of 25ºC±2ºC and 60%±5% RH. The test results are shown in Table 4.

[0147] Table 4. Stability data of Haizemib tablets (10mg strength)

[0148]

[0149] The results showed that after 24 months of storage at 25ºC±2ºC and RH60%±5%, the content and dissolution of Haizemabu tablets (10mg) did not change significantly, while the impurities increased slightly, indicating that the sample was relatively stable.

[0150] Example 4: Stability data from the stability study of Haizemib tablets (5mg strength).

[0151] The tablets prepared in Example 6 were aluminum-plasticized and packaged in blank sealed bags (containing 2g of desiccant). Stability studies were conducted under conditions of 25ºC±2ºC and 60%±5% RH. The test results are shown in Table 5.

[0152] Table 5. Stability data of Haizemib tablets (5mg strength)

[0153]

[0154] The results showed that after 24 months of storage at 25ºC±2ºC and RH60%±5%, the content and dissolution of Haizemabu tablets (5mg) did not change significantly, while the impurities increased slightly, indicating that the sample was relatively stable.

[0155] Example 5: Stability data from the stability study of Haizemib tablets (10mg strength).

[0156] The tablets prepared in Example 8 were aluminum-plasticized and packaged in blank sealed bags (containing 2g of desiccant). Stability studies were conducted under conditions of 25ºC±2ºC and 60%±5% RH. The test results are shown in Table 6.

[0157] Table 6. Stability data for Haizemib tablets (10mg strength)

[0158]

[0159] The results showed that after 36 months of storage at 25ºC±2ºC and RH60%±5%, the content and dissolution of Haizemabu tablets (10mg) did not change significantly, while the impurities increased slightly, indicating that the sample was relatively stable.

[0160] Example 6: Stability data from the stability study of Haizemib tablets (20mg strength)

[0161] The tablets prepared in Example 9 were aluminum-plasticized and packaged in blank sealed bags (containing 2g of desiccant). Stability studies were conducted under conditions of 25ºC±2ºC and 60%±5% RH. The test results are shown in Table 7.

[0162] Table 7. Stability data of Haizemib tablets (20mg strength)

[0163]

[0164] The results showed that after 36 months of storage at 25ºC±2ºC and RH60%±5%, the content and dissolution of Haizemabu tablets (20mg) did not change significantly, while the impurities increased slightly, indicating that the sample was relatively stable.

[0165] Experimental Example 7: Stability data of BHT-free Haizemib tablets

[0166] The tablets from Examples 9 and 10 were aluminum-plasticized, packaged in blank sealed bags (containing 2g of desiccant), and placed under conditions of 40ºC±2ºC and 75%±5% RH for stability studies. The test results are shown in Table 8.

[0167] Table 8. Stability data of Haizemib tablets (20mg strength)

[0168]

[0169] Experimental Example 8: Effect of Sodium Lauryl Sulfate (SDS) on the Dissolution of Hezemib Tablets

[0170] Dissolution test method: paddle method; dissolution medium: 0.1N hydrochloric acid solution containing 0.5% SDS; rotation speed: 50 rpm; medium volume: 900 mL.

[0171] The dissolution rates of the tablets from Examples 3 and 8 were determined, and the results are shown in Table 9.

[0172] Table 9. Comparison of dissolution data for Haizemib tablets (10mg strength)

[0173]

[0174] The results showed that the dissolution of hydatid in the tablets of Example 8 was faster than that of the tablets of Example 3, indicating that the presence of sodium dodecyl sulfate in the formulation could promote the dissolution of hydatid.

[0175] Experimental Example 9: Study of the Crystal Form of Haizemab

[0176] The placebo and raw material (crystalline form I) of zebufenib were mixed at a weight ratio of 98:2. The resulting mixture was subjected to X-ray diffraction (XRD) analysis, and the XRD pattern of the mixture of placebo and raw material (crystalline form I) of zebufenib was obtained (see...). Figure 3 ), and then Figure 3 XRD patterns of hezemib placebo (see) Figure 1 XRD patterns of ) and Haizemab raw material (crystal form I) (see) Figure 2 Compare them, in Figure 3 At the 18° position, a characteristic peak of cycloheximetrix I was detected, indicating that the detection limit of the XRD instrument for cycloheximetrix I is 2%. This means that cycloheximetrix I can be detected when it accounts for more than 2% of the total tablet weight. XRD analysis of the 20% cycloheximetrix tablets prepared in Example 11 showed no peak at 18° (see...). Figure 4 This indicates that the active pharmaceutical ingredient (API) present in crystal form I in the tablets prepared according to the method of Example 11 is at least less than 2% of the tablet weight, meaning that more than 18% of the API in the tablets of Example 11 is present in an amorphous form. Therefore, it is determined that the amorphous content of zebufenib in the tablets of Example 11 accounts for more than 90% of the total API. The stability of the tablets of Example 11 (zebufenib 20 mg, alcohol-granulated tablets) was examined under accelerated conditions (temperature 40ºC ± 2ºC, humidity (RH) 75% ± 5%), and the results are as follows. Figure 5 and Figure 6 As shown:

[0177] Figure 5 The results showed that the amorphous content remained above 90% even under accelerated conditions for 3 months.

[0178] Figure 6 The results showed that the amorphous content remained above 90% even under accelerated conditions for 9 months.

Claims

1. A type of Haizemabu tablet, comprising Haizemabu, fillers, binders, disintegrants, and lubricants, etc., wherein, Haizemab accounts for 1-20% of the tablet weight.

2. The Haizemabu tablets according to claim 1, wherein, The filler is at least one of lactose, microcrystalline cellulose, and pregelatinized starch; the binder is at least one of hydroxypropyl cellulose and povidone; the disintegrant is at least one of crospovidone and crospovidone sodium carboxymethyl cellulose; and the lubricant is at least one of magnesium stearate and talc.

3. The Haizemabu tablets according to claim 1 or 2, further comprising a stabilizer and / or a surfactant.

4. The Haizemabu tablets according to claim 3, wherein the stabilizer is at least one of butylated hydroxyanisole and butylated hydroxytoluene, and the surfactant is at least one of sodium dodecyl sulfate and polysorbate.

5. The Haizemabu sheet according to any one of claims 1-4, characterized in that, It contains 30-60% by weight lactose, 20-60% by weight microcrystalline cellulose, 1-5% by weight povidone, 1-10% by weight crospovidone or crospovidone sodium carboxymethyl cellulose, 0-0.1% by weight butylated hydroxytoluene, 0-5% by weight sodium dodecyl sulfate, and 0.5-2% by weight magnesium stearate.

6. The Haizemabu tablets according to claim 5, wherein the tablets contain 0.005 to 0.1% by weight of butylated hydroxytoluene.

7. The Haizemabu tablets according to claim 5, wherein the content of sodium dodecyl sulfate is 1-5% by weight.

8. The Haizemabu sheet according to any one of claims 1-7, characterized in that, It can be granulated using water, alcohol, acetone, or similar solvents, and mixtures thereof, and then compressed into tablets.

9. The haizemab tablets according to any one of claims 1 to 8, comprising a haizemab solid dispersion containing haizemab and povidone.

10. A solid dispersion composition of zebumi, comprising zebumi and povidone.

11. A Hazemabu tablet comprising the Hazemabu solid dispersion composition of claim 10.

12. Use of the Hazemab solid dispersion composition according to claim 10 in the preparation of Hazemab solid dosage forms.

13. The use according to claim 12, wherein the solid dosage form is selected from tablets, capsules, granules, and powders.

14. A method for preparing the Haizemib solid dispersion composition of claim 10, comprising the following steps: Dissolve Hezemib in an organic solvent containing povidone.

15. The preparation method according to claim 14 further includes pouring or spraying the obtained Haizemib solution into the excipients.

16. The preparation method according to claim 14 or 15, wherein the organic solvent is selected from ethanol, isopropanol, and mixtures thereof with water.

17. A method for preparing the Haizemabu tablets according to claim 8, comprising the following steps: (1) Mix Haizemab with lactose, microcrystalline cellulose, sodium dodecyl sulfate and croscarmellose sodium evenly; (2) Dissolve povidone in water; (3) Add the povidone solution from step (2) to the mixture from step (1) for granulation, drying, and granulation; (4) Mix the granules after granulation in step (3) with magnesium stearate evenly and compress into tablets.

18. The method for preparing Hazelmab tablets according to claim 17, wherein the Hazelmab used in the preparation process is Hazelmab crystal form I.

19. The method for preparing Haizemab tablets according to claim 17, wherein the particle size range of Haizemab used in the preparation process is 1μm≤D90≤100μm, preferably 1μm≤D90≤50μm.

20. A method for preparing the Haizemabu sheet according to claim 8 or 9, comprising the following steps: (1) Mix lactose, microcrystalline cellulose, sodium lauryl sulfate and crospovidone evenly, or mix lactose, microcrystalline cellulose and crospovidone evenly; (2) Dissolve Hazemab, Povidone, and Butylated Hydroxytoluene in an alcohol solvent, or dissolve Hazemab and Povidone in an alcohol solvent; (3) Add the solution obtained in step (2) to the mixture obtained in step (1) for granulation, drying and granulation; (4) Mix the granules obtained in step (3) with magnesium stearate evenly and compress into tablets.

21. The method for preparing Haizemab tablets according to claim 20, wherein the alcohol solvent for dissolving Haizemab in the preparation method is an aqueous ethanol solution, preferably, the concentration of the aqueous ethanol solution is ≥60% (w / w), more preferably, the concentration of the aqueous ethanol solution is ≥75% (w / w), and most preferably, the concentration of the aqueous ethanol solution is 80-90% (w / w); the amount of the ethanol solution used is 30%~50% (w / w) of the prescription amount, more preferably, 35%~45% (w / w) of the prescription amount.

22. The method for preparing Haizemabu tablets according to claim 20 or 21, characterized in that, In the preparation method, the weight ratio of zebufen to povidone ranges from 10:1 to 1:1; more preferably, the weight ratio ranges from 5:1 to 5:

3.

23. The method for preparing Haizemabu tablets according to claim 20, characterized in that, The granulation methods in the preparation process include high-speed stirring granulation or fluidized bed granulation.

24. The method for preparing Haizemabu tablets according to claim 20, characterized in that, The preparation method used to prepare Haizemab tablets has more than 90% of Haizemab existing in an amorphous form.

25. Haizemabu tablets prepared by the method according to any one of claims 17 to 24.

26. The haizemab tablets according to any one of claims 1-9 and 25, wherein each drug dosage unit contains 5-20 mg of haizemab.

27. The zebucil tablets according to claim 26, wherein each drug dosage unit contains a dose of zebucil of 5 mg, 10 mg, or 20 mg.

28. The Haizemab tablets according to claim 26 or 27, wherein each drug dose unit contains 20-250 mg of lactose, 20-200 mg of microcrystalline cellulose, 1-10 mg of croscarmellose sodium or 5-30 mg of croscarmellose, 1-15 mg of povidone K30, 0-0.2 mg of butylated hydroxytoluene, 0-15 mg of sodium dodecyl sulfate, and 0.5-10 mg of magnesium stearate.

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