Nanocrystalline particle of pyridazine derivative, composition and preparation method of nanocrystalline particle

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to a nanocrystal suspension, nanocrystal dry particles and nanocrystal composition of pyridazine derivatives and a preparation method of the nanocrystal suspension, the nanocrystal dry particles and the nanocrystal composition. The pyridazine derivative nanocrystal obtained by selecting a proper formula, especially a proper stabilizer and disintegrating agent formula is small in particle size and good in stability, the bioavailability of the compound (I) can be remarkably improved, and the stable clinical composition can be obtained after the obtained nanocrystal suspension is subjected to fluidized bed granulation, so that the pyridazine derivative nanocrystal is suitable for clinical application. The bioavailability is high, and the clinical use is convenient.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical preparations, and in particular to a nanocrystalline suspension, nanocrystalline dry particles, a nanocrystalline composition of a pyridazine derivative and a preparation method thereof. Background Art

[0002] Extracellular 5'-nucleotidase (ecto-5'-nucleotidase, CD73) is a glycoprotein on the cell membrane, which exists on the cell membrane surface of various cell types, including endothelial cells, lymphocytes, stromal cells and tumor cells. CD73 can catalyze extracellular 5'-adenosine phosphate (5'-AMP) to produce adenosine, which can induce immunosuppressive effects and promote tumor proliferation and / or metastasis. In addition, CD73 can also promote tumor formation by non-immune related mechanisms, such as promoting tumor angiogenesis and promoting the adhesion of tumor cells to extracellular matrix proteins. Clinically, high levels of CD73 expression are associated with lymph node metastasis and poor prognosis in various types of cancer. CD73 has been found to be an independent prognostic factor for patients with prostate cancer and triple-negative breast cancer.

[0003] Compound (I) (5-(6-chloro-5-((1S, 2S)-2-phenylcyclopropyl) pyridazin-3-yl) pyrimidine-2,4(1H, 3H)-dione) is a small molecule CD73 inhibitor with a novel structure developed by the Company, which has a significant inhibitory effect on CD73;

[0004]

[0005] The solubility of compound (I) in pure water and pH 1.0-6.8 aqueous solution is very low, both less than 5 μg / mL, which greatly limits the oral absorption of the compound. By examining the dissolution of the compound in different latent solvents, surfactants, lipid excipients and different pH media, it was found that its solubility was not high, and it was impossible to obtain a solution with a concentration of more than 15 mg / mL by the commonly used solubilization means. It was also found in rats that when the dose exceeded 150 mg / kg, that is, the concentration of the preparation exceeded 15 mg / mL, the oral exposure of the compound basically no longer increased, and oral absorption reached saturation. On the one hand, the exposure of the compound in the body is not high enough, and the toxic and side effects of the compound cannot be well demonstrated in non-clinical studies. On the other hand, it can be expected that the compound cannot reach a sufficiently high blood drug concentration and exposure in clinical studies, which restricts its efficacy. There will be problems such as large dosage and frequent administration in clinical use. Summary of the invention

[0006] In order to solve the problems of low solubility, poor stability and low bioavailability of compound (I) in different common preparations, the present invention provides a nanocrystalline suspension, nanocrystalline dry particles, a nanocrystalline composition of a pyridazine derivative and a preparation method thereof.

[0007] In one aspect, the present invention provides a nanocrystalline suspension of a pyridazine derivative, comprising the following components based on total weight:

[0008]

[0009] Preferably, based on the total weight percentage, the following components are included:

[0010]

[0011] In some embodiments of the present invention, the wetting agent is selected from a combination of one or more of polysorbate 20, polysorbate 80, sodium lauryl sulfate, poloxamer 188, poloxamer 407, and docusate sodium, preferably docusate sodium.

[0012] In some embodiments of the present invention, the stabilizer 1 is selected from celluloses, such as hydroxymethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl carboxymethyl cellulose, sodium carboxymethyl cellulose; gums, such as gum arabic, tragacanth, peach gum; sugars, such as glucose, fructose, sucrose; sodium alginate; povidone; poloxamer (polyoxyethylene and polyoxypropylene block copolymer), such as one or more combinations of poloxamer-188, poloxamer-237, poloxamer-407; preferably hydroxypropyl cellulose or hypromellose.

[0013] In some embodiments of the present invention, the solvent is purified water.

[0014] A method for preparing a nanocrystalline suspension of a pyridazine derivative comprises the following steps:

[0015] 1) adding a wetting agent and a stabilizer 1 to a prescribed amount of solvent, stirring to dissolve, and then adding compound (I), stirring to disperse uniformly;

[0016] 2) Add the above dispersion system into a grinder for cyclic grinding to make the D90 particle size of compound (I) less than or equal to 700 nm.

[0017] In some embodiments of the present invention, the D90 particle size of compound (I) after grinding is less than or equal to 500 nm, preferably less than or equal to 350 nm.

[0018] In one aspect, the present invention provides a nanocrystalline dry particle of a pyridazine derivative, comprising the following components based on total weight:

[0019] Nanocrystal suspension 50%-80%

[0020] Stabilizer 2 10%-20%

[0021] Carrier 10%-30%

[0022] Preferably, based on the total weight percentage, the following components are included:

[0023] Nanocrystal suspension 60%-75%

[0024] Stabilizer 2 12%-16%

[0025] Carrier 10%-28%

[0026] Further preferably, based on the total weight percentage, the following components are included:

[0027] Nanocrystal suspension 60%-70.5%

[0028] Stabilizer 2 12.5%-14.1%

[0029] Carrier 15.4%-26.5%

[0030] In some embodiments of the present invention, the stabilizer 2 is selected from a combination of one or more of sucrose, glucose, fructose, trehalose, sorbitol, mannitol, and lactose; preferably sucrose.

[0031] In some embodiments of the present invention, the carrier is selected from a combination of one or more of sucrose, glucose, fructose, trehalose, sorbitol, mannitol, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, and pregelatinized starch; preferably lactose.

[0032] A method for preparing nanocrystalline dry particles of pyridazine derivatives comprises the following steps:

[0033] 1) adding stabilizer 2 to the nanocrystal suspension and stirring to dissolve;

[0034] 2) placing the carrier into the fluidized bed pot and preheating it;

[0035] 3) After preheating, the nanocrystalline suspension to which the stabilizer 2 is added in step 1) is sprayed onto the surface of the fluidized carrier in step 2) by atomization for granulation; the inlet air temperature, product temperature, spray flow rate, atomization pressure and inlet air volume are controlled to ensure a good fluidization state of the material;

[0036] 4) After spraying, dry, crush and sieve.

[0037] In another aspect, the present invention provides a nanocrystalline composition of a pyridazine derivative, comprising the following components based on total weight:

[0038]

[0039] Preferably, based on the total weight percentage, the following components are included:

[0040]

[0041] Further preferably, based on the total weight percentage, the following components are included:

[0042]

[0043] Optionally, a coating agent may be added to the nanocrystalline composition, and the weight ratio of the coating agent to the weight of the nanocrystalline composition is 0-4%.

[0044] In some embodiments of the present invention, the diluent is selected from a combination of one or more of pregelatinized starch, sucrose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, mannitol, sorbitol, and anhydrous calcium hydrogen phosphate; preferably silicified microcrystalline cellulose.

[0045] In some embodiments of the present invention, the disintegrant is selected from a combination of one or more of crospovidone, starch, sodium carboxymethyl starch, croscarboxymethyl cellulose sodium, and low-substituted hydroxypropyl cellulose; preferably sodium carboxymethyl starch;

[0046] In some embodiments of the present invention, the lubricant is selected from a combination of one or more of magnesium stearate, sodium stearyl fumarate, talc, stearic acid, zinc stearate, and poloxamer; preferably magnesium stearate.

[0047] In some embodiments of the present invention, the coating agent is selected from a combination of one or more of syrup, glue, talc, white wax, hydroxypropyl methylcellulose HPMC, hydroxypropyl cellulose HPC, acrylic resin No. 4, polyvinyl pyrrolidone PVP, polyvinyl alcohol, carboxymethyl cellulose, ethyl cellulose, polyvinyl acetal diethylaminoacetic acid, shellac, cellolacetate CAP, acrylic resin No. 123, hydroxypropyl methylcellulose phthalate HPMCP or polyvinyl alcohol phthalate PVAP; preferably hydroxypropyl methylcellulose HPMC or polyvinyl alcohol.

[0048] The coating agent in the present invention can be selectively added according to different dosage forms. When the addition ratio of the coating agent is 0%, it means that no coating agent is added.

[0049] A method for preparing a nanocrystalline composition of a pyridazine derivative comprises the following steps:

[0050] a) mixing the nanocrystalline dry particles obtained above with a diluent, a disintegrant and a lubricant;

[0051] b) tableting or capsule filling the mixed materials;

[0052] c) Optionally, the obtained plain tablets are coated.

[0053] The present invention selects a suitable formula, especially a suitable stabilizer and disintegrant formula, so that the obtained pyridazine derivative nanocrystals have a small particle size and good stability, and can significantly improve the bioavailability of compound (I). The obtained nanocrystal suspension can be granulated in a fluidized bed to obtain a stable clinically applicable composition, which has high bioavailability and is convenient for clinical use.

[0054] The specifications of existing nanocrystalline oral solid preparations on the market are generally low. This is because high specifications require a higher proportion of raw materials and stabilizer dosage. After the proportion of raw materials increases, the nanocrystalline particles may aggregate after tableting and thus fail to maintain the nano state. As the dosage of raw materials and stabilizers increases at the same time, the size of the tablet will also increase, making it difficult for patients to swallow. The oral nanocrystalline solid preparation obtained by the present invention has a specification of up to 200 mg, can still maintain the nanoparticle size after disintegration, has a high bioavailability, and the tablet weight does not exceed 1g, which is convenient for clinical use.

[0055] As used herein, the term "particulate" refers to a state of matter characterized by the presence of discrete particles, pellets, beads or agglomerates, regardless of size, shape or morphology.

[0056] The term "nanoparticle" as used herein refers to particles having a size (ie, diameter in the longest dimension of the particle) in the nanometer range, such as particles having a size of less than 1,000 nm, less than 500 nm, less than 350 nm.

[0057] The term "nanocomposition" as used in the present invention refers to a composition comprising nanoparticles as defined above.

[0058] The term "nanocrystal" used in the present invention has the same meaning as the term "nanoparticle" and can be used interchangeably, emphasizing the "nano" state rather than the "crystalline" form, and does not exclude non-crystalline forms such as amorphous states.

[0059] The term "stabilizer" used in the present invention refers to a substance that can maintain or enhance the stability of the composition. The stabilizer described in the present invention includes a steric stabilizer and a charge stabilizer.

[0060] The term "steric stabilizer" used in the present invention refers to a substance that can be effectively adsorbed to the surface of particles in a dispersed system and can force the particles to separate through the steric hindrance effect when the particles contact each other. The steric stabilizer described in the present invention includes but is not limited to: celluloses, such as hydroxymethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl carboxymethyl cellulose, sodium carboxymethyl cellulose; gums, such as gum arabic, tragacanth gum, peach gum; sugars, such as glucose, fructose, sucrose, trehalose; sodium alginate; povidone; sorbitol, mannitol; poloxamer (polyoxyethylene and polyoxypropylene block copolymer), such as poloxamer-188, poloxamer-237, poloxamer-407.

[0061] The term "charge stabilizer" used in the present invention refers to a substance that can effectively adsorb to the surface of particles in a dispersed system and force the particles to separate by electrostatic repulsion when the particles contact each other. The charge stabilizer described in the present invention includes but is not limited to: sodium lauryl sulfate, sodium docusate, arginine salts, etc.

[0062] The "wetting agent" used in the present invention is also called a surfactant, and includes, but is not limited to, compounds such as sodium lauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, dioctyl sulfosuccinate, gelatin, casein, lecithin (phospholipid), dextran, gum arabic, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetearyl alcohol, cetostearyl emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol, polyoxyethylene stearate, colloidal silicon dioxide, phosphates, carboxymethyl cellulose. Calcium sulfate, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose phthalate, non-crystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), poloxamer 188, poloxamer 407, poloxamine PEG-phospholipids, PEG-cholesterol, PEG-cholesterol derivatives, polyethylene glycol-vitamin A, polyethylene glycol-vitamin E, lysozyme, etc.

[0063] The "carrier" used in the present invention generally refers to a non-toxic inert solid filler, diluent, encapsulating material or any type of formulation auxiliary agent, including but not limited to sugars, such as lactose, glucose, fructose, trehalose; starch, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; mannitol; talc, etc.

[0064] The term "diluent" used in the present invention refers to a diluent used to dilute or carry the active ingredient of the composition. Suitable diluents include any substance that can reduce the viscosity of the pharmaceutical preparation and increase the feasibility of the preparation production, including but not limited to pregelatinized starch, sucrose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, mannitol, sorbitol, anhydrous calcium hydrogen phosphate, etc.

[0065] The term "disintegrant" used in the present invention is used to promote the disintegration of the preparation prepared by the composition when it comes into contact with an aqueous medium, including but not limited to cross-linked polyvinyl cellulose (LHPC), cross-linked polyvinyl pyrrolidone (PVPP), Amberlite IRP-88, sodium carboxymethyl cellulose (CMC-Na), cross-linked sodium carboxymethyl cellulose (cCMC-Na), calcium carboxymethyl cellulose or microcrystalline cellulose (MCC), etc.

[0066] The term "lubricant" used in the present invention refers to an agent or agent mixture that improves the fluidity of a powder mixture to reduce or prevent friction. Including but not limited to talc, calcium stearate, magnesium stearate, solid polyethylene glycol, tristearin, glyceryl behenate, sodium lauryl sulfate, silicon dioxide, stearic acid, sodium stearyl fumarate, oleic acid, potassium tripalmitoleate, caprylic acid, glyceryl palmitostearyl sodium benzoate, zinc stearate, zinc oleate, zinc palmitate or a mixture thereof.

[0067] The term "coating agent" used in the present invention includes sugar coating, film coating, enteric coating or sustained-release coating, controlled-release coating materials, etc., including but not limited to syrup, glue, talc, white wax, hydroxypropyl methylcellulose HPMC, hydroxypropyl cellulose HPC, acrylic resin No. 4, polyvinyl pyrrolidone PVP, polyvinyl acetal diethylaminoacetic acid, shellac, cellulose acetate CAP, acrylic resin No. 123, hydroxypropyl methylcellulose phthalate HPMCP, polyvinyl alcohol phthalate PVAP, etc.

[0068] The term "suspension" used in the present invention refers to a liquid dispersion system in which a poorly soluble solid is dispersed in a liquid dispersion medium in the form of fine particles.

[0069] The term "nanocrystalline suspension" as used in the present invention refers to a suspension comprising nanoparticles as defined above.

[0070] The term "dispersed system" used in the present invention refers to a system formed by dispersing one or more substances in another substance.

[0071] The term "dispersion medium" used in the present invention refers to a substance that disperses other substances in a dispersion system. The dispersion medium described in the present invention includes, but is not limited to: aqueous media, such as water, sucrose aqueous solution, phosphate buffer solution; organic media, such as ethanol, vegetable oil (such as peanut oil), Tween 80, etc.

[0072] The term "particle size" or "equivalent particle size" used in the present invention means that when a certain physical property or physical behavior of the measured particle is closest to a homogeneous sphere (or combination) of a certain diameter, the diameter (or combination) of the sphere is taken as the equivalent particle size (or particle size distribution) of the measured particle.

[0073] The terms "D10, D50 and D90" refer to the particle sizes corresponding to the cumulative particle size distribution of the sample when the number reaches 10%, 50% and 90%. Its physical meaning is that the particles with a particle size smaller than it account for 10%, 50% and 90%.

[0074] The term "room temperature" used in the present invention refers to 25±5°C.

[0075] The term "stable" used in the present invention means that over time, the particles of the pyridazine derivatives do not undergo significant flocculation or agglomeration due to the attraction between the particles, and / or the particle size significantly increases. The "significant flocculation or agglomeration" refers to flocculation or agglomeration visible to the naked eye, and the "significant increase in particle size" refers to an increase in particle size of more than 50% when left at room temperature for no longer than seven days. BRIEF DESCRIPTION OF THE DRAWINGS

[0076] Figure 1 The effect of hardness of nanochips with different formulations on disintegration time. DETAILED DESCRIPTION

[0077] The present invention is described below with reference to specific examples. It will be appreciated by those skilled in the art that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention in any way.

[0078] Example 1: Preparation of Nanocrystalline Suspension of Compound (I)

[0079] Table 1 Prescription composition of nanocrystalline suspension of sample 1-11 compound (I)

[0080]

[0081] The preparation methods of samples 1 to 11 are as follows:

[0082] 1) Weigh docusate sodium according to the prescription, then weigh hydroxypropyl cellulose or hypromellose or povidone or poloxamer, add them into purified water, and stir to dissolve;

[0083] 2) Weighing compound (I) and slowly adding it into the above solution while stirring and dispersing continuously;

[0084] 3) Select 0.3 mm zirconium oxide beads, the amount of zirconium oxide beads is 65% of the volume of the grinding chamber, and cyclically grind the above samples 1-11 respectively, at a grinding speed of 3500 rpm until the D90 particle size is less than 350 nm, or when the D90 particle size of the sample cannot meet the requirement of less than 350 nm, grind until the particle size no longer decreases, to obtain nanocrystalline suspension samples 1-11 containing compound (I).

[0085] The particle sizes of the nanocrystalline suspension samples 1-11 were detected at 0 day and after being placed at room temperature for 14 days or 22 days. The particle size detection method: the instrument parameters of the Malvern laser particle size analyzer are shown in Table 2. The particle size stability of the nanocrystalline suspension samples 1-11 is shown in Table 3.

[0086] Table 2 Nanocrystal suspension particle size detection parameters

[0087]

[0088] Table 3 Particle size stability of nanocrystalline suspension samples 1-11

[0089]

[0090]

[0091] The results show that the preparation method of the nanocrystalline suspension of the present invention is simple, and the nanocrystalline suspension obtained by using hydroxypropyl cellulose or hydroxypropyl methyl cellulose as stabilizer 1 has a smaller particle size and good stability.

[0092] Example 2: Preparation of Nanocrystalline Dry Particles of Compound (I)

[0093] Table 4 Formula composition of compound (I) nanocrystalline dry granules and particle size after resuspension

[0094]

[0095] "Total amount*" refers to the theoretical total amount of dry particles. Purified water is removed during the drying process and is not included in the total amount.

[0096] Preparation method of sample 12-sample 14:

[0097] a. A nanocrystalline suspension of compound (I) was prepared according to the preparation method of sample 1-11;

[0098] b. Add the prescribed amount of sucrose to the nanocrystal suspension and stir to dissolve. At the same time, put lactose into the fluidized bed pot and set the air inlet temperature to 72°C and the air volume to 15m 3 / h, capture bag: oscillation frequency 2 times / s, oscillation duration 5s, oscillation interval 120s for preheating;

[0099] c. After the product temperature rises to 45°C, the nanocrystal suspension is sprayed for granulation, and the product temperature is controlled at 41°C (37-50°C). The spray flow rate and air intake volume increase slowly with the increase of granulation time;

[0100] d. After the spraying is completed, adjust the inlet air temperature to 50℃ and the air volume to 20m 3 / h for drying until the moisture content is ≤2.0%. After drying, the material is crushed and sieved once, the sieve aperture is 1.14mm, and the granulator speed is 500±100rpm, so as to obtain nanocrystalline dry particles.

[0101] The nanocrystal dry particles were resuspended in water and the particle size was detected according to the method in Table 2, and the results are shown in Table 4. The particle sizes of samples 12-14 after resuspension were all less than 350 nm, indicating that with lactose as a carrier and sucrose as a stabilizer 2, the nanocrystals would not aggregate during the drying process and could still maintain the nanometer size after being dispersed in water.

[0102] Example 3: Preparation of Compound (I) Nanocrystalline Chips

[0103] Table 5 Prescription of Compound (I) Nanocrystal Pharmaceutical Composition

[0104]

[0105] “Total amount*” refers to the theoretical total amount of the nanocrystalline pharmaceutical composition. Purified water is removed during the fluidized bed granulation process and is not included in the total amount.

[0106] Preparation method of samples 15-19:

[0107] a. Prepare a nanocrystalline suspension of compound (I) according to the method of sample 1-11;

[0108] b. Prepare nanocrystalline dry particles according to the method of samples 12-14;

[0109] c. The obtained dry granules were added to a laboratory hopper mixer, and then the prescribed amount of silicified microcrystalline cellulose and / or sodium carboxymethyl starch was added in sequence for mixing at a speed of 15 rpm for 20 min;

[0110] d. Add magnesium stearate that has passed through a 40-mesh sieve into the mixer hopper for total mixing at a speed of 15 rpm for 5 min; g. Use a 18.7×8.7 mm capsule-shaped punch die for tableting at a tablet press speed of 20-40 rpm.

[0111] The stability of the compound (I) nanocrystalline wafer obtained from sample 19 is shown in Table 6. The related substances and isomers were detected by high performance liquid chromatography, the particle size of the nanocrystalline wafer after resuspension was detected by Malvern 3000 laser particle size analyzer, and the dissolution was detected using the following parameters: dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Four General Rules 0931 Second Method) n = 6, 900 ml of 0.1 mol / L hydrochloric acid solution containing 1% sodium dodecyl sulfate was used as the dissolution medium, the speed was 75 rpm, sampling was performed for 45 min, and the dissolution was detected by high performance liquid chromatography.

[0112] Table 6 Stability study of compound (I) nanocrystal composition

[0113]

[0114] The results show that the related substances, particle size and solubility of the nanocrystalline composition of the present invention remain stable.

[0115] Example 4: Study on the effect of different prescriptions on disintegration time

[0116] The effect of hardness on disintegration time of nanocrystalline chips prepared by recipes of sample 18 and sample 19 is shown in Figure 1 , Experimental method: Nano wafer tablets with different hardness were prepared according to the prescription and preparation method described in Sample 18 and Sample 19, and the disintegration time was investigated according to the disintegration time test method of Part 4 0921 of the 2020 edition of the Chinese Pharmacopoeia. The results showed that when 15% sodium carboxymethyl starch was used as a disintegrant, the hardness of the nano wafer tablet did not affect its disintegration time, and tablets of different hardness were expected to obtain similar dissolution curves.

[0117] Example 5: Study on the oral bioavailability of compound (I) and its nanocrystalline suspension and nanocrystalline tablets in animals

[0118] Experimental method: Beagle dogs were used as experimental animals, and sample 2 and sample 15 were orally administered, respectively. After administration, blood was collected for LC-MS / MS detection of drug concentration.

[0119] The control group was a common preparation. The solution for intravenous injection was 2% dimethyl sulfoxide + 98% aqueous solution containing 20% ​​hydroxypropyl β-cyclodextrin, and the suspension for oral administration was 20% polyethylene glycol 300 + 10% Solutol HS15 + 70% aqueous solution containing 0.5% CMC-Na and 0.5% sodium lauryl sulfate.

[0120] The results are shown in Table 7.

[0121] Table 7 Oral bioavailability of compound (I) and its nanocrystalline suspension and nanocrystalline tablets in animals

[0122]

[0123] The conclusion shows that the bioavailability of the nanocrystalline suspension of sample 2 and the nanocrystalline tablet of sample 15 of the present invention is more than 3 times higher than that of ordinary tablets, and can achieve oral administration of compound (I).

[0124] Example 6: Oral bioavailability study of nanocrystalline wafers with different formulations in animals

[0125] Experimental method: Beagle dogs were used as test animals. Samples 15 to 19 were orally administered. Blood was taken after administration to detect changes in drug concentration within 24 hours, and the bioavailability was calculated. The results are shown in Table 8.

[0126] Table 8 Oral bioavailability of sample 15-19 compound (I) nanochips

[0127] parameter Sample 15 Sample 16 Sample 17 Sample 18 Sample 19 Dosage (mg / kg) 300 500 500 500 500 Cmax(ng / ml) 3415 580 6000 4340 5108 AUClast(h*ng / mL) 13143 2183 23718 21669 25478 Fa(%) 9.2 0.9 10.0 9.1 10.8

[0128] The conclusion shows that: from the results of samples 15, 17, 18 and 19, it can be seen that the changes in the dosage of lactose, sodium carboxymethyl starch and silicified microcrystalline cellulose have no significant effect on the oral bioavailability of compound (I). From the results of samples 15 and 16, it can be seen that the type of disintegrant has a greater impact on the oral bioavailability of the nanocrystalline composition.

[0129] Implementation

[0130] The following clauses describe specific embodiments of the invention.

[0131] 1. A nanocrystalline suspension of a pyridazine derivative, characterized in that, based on the total weight percentage, the nanocrystalline suspension comprises the following components:

[0132]

[0133] Wherein, the structure of compound (I) is:

[0134]

[0135] 2. A nanocrystalline suspension of a pyridazine derivative according to Embodiment 1, characterized in that, based on the total weight percentage, the nanocrystalline suspension comprises the following components:

[0136]

[0137] 3. A nanocrystalline suspension of a pyridazine derivative according to embodiment 1 or 2, characterized in that the wetting agent is selected from a combination of one or more of polysorbate 20, polysorbate 80, sodium lauryl sulfate, poloxamer 188, poloxamer 407, and docusate sodium; preferably docusate sodium.

[0138] 4. A nanocrystalline suspension of a pyridazine derivative according to any one of embodiments 1-3, characterized in that the stabilizer 1 is selected from celluloses, such as hydroxymethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl carboxymethyl cellulose, sodium carboxymethyl cellulose; gums, such as gum arabic, tragacanth gum, peach gum; sugars, such as glucose, fructose, sucrose; sodium alginate; povidone; poloxamer (polyoxyethylene and polyoxypropylene block copolymer), such as a combination of one or more of poloxamer-188, poloxamer-237, and poloxamer-407; preferably hydroxypropyl cellulose or hypromellose.

[0139] 5. A nanocrystalline suspension of a pyridazine derivative according to any one of embodiments 1-4, characterized in that the solvent is purified water.

[0140] 6. A method for preparing a nanocrystalline suspension of a pyridazine derivative according to any one of embodiments 1 to 5, characterized in that it comprises the following steps:

[0141] 1) adding a wetting agent and a stabilizer 1 to a prescribed amount of solvent, stirring to dissolve, and then adding compound (I), stirring to disperse uniformly;

[0142] 2) Add the above dispersion system into a grinder for cyclic grinding to make the D90 particle size of compound (I) less than or equal to 700 nm.

[0143] 7. A method for preparing a nanocrystalline suspension of a pyridazine derivative according to Embodiment 6, characterized in that the D90 particle size of compound (I) after grinding in step 2) is less than or equal to 500 nm; preferably less than or equal to 350 nm.

[0144] 8. A nanocrystalline dry particle of a pyridazine derivative, characterized in that, based on the total weight percentage, the nanocrystalline dry particle comprises the following components:

[0145] 50%-80% of the nanocrystal suspension described in any one of embodiments 1-5

[0146] Stabilizer 2 10%-20%

[0147] Carrier 10%-30%.

[0149] 9. A nanocrystalline dry particle of a pyridazine derivative according to Embodiment 8, characterized in that, based on the total weight percentage, the nanocrystalline dry particle comprises the following components:

[0150] 65%-75% of the nanocrystal suspension described in any one of embodiments 1-5

[0151] Stabilizer 2 12%-16%

[0152] Carrier 10%-28%.

[0154] 10. A nanocrystalline dry particle of a pyridazine derivative according to embodiment 8 or 9, characterized in that, based on the total weight percentage, the nanocrystalline dry particle comprises the following components:

[0155] 60%-70.5% of the nanocrystal suspension described in any one of embodiments 1-5

[0156] Stabilizer 2 12.5%-14.1%

[0157] Carrier 15.4%-26.5%.

[0159] 11. A nanocrystalline dry particle of a pyridazine derivative according to any one of embodiments 8-10, characterized in that the stabilizer 2 is selected from a combination of one or more of sucrose, glucose, fructose, trehalose, sorbitol, mannitol, and lactose; preferably sucrose.

[0160] 12. A nanocrystalline dry particle of a pyridazine derivative according to any one of embodiments 8-11, characterized in that the carrier is selected from a combination of one or more of sucrose, glucose, fructose, trehalose, sorbitol, mannitol, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, and pregelatinized starch; preferably lactose.

[0161] 13. A method for preparing nanocrystalline dry particles of pyridazine derivatives according to any one of embodiments 8 to 12, characterized in that it comprises the following steps:

[0162] 1) adding stabilizer 2 to the nanocrystal suspension according to any one of embodiments 1 to 5 and stirring to dissolve;

[0163] 2) placing the carrier into the fluidized bed pot and preheating it;

[0164] 3) after preheating, the nanocrystalline suspension to which the stabilizer 2 is added in step 1) is sprayed onto the surface of the fluidized carrier in step 2) by atomization for granulation;

[0165] 4) After spraying, dry, crush and sieve.

[0166] 14. A nanocrystalline composition of a pyridazine derivative, characterized in that, based on the total weight percentage, the nanocrystalline composition comprises the following components:

[0167]

[0168] 15. A nanocrystalline composition of a pyridazine derivative according to embodiment 14, characterized in that, based on the total weight percentage, the nanocrystalline composition comprises the following components:

[0169]

[0170] 16. A nanocrystalline composition of a pyridazine derivative according to embodiment 14 or 15, characterized in that, based on the total weight percentage, the nanocrystalline composition comprises the following components:

[0171]

[0172] 17. A nanocrystalline composition of a pyridazine derivative according to any one of embodiments 14-16, characterized in that a coating agent can be optionally added to the nanocrystalline composition, and the weight ratio of the coating agent to the weight of the nanocrystalline composition is 0-4%.

[0173] 18. A nanocrystalline composition of a pyridazine derivative according to any one of embodiments 14-17, characterized in that the diluent is selected from a combination of one or more of pregelatinized starch, sucrose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, mannitol, sorbitol, and anhydrous calcium hydrogen phosphate; preferably silicified microcrystalline cellulose.

[0174] 19. A nanocrystalline composition of a pyridazine derivative according to any one of embodiments 14-18, characterized in that the disintegrant is selected from a combination of one or more of cross-linked polyvinylpyrrolidone, starch, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; preferably sodium carboxymethyl starch.

[0175] 20. A nanocrystalline composition of a pyridazine derivative according to any one of embodiments 14-19, characterized in that the lubricant is selected from a combination of one or more of magnesium stearate, sodium stearyl fumarate, talc, stearic acid, zinc stearate, and poloxamer; preferably magnesium stearate.

[0176] 21. A nanocrystalline composition of a pyridazine derivative according to Embodiment 17, characterized in that the coating agent is selected from a combination of one or more of syrup, glue, talc, wax, hydroxypropyl methylcellulose HPMC, hydroxypropyl cellulose HPC, acrylic resin No. 4, polyvinyl pyrrolidone PVP, polyvinyl alcohol, carboxymethyl cellulose, ethyl cellulose, polyvinyl acetal diethylaminoacetic acid, shellac, cellolacetate CAP, acrylic resin No. 123, hydroxypropyl methylcellulose phthalate HPMCP or polyvinyl alcohol phthalate PVAP; preferably hydroxypropyl methylcellulose HPMC or polyvinyl alcohol.

[0177] 22. A method for preparing a nanocrystalline composition of a pyridazine derivative according to any one of embodiments 14 to 21, characterized in that it comprises the following steps:

[0178] a) mixing the nanocrystalline dry particles according to any one of embodiments 8 to 12 with a diluent, a disintegrant and a lubricant;

[0179] b) tableting or capsule filling the mixed materials;

[0180] c) Optionally, the obtained plain tablets are coated.

Claims

1. A nanocrystalline suspension of a pyridazine derivative, characterized in that: Based on the total weight percentage, the nanocrystal suspension includes the following components: Wherein, the structure of compound (I) is:

2. The nanocrystalline suspension of a pyridazine derivative according to claim 1, characterized in that: Based on the total weight percentage, the nanocrystal suspension includes the following components:

3. A nanocrystalline suspension of a pyridazine derivative according to claim 1 or 2, characterized in that: The wetting agent is selected from one or more combinations of polysorbate 20, polysorbate 80, sodium lauryl sulfate, poloxamer 188, poloxamer 407, and docusate sodium; preferably docusate sodium.

4. A nanocrystalline suspension of a pyridazine derivative according to any one of claims 1 to 3, characterized in that: The stabilizer 1 is selected from celluloses, such as hydroxymethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, hydroxypropyl carboxymethyl cellulose, sodium carboxymethyl cellulose; gums, such as gum arabic, gum tragacanth, peach gum; sugars, such as glucose, fructose, sucrose; sodium alginate; povidone; poloxamer (polyoxyethylene and polyoxypropylene block copolymer), such as one or more combinations of poloxamer-188, poloxamer-237, poloxamer-407; preferably hydroxypropyl cellulose or hypromellose.

5. A nanocrystalline suspension of a pyridazine derivative according to any one of claims 1 to 4, characterized in that: The solvent is purified water.

6. A method for preparing a nanocrystalline suspension of a pyridazine derivative according to any one of claims 1 to 5, characterized in that: The following steps are involved: 1) adding a wetting agent and a stabilizer 1 to a prescribed amount of solvent, stirring to dissolve, and then adding compound (I), stirring to disperse uniformly; 2) Add the above dispersion system into a grinder for cyclic grinding to make the D90 particle size of compound (I) less than or equal to 700 nm.

7. The method for preparing a nanocrystalline suspension of a pyridazine derivative according to claim 6, characterized in that: In the step 2), the D90 particle size of the compound (I) after grinding is less than or equal to 500 nm; preferably less than or equal to 350 nm.

8. A nanocrystalline dry particle of a pyridazine derivative, characterized in that: Based on the total weight percentage, the nanocrystalline dry particles include the following components: 50%-80% of the nanocrystal suspension according to any one of claims 1 to 5 Stabilizer 2 10%-20% Carrier 10%-30%.

9. The nanocrystalline dry particles of pyridazine derivatives according to claim 8, characterized in that: Based on the total weight percentage, the nanocrystalline dry particles include the following components: 65%-75% of the nanocrystal suspension according to any one of claims 1 to 5 Stabilizer 2 12%-16% Carrier 10%-28%.

10. The nanocrystalline dry particles of pyridazine derivatives according to claim 8 or 9, characterized in that: Based on the total weight percentage, the nanocrystalline dry particles include the following components: 60%-70.5% of the nanocrystal suspension according to any one of claims 1 to 5 Stabilizer 2 12.5%-14.1% Carrier 15.4%-26.5%.

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