Pharmaceutical composition and pharmaceutical preparation for treating IgA nephropathy and preparation method thereof

Abstract

The invention relates to the technical field of medicine preparation, and discloses a medicine composition and a medicine preparation for treating IgA nephropathy and a preparation method of the medicine composition and the medicine preparation. The pharmaceutical composition for treating the IgA nephropathy, provided by the invention, comprises ambrisentan and azilsartan, and has effects of enhancing effects and reducing toxicity on the treatment of the IgA nephropathy.

Description

Technical Field

[0001] The present application belongs to the technical field of drug preparation, and specifically relates to a drug composition and drug preparation for treating IgA nephropathy and a preparation method thereof. Background Art

[0002] IgA nephropathy (IgAN) was first described by Berger in 1968: a type of chronic kidney disease caused by glycosylation defects in human IgA immunoglobulin. This disease is a common primary glomerular disease worldwide, with diverse clinical and pathological manifestations and different clinical outcomes. It is often clinically manifested as proteinuria, hematuria, hypertension, and may be accompanied by renal insufficiency. IgA nephropathy can be diagnosed and pathologically graded by renal biopsy. According to the cause, IgA nephropathy can be divided into primary IgA nephropathy and secondary IgA nephropathy.

[0003] IgAN generally occurs in young and middle-aged people. According to statistics, more than 80% of confirmed patients are aged between 18 and 44 years old. IgAN often occurs after an upper respiratory tract infection or acute gastroenteritis, usually manifested as macroscopic hematuria or persistent microscopic hematuria. In addition, most IgAN patients also have varying degrees of proteinuria, edema, and hypertension. Most IgAN patients present with benign hematuria and lifelong stable renal function, but 20%-40% of patients still develop renal failure within 10 to 20 years after diagnosis and require dialysis or kidney transplantation. Compared with other types of glomerulonephritis, IgAN is more likely to develop into renal failure.

[0004] In the past, the treatment of IgAN was mainly empirical, focusing on so-called supportive treatment, which is a general measure to slow the progression of glomerular disease and nonspecific immunosuppression. These drugs usually have large toxic side effects due to their non-specificity, and there is still a lack of specific treatment for the pathogenesis of IgAN. With the continuous understanding of the autoimmune pathogenesis of IgAN, a variety of pharmacological treatment targets for IgAN have been discovered, and research on IgAN-specific treatment has become a new trend.

[0005] On February 17, 2023, the dual endothelin-angiotensin receptor antagonist Sparsentan (trade name FILSPARI) jointly developed by Travere / CSL was approved by the FDA for accelerated marketing for the treatment of IgAN. The IgAN treatment field has also ushered in the first non-immunosuppressive therapy. Sparsentan is the first single-molecule dual endothelin-angiotensin receptor antagonist that can selectively block two pathways related to the progression of IgA nephropathy: by blocking endothelin A receptors and angiotensin II receptors, it prevents glomerular sclerosis and mesangial cell growth, and reduces proteinuria production. The Phase III PROTECT study showed that after 36 weeks of sparsentan administration, patients' UPCR was reduced by 49.8%.

[0006] However, although sparsentan has excellent IgAN treatment effects, it also has major safety risks. For example, the FDA also added black box warnings for hepatotoxicity and embryo / fetal toxicity while accelerating its approval, and the dosage of sparsentan is relatively high, at 400 mg, which further increases its unsafety. As IgAN is a chronic disease, patients need to take medication for a long time, so the safety requirements for IgAN treatment drugs are obviously higher than those for staged use. Summary of the invention

[0007] The purpose of the present application is to provide a pharmaceutical composition and a pharmaceutical preparation for treating IgA nephropathy and a preparation method thereof, so as to solve the problem of poor safety of existing IgAN therapeutic drugs.

[0008] In order to achieve the above invention purpose, the technical solution adopted in this application is:

[0009] In a first aspect, the present application provides a pharmaceutical composition for treating IgA nephropathy, wherein the pharmaceutical composition comprises the following components in parts by weight:

[0010] 5-10 parts of Ambrisentan and 10-40 parts of Azilsartan.

[0011] In an optional embodiment, the pharmaceutical composition comprises the following components in parts by weight:

[0012] 5-10 parts of Ambrisentan and 20-40 parts of Azilsartan.

[0013] In a second aspect, the present application provides a pharmaceutical preparation for treating IgA nephropathy, wherein the pharmaceutical preparation comprises the above-mentioned pharmaceutical composition.

[0014] In an optional embodiment, the pharmaceutical preparation is a tablet, and the raw materials of the pharmaceutical preparation further include at least one of a filler, a disintegrant, a binder, a stabilizer, a lubricant and a coating material.

[0015] In an optional embodiment, in terms of weight percentage, the content of ambrisentan is 3.2% to 7.0%, the content of azilsartan is 6.4% to 27%, the content of the filler is 50% to 75%, the content of the disintegrant is 5% to 20%, the content of the binder is 1% to 5%, the content of the stabilizer is 1% to 5%, the content of the lubricant is 0.5 to 2.5%, and the content of the coating material is 2% to 6%.

[0016] In an optional embodiment, the filler includes at least one of lactose monohydrate, corn starch, microcrystalline cellulose, sucrose, mannitol and dextrin;

[0017] and / or, the disintegrant comprises at least one of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone and cross-linked polyvinyl pyrrolidone;

[0018] and / or, the binder comprises at least one of hydroxypropyl cellulose, hypromellose, sodium hydroxymethyl cellulose and povidone;

[0019] and / or, the stabilizer comprises at least one of polyethylene glycol, poloxamer and glyceryl monostearate;

[0020] and / or, the lubricant comprises at least one of magnesium stearate, talc and colloidal silicon dioxide;

[0021] And / or, the coating material comprises a film coating premix.

[0022] In a third aspect, the present application provides a method for preparing the above-mentioned pharmaceutical preparation, wherein the preparation method is a wet granulation method, comprising the following steps:

[0023] mixing a binder, a stabilizer and water to obtain a binder solution;

[0024] Adding filler, disintegrant, ambrisentan and azilsartan into a wet granulator, spraying the binder solution after mixing, granulating, and drying to obtain dry granules;

[0025] Granulating the dried particles to obtain granulated particles;

[0026] Mixing the sized particles with a lubricant to obtain mixed particles;

[0027] The total mixed granules are tableted and coated.

[0028] Specifically, wet granulation may include the following steps:

[0029] 1) Grinding: Grind the two APIs to a particle size D50 of less than 10 μm and D90 of 5 to 30 μm;

[0030] 2) Weighing: weigh the raw and auxiliary materials according to the input amount;

[0031] 3) Granulation:

[0032] ① Preparation of adhesive: Weigh an appropriate amount of purified water, add the adhesive and stabilizer into the purified water, and stir until completely dissolved;

[0033] ② Add the weighed filler, disintegrant and API into the wet granulator in sequence;

[0034] ③ Mixing, adding adhesive (spraying), granulating and unloading in sequence;

[0035] ④ Drying: Drying the wet granules;

[0036] 4) Granulation: The dried granules are transferred to a granulator for granulation;

[0037] 5) Total mixing: transfer the granules after granulation to the total mixing barrel, and add the prescribed amount of lubricant for total mixing;

[0038] 6) Tableting: According to the content of the intermediate product, the standard tablet weight is converted for tableting;

[0039] 7) Coating: Coat the plain tablets. When the coating weight gain reaches the target value, stop spraying, dry and air-dry the tablets.

[0040] In a fourth aspect, the present application provides another method for preparing the above-mentioned pharmaceutical preparation, wherein the preparation method is a powder direct compression method, comprising the following steps:

[0041] Mixing ambrisentan, azilsartan and a filler and sieving to obtain a first material;

[0042] Mixing the disintegrant, the binder and the stabilizer and sieving them to obtain a second material;

[0043] Mixing the first material and the second material, adding a lubricant and continuing to mix to obtain a total mixed material;

[0044] The total mixed material is tableted and coated.

[0045] Specifically, powder direct pressing may include the following steps:

[0046] 1) Grinding: Grind the two raw materials to make the particle size D50 ≥ 15 μm and D90 100-300 μm.

[0047] 2) Weighing: weigh the raw and auxiliary materials according to the input amount;

[0048] 3) Sieving: The filler and the two APIs are sieved and mixed as the first material, and the disintegrant, stabilizer and binder are sieved and mixed as the second material;

[0049] 4) Total mixing: Add the first material and the second material into the total mixer, set the parameters for mixing, and then add the lubricant after a certain period of time and mix for 5 minutes;

[0050] 5) Tableting: According to the content of the intermediate product, the standard tablet weight is converted for tableting;

[0051] 6) Coating: Coat the plain tablets. When the coating weight gain reaches the target value, stop spraying, dry and air-dry the tablets.

[0052] In a fifth aspect, the present application provides another method for preparing the above-mentioned pharmaceutical preparation, wherein the preparation method is a dry granulation method, comprising the following steps:

[0053] Mixing ambrisentan, azilsartan, a filler, a disintegrant, a stabilizer and a portion of a lubricant to obtain a mixed material;

[0054] Dry granulating the mixed material to obtain a granular material;

[0055] Mixing the granular material with the remaining amount of lubricant to obtain mixed granules;

[0056] The mixed granules are tableted and coated.

[0057] Specifically, dry granulation may include the following steps:

[0058] 1) Grind the two raw materials to make the particle size D50 less than 10 μm and D90 5 to 30 μm;

[0059] 2) Weighing: weigh the raw and auxiliary materials according to the input amount;

[0060] 3) Mixing: Put the two APIs, filler, disintegrant and part of lubricant into the mixer for mixing;

[0061] 4) Dry granulation: The mixed materials are transferred to a dry granulator to prepare granules;

[0062] 5) Mixing: put the granules and the remaining lubricant into a mixer and mix for 5 minutes;

[0063] 6) Tableting: According to the content of the intermediate product, the standard tablet weight is converted for tableting;

[0064] 7) Coating: Coat the plain tablets. When the coating weight gain reaches the target value, stop spraying, dry and air-dry the tablets.

[0065] In a sixth aspect, the present application provides the use of the above-mentioned pharmaceutical composition or pharmaceutical preparation in the preparation of a product for treating IgA nephropathy.

[0066] Based on the above technical solution, this application has at least the following beneficial effects:

[0067] (1) The pharmaceutical composition for treating IgA nephropathy provided in the present application comprises ambrisentan and azilsartan, which has the effect of enhancing efficacy and reducing toxicity in the treatment of IgA nephropathy.

[0068] Specifically, in the related art, the indications of ambrisentan and azilsartan are both hypertension, and their respective therapeutic doses are difficult to meet the optimal therapeutic dose for IgA nephropathy, so the therapeutic effect on IgA nephropathy is poor. In this application, ambrisentan and azilsartan are reused, which can treat IgA nephropathy through the dual action channels of angiotensin II and endothelin, and the two complement each other to achieve excellent therapeutic effects; at the same time, no serious toxic side effects were found after the combination of ambrisentan and azilsartan, which has a high drug safety, and has significant clinical advantages for IgA nephropathy patients who need long-term medication.

[0069] In addition, the present application multiplexes ambrisentan and azilsartan, and compared with single-molecule sparsentan, can optimize the drug's blocking effect on the dual-action channels of angiotensin II and endothelin by adjusting the ratio of the two, which is more flexible in terms of therapeutic medication and can also achieve better therapeutic effects.

[0070] (2) The pharmaceutical preparation for treating IgA nephropathy provided in the present application has no interaction between the excipients and raw materials involved, can be well formed and remain stable in vitro, and thus the pharmaceutical preparation is a stable, more effective and less toxic drug for treating IgA nephropathy. DETAILED DESCRIPTION

[0071] In order to further explain the technical means and results taken by the present application to achieve the predetermined invention purpose, the specific implementation methods, technical solutions and features of the present application are described in detail below with preferred embodiments. The specific features, structures, or characteristics of the multiple embodiments in the following description can be combined in any suitable form.

[0072] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagent products that can be obtained commercially.

[0073] The principles involved in this application are explained below. The development of compound preparations needs to have obvious clinical advantages, which can be explained from two aspects: improving drug efficacy and improving drug safety:

[0074] Improving drug efficacy: There is a mutual influence between hypertension and kidneys. The kidney is one of the target organs that is vulnerable to "attack" by hypertension. Long-term high blood pressure, in addition to the manifestation of water and sodium metabolism disorders in the body, will further aggravate the ischemia and hypoxia of the kidneys, thereby damaging the kidneys. Glomerulonephritis will inhibit the kidney's role in regulating blood pressure, so hypertension is a common symptom after the development of kidney disease to the middle and late stages. Studies have shown that angiotensin II is a key factor in changes in glomerular hemodynamics and the core of progressive renal injury. In vitro experimental studies have revealed several non-hemodynamic effects of angiotensin II associated with the progression of kidney disease. They include stimulation of mesangial cell proliferation and extracellular matrix deposition, and endothelial cells to produce plasminogen activator inhibitor type 1 (PAI1). In addition, angiotensin II changes the size selectivity of the glomerular capillary barrier by binding to the angiotensin II subtype 1 receptor on the foot process of podocytes. This leads to the rearrangement of the cytoskeleton and the distribution or expression of slit diaphragm protein components, ultimately allowing excess plasma proteins to enter the urinary tract. In summary, there is strong experimental and clinical evidence that the progression of chronic kidney disease is multifactorial, but glomerular hemodynamic changes and proteinuria play a key role in this process. Angiotensin II (Ang II) and endothelin (ET) have many similarities in their effects on the cardiovascular system, and both are potent vasoconstrictors. At the same time, an increase in Ang II concentration promotes the synthesis of ET-1 and increases vasoconstrictor activity; an increase in ET-1 levels also promotes the synthesis of Ang II and increases vasoconstrictor activity. Therefore, azilsartan is a potent angiotensin II antagonist, and ambrisentan is a specific endothelin ETA receptor antagonist. The combination of the two has a synergistic effect on the inhibition of Ang II, so the antihypertensive effect and renal protective effect are more significant. Animal data have shown that the combined blockade of the endothelin system and RAAS produces greater hemodynamic changes and greater renal protective effects than blocking either system alone. This synergistic effect is based on the interaction between endothelin and angiotensin II at the molecular level.

[0075] Therefore, in IgAN patients, azilsartan and ambrisentan combination, as a dual inhibitor of angiotensin II and endothelin, can not only lower blood pressure, reduce glomerular filtration rate, and improve proteinuria, but also have a direct beneficial effect on podocytes and reduce renal damage; endothelin receptor antagonists can also reduce inflammation and may further delay the progression of kidney disease. Therefore, from the perspective of drug mechanism of action, the development of azilsartan and ambrisentan combination preparations is feasible in terms of improving efficacy.

[0076] Improve drug safety: IgAN is a chronic disease, and patients need to take medication for a long time, so the safety of drugs needs to be paid special attention. The two main ingredients of the compound product, azilsartan and ambrisentan, have no obvious toxic side effects. Furthermore, among the adverse reactions of ambrisentan is peripheral edema, which is common with antihypertensive drugs. However, studies have shown that the combination of azilsartan and calcium ion antagonist antihypertensive drugs (amlodipine) can reduce the occurrence of peripheral edema. Therefore, the combination of azilsartan and ambrisentan can theoretically reduce the occurrence of adverse reactions such as peripheral edema. Therefore, from the perspective of drug safety, the development of azilsartan-ambrisentan compound preparations is feasible in improving drug safety.

[0077] At the same time, the feasibility of the combined use of the two main components also requires an evaluation of drug interactions. From the perspective of the matching of the pharmacokinetic characteristics of azilsartan and ambrisentan, the Tmax of the two is similar, eating does not affect the bioavailability of the drugs, and there is no significant difference in the effective half-life. In theory, the time for azilsartan and ambrisentan to produce effective effects matches, and both are eliminated mainly through non-renal pathways, which puts less burden on the kidneys. Therefore, the combined use of the two is feasible.

[0078] At the same time, we can once again prove the drugability, stability and effectiveness of this compound drug combination in treating IgA nephropathy from the data of the compatibility test, stability test and rat efficacy test of this compound drug combination, that is, this compound drug combination has a high feasibility of becoming a new targeted drug for the treatment of IgA nephropathy.

[0079] The present application is further described in detail below in conjunction with specific embodiments. These embodiments should not be construed as limiting the scope of protection claimed in the present application.

[0080] Example 1

[0081] The compound coated tablets were prepared according to the prescription shown in Table 1 and the following method:

[0082] Table 1 Prescription of the composite coated tablets prepared in Example 1

[0083]

[0084]

[0085] 1) Grinding: The two raw materials are ground by a jet mill to a particle size D50 of less than 10 μm and D90 of 5-30 μm;

[0086] 2) Weighing: weigh the raw and auxiliary materials according to the amount of each feed;

[0087] 3) Wet granulation:

[0088] ① Preparation of adhesive: Weigh an appropriate amount of purified water, add hydroxypropyl cellulose and polyethylene glycol into the purified water, and stir until completely dissolved;

[0089] ② Add the weighed amount of microcrystalline cellulose, corn starch, low-substituted hydroxypropyl cellulose, raw material powder and lactose into the wet granulator in sequence;

[0090] ③ Start the wet granulation process, mixing, adding adhesive (spraying), granulation, and unloading in sequence;

[0091] ④ Drying: Drying the wet granules;

[0092] 4) Granulation: The dried granules are transferred to a granulator for granulation;

[0093] 5) Total mixing: transfer the granules after granulation to the total mixing barrel, and add the prescribed amount of magnesium stearate for total mixing;

[0094] 6) Tableting: Tableting is performed by converting the standard tablet weight according to the intermediate content;

[0095] 7) Coating: Put the plain tablets into the coating pot for coating. When the coating weight gain reaches the target value, stop spraying, dry and air the tablets.

[0096] Test conclusion: According to the compatibility test results of raw materials and excipients, the above excipients are selected as the excipients of the compound preparation of this embodiment. The process is wet granulation. The prepared particles are uniform in size, the overall tableting particles have good fluidity and compressibility, the hardness of the plain tablets is about 50N, the fluctuations in tablet weight and hardness during the tableting process are within an acceptable range, the friability meets the standard, and the surface of the coated tablets is smooth and has no mottled surface.

[0097] Example 2

[0098] The compound coated tablets were prepared according to the prescription shown in Table 2 and the following method:

[0099] Table 2 Prescription of the composite coated tablets prepared in Example 2

[0100]

[0101]

[0102] 1) Grinding: Grind the two APIs to a particle size of D50 ≥ 15 μm and D90 of 100-300 μm;

[0103] 2) Weighing: weigh the raw and auxiliary materials according to the input amount;

[0104] 3) Sieving: Lactose, corn starch and two APIs are sieved and mixed to form material I, and cross-linked sodium carboxymethyl cellulose, poloxamer and hydroxypropyl cellulose are sieved and mixed to form material II;

[0105] 4) Total mixing: Add material I and material II into the total mixer, set the parameters and mix for a certain time, then add magnesium stearate and mix for 5 minutes;

[0106] 5) Tableting: Tableting is performed by converting the standard tablet weight according to the intermediate content;

[0107] 6) Coating: Coating the plain tablets, stop spraying when the coating weight gain reaches the target value, dry the tablets, and air-dry them;

[0108] Test conclusion: According to the compatibility test results of raw materials and excipients, the above excipients are selected as the excipients of the compound preparation of this embodiment. The process is direct powder compression. The material has good fluidity and compressibility. The hardness of the plain tablet is about 45N. The fluctuations in tablet weight and hardness during the tableting process are within an acceptable range. The friability meets the standard, and the surface of the coated tablet is smooth and has no spots.

[0109] Example 3

[0110] The compound coated tablets were prepared according to the prescription shown in Table 3 and the following method:

[0111] Table 3 Prescription of the composite coated tablets prepared in Example 3

[0112] Element Content (mg) Azilsartan 20.0 Ambrisentan 10.0 lactose 60.0 Corn starch 42.0 Low substituted hydroxypropyl cellulose 10.0 Polyethylene glycol 5.0 Magnesium Stearate 3.0 Film coating premix 5.0

[0113] 1) crushing the two raw materials to make the particle size D50 less than 10 μm and D90 5-30 μm;

[0114] 2) Weighing: weigh the raw and auxiliary materials according to the input amount;

[0115] 3) Mixing: Put the two APIs, lactose, corn starch, low-substituted hydroxypropyl cellulose, polyethylene glycol and 1 / 2 of magnesium stearate into a total mixer for mixing;

[0116] 4) Dry granulation: The mixed materials are transferred to a dry granulator to prepare granules;

[0117] 5) Total mixing: put the granules and the remaining amount of magnesium stearate into a total mixer and mix for 5 minutes;

[0118] 6) Tableting: Tableting is performed by converting the standard tablet weight according to the intermediate content;

[0119] 7) Coating: Coat the plain tablets. When the coating weight gain reaches the target value, stop spraying, dry and air-dry the tablets.

[0120] Test conclusion: According to the compatibility test results of raw materials and excipients, the above excipients were selected as the excipients for this compound preparation. The process was dry granulation. The prepared particles were uniform in size, the overall tablet granules had good fluidity and compressibility, the hardness of the plain tablets was about 40N, the fluctuations in tablet weight and hardness during the tableting process were within an acceptable range, the friability met the standards, and the surface of the coated tablets was smooth and without spots.

[0121] Example 4

[0122] The composite coated tablets were prepared according to the method of Example 1, except that the prescription used in this example is shown in Table 4.

[0123] Table 4 Prescription of the composite coated tablets prepared in Example 4

[0124] Components Content (mg) Azilsartan 20.0 Ambrisentan 5.0 lactose 65.0 Corn starch 20.0 Microcrystalline Cellulose 20.0 Low substituted hydroxypropyl cellulose 10.0 Hydroxypropylcellulose 3.0 Polyethylene glycol 5.0 Magnesium Stearate 2.0 Film coating premix 5.0

[0125] 1) Grinding: The two raw materials are ground by a jet mill to a particle size D50 of less than 10 μm and D90 of 5-30 μm;

[0126] 2) Weighing: weigh the raw and auxiliary materials according to the amount of each feed;

[0127] 3) Wet granulation:

[0128] ① Preparation of adhesive: Weigh an appropriate amount of purified water, add hydroxypropyl cellulose and polyethylene glycol into the purified water, and stir until completely dissolved;

[0129] ② Add the weighed amount of microcrystalline cellulose, corn starch, low-substituted hydroxypropyl cellulose, raw material powder and lactose into the wet granulator in sequence;

[0130] ③ Start the wet granulation process, mixing, adding adhesive (spraying), granulation, and unloading in sequence;

[0131] ④ Drying: Drying the wet granules;

[0132] 4) Granulation: The dried granules are transferred to a granulator for granulation;

[0133] 5) Total mixing: transfer the granules after granulation to the total mixing barrel, and add the prescribed amount of magnesium stearate for total mixing;

[0134] 6) Tableting: Tableting is performed by converting the standard tablet weight according to the intermediate content;

[0135] 7) Coating: Put the plain tablets into the coating pot for coating. When the coating weight gain reaches the target value, stop spraying, dry and air the tablets.

[0136] Test conclusion: According to the compatibility test results of raw materials and excipients, the above excipients are selected as the excipients of the compound preparation of this embodiment. The process is wet granulation. The prepared particles are uniform in size, the overall tableting particles have good fluidity and compressibility, the hardness of the plain tablets is about 45N, the fluctuations in tablet weight and hardness during the tableting process are within an acceptable range, the friability meets the standard, and the surface of the coated tablets is smooth and has no spots.

[0137] Example 5

[0138] The composite coated tablets were prepared according to the method of Example 1, except that the prescription used in this example is shown in Table 5.

[0139] Table 5 Prescription of the composite coated tablets prepared in Example 5

[0140] Components Content (mg) Azilsartan 40.0 Ambrisentan 10.0 lactose 50.0 Corn starch 15.0 Microcrystalline Cellulose 15.0 Low substituted hydroxypropyl cellulose 10.0 Hydroxypropylcellulose 3.0 Polyethylene glycol 5.0 Magnesium Stearate 2.0 Film coating premix 5.0

[0141] 1) Grinding: The two raw materials are ground by a jet mill to a particle size D50 of less than 10 μm and D90 of 5-30 μm;

[0142] 2) Weighing: weigh the raw and auxiliary materials according to the amount of each feed;

[0143] 3) Wet granulation:

[0144] ① Preparation of adhesive: Weigh an appropriate amount of purified water, add hydroxypropyl cellulose and polyethylene glycol into the purified water, and stir until completely dissolved;

[0145] ② Add the weighed amount of microcrystalline cellulose, corn starch, low-substituted hydroxypropyl cellulose, raw material powder and lactose into the wet granulator in sequence;

[0146] ③ Start the wet granulation process, mixing, adding adhesive (spraying), granulation, and unloading in sequence;

[0147] ④ Drying: Drying the wet granules;

[0148] 4) Granulation: The dried granules are transferred to a granulator for granulation;

[0149] 5) Total mixing: transfer the granules after granulation to the total mixing barrel, and add the prescribed amount of magnesium stearate for total mixing;

[0150] 6) Tableting: Tableting is performed by converting the standard tablet weight according to the intermediate content;

[0151] 7) Coating: Put the plain tablets into the coating pot for coating. When the coating weight gain reaches the target value, stop spraying, dry and air the tablets.

[0152] Test conclusion: According to the compatibility test results of raw materials and excipients, the above excipients are selected as the excipients of the compound preparation of this embodiment. The process is wet granulation. The prepared particles are uniform in size, the overall tableting particles have good fluidity and compressibility, the hardness of the plain tablets is about 50N, the fluctuations in tablet weight and hardness during the tableting process are within an acceptable range, the friability meets the standard, and the surface of the coated tablets is smooth and has no mottled surface.

[0153] Example 6

[0154] The composite coated tablets were prepared according to the method of Example 1, except that the prescription used in this example is shown in Table 6.

[0155] Table 6 Prescription of the composite coated tablets prepared in Example 6

[0156] Components Content (mg) Azilsartan 40.0 Ambrisentan 5.0 lactose 55.0 Corn starch 15.0 Microcrystalline Cellulose 15.0 Low substituted hydroxypropyl cellulose 10.0 Hydroxypropylcellulose 3.0 Polyethylene glycol 5.0 Magnesium Stearate 2.0 Film coating premix 5.0

[0157] 1) Grinding: The two raw materials are ground by a jet mill to a particle size D50 of less than 10 μm and D90 of 5-30 μm;

[0158] 2) Weighing: weigh the raw and auxiliary materials according to the amount of each feed;

[0159] 3) Wet granulation:

[0160] ① Preparation of adhesive: Weigh an appropriate amount of purified water, add hydroxypropyl cellulose and polyethylene glycol into the purified water, and stir until completely dissolved;

[0161] ② Add the weighed amount of microcrystalline cellulose, corn starch, low-substituted hydroxypropyl cellulose, raw material powder and lactose into the wet granulator in sequence;

[0162] ③ Start the wet granulation process, mixing, adding adhesive (spraying), granulation, and unloading in sequence;

[0163] ④ Drying: Drying the wet granules;

[0164] 4) Granulation: The dried granules are transferred to a granulator for granulation;

[0165] 5) Total mixing: transfer the granules after granulation to the total mixing barrel, and add the prescribed amount of magnesium stearate for total mixing;

[0166] 6) Tableting: Tableting is performed by converting the standard tablet weight according to the intermediate content;

[0167] 7) Coating: Put the plain tablets into the coating pot for coating. When the coating weight gain reaches the target value, stop spraying, dry and air the tablets.

[0168] Test conclusion: According to the compatibility test results of raw materials and excipients, the above excipients are selected as the excipients of the compound preparation of this embodiment. The process is wet granulation. The prepared particles are uniform in size, the overall tableting particles have good fluidity and compressibility, the hardness of the plain tablets is about 40N, the fluctuations in tablet weight and hardness during the tableting process are within an acceptable range, the friability meets the standard, and the surface of the coated tablets is smooth and has no spots.

[0169] Experimental Example 1 Compatibility test of raw materials and auxiliary materials

[0170] Some common pharmaceutical excipients were selected for raw material compatibility test. The inspection conditions were high temperature (60°C), high humidity (92.5%RH) and light. The inspection time was 30 days. The compatibility between the selected excipients and the two raw materials was investigated. Among them: blank excipient 1 contains lactose monohydrate, corn starch, microcrystalline cellulose, low-substituted cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, cross-linked sodium carboxymethyl cellulose, polyethylene glycol, poloxamer, glyceryl monostearate; blank excipient 2 contains corn starch, low-substituted cellulose, hydroxypropyl cellulose; blank excipient 3 contains sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, povidone, cross-linked polyvinyl pyrrolidone, mannitol. The inspection results are shown in Tables 7-9, where Table 7 is the relevant substance detection results on the 0th day after the start of the inspection, Table 8 is the relevant substance detection results on the 10th day after the start of the inspection, and Table 9 is the relevant substance detection results on the 30th day after the start of the inspection. In Tables 7-9, "A" represents azilsartan, "An" represents ambrisentan, "Blank 1" represents blank excipient 1, "Blank 2" represents blank excipient 2, and "Blank 3" represents blank excipient 3.

[0171] Table 7 Test results of relevant substances on day 0 after the start of the investigation

[0172]

[0173] Table 8 Test results of relevant substances on the 10th day after the start of the investigation

[0174]

[0175]

[0176] Table 9 Results of relevant substance testing on the 30th day after the start of the investigation

[0177]

[0178]

[0179] Test conclusion:

[0180] (1) From the storage conditions of ambrisentan API alone, it can be seen that a small amount of impurities will be produced under all three conditions compared with day 0, so it is necessary to avoid high temperature for a long time, pay attention to humidity control, and store away from light.

[0181] (2) From the storage of azilsartan API alone, it can be seen that compared with day 0, a small amount of impurities B and D will be produced. Impurities C and G will grow rapidly under high temperature conditions, and unknown impurities will grow rapidly under light. Therefore, it is necessary to avoid high temperatures for a long time, pay attention to humidity control, and store in a dark place.

[0182] (3) From the storage conditions of ambrisentan + azilsartan, it can be seen that the impurities generated under the three conditions compared with day 0 are consistent with the conditions of a single API storage, so it can be seen that there will be no reaction between the two APIs leading to instability.

[0183] (4) From the placement of the excipient combination of ambrisentan and azilsartan, it can be seen that the growth of the excipient combination is consistent with that of the API placed alone, that is, the selected excipients will not aggravate the degradation of the API with azilsartan and ambrisentan, indicating that the selected excipients have good compatibility with the two APIs.

[0184] Experimental Example 2 Influencing Factors Test

[0185] The tablets prepared in Example 1 were used to conduct an influencing factor test to examine the stability of the compound preparation of the present application under relatively severe conditions. The test conditions were high temperature 60°C, high humidity 92.5% RH and light, and the test time was 30 days. The test results are shown in Table 10.

[0186] Table 10 Stability test results of the tablets of Example 1

[0187]

[0188] Test conclusion: First, the results of the 0-day related substance detection showed that the wet granulation process would not cause instability in the compound preparation, that is, the selected process was feasible. At the same time, the stability of the tablets made of the selected excipients was similar to that of the raw excipients: most stable under high humidity conditions. Impurities increased slightly under high temperature conditions, so long-term high temperature storage should be avoided. However, although the raw material is slightly unstable under light conditions, the tablets are protected by the coating, so the light condition results of the influencing factor test are more stable than the compatibility of the raw excipients, which also proves the correctness of the selected film coating premix, and light-proof packaging materials can be used for secondary protection later. In summary, this compound preparation has good preparation feasibility.

[0189] Experimental Example 3 The therapeutic effect of compound azilsartan and ambrisentan on IgA model rats

[0190] 1. Grouping and Modeling

[0191] 75 male Wistar rats, weighing 200 - 220 g, were fed with a normal diet. After 7 days of quarantine, animals with a body weight deviation exceeding 10% were excluded. Five rats were randomly selected as the normal control group, and the remaining animals were grouped according to the type and dose of the drug. The grouping table is shown in Table 11.

[0192] Table 11 Grouping of rats

[0193]

[0194] Except for the normal group, rats in the other groups were injected with a single dose of anti-Thy1.1 antibody (500 μg) via the tail vein to induce kidney injury and mesangial proliferative glomerulonephritis for modeling.

[0195] II. Drug administration and detection

[0196] On the second day after modeling, rats in each group were administered drugs according to the group and dose. The normal group was not administered drugs, and the solvent group was administered the corresponding dose of solvent (normal saline). The drugs were administered once a day. After 13 days of drug administration, 24-hour urine protein, urinary microalbumin, and urinary creatinine were detected, and rat serum was collected to detect blood creatinine and blood urea nitrogen indicators.

[0197] III. Test results

[0198] The test results are shown in Table 12 and Table 13. In Table 12 and 13, "A" represents azilsartan, and "A" represents ambrisentan.

[0199] Table 12 Effects of azilsartan ambrisentan compound composition on urinary biochemical indexes in IgA nephropathy rats

[0200]

[0201] Note: Compared with the normal group, *P < 0.05, **P < 0.01; compared with the solvent group, #P < 0.05, ##P < 0.01; compared with the azilsartan group, △P < 0.05, △△P < 0.01; compared with the ambrisentan group, ▲P < 0.05, ▲▲P < 0.01.

[0202] Table 13 Effects of azilsartan ambrisentan compound composition on blood biochemical indexes in IgA nephropathy rats

[0203]

[0204] Note: Compared with the normal group, *P < 0.05, **P < 0.01; compared with the solvent group, #P < 0.05, ##P < 0.01; compared with the azilsartan group, △P < 0.05, △△P < 0.01; compared with the ambrisentan group, ▲P < 0.05, ▲▲P < 0.01.

[0205] IV. Test Conclusion

[0206] Compared with the normal group, the 24-hour urine protein and urine microalbumin in the IgA nephropathy model group (i.e., the solvent group) increased significantly (P<0.01). Compared with the IgA nephropathy model group, the 24-hour urine protein and urine microalbumin in the drug-treated group decreased significantly, and the decrease was more obvious in the azilsartan + ambrisentan (4+0.5) mg / kg group and the azilsartan + ambrisentan (4+1) mg / kg group (P<0.01). Compared with the single-drug azilsartan group and the ambrisentan group, the urine protein in the azilsartan + ambrisentan (4+0.5) mg / kg group and the azilsartan + ambrisentan (4+1) mg / kg group decreased more significantly (P<0.01, P<0.05), and the urine microalbumin in the azilsartan + ambrisentan (4+1) mg / kg group also decreased significantly compared with the single-drug group (P<0.01, P<0.05). The urine creatinine in the IgA nephropathy model group decreased significantly (P<0.01), and the urine creatinine in the drug-treated group increased significantly. The increase in urine creatinine in the azilsartan + ambrisentan (4+1) mg / kg group was significantly higher than that in the single drug group (P<0.05).

[0207] According to the research findings of Jenkinson C, Diva U et al. (Effect of sparsentan, a dualangiotensin II type1 (AT1) and endothelin type A (ETA) receptor antagonist, in the rat anti-thy1 model of glomerulonephritis), after rats were given sparsentan at doses of 20 mg / kg and 60 mg / kg for 7 days, the 24-hour urine protein levels were between 40-60 mg and 20-40 mg, respectively, which were higher than the 24-hour urine protein levels in the combination drug dosage group, indicating that the combination drug has certain advantages.

[0208] The levels of serum creatinine and urea nitrogen in the IgA nephropathy model group were significantly higher than those in the normal group (P<0.01). The levels of serum creatinine and urea nitrogen in the compound administration group were significantly lower than those in the IgA nephropathy model group (P<0.01, P<0.05). Compared with the single-drug azilsartan group and the ambrisentan group, the urea nitrogen in the azilsartan + ambrisentan (4+0.5) mg / kg group and the azilsartan + ambrisentan (4+1) mg / kg group decreased more significantly (P<0.01, P<0.05). The decrease in serum creatinine was different from that in the ambrisentan group (P<0.05). Compared with the azilsartan group, the decrease in serum creatinine in the two groups was not statistically significant.

[0209] From the results of the efficacy test, it can be seen that both azilsartan and ambrisentan alone have certain therapeutic effects on improving proteinuria and alleviating kidney damage in IgA nephropathy rats, while the effect of azilsartan and ambrisentan combined is better than that of the single drug group, and the effect of the high-dose group is better than that of the low-dose group.

[0210] The above is only a preferred specific implementation of the present application; however, the protection scope of the present application is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical solution and its improved ideas of the present application within the technical scope disclosed in the present application, which should be included in the protection scope of the present application.

Claims

1. A pharmaceutical composition for treating IgA nephropathy, characterized in that: In parts by weight, it includes the following components: 5-10 parts of Ambrisentan and 10-40 parts of Azilsartan.

2. The pharmaceutical composition according to claim 1, characterized in that In parts by weight, the pharmaceutical composition comprises the following components: 5-10 parts of Ambrisentan and 20-40 parts of Azilsartan.

3. A pharmaceutical preparation for treating IgA nephropathy, characterized in that: The pharmaceutical preparation comprises the pharmaceutical composition according to claim 1 or 2.

4. The pharmaceutical preparation according to claim 3, characterized in that The pharmaceutical preparation is a tablet, and the raw materials of the pharmaceutical preparation further include at least one of a filler, a disintegrant, a binder, a stabilizer, a lubricant and a coating material.

5. The pharmaceutical preparation according to claim 4, characterized in that The content is expressed as percentage by weight. The content of ambrisentan is 3.2% to 7.0%, the content of azilsartan is 6.4% to 27%, the content of the filler is 50% to 75%, the content of the disintegrant is 5% to 20%, the content of the binder is 1% to 5%, the content of the stabilizer is 1% to 5%, the content of the lubricant is 0.5 to 2.5%, and the content of the coating material is 2% to 6%.

6. The pharmaceutical preparation according to claim 4 or 5, characterized in that The filler comprises at least one of lactose monohydrate, corn starch, microcrystalline cellulose, sucrose, mannitol and dextrin; and / or, the disintegrant comprises at least one of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone and cross-linked polyvinyl pyrrolidone; and / or, the binder comprises at least one of hydroxypropyl cellulose, hypromellose, sodium hydroxymethyl cellulose and povidone; and / or, the stabilizer comprises at least one of polyethylene glycol, poloxamer and glyceryl monostearate; and / or, the lubricant comprises at least one of magnesium stearate, talc and colloidal silicon dioxide; And / or, the coating material comprises a film coating premix.

7. The method for preparing the pharmaceutical preparation according to any one of claims 3 to 6, characterized in that: The preparation method is a wet granulation method, comprising the following steps: mixing a binder, a stabilizer and water to obtain a binder solution; Adding filler, disintegrant, ambrisentan and azilsartan into a wet granulator, spraying the binder solution after mixing, granulating, and drying to obtain dry granules; Granulating the dried particles to obtain granulated particles; Mixing the sized particles with a lubricant to obtain mixed particles; The total mixed granules are tableted and coated.

8. The method for preparing the pharmaceutical preparation according to any one of claims 3 to 6, characterized in that: The preparation method is a powder direct compression method, comprising the following steps: Mixing ambrisentan, azilsartan and a filler and sieving to obtain a first material; Mixing the disintegrant, the binder and the stabilizer and sieving them to obtain a second material; Mixing the first material and the second material, adding a lubricant and continuing to mix to obtain a total mixed material; The total mixed material is tableted and coated.

9. The method for preparing the pharmaceutical preparation according to any one of claims 3 to 6, characterized in that: The preparation method is a dry granulation method, comprising the following steps: Mixing ambrisentan, azilsartan, a filler, a disintegrant, a stabilizer and a portion of a lubricant to obtain a mixed material; Dry granulating the mixed material to obtain a granular material; Mixing the granular material with the remaining amount of lubricant to obtain mixed granules; The mixed granules are tableted and coated.

10. Use of the pharmaceutical composition according to claim 1 or 2 or the pharmaceutical preparation according to any one of claims 3 to 6 in the preparation of a product for treating IgA nephropathy.

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