Pharmaceutical composition and pharmaceutical formulation for treating iga nephropathy and method for preparing same

Abstract

Provided are a pharmaceutical composition and a pharmaceutical formulation for treating IgA nephropathy and a method for preparing same. The present invention relates to the technical field of drug preparation. The pharmaceutical composition comprises ambrisentan and azilsartan and has the effect of enhancing efficacy and reducing toxicity on the treatment of IgA nephropathy.

Description

Pharmaceutical compositions and pharmaceutical preparations for treating IgA nephropathy and methods for their preparation Technical Field

[0001] This application belongs to the field of pharmaceutical preparation technology, specifically relating to a pharmaceutical composition and pharmaceutical preparation for treating IgA nephropathy and a method for preparing the same. Background Technology

[0002] IgA nephropathy (IgAN) was first described by Berger in 1968 as a chronic kidney disease caused by defects in the glycosylation of human IgA immunoglobulin. It is a common primary glomerular disease worldwide, with diverse clinical and pathological manifestations and varying clinical outcomes. Clinically, it often presents with proteinuria, hematuria, and hypertension, and may be accompanied by renal insufficiency. IgA nephropathy can be diagnosed and pathologically graded through renal biopsy. Based on etiology, IgA nephropathy can be divided into primary IgA nephropathy and secondary IgA nephropathy.

[0003] IgAN typically affects young and middle-aged adults; statistics show that over 80% of diagnosed patients are between 18 and 44 years old. IgAN often develops after upper respiratory tract infections or acute gastroenteritis, usually presenting as gross hematuria or persistent microscopic hematuria. In addition, most IgAN patients also have varying degrees of proteinuria, edema, and hypertension. While most IgAN patients exhibit benign hematuria and stable renal function throughout their lives, 20%-40% develop renal failure within 10 to 20 years of diagnosis, requiring dialysis or a kidney transplant. Compared to other types of glomerulonephritis, IgAN is more likely to progress to renal failure.

[0004] Treatment of IgAN has historically been primarily empirical, focusing on so-called supportive care, namely general measures to slow the progression of glomerular disease and nonspecific immunosuppression. These drugs often have significant toxic side effects due to their lack of specificity, and there is a lack of specific treatments targeting the pathogenesis of IgAN. However, with a deeper understanding of the autoimmune pathogenesis of IgAN, various pharmacological therapeutic targets have been discovered, making research into specific treatments for IgAN a new trend.

[0005] On February 17, 2023, Sparsentan (brand name FILSPARI), a dual endothelin-angiotensin receptor antagonist jointly developed by Travele and CSL, received accelerated approval from the FDA for the treatment of IgAN. This marked the first non-immunosuppressive therapy in the field of IgAN treatment. Sparsentan is the first single-molecule dual endothelin-angiotensin receptor antagonist that selectively blocks two pathways associated with the progression of IgA nephropathy: by blocking endothelin A receptors and angiotensin II receptors, it prevents glomerular sclerosis and mesangial cell proliferation, and reduces proteinuria. The Phase III PROTECT study showed that after 36 weeks of sparsentan administration, patients experienced a 49.8% reduction in UPCR.

[0006] However, while sparsentan has excellent therapeutic effects on IgAN, it also poses significant safety risks. For example, while granting accelerated approval, the FDA also added black box warnings regarding hepatotoxicity and embryo / fetal toxicity. Furthermore, the high dosage of sparsentan (400 mg) further increases its safety concerns. Since IgAN is a chronic disease requiring long-term medication, the safety requirements for IgAN treatment drugs are clearly higher than for drugs used only in short-term settings. Summary of the Invention

[0007] The purpose of this application is to provide a pharmaceutical composition and pharmaceutical preparation for treating IgA nephropathy, and a method for preparing the same, in order to address the problem of poor safety of existing IgAN treatment drugs.

[0008] To achieve the above-mentioned objectives, the technical solution adopted in this application is as follows:

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

[0010] Ambrisentan 5-10 parts, Azisartan 10-40 parts.

[0011] In one alternative embodiment, the pharmaceutical composition comprises, by weight, the following components:

[0012] Ambrisentan 5-10 parts, Azisartan 20-40 parts.

[0013] Secondly, this application provides a pharmaceutical preparation for treating IgA nephropathy, the pharmaceutical preparation comprising the above-mentioned pharmaceutical composition.

[0014] In one optional embodiment, the pharmaceutical formulation is a tablet, and the raw materials of the pharmaceutical formulation further include at least one of fillers, disintegrants, binders, stabilizers, lubricants, and coating materials.

[0015] In one optional embodiment, by weight percentage, the ambrisentan content is 3.2%–7.0%, the azisartan content is 6.4%–27%, the filler content is 50%–75%, the disintegrant content is 5%–20%, the binder content is 1%–5%, the stabilizer content is 1%–5%, the lubricant content is 0.5%–2.5%, and the coating material content is 2%–6%.

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

[0017] And / or, the disintegrant includes at least one of low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethyl starch sodium, croscarmellose and croscarmellose polyvinylpyrrolidone;

[0018] And / or, the adhesive comprises at least one of hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium hydroxypropyl cellulose, and povidone;

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

[0020] And / or, the lubricant includes at least one of magnesium stearate, talc, and colloidal silica;

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

[0022] Thirdly, this application provides a method for preparing the above-mentioned pharmaceutical formulation, wherein the preparation method is a wet granulation method, comprising the following steps:

[0023] The adhesive, stabilizer, and water are mixed to obtain an adhesive solution;

[0024] The filler, disintegrant, ambrisentan and azisartan are added into a wet granulator, mixed well and then sprayed with the binder solution, granulated and dried to obtain dry granules.

[0025] The dried granules are granulated to obtain granulated granules;

[0026] The granulated particles are mixed with a lubricant to obtain a total mixed particle;

[0027] The total mixture of particles is compressed into tablets and then coated.

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

[0029] 1) Pulverization: Pulverize the two raw materials to make the particle size D50 less than 10μm and D90 5-30μm;

[0030] 2) Weighing: Weigh the raw and auxiliary materials according to the amount to be fed;

[0031] 3) Granulation:

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

[0033] ② Add the weighed filler, disintegrant, and active pharmaceutical ingredient into the wet granulation machine in sequence;

[0034] ③ Mix, add adhesive (spray), granulate, and unload in sequence;

[0035] ④ Drying: The wet granules are dried.

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

[0037] 5) Blending: Transfer the granulated particles to the blending tank and add the prescribed amount of lubricant for blending;

[0038] 6) Tableting: Based on the content of the intermediate product, calculate the weight of the standard tablets and then compress the tablets.

[0039] 7) Coating: Coat the uncoated film. Stop spraying liquid when the coating weight reaches the target value, then dry and air-dry the film.

[0040] Fourthly, this application provides another method for preparing the above-mentioned pharmaceutical formulation, wherein the preparation method is a direct powder compression method, comprising the following steps:

[0041] Ambrisentan, azisartan, and the filler were mixed and sieved to obtain the first material;

[0042] The disintegrant, binder and stabilizer are mixed and sieved to obtain the second material;

[0043] The first material and the second material are mixed, a lubricant is added and mixing continues to obtain the total mixture.

[0044] The total mixture is then compressed into tablets and coated.

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

[0046] 1) Pulverization: Pulverize the two raw materials to make the particle size D50≥15μm and D90100~300μm.

[0047] 2) Weighing: Weigh the raw and auxiliary materials according to the amount to be fed;

[0048] 3) Sieving: The filler and the two raw materials are sieved and mixed to form the first material, and the disintegrant, stabilizer and binder are sieved and mixed to form the second material;

[0049] 4) General mixing: Add the first material and the second material to the general mixer, set the parameters and mix. After a certain time, add the lubricant and mix for 5 minutes.

[0050] 5) Tableting: Based on the content of the intermediate product, calculate the weight of the standard tablets and then compress the tablets.

[0051] 6) Coating: Coat the uncoated film. Stop spraying liquid when the coating weight reaches the target value, then dry and air-dry the film.

[0052] Fifthly, this application provides another method for preparing the above-mentioned pharmaceutical formulation, wherein the preparation method is a dry granulation method, comprising the following steps:

[0053] Ambrisentan, azisartan, fillers, disintegrants, stabilizers, and some lubricants are mixed to obtain a mixture.

[0054] The mixture is subjected to dry granulation to obtain granular material;

[0055] The particulate material is mixed with the remaining lubricant to obtain mixed particles;

[0056] The mixed particles are compressed into tablets and then coated.

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

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

[0059] 2) Weighing: Weigh the raw and auxiliary materials according to the amount to be fed;

[0060] 3) Mixing: The two active pharmaceutical ingredients, filler, disintegrant, and a portion of lubricant are mixed in a master mixer;

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

[0062] 5) Blending: Place the granules and the remaining lubricant into a blender and blend for 5 minutes;

[0063] 6) Tableting: Based on the content of the intermediate product, calculate the weight of the standard tablets and then compress the tablets.

[0064] 7) Coating: Coat the uncoated film. Stop spraying liquid when the coating weight reaches the target value, then dry and air-dry the film.

[0065] Sixthly, this 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 this application includes ambrisentan and azisartan, which have a synergistic and toxicity-reducing effect on the treatment of IgA nephropathy.

[0068] Specifically, in related technologies, both ambrisentan and azilsartan are indicated for hypertension, and their individual therapeutic doses are insufficient to meet the optimal therapeutic dose for IgA nephropathy, resulting in poor treatment efficacy. This application combines ambrisentan and azilsartan, which can treat IgA nephropathy through a dual-action pathway of angiotensin II and endothelin, achieving excellent therapeutic effects through their complementary effects. Furthermore, no serious toxic side effects were observed with the combined use of ambrisentan and azilsartan, demonstrating high drug safety and significant clinical advantages for IgA nephropathy patients requiring long-term medication.

[0069] Furthermore, this application combines ambrisentan and azisartan, which, compared to the single-molecule sparsentan, can optimize the blocking effect of the drug on the dual-action pathway of angiotensin II and endothelin by adjusting the ratio of the two, making the treatment more flexible and achieving better therapeutic effects.

[0070] (2) The pharmaceutical preparation for treating IgA nephropathy provided in this application has no interaction between the excipients and active pharmaceutical ingredients involved, and can be well formed and remain stable in vitro. Therefore, the pharmaceutical preparation is a stable, more effective and less toxic IgA nephropathy treatment drug. Detailed Implementation

[0071] To further illustrate the technical means and results adopted by this application to achieve the intended inventive purpose, the following preferred embodiments are used to describe in detail the specific implementation methods, technical solutions, and features according to this application. Specific features, structures, or characteristics in the various embodiments described below can be combined in any suitable form.

[0072] For experiments not specifically described in the examples, the procedures or conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products.

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

[0074] Improving Drug Efficacy: There is a reciprocal relationship between hypertension and the kidneys. The kidneys are one of the target organs most vulnerable to hypertension. Long-term elevated blood pressure, in addition to causing water and sodium metabolism disorders, further exacerbates renal ischemia and hypoxia, thus damaging the kidneys. Glomerulonephritis, in turn, inhibits the kidneys' ability to regulate blood pressure; therefore, hypertension is a common symptom in the middle and late stages of kidney disease. Studies have shown that angiotensin II is a key factor in glomerular hemodynamic changes and is central to progressive kidney injury. In vitro studies have revealed several non-hemodynamic effects of angiotensin II associated with the progression of kidney disease. These include stimulating mesangial cell proliferation and extracellular matrix deposition, and endothelial cells producing plasminogen activator inhibitor type 1 (PAI1). Furthermore, angiotensin II alters the size-selective properties of the glomerular capillary barrier by binding to angiotensin II subtype 1 receptors on podocyte foot processes. This leads to cytoskeleton rearrangement and the distribution or expression of slit septum protein components, ultimately resulting in excessive plasma proteins entering the urinary tract. In summary, strong experimental and clinical evidence suggests that the progression of chronic kidney disease is multifactorial, but intraglomerular hemodynamic changes and proteinuria play a crucial role in this process. Angiotensin II (Ang II) and endothelin (ET) share many similarities in their roles in the cardiovascular system, both being potent vasoconstrictors. Simultaneously, increased Ang II concentrations promote ET-1 synthesis, increasing vasoconstrictive activity; conversely, increased ET-1 levels also promote Ang II synthesis and increase vasoconstrictive activity. Therefore, azisartan, a potent angiotensin II antagonist, and ambrisentan, a specific endothelin-ETA receptor antagonist, when used in combination, have a synergistic effect in inhibiting Ang II, thus resulting in more significant antihypertensive and renal protective effects. Animal data indicate that combined blockade of the endothelin system and the RAAS produces greater hemodynamic changes and greater renal protective effects than blocking either system alone. This synergistic effect is based on the molecular-level interaction between endothelin and angiotensin II.

[0075] Therefore, in IgAN patients, the azilsartan and ambrisentan combination, as a dual inhibitor of angiotensin II and endothelin, not only lowers blood pressure, reduces glomerular filtration rate, and improves proteinuria, but also has a direct beneficial effect on podocytes, reducing kidney damage; the endothelin receptor antagonist can also reduce inflammation, potentially further delaying the progression of kidney disease. Therefore, from the perspective of pharmacological mechanism of action, the development of azilsartan-ambrisentan combination formulations is feasible in terms of improving efficacy.

[0076] Improving drug safety: IgAN is a chronic disease requiring long-term medication, making drug safety a top priority. The two main components of the combination product, azilsartan and ambrisentan, have no significant toxic side effects. Furthermore, while peripheral edema, a common adverse reaction to antihypertensive drugs, is a common side effect of ambrisentan, studies have shown that combining azilsartan with calcium channel blockers (amlodipine) can reduce the incidence of peripheral edema. Therefore, theoretically, combining azilsartan and ambrisentan could also reduce the occurrence of peripheral edema. Thus, from a drug safety perspective, the development of the azilsartan-ambrisentan combination formulation is feasible in terms of improving drug safety.

[0077] Meanwhile, the feasibility of using the two main components in combination also needs to be evaluated for drug interactions. From the perspective of matching the pharmacokinetic characteristics of azisartan and ambrisentan, their Tmax is similar, food intake does not affect drug bioavailability, and there is no significant difference in effective half-life. Theoretically, azisartan and ambrisentan have matching time to produce pharmacodynamic effects, and both are mainly eliminated through non-renal routes, which puts less burden on the kidneys. Therefore, the combination of the two is feasible.

[0078] At the same time, the data from the modeling test, stability test, and rat efficacy test of this compound drug combination can further prove the drug-likeness, stability, and effectiveness of this compound drug combination in treating IgA nephropathy. In other words, this compound drug combination has high feasibility as a novel targeted drug for the treatment of IgA nephropathy.

[0079] The present application will be further described in detail below with reference to specific embodiments. These embodiments should not be construed as limiting the scope of protection claimed in this application. Example 1

[0080] Prepare compound coated tablets according to the prescription shown in Table 1 and the following method:

[0081] Table 1. Formula for the compound coated tablets prepared in Example 1

[0082]

[0083] 1) Pulverization: The two raw materials are pulverized using an air jet mill to make the particle size D50 less than 10μm and D90 5-30μm;

[0084] 2) Weighing: Weigh the raw and auxiliary materials according to the amount of material to be added each time;

[0085] 3) Wet granulation:

[0086] ① Adhesive preparation: Weigh an appropriate amount of purified water, add hydroxypropyl cellulose and polyethylene glycol to the purified water, and stir until completely dissolved;

[0087] ② Add the weighed amounts of microcrystalline cellulose, corn starch, low-substituted hydroxypropyl cellulose, raw material powder, and lactose sequentially into the wet granulation machine;

[0088] ③ Start the wet granulation process, and mix, add binder (spraying), granulate, and unload in sequence;

[0089] ④ Drying: The wet granules are dried.

[0090] 4) Granulation: The dried granules are transferred to a granulator for granulation;

[0091] 5) Blending: Transfer the granulated particles to the blending tank and add the prescribed amount of magnesium stearate for blending;

[0092] 6) Tableting: Based on the content of intermediates, calculate the weight of standard tablets and then compress the tablets;

[0093] 7) Coating: Put the raw film into the coating pot for coating. When the coating weight reaches the target value, stop spraying liquid, dry and air-dry the film.

[0094] Experimental conclusion: Based on the results of the raw material compatibility test, the above-mentioned excipients were selected as the excipients for the compound preparation in this embodiment. The process was wet granulation. The prepared particles were uniform in size, and the overall tableted particles had good flowability and compressibility. The hardness of the uncoated tablets was about 50N. The tablet weight and hardness fluctuations during the tableting process were within acceptable ranges. The brittleness met the standard, and the surface of the coated tablets was smooth and free of blemishes. Example 2

[0095] Prepare compound coated tablets according to the prescription shown in Table 2 and the following method:

[0096] Table 2. Formula for the compound coated tablets prepared in Example 2

[0097]

[0098] 1) Pulverization: Pulverize the two raw materials to make the particle size D50≥15μm and D90100-300μm;

[0099] 2) Weighing: Weigh the raw and auxiliary materials according to the amount to be fed;

[0100] 3) Sieving: Lactose, corn starch and the two raw materials are sieved and mixed as material I, and croscarmellose sodium, poloxamer and hydroxypropyl cellulose are sieved and mixed as material II;

[0101] 4) General mixing: Add material I and material II to the general mixer, set the parameters and mix for a certain time, then add magnesium stearate and mix for 5 minutes;

[0102] 5) Tableting: Based on the content of intermediates, calculate the weight of standard tablets and then compress the tablets;

[0103] 6) Coating: Coat the uncoated film. Stop spraying the coating solution when the coating weight reaches the target value, then dry and air-dry the film.

[0104] Experimental conclusion: Based on the results of the raw material compatibility test, the above-mentioned excipients were selected as the excipients for the compound preparation in this embodiment. The process is direct compression of powder. The material has good flowability and compressibility. The hardness of the uncoated tablets is about 45N. The tablet weight and hardness fluctuations during the compression process are within acceptable ranges. The brittleness meets the standard. The surface of the coated tablets is smooth and free of blemishes. Example 3

[0105] Prepare compound coated tablets according to the prescription shown in Table 3 and the following method:

[0106] Table 3. Formula for the compound coated tablets prepared in Example 3

[0107]

[0108] 1) Pulverize the two raw materials to make the particle size D50 less than 10μm and D90 5-30μm;

[0109] 2) Weighing: Weigh the raw and auxiliary materials according to the amount to be fed;

[0110] 3) Mixing: Put the two raw materials, lactose, corn starch, low-substituted hydroxypropyl cellulose, polyethylene glycol and 1 / 2 magnesium stearate into a mixer and mix them.

[0111] 4) Dry granulation: The mixed materials are transferred to a dry granulator to prepare granules;

[0112] 5) Blending: Place the granules and the remaining magnesium stearate into a blender and blend for 5 minutes;

[0113] 6) Tableting: Based on the content of intermediates, calculate the weight of standard tablets and then compress the tablets;

[0114] 7) Coating: Coat the uncoated film. Stop spraying liquid when the coating weight reaches the target value, then dry and air-dry the film.

[0115] Experimental conclusion: Based on the results of the raw material compatibility test, the above-mentioned excipients were selected as the excipients for this compound preparation. The process was dry granulation. The prepared particles were uniform in size, and the overall tableted particles had good flowability and compressibility. The hardness of the uncoated tablets was about 40N. The fluctuations in tablet weight and hardness during the tableting process were within acceptable ranges. The brittleness met the standard, and the surface of the coated tablets was smooth and free of blemishes. Example 4

[0116] The compound coated tablets were prepared according to the method of Example 1, except that the prescription used in this example is shown in Table 4.

[0117] Table 4. Formula for the compound coated tablets prepared in Example 4

[0118]

[0119] 1) Pulverization: The two raw materials are pulverized using an air jet mill to make the particle size D50 less than 10μm and D90 5-30μm;

[0120] 2) Weighing: Weigh the raw and auxiliary materials according to the amount of material to be added each time;

[0121] 3) Wet granulation:

[0122] ① Adhesive preparation: Weigh an appropriate amount of purified water, add hydroxypropyl cellulose and polyethylene glycol to the purified water, and stir until completely dissolved;

[0123] ② Add the weighed amounts of microcrystalline cellulose, corn starch, low-substituted hydroxypropyl cellulose, raw material powder, and lactose sequentially into the wet granulation machine;

[0124] ③ Start the wet granulation process, and mix, add binder (spraying), granulate, and unload in sequence;

[0125] ④ Drying: The wet granules are dried.

[0126] 4) Granulation: The dried granules are transferred to a granulator for granulation;

[0127] 5) Blending: Transfer the granulated particles to the blending tank and add the prescribed amount of magnesium stearate for blending;

[0128] 6) Tableting: Based on the content of intermediates, calculate the weight of standard tablets and then compress the tablets;

[0129] 7) Coating: Put the raw film into the coating pot for coating. When the coating weight reaches the target value, stop spraying liquid, dry and air-dry the film.

[0130] Experimental conclusion: Based on the results of the raw material compatibility test, the above-mentioned excipients were selected as the excipients for the compound preparation in this embodiment. The process was wet granulation. The prepared particles were uniform in size, and the overall tableted particles had good flowability and compressibility. The hardness of the uncoated tablets was about 45N. The tablet weight and hardness fluctuations during the tableting process were within acceptable ranges. The brittleness met the standard, and the surface of the coated tablets was smooth and free of blemishes. Example 5

[0131] The compound coated tablets were prepared according to the method of Example 1, except that the prescription used in this example is shown in Table 5.

[0132] Table 5. Formula for the compound coated tablets prepared in Example 5

[0133]

[0134] 1) Pulverization: The two raw materials are pulverized using an air jet mill to make the particle size D50 less than 10μm and D90 5-30μm;

[0135] 2) Weighing: Weigh the raw and auxiliary materials according to the amount of material to be added each time;

[0136] 3) Wet granulation:

[0137] ① Adhesive preparation: Weigh an appropriate amount of purified water, add hydroxypropyl cellulose and polyethylene glycol to the purified water, and stir until completely dissolved;

[0138] ② Add the weighed amounts of microcrystalline cellulose, corn starch, low-substituted hydroxypropyl cellulose, raw material powder, and lactose sequentially into the wet granulation machine;

[0139] ③ Start the wet granulation process, and mix, add binder (spraying), granulate, and unload in sequence;

[0140] ④ Drying: The wet granules are dried.

[0141] 4) Granulation: The dried granules are transferred to a granulator for granulation;

[0142] 5) Blending: Transfer the granulated particles to the blending tank and add the prescribed amount of magnesium stearate for blending;

[0143] 6) Tableting: Based on the content of intermediates, calculate the weight of standard tablets and then compress the tablets;

[0144] 7) Coating: Put the raw film into the coating pot for coating. When the coating weight reaches the target value, stop spraying liquid, dry and air-dry the film.

[0145] Experimental conclusion: Based on the results of the raw material compatibility test, the above-mentioned excipients were selected as the excipients for the compound preparation in this embodiment. The process was wet granulation. The prepared particles were uniform in size, and the overall tableted particles had good flowability and compressibility. The hardness of the uncoated tablets was about 50N. The tablet weight and hardness fluctuations during the tableting process were within acceptable ranges. The brittleness met the standard, and the surface of the coated tablets was smooth and free of blemishes. Example 6

[0146] The compound coated tablets were prepared according to the method of Example 1, except that the prescription used in this example is shown in Table 6.

[0147] Table 6. Formula for the compound coated tablets prepared in Example 6

[0148]

[0149] 1) Pulverization: The two raw materials are pulverized using an air jet mill to make the particle size D50 less than 10μm and D90 5-30μm;

[0150] 2) Weighing: Weigh the raw and auxiliary materials according to the amount of material to be added each time;

[0151] 3) Wet granulation:

[0152] ① Adhesive preparation: Weigh an appropriate amount of purified water, add hydroxypropyl cellulose and polyethylene glycol to the purified water, and stir until completely dissolved;

[0153] ② Add the weighed amounts of microcrystalline cellulose, corn starch, low-substituted hydroxypropyl cellulose, raw material powder, and lactose sequentially into the wet granulation machine;

[0154] ③ Start the wet granulation process, and mix, add binder (spraying), granulate, and unload in sequence;

[0155] ④ Drying: The wet granules are dried.

[0156] 4) Granulation: The dried granules are transferred to a granulator for granulation;

[0157] 5) Blending: Transfer the granulated particles to the blending tank and add the prescribed amount of magnesium stearate for blending;

[0158] 6) Tableting: Based on the content of intermediates, calculate the weight of standard tablets and then compress the tablets;

[0159] 7) Coating: Put the raw film into the coating pot for coating. When the coating weight reaches the target value, stop spraying liquid, dry and air-dry the film.

[0160] Experimental conclusion: Based on the results of the raw material compatibility test, the above-mentioned excipients were selected as the excipients for the compound preparation in this embodiment. The process was wet granulation. The prepared particles were uniform in size, and the overall tableted particles had good flowability and compressibility. The hardness of the uncoated tablets was about 40N. The tablet weight and hardness fluctuations during the tableting process were within acceptable ranges. The brittleness met the standard, and the surface of the coated tablets was smooth and free of blemishes.

[0161] Experimental Example 1: Raw Material Compatibility Test

[0162] Some common pharmaceutical excipients were selected for compatibility testing. The testing conditions were high temperature (60℃), high humidity (92.5%RH), and light exposure, and the testing period was 30 days. The compatibility between the selected excipients and two active pharmaceutical ingredients (APIs) was investigated. The excipients included: Blank 1: lactose monohydrate, corn starch, microcrystalline cellulose, low-substituted cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, croscarmellose sodium, polyethylene glycol, poloxamer, and glyceryl monostearate; Blank 2: corn starch, low-substituted cellulose, and hydroxypropyl cellulose; Blank 3: sodium carboxymethyl starch, croscarmellose, povidone, croscarmellose, and mannitol. The results are shown in Tables 7-9. Table 7 shows the results of related substance testing on day 0 of the test, Table 8 shows the results on day 10 of the test, and Table 9 shows the results on day 30 of the test. In Table 7-9, "A" represents azisartan, "An" represents ambrisentan, "blank 1" represents blank excipient 1, "blank 2" represents blank excipient 2, and "blank 3" represents blank excipient 3.

[0163] Table 7. Results of relevant substance testing on day 0 after the start of the investigation.

[0164]

[0165] Table 8. Results of relevant substance testing on the 10th day after the start of the investigation.

[0166]

[0167] Table 9. Results of relevant substance testing on day 30 after the start of the investigation.

[0168]

[0169] Experimental conclusion:

[0170] (1) As can be seen from the individual placement of ambrisentan API, a small amount of impurities will be generated under all three conditions compared to day 0. Therefore, it is necessary to avoid prolonged high temperature, pay attention to humidity control, and store in the dark.

[0171] (2) From the individual placement of Azisartan API, it can be seen that a small amount of impurities B and D will be generated compared with 0 days. Impurities C and G grow rapidly under high temperature conditions and unknown impurities grow rapidly under light. Therefore, it is necessary to avoid prolonged high temperature, pay attention to humidity control, and store away from light.

[0172] (3) From the placement of ambrisentan + azisartan, it can be seen that the impurities generated under the three conditions are consistent with the placement of a single active pharmaceutical ingredient compared to day 0. Therefore, it can be concluded that there will be no reaction between the two active pharmaceutical ingredients that would lead to instability.

[0173] (4) From the excipient combination of ambrisentan and azisartan, it can be seen that the growth of the excipient combination is consistent with that of the raw material when placed alone. That is, the selected excipients will not aggravate the degradation of the raw material with azisartan and ambrisentan, indicating that the selected excipients have good compatibility with the two raw materials.

[0174] Experiment Example 2: Influencing Factors Experiment

[0175] The tablets prepared in Example 1 were subjected to an influencing factor test to investigate the stability of the compound formulation of this application under relatively harsh conditions. The test conditions were high temperature (60°C), high humidity (92.5% RH), and light exposure, and the test period was 30 days. The results are shown in Table 10.

[0176] Table 10. Results of stability study of the tablets in Example 1

[0177]

[0178] Experimental Conclusions: First, the 0-day related substance test results show that the wet granulation process does not cause instability in the compound preparation, indicating that the selected process is feasible. Simultaneously, the stability of the tablets made from the selected excipients is similar to that of the raw materials: they are most stable under high humidity conditions. Impurities increase slightly under high temperature conditions, therefore prolonged high-temperature storage should be avoided. Although the active pharmaceutical ingredient is slightly unstable under light exposure, the tablets are protected by coating, so the light condition results in the influencing factor test are more stable than the compatibility of the raw materials and excipients, further proving the correctness of the selected film-coating premix. Subsequent secondary protection can be achieved using light-protected packaging materials. In summary, this compound preparation demonstrates good formulation feasibility.

[0179] Experimental Example 3: The therapeutic effect of compound azilsartan and ambrisentan on IgA model rats

[0180] I. Grouping and Modeling

[0181] Seventy-five male Wistar rats, weighing 200-220g, were quarantined after being fed a normal diet for 7 days. Animals with a weight deviation of more than 10% were excluded, and five rats were randomly selected as the normal control group. The remaining animals were grouped according to the type and dosage of the drug administered. The grouping table is shown in Table 11.

[0182] Table 11 Grouping of rats

[0183]

[0184] Except for the normal group, the other groups of rats were given a single dose of anti-Thy1.1 antibody (500 pug) via tail vein injection to induce kidney damage and mesangial proliferative glomerulonephritis in rats for modeling.

[0185] II. Drug administration and testing

[0186] On the second day after modeling, rats in each group were given drugs according to their group and dosage. The normal group was not given any drugs, while the solvent group was given the corresponding dose of solvent (physiological saline). The drugs were administered once a day. After 13 days of administration, 24-hour urinary protein, urinary microalbumin, and urinary creatinine were measured. Serum samples were collected from rats to measure serum creatinine and blood urea nitrogen levels.

[0187] III. Test Results

[0188] The experimental results are shown in Tables 12 and 13. In Tables 12 and 13, "A" represents azisartan and "An" represents ambrisentan.

[0189] Table 12 Effects of the azisartan-ambrisentan combination on urinary biochemical parameters in IgA nephropathy rats (±s)

[0190]

[0191] 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 azisartan group, △P<0.05, △△P<0.01; compared with the ambrisentan group, ▲P<0.05, ▲▲P<0.01.

[0192] Table 13 Effects of the azisartan-ambrisentan combination on blood biochemical parameters in IgA nephropathy rats (±s)

[0193]

[0194] 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 azisartan group, △P<0.05, △△P<0.01; compared with the ambrisentan group, ▲P<0.05, ▲▲P<0.01.

[0195] IV. Experimental Conclusions

[0196] Compared with the normal group, the 24-hour urinary protein and urinary microalbumin levels were significantly increased in the IgA nephropathy model group (i.e., the solvent group) (P<0.01). Compared with the IgA nephropathy model group, the 24-hour urinary protein and urinary microalbumin levels were significantly decreased in the drug-treated groups, with more significant decreases 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 azilsartan monotherapy group and the ambrisentan group, the decrease in urinary protein was more significant in the azilsartan + ambrisentan (4+0.5) mg / kg group and the azilsartan + ambrisentan (4+1) mg / kg group (P<0.01, P<0.05), and the decrease in urinary microalbumin in the azilsartan + ambrisentan (4+1) mg / kg group was also significant compared with the monotherapy group (P<0.01, P<0.05). In the IgA nephropathy model group, urinary creatinine decreased significantly (P<0.01), while in the drug-treated groups, urinary creatinine increased significantly. The increase in urinary creatinine in the azisartan + ambrisentan (4+1) mg / kg group was significantly different from that in the single-drug group (P<0.05).

[0197] Furthermore, according to a study by Jenkinson C, Diva U, et al. (Effect of sparsentan, a dual angiotensin II type 1 (AT1) and endothelin type A (ETA) receptor antagonist, in the rat anti-thy1 model of glomerulonephritis), after rats were administered sparsentan at doses of 20 mg / kg and 60 mg / kg for 7 days, the 24-hour urinary protein levels were between 40-60 mg and 20-40 mg, respectively, both higher than those in the compound drug dose group, suggesting that the compound drug has certain advantages.

[0198] Serum creatinine and blood urea nitrogen levels in the IgA nephropathy model group were significantly higher than those in the normal group (P<0.01). Serum creatinine and blood urea nitrogen levels in the compound drug treatment group were significantly lower than those in the IgA nephropathy model group (P<0.01, P<0.05). Compared with the azilsartan and ambrisentan single-drug groups, the azilsartan + ambrisentan (4+0.5) mg / kg and azilsartan + ambrisentan (4+1) mg / kg groups showed a more significant decrease in blood urea nitrogen (P<0.01, P<0.05), and the decrease in serum creatinine was significantly different from that in the ambrisentan group (P<0.05). Compared with the azilsartan group, there was no statistically significant decrease in serum creatinine between the two groups.

[0199] The results of the pharmacodynamic test showed that both azisartan and ambrisentan alone had certain effects on improving proteinuria and alleviating kidney damage in rats with IgA nephropathy. The combined use of azisartan and ambrisentan was more effective than the single drug group, and the high-dose group was more effective than the low-dose group.

[0200] The above description is merely a preferred embodiment of this application; however, the scope of protection of this application is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in this application, based on the technical solution and its improved concept, should be covered within the scope of protection of this application.

Claims

1. A pharmaceutical composition for treating IgA nephropathy, characterized in that, By weight, it includes the following components: Ambrisentan 5-10 parts, Azisartan 10-40 parts.

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

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 the following: filler, disintegrant, binder, stabilizer, lubricant and coating material.

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

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

7. The method for preparing the pharmaceutical formulation according to any one of claims 3 to 6, characterized in that, The preparation method is a wet granulation method, which includes the following steps: The adhesive, stabilizer, and water are mixed to obtain an adhesive solution; The filler, disintegrant, ambrisentan and azisartan are added into a wet granulator, mixed well and then sprayed with the binder solution, granulated and dried to obtain dry granules. The dried granules are granulated to obtain granulated granules; The granulated particles are mixed with a lubricant to obtain a total mixed particle; The total mixture of particles is compressed into tablets and then coated.

8. The method for preparing the pharmaceutical formulation according to any one of claims 3 to 6, characterized in that, The preparation method is a powder direct pressing method, which includes the following steps: Ambrisentan, azisartan, and the filler were mixed and sieved to obtain the first material; The disintegrant, binder and stabilizer are mixed and sieved to obtain the second material; The first material and the second material are mixed, a lubricant is added and mixing continues to obtain the total mixture. The total mixture is then compressed into tablets and coated.

9. The method for preparing the pharmaceutical formulation according to any one of claims 3 to 6, characterized in that, The preparation method is a dry granulation method, which includes the following steps: Ambrisentan, azisartan, fillers, disintegrants, stabilizers, and some lubricants are mixed to obtain a mixture. The mixture is subjected to dry granulation to obtain granular material; The particulate material is mixed with the remaining lubricant to obtain mixed particles; The mixed particles are compressed into tablets and then coated.

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

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