Azilsartan and amlodipine besylate oral suspension and preparation method thereof

Abstract

The present invention relates to an oral suspension of azilsartan and amlodipine besylate and a preparation method thereof. The suspension uses azilsartan and amlodipine besylate as active ingredients, uses xanthan gum and cross-linked carboxymethyl cellulose sodium as suspending agents, and uses water and glycerol as solvents; the mass ratio of xanthan gum to cross-linked carboxymethyl cellulose sodium is 20-30:5-8. The present invention uses the compound of cross-linked carboxymethyl cellulose sodium and xanthan gum as a suspending agent, which can ensure that azilsartan and amlodipine besylate in the oral suspension are dispersed in a colloid, will not settle or aggregate, and has high stability. When taking the suspension, it is convenient for adult patients with difficulty in swallowing to use, ensures the accuracy of the dosage, improves the safety and effectiveness of the drug, and improves the high viscosity and agglomeration problems caused by long-term placement of ordinary suspension liquids.

Description

Technical Field

[0001] The invention belongs to the field of medicines, and specifically relates to an azilsartan benzene and amlodipine sulfonate oral suspension and a preparation method thereof. Background Art

[0002] Hypertension is not only the most common chronic disease, but also one of the risk factors for coronary heart disease. Many patients with coronary heart disease have a history of hypertension, especially some elderly patients with coronary heart disease. According to statistics, about 60% to 70% of patients with coronary heart disease suffer from hypertension, and the probability of hypertensive patients suffering from atherosclerosis is 3 to 4 times higher than those with normal blood pressure. For the stable treatment of hypertension, a combination of two or more drugs with different therapeutic mechanisms can play a better preventive and therapeutic role than a single drug. In addition, combination therapy with two or more different drugs reduces the dose of a single drug and thus reduces the side effects that may occur during long-term administration of the drug.

[0003] Based on the mechanism of action, drugs used in the treatment of hypertension are generally classified as: diuretics, sympathetic blockers, vasodilators. Most vasodilators currently used are further divided into: ACE (angiotensin converting enzyme) inhibitors, angiotensin II receptor blockers (ARBs), and calcium channel blockers.

[0004] Amlodipine besylate is a dihydropyridine (DHP) calcium channel blocker used to lower blood pressure and treat angina chest pain. Once absorbed, amlodipine lowers blood pressure by relaxing arterial smooth muscle, reducing total peripheral resistance and thereby lowering blood pressure and increasing blood flow to the myocardium.

[0005] Azilsartan is a new generation of selective AT1 subtype angiotensin II (AT1) receptor antagonists (ARBS) antihypertensive drugs, which inhibit vasoconstriction and reduce peripheral vascular resistance to exert antihypertensive effects. Compared with angiotensin converting enzyme inhibitor antihypertensive drugs, it has the advantages of stabilizing blood pressure and not causing dry cough. As a new generation of dual-function ARBS, azilsartan can not only antagonize angiotensin II (AT1) receptors, but also reduce the risk of cardiovascular disease and diabetes.

[0006] Prior art discloses a composition including amlodipine besylate and azilsartan, such as CN106668016A, CN105853418A, CN118717693A, CN118141775A, CN116440132A, CN107536818A, respectively, including solid preparations of amlodipine besylate and azilsartan. Most of the antihypertensive drugs currently on the market are tablets and granules, which are difficult to meet clinical medication needs for some patients with dysphagia. Based on medication compliance considerations, the present invention provides an azilsartan and amlodipine besylate oral suspension, which is easier to take, especially for the elderly or children. It is also easier to adjust the dosage to meet the needs of individual patients. However, the inventors have found that the product produced according to the current conventional oral suspension preparation process, the suspension after azilsartan and amlodipine besylate compounding, is prone to high viscosity and caking during long-term storage, and has poor stability. Although the reason is unknown, it may be due to some interaction between the two active ingredients of azilsartan and amlodipine besylate, which makes the suspension of the two drugs unstable. Long-term storage is prone to high viscosity and agglomeration of the drug solution, which makes it difficult to pour and affects the accuracy of the dosage, especially for patients with difficulty in taking medicine, affecting the safety and effectiveness of their medication. This is also the reason why there has been a lack of effective suspension dosage forms, although a large number of pharmaceutical compositions of azilsartan and amlodipine besylate have been reported in the prior art. Summary of the invention

[0007] In order to solve the problem that the suspension after compounding of azilsartan and amlodipine besylate is unstable, easy to become viscous and agglomerate, the present invention provides an azilsartan amlodipine besylate oral suspension and a preparation method thereof, which improves the high viscosity and agglomeration problems caused by long-term storage of ordinary suspension liquids through the compounded suspending agent, can ensure the accuracy of the dosage, and has good stability. It has the characteristics of simple ingredients, convenient administration, fast release of drug effect, and high utilization rate. The present invention achieves the above object through the following technical solutions:

[0008] The invention discloses an oral suspension of azilsartan and amlodipine besylate. The suspension comprises azilsartan and amlodipine besylate as active ingredients, xanthan gum and cross-linked sodium carboxymethyl cellulose as suspending agents, and water and glycerol as solvents. The mass ratio of xanthan gum to cross-linked sodium carboxymethyl cellulose is 20-30:5-8.

[0009] The inventor unexpectedly found that the above-mentioned compounded suspending agent and solvent are used to disperse azilsartan and amlodipine besylate in the suspension to form a thixotropic colloid, which can ensure that azilsartan and amlodipine besylate in the oral suspension are dispersed in the colloid without sedimentation and aggregation, and have high stability, which can smoothly solve the problem of instability of the suspension after azilsartan and amlodipine besylate are compounded. After testing, the sedimentation volume ratio was above 0.97 after being placed in a constant temperature and humidity incubator at a temperature of 40°C ± 2°C and a relative humidity of 75%RH ± 5%RH for 6 consecutive months.

[0010] Furthermore, the mass ratio of the active ingredient to the suspending agent is 1:0.28-1.5, preferably 1:0.5-1.2.

[0011] Further, the degree of substitution of croscarmellose sodium is 0.7-0.8, and the sedimentation volume is 16-25 mL. Preferably, the degree of substitution of croscarmellose sodium is 0.72-0.76, and the sedimentation volume is 18-22 mL.

[0012] Furthermore, the particle size D90 of azilsartan and amlodipine besylate is controlled to be 10-30 μm.

[0013] Furthermore, the oral suspension of azilsartan and amlodipine besylate provided by the present invention comprises the following ingredients: 2-6 mg / mL azilsartan, 0.6-1.5 mg / mL amlodipine besylate, 1-5 mg / mL suspending agent, 350-500 mg / mL glycerol, and water.

[0014] Furthermore, the azilsartan and amlodipine besylate oral suspension also includes the following excipients: sweeteners, flavoring agents, and antibacterial agents.

[0015] Furthermore, the sweetener is selected from at least one of maltitol, sucrose, sucralose, sodium saccharin, maltitol, acesulfame potassium, steviol glycosides, etc.; the antibacterial agent is selected from at least one of sodium benzoate, potassium benzoate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, potassium sorbate, chlorobutanol, benzalkonium chloride, and benzalkonium bromide; the flavoring agent is selected from at least one of strawberry flavor, menthol, orange flavor, pineapple flavor, cherry flavor, apple flavor, banana flavor, blueberry flavor, peach flavor, mango flavor, grape flavor, milk flavor, clove oil, and cardamom oil.

[0016] Furthermore, the concentration of the sweetener is 100-400 mg / mL, the concentration of the flavoring agent is 0.1-10 mg / mL, and the concentration of the antibacterial agent is 0.3-5 mg / mL.

[0017] The present invention also provides a method for preparing the azilsartan and amlodipine besylate oral suspension, comprising the following steps:

[0018] (1) The suspending agent is added to water and dispersed evenly by shearing equipment to form a uniform suspension system;

[0019] (2) Heat glycerol to 40-60°C, add an antibacterial agent, and dissolve it to prepare an antibacterial agent solution;

[0020] (3) Evenly mixing the sweetener, the flavoring agent, the suspension system obtained in step (1), and the antibacterial agent solution obtained in step (2) to obtain a dispersion for later use;

[0021] (4) The micronized azilsartan, amlodipine besylate and the dispersion obtained in step (3) are mixed uniformly and passed through a colloid mill to obtain a dispersion.

[0022] The present invention can achieve the following technical effects:

[0023] The present invention uses the compounding of cross-linked sodium carboxymethyl cellulose and xanthan gum as a suspending agent, disperses azilsartan and amlodipine besylate in the suspension, forms a thixotropic colloid, can ensure that azilsartan and amlodipine besylate in the oral suspension are dispersed in the colloid, will not settle, aggregate, and have high stability. When taken, it is convenient for adult patients with difficulty in swallowing to use, ensure the accuracy of the dosage, and improve the safety and effectiveness of the drug. The inventor has also tried a single-component suspending agent, or a suspending agent compounded with other components, but only a specific proportion of cross-linked sodium carboxymethyl cellulose and xanthan gum could achieve the best suspending effect.

[0024] The azilsartan amlodipine besylate oral suspension prepared by the present invention greatly improves the high viscosity and caking problems of common suspension liquids after long-term storage, thereby solving the key problem of affecting the accuracy of the dosage. The drug combination has good stability, good taste and good tolerance. DETAILED DESCRIPTION

[0025] The following examples will illustrate the present invention in more detail, but the present invention is not limited thereto.

[0026] Croscarmellose sodium was purchased from Shanghai Yuanye Biotechnology Co., Ltd. The degree of substitution of croscarmellose sodium 1 was 0.72, and the sedimentation volume was 18 mL. The degree of substitution of croscarmellose sodium 2 was 0.76, and the sedimentation volume was 22 mL.

[0027] Example 1

[0028] The raw materials and auxiliary materials are shown in Table 1 below.

[0029] Table 1 Example 1 Formulation

[0030] .

[0031] Preparation method:

[0032] Step 1: Add xanthan gum and cross-linked sodium carboxymethyl cellulose as suspending agents into water, and use high shear equipment at a shear speed of 2000 rpm for a shear time of 10 min to disperse them uniformly to form a uniform suspension system.

[0033] Step 2: Heat glycerol to 50°C and add methyl paraben to prepare an antibacterial solution;

[0034] Step 3: Evenly mix maltitol, strawberry essence, the suspension system obtained in step 1, and the antibacterial agent solution obtained in step 2 to obtain a dispersion for later use;

[0035] Step 4: Add the micronized azilsartan (20 μm), amlodipine besylate (20 μm), and the dispersion obtained in step 3 to a high shear device for high-speed shear stirring at a shear rate of 3000 rpm for a shear time of 10 min, and then pass through a colloid mill for 3 times to obtain the product.

[0036] Example 2

[0037] Other conditions were the same as those in Example 1, except that the amount of xanthan gum was changed to 4.0 mg / mL, and 0.8 mg / mL of croscarmellose sodium 1 was replaced with 1.0 mg / mL.

[0038] Example 3

[0039] The other conditions were the same as those in Example 1, except that the amount of croscarmellose sodium 1 was changed to 0.5 mg / mL.

[0040] Example 4

[0041] The other conditions were the same as those in Example 1, except that the amount of xanthan gum was changed to 2.0 mg / mL, and the amount of croscarmellose sodium 1 was changed to 0.5 mg / mL.

[0042] Example 5

[0043] The other conditions were the same as those in Example 1, except that the amount of xanthan gum was changed to 1.0 mg / mL, and the amount of croscarmellose sodium 1 was changed to 0.25 mg / mL.

[0044] Comparative Example 1

[0045] The other conditions were the same as those in Example 1, except that the suspending agent was 3.8 mg / L xanthan gum and no cross-linked sodium carboxymethyl cellulose was added.

[0046] Comparative Example 2

[0047] The other conditions were the same as those in Example 1, except that the suspending agent was 3.8 mg / L croscarmellose sodium and xanthan gum was not added.

[0048] Comparative Example 3

[0049] The other conditions were the same as those in Example 1, except that the xanthan gum was replaced with guar gum of equal mass concentration.

[0050] Comparative Example 4

[0051] The other conditions were the same as those in Example 1, except that the xanthan gum was replaced with an equal mass concentration of forsythia gum.

[0052] Comparative Example 5

[0053] The other conditions are the same as those in Example 1, except that the cross-linked sodium carboxymethylcellulose 1 is replaced by sodium carboxymethylcellulose of equal mass concentration, that is, the sodium carboxymethylcellulose is not cross-linked.

[0054] Comparative Example 6

[0055] The other conditions were the same as those in Example 1, except that the cross-linked carboxymethylcellulose sodium 1 was replaced with hypromellose of equal mass concentration.

[0056] Comparative Example 7

[0057] The other conditions were the same as those in Example 1, except that crosslinked sodium carboxymethylcellulose 1 was replaced with microcrystalline cellulose sodium carboxymethylcellulose of equal mass concentration.

[0058] Comparative Example 8

[0059] The other conditions were the same as those in Example 1, except that the amount of xanthan gum was changed to 1.9 mg / mL, and the amount of croscarmellose sodium 1 was changed to 1.9 mg / mL.

[0060] Application Examples

[0061] The samples of the above examples and comparative examples were placed in a constant temperature and humidity incubator at a temperature of 40°C ± 2°C and a relative humidity of 75 ± 5% RH for 6 consecutive months, and samples were taken for testing at 0, 3, and 6 months. The results of the test samples' taste, content, related substances, and sedimentation volume ratio are shown in Table 2 below.

[0062] Table 2 Example index test

[0063] .

[0064] According to the evaluation criteria for oral suspensions, the closer the sedimentation volume ratio is to 1, the more uniform the drug dispersion is. As can be seen from Table 2, the samples of Examples 1-4 of the present invention have ideal related substances and sedimentation volumes, indicating that the azilsartan and amlodipine besylate oral suspensions provided by the present invention have improved properties in terms of sedimentation volume ratio, are convenient for adult patients with difficulty in swallowing oral solid preparations, ensure the accuracy of the dosage, and improve the safety and effectiveness of the drug.

[0065] The suspension prepared in the comparative example was tested for sedimentation volume ratio under the same conditions. The results are shown in Table 3 below.

[0066] Table 3 Comparative example stability test

[0067] .

[0068] By comparing the examples and the comparative examples, it can be found that the azilsartan and amlodipine besylate oral suspension prepared by the present invention adopts the composite suspending agent of xanthan gum and cross-linked sodium carboxymethylcellulose, which significantly improves the stability of the suspension. If the composite system of xanthan gum and cross-linked sodium carboxymethylcellulose is changed, such as using a single xanthan gum or cross-linked sodium carboxymethylcellulose, or when xanthan gum / cross-linked sodium carboxymethylcellulose is replaced by other suspending agents, the above effect cannot be achieved. In addition, the ratio of xanthan gum and cross-linked sodium carboxymethylcellulose is also more important, and it is controlled within the range of suitable ratio to improve the stability of the suspension to the greatest extent.

Claims

1. An azilsartan and amlodipine besylate oral suspension, characterized in that: The suspension contains azilsartan and amlodipine besylate as active ingredients, xanthan gum and cross-linked carboxymethyl cellulose sodium as suspending agents, and water and glycerol as solvents; the mass ratio of xanthan gum to cross-linked carboxymethyl cellulose sodium is 20-30:5-8; The preparation method of the azilsartan and amlodipine besylate oral suspension comprises the following steps: (1) The suspending agent is added to water and dispersed evenly by shearing equipment to form a uniform suspension system; (2) Heat glycerol to 40-60°C, add an antibacterial agent, and dissolve it to prepare an antibacterial agent solution; (3) Evenly mixing the sweetener, the flavoring agent, the suspension system obtained in step (1), and the antibacterial agent solution obtained in step (2) to obtain a dispersion for later use; (4) The micronized azilsartan, amlodipine besylate and the dispersion prepared in step (3) are mixed uniformly and passed through a colloid mill to obtain a dispersion.

2. The oral suspension according to claim 1, characterized in that The mass ratio of active ingredient to suspending agent is 1:0.28-1.

5.

3. The oral suspension according to claim 1, characterized in that The mass ratio of active ingredient to suspending agent is 1:0.5-1.

2.

4. The oral suspension according to claim 1, characterized in that The degree of substitution of cross-linked carboxymethyl cellulose sodium is 0.7-0.8, and the sedimentation volume is 16-25 mL.

5. The oral suspension according to claim 1, characterized in that The particle size D90 of azilsartan and amlodipine besylate is 10~30μm.

6. The oral suspension according to claim 1, characterized in that Azilsartan and amlodipine besylate oral suspension comprises the following ingredients: 2-6 mg / mL azilsartan, 0.6-1.5 mg / mL amlodipine besylate, 1-5 mg / mL suspending agent, 350-500 mg / mL glycerol, and water.

7. The oral suspension according to claim 1, characterized in that The azilsartan and amlodipine besylate oral suspension is also Includes the following excipients: sweeteners, flavoring agents and antibacterial agents.

8. The oral suspension according to claim 7, characterized in that The sweetener is selected from at least one of maltitol, sucrose, sucralose, sodium saccharin, acesulfame potassium, and steviol glycosides; the antibacterial agent is selected from at least one of sodium benzoate, potassium benzoate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, potassium sorbate, chlorobutanol, benzalkonium chloride, and benzalkonium bromide; the flavoring agent is selected from at least one of strawberry flavor, menthol, orange flavor, pineapple flavor, cherry flavor, apple flavor, banana flavor, blueberry flavor, peach flavor, mango flavor, grape flavor, milk flavor, clove oil, and cardamom oil.

9. The oral suspension according to claim 7, characterized in that The concentration of the sweetener is 100-400 mg / mL, the concentration of the flavoring agent is 0.1-10 mg / mL, and the concentration of the antibacterial agent is 0.3-5 mg / mL.