Azilsartan pharmaceutical composition and preparation method thereof

Abstract

The invention relates to the technical field of medicines, in particular to an azilsartan pharmaceutical composition and a preparation method thereof, and the pharmaceutical composition comprises azilsartan, light calcium carbonate, polyethylene glycol 6000, a filler, an adhesive, a disintegrating agent and a lubricant. The azilsartan pharmaceutical composition has the beneficial effects that the prepared azilsartan pharmaceutical composition sample generates few degradation impurities in the production and storage processes, is good in stability, has no obvious difference from an original product, and has a slight advantage potential.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to an azilsartan pharmaceutical composition and a preparation method thereof. Background Art

[0002] Hypertension is the most common cardiovascular disease, which can cause changes in the function and structure of the heart and blood vessels. According to statistics, the prevalence of hypertension in my country has reached 18.8%, but the control rate is only. At present, the commonly used drugs for the treatment of hypertension in clinical practice include diuretics, angiotensin-converting enzyme inhibitors (ACEI), calcium antagonists, α-receptor blockers, imidazoline receptor agonists, and angiotensin II receptor blockers (ARB). ARB drugs are widely used in the treatment of cardiovascular diseases because of their stable and effective antihypertensive effects, protective effects on target organs such as the heart, brain and kidneys, improved lipid metabolism, no effect on bradykinin degradation and prostaglandin synthesis, thus avoiding adverse reactions such as dry cough and angioedema. Currently available ARB drugs include valsartan, telmisartan, olmesartan, irbesartan, losartan, candesartan cilexetil, tasosartan and eprosartan.

[0003] Angiotensin II (Ang II) is converted from angiotensin I (Ang I) by angiotensin converting enzyme (ACE, kininase II). It is a key product of the renin-angiotensin system (RAS) and plays a major role in the pathophysiological process of hypertension. There are two types of Ang II receptors: type 1 (AT1) and type 2 (AT2). In many tissues (such as vascular smooth muscle, adrenal glands, kidneys and heart), Ang II binds to AT1 receptors, causing several important biological effects, including vasoconstriction, aldosterone release, cardiac contraction, sodium reabsorption and stimulation of smooth muscle cell proliferation. AT2 receptors are also widely distributed, but their role in the functional homeostasis of the cardiovascular system is still unclear.

[0004] Azilsartan (Azi) is a new generation of selective AT1 subtype angiotensin II receptor antagonists (ARBs) antihypertensive drugs, developed by Takeda Pharmaceuticals (Takeda) of Japan, and approved for marketing in Japan in 2012 under the trade name "Azilva". As a new generation of angiotensin II receptor antagonists, azilsartan is mainly used in the clinical treatment of hypertension. It can inhibit the activity of angiotensin II, thereby dilating blood vessels and lowering blood pressure, and at the same time has a protective effect on target organs such as the cardiovascular system and kidneys. As an antihypertensive drug, azilsartan has been widely used in clinical treatment. In addition to its antihypertensive effect, azilsartan also has a good protective effect on target organs such as the kidneys, which can reduce the risk of cardiovascular events in patients with hypertension.

[0005] The molecular formula of Azilsartan is C25H20N4O5, and its chemical name is 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid. Azilsartan has the following obvious advantages: 1. It has many binding sites. Compared with other RAB drugs, Azilsartan is one of the drugs with the most binding sites with AT1, with 4 binding sites like candesartan and olmesartan medoxomil; 2. It has outstanding pharmacokinetic characteristics, with a fast peak time of about 2 hours, an absorption bioavailability of 75%, and a plasma protein binding rate of more than 99%; 3. It has a stable blood pressure reduction, a half-life of up to 13 hours, a single dose lasts for 24 hours, and a low rebound after drug withdrawal; 4. It can improve ventricular diastolic function in patients with heart failure and hypertension and reduce arrhythmias; 5. It is rarely excreted from the kidneys, protecting renal function.

[0006] The current marketed preparations of azilsartan are mainly tablets, namely azilsartan tablets. Although azilsartan has many obvious advantages, due to the presence of carboxylate and ethoxy groups in its chemical structure, it is easy to produce degradation impurities during the production and storage process. Summary of the invention

[0007] In view of the above-mentioned shortcomings of the prior art, the present invention provides an azilsartan pharmaceutical composition and a preparation method thereof, wherein the azilsartan pharmaceutical composition is prepared by using a dual stabilizer, thereby reducing degradation impurities generated during its production and storage process, and having better drug stability. The stability thereof is not significantly different from that of the original product, and has a slight advantage.

[0008] The objective of the present invention is achieved through the following technical solutions:

[0009] The invention provides an azilsartan pharmaceutical composition, comprising: azilsartan, light calcium carbonate, polyethylene glycol 6000, a filler, a binder, a disintegrant and a lubricant.

[0010] Furthermore, the pharmaceutical composition comprises, by weight: 10 to 40 parts of azilsartan, 10 to 20 parts of light calcium carbonate, 4 to 8 parts of polyethylene glycol, 75 to 150 parts of filler, 2 to 4 parts of binder, 13 to 26 parts of disintegrant, and 1 to 2 parts of lubricant.

[0011] Furthermore, the polyethylene glycol is polyethylene glycol 6000.

[0012] The current marketed preparations of azilsartan are mainly tablets, with marketed specifications of 20mg and 40mg. Azilsartan is prone to produce degradation impurities during production and storage. The original research uses polyethylene glycol 6000 as a single stabilizer, which has a good effect. However, under the premise of using the same excipients as the original research (domestic excipients, the variety is consistent with the original research) and the same process, the impurity spectrum of the obtained product is still quite different from that of the original research. The inventors of the present disclosure have found through research that the use of polyethylene glycol 6000 and light calcium carbonate as dual stabilizers, the impurity spectrum of the obtained sample has no significant difference from the original product after stability inspection and has a slight advantage.

[0013] Furthermore, the filler includes one or more of lactose monohydrate, microcrystalline cellulose, and starch.

[0014] Furthermore, the disintegrant is low-substituted hydroxypropyl cellulose; and / or the lubricant is magnesium stearate; and / or the binder is hydroxypropyl cellulose EF.

[0015] Furthermore, the particle size of the azilsartan is D90≤8μm.

[0016] Furthermore, the azilsartan pharmaceutical composition also includes a pharmaceutically acceptable adjuvant.

[0017] The present invention also provides a preparation method, which can be used to prepare the above-mentioned azilsartan pharmaceutical composition, comprising the following steps:

[0018] S1. Mix azilsartan, stabilizer polyethylene glycol 6000 and light calcium carbonate evenly;

[0019] S2, mixing the mixture obtained in step S1 with a filler, a disintegrant, and a lubricant to obtain a powder;

[0020] S3, mixing the adhesive with water to obtain an adhesive solution;

[0021] S4, adding the powder into the adhesive solution, stirring evenly to obtain a soft material;

[0022] S5, wet granulating the prepared soft material to obtain wet granules;

[0023] S6. Dry the wet granules at 55-65° C. until the moisture content is less than 5%, and sieve the granules to obtain the azilsartan pharmaceutical composition.

[0024] Furthermore, in step S3, the solubility of the prepared adhesive solution is 4%.

[0025] Furthermore, in step S6, the wet granules are dried and then sieved through a 24-mesh sieve for size adjustment.

[0026] The beneficial effects of the present invention are:

[0027] The present invention provides an azilsartan pharmaceutical composition and a preparation method thereof. Compared with the prior art, the present invention has the following beneficial effects: in this scheme, polyethylene glycol 6000 and light calcium carbonate are used as dual stabilizers to prepare an azilsartan pharmaceutical composition sample, which produces less degradation impurities during production and storage, has good stability, has no significant difference from the original research product, and has a slight advantage. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 is the chemical structural formula of azilsartan;

[0029] Figure 2 is the chemical structural formula of impurity A, whose molecular formula is C 23 H 16 N4O5;

[0030] Figure 3 is the chemical structural formula of impurity B, whose molecular formula is C 27 H 24 N4O5;

[0031] Figure 4 is the chemical structural formula of impurity C, whose molecular formula is C 25 H 23 N3O4;

[0032] Figure 5 is the chemical structural formula of impurity D, whose molecular formula is C 24 H 21 N3O4;

[0033] Figure 6 is the chemical structural formula of impurity E, whose molecular formula is C24H22N4O4;

[0034] Figure 7 is the chemical structural formula of impurity F, whose molecular formula is C26H22N4O5;

[0035] Figure 8 is the chemical structural formula of impurity G, whose molecular formula is C24H22N4O3;

[0036] Fig. 9 is the chemical structural formula of impurity H, and its molecular formula is C24H18N4O4;

[0037] Fig.10 is the chemical structural formula of impurity J, and its molecular formula is C26H25N3O4. DETAILED DESCRIPTION

[0038] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0039] The present invention will be further described below in conjunction with the embodiments.

[0040] Example

[0041] Wet granulation, prescription:

[0042] Table 1 Prescription table

[0043]

[0044]

[0045] Process: Azilsartan is first mixed evenly with the stabilizer polyethylene glycol 6000 and light calcium carbonate, and then mixed evenly with the filler lactose monohydrate, microcrystalline cellulose, starch and disintegrant low-substituted hydroxypropyl cellulose; hydroxypropyl cellulose EF is prepared into a 4% low-viscosity solution as a binder; the prepared powder is added to the above mixed materials, stirred and wet granulated with a 24-mesh sieve, dried at 55-65°C to a moisture content of <5%, and sieved through a 24-mesh sieve before adding.

[0046] Among them, the particle size of azilsartan is controlled at D90 of no more than 8 microns;

[0047] Comparative test of dissolution rate of self-made example samples and original research samples at each time point:

[0048] Method: According to the dissolution and release test method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules, 0931, Method 2);

[0049] Dissolution conditions: Use 900 ml of 0.5% sodium dodecyl sulfate solution as the dissolution medium and rotate at 50 rpm in accordance with the law.

[0050] Preparation of test solution: Take an appropriate amount of dissolution solution, filter, accurately measure 5 ml of the filtrate injection solution, place it in a 10 ml volumetric flask, and dilute to the scale with 0.5% sodium dodecyl sulfate solution.

[0051] Preparation of reference solution: Take an appropriate amount of reference substance, accurately weigh it, add an appropriate amount of methanol to dissolve azilsartan, and dilute it with methanol to make a solution containing 10 mg of azilsartan per ml. Filter, accurately measure 1 ml and place it in a 100 ml volumetric flask, and dilute to the scale with 0.5% sodium dodecyl sulfate solution.

[0052] Test results (as shown in Table 2): The similarity between Example 1 and the original research is 67.6, and the similarity between Example 2 and the original research is 67.5, both of which are greater than 50. This shows that the preparation method of the present invention is feasible.

[0053] Table 2

[0054] Sampling time point Original research, % Example 1, % Example 2, % 5min 30 22 25 10min 58 59 62 15min 81 84 85 20min 94 93 96 30min 99 98 101

[0055] The dissolution limit standard stipulates that no less than 80% should be achieved in 30 minutes. Both the original research and the examples meet the requirements.

[0056] Comparative Examples 1 to 3

[0057] Specification: 20 mg. For detailed prescription, please see Table 3:

[0058] Table 3 Prescription table

[0059]

[0060]

[0061] The samples of Example 2 and Comparative Examples 1, 2 and 3 were subjected to stability tests, and the impurity spectra of each impurity were recorded.

[0062] Detection of impurities (related substances):

[0063] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Part IV General Rules 0512);

[0064] Preparation of test solution: Grind the sample prepared in the above example into fine powder, take an appropriate amount (equivalent to 10 mg of azilsartan), accurately weigh, place in a 20 ml volumetric flask, add an appropriate amount of methanol, shake to dissolve azilsartan and dilute to the scale, shake well, filter, and take the filtrate for testing.

[0065] Control solution: Accurately measure 1 ml of the test solution, place it in a 100 ml volumetric flask, dilute to the mark with methanol, and shake well.

[0066] Sensitivity solution: Accurately measure 1 ml of the control solution and place it in a 50 ml volumetric flask, dilute to the mark with methanol, and shake well.

[0067] System suitability solution: Weigh approximately 10 mg each of impurity A, impurity B, impurity C, impurity D, impurity E, impurity F, impurity G, impurity J and azilsartan reference substance, place each in a 200 ml volumetric flask, dilute to the mark with methanol, shake well, and use as the test stock solution; accurately measure 1 ml of the stock solution and place it in a 10 ml volumetric flask, dilute to the mark with methanol, and shake well.

[0068] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler, 10 mmol / L sodium octane sulfonate buffer (pH adjusted to 3.0 with phosphoric acid) was used as mobile phase A, acetonitrile was used as mobile phase B, gradient elution was performed according to Table 4 below, the flow rate was 1.0 ml / min, the detection wavelength was 250 nm, and the injection volume was 10 μl.

[0069] Table 4

[0070] Time (min) Mobile phase A (%) Mobile phase B (%) 0 70 30 5 70 30 30 35 65 40 35 65 40.1 70 30 50 70 30

[0071] System suitability requirements: In the system suitability solution chromatogram, the peak separation of each substance should meet the requirements; in the sensitivity solution chromatogram, the signal-to-noise ratio of the main component peak height should be greater than 10.

[0072] Determination method: Accurately measure 10 ml each of system suitability test solution, test solution, control solution, and sensitivity solution, and inject them into the chromatograph to record the chromatogram.

[0073] Limits: If there are impurity peaks in the chromatogram of the test solution, calculated by the corrected peak area (divided by the relative response factor 0.8), impurity A and impurity B shall not be greater than 0.5 times (0.5%) the main peak area of ​​the control solution; other single impurity peaks shall not be greater than 0.2 times (0.2%) the main peak area of ​​the control solution; the total area of ​​all impurity peaks (i.e., total impurities) shall not be greater than 1.5 times (1.5%) the main peak area of ​​the control solution.

[0074] The comparison results of the impurity profiles of the samples of the present invention, comparative examples 1 to 3, and the original research are shown in Table 5. The molecular formula of Azilsartan is as follows Figure 1 As shown, the molecular formulas of impurities A to J are as follows Figures 2 to 10 shown.

[0075] Experimental results: The total impurity amount of the sample in this embodiment after acceleration for 6 months is 0.88, and the total impurity amount after a length of 12 months is 0.79, both of which are better than those of Comparative Examples 1 to 3. It can be seen that the azilsartan pharmaceutical composition prepared by using polyethylene glycol 6000 and light calcium carbonate as dual stabilizers has better stability than the azilsartan pharmaceutical composition prepared by using only polyethylene glycol 6000 or light calcium carbonate as stabilizers. It can be seen from Table 5 that the sample in this embodiment also has a slight advantage over the original drug.

[0076] Table 5 Impurity spectrum comparison results

[0077]

[0078] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Anyone familiar with the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by a person of ordinary skill in the art without departing from the spirit and technical concept disclosed by the present invention shall still be covered by the claims of the present invention.

Claims

1. An azilsartan pharmaceutical composition, characterized in that: Include: Azilsartan, light calcium carbonate, polyethylene glycol 6000, filler, binder, disintegrant, lubricant.

2. An azilsartan pharmaceutical composition according to claim 1, characterized in that: The pharmaceutical composition comprises, by weight, 10 to 40 parts of azilsartan, 10 to 20 parts of light calcium carbonate, 4 to 8 parts of polyethylene glycol, 75 to 150 parts of a filler, 2 to 4 parts of a binder, 13 to 26 parts of a disintegrant, and 1 to 2 parts of a lubricant.

3. An azilsartan pharmaceutical composition according to claim 1, characterized in that: The polyethylene glycol is polyethylene glycol 6000.

4. An azilsartan pharmaceutical composition according to claim 1, characterized in that: The filler includes one or more of lactose monohydrate, microcrystalline cellulose, and starch.

5. An azilsartan pharmaceutical composition according to claim 1, characterized in that: The disintegrant is low-substituted hydroxypropyl cellulose; and / or The lubricant is magnesium stearate; and / or The binder is hydroxypropylcellulose EF.

6. An azilsartan pharmaceutical composition according to claim 1, characterized in that: The azilsartan particle size D90≤8μm.

7. An azilsartan pharmaceutical composition according to any one of claims 1 to 6, characterized in that: The azilsartan pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant.

8. A preparation method, which can be used to prepare an azilsartan pharmaceutical composition according to any one of claims 1 to 6, characterized in that: The following steps are involved: S1. Mix azilsartan, stabilizer polyethylene glycol 6000 and light calcium carbonate evenly; S2, mixing the mixture obtained in step S1 with a filler, a disintegrant, and a lubricant to obtain a powder; S3, mixing the adhesive with water to obtain an adhesive solution; S4, adding the powder into the adhesive solution, stirring evenly to obtain a soft material; S5, wet granulating the prepared soft material to obtain wet granules; S6. Dry the wet granules at 55-65° C. until the moisture content is less than 5%, and sieve the granules to obtain the azilsartan pharmaceutical composition.

9. The preparation method according to claim 8, characterized in that: In step S3, the solubility of the prepared adhesive solution is 4%.

10. The preparation method according to claim 8, characterized in that: In the step S6, the wet granules are dried and sieved through a 24-mesh sieve for size adjustment.

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