Candihydro-thiadiazole tablet and application thereof in treating hypertension

Abstract

The invention belongs to the field of medicaments, and provides candesartan cilexetil, 5-8 mg of hydrochlorothiazide, 7-10 mg of PEG (polyethylene glycol) 8000, 60-90 mg of lactose monohydrate, 3-8 mg of HPMC (hydroxypropyl methyl cellulose), 0.1-1 mg of magnesium stearate and 3-8 mg of disintegrating agent per 110 mg of the candesartan cilexetil, the hydrochlorothiazide, the PEG 8000, the lactose monohydrate, the HPMC, the magnesium stearate and the disintegrating agent. By selecting a proper disintegrating agent combination, the candesthia tablet disclosed by the invention effectively improves the dissolution performance in artificial gastric juice, and a basis is provided for further improvement of the drug effect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicaments, and in particular, the present application provides a candihydrothiazide tablet and its application in treating hypertension. BACKGROUND

[0002] Candesartan cilexitil is a diphenyl tetramimazole angiotensin II receptor antagonist, which can effectively reduce the blood pressure of patients with mild and moderate hypertension, while providing lower side effects; hydrochlorothiazide is a common diuretic antihypertensive drug. The combination of the two effects of candihydrothiazide preparation (mainly tablets) is a commonly used drug for treating primary hypertension with poor single-drug control effect.

[0003] Candesartan cilexitil and hydrochlorothiazide have very low solubility and certain hydrophobicity, and the mutual influence of the two in the candihydrothiazide tablet will further reduce the dissolution performance, especially the dissolution performance of candesartan cilexitil, which brings obstacles to the exertion of the effect of the drug. SUMMARY

[0004] To solve the above problems, on the one hand, the present application provides a candihydrothiazide tablet, which contains 6-10 mg of candesartan cilexitil, 5-8 mg of hydrochlorothiazide, 7-10 mg of PEG 8000, 60-90 mg of lactose monohydrate, 3-8 mg of HPMC, 0.1-1 mg of magnesium stearate, and 3-8 mg of disintegrant per 110 mg.

[0005] Further, the candihydrothiazide tablet consists of 8 mg of candesartan cilexitil, 6.25 mg of hydrochlorothiazide, 8.75 mg of PEG 8000, 78 mg of lactose monohydrate, 4 mg of HPMC, 0.5 mg of magnesium stearate, and 4.5 mg of disintegrant per 110 mg.

[0006] Further, the disintegrant is calcium alginate or chitosan and Span 60.

[0007] Further, the disintegrant is calcium alginate and Span 60 with a mass ratio of 3.5:1.

[0008] Further, the disintegrant is chitosan and Span 60 with a mass ratio of 3:1.5.

[0009] Further, the preparation method of the candihydrothiazide tablet comprises: Mixing candesartan cilexitil, hydrochlorothiazide, PEG 8000, lactose monohydrate and disintegrant uniformly; adding 10% HPMC solution to the mixture to prepare soft material, sieving and granulating, drying and granulating; adding magnesium stearate and mixing uniformly; and tabletting.

[0010] Further, the preparation method of the candihydrothiazide tablet further comprises a raw material sieving step.

[0011] Furthermore, the preparation method of the candelabihydrothiazide tablets also includes a packaging step.

[0012] On the other hand, this application provides the use of the above-mentioned candehydrothiazide tablets in the preparation of a drug for treating essential hypertension.

[0013] Furthermore, the primary hypertension referred to is primary hypertension that is not well controlled by a single drug.

[0014] The various parameters in the preparation method of the drug in this application, including but not limited to sieve mesh size, temperature, rotation speed, and HPMC concentration, can be routinely adjusted by those skilled in the art based on specific equipment and raw materials.

[0015] By selecting a suitable combination of disintegrants, the candelabiol tablets of this application effectively improve the dissolution performance in artificial gastric juice, providing a solution for the rapid dissolution of the two components under various conditions and further improving the efficacy. Attached Figure Description

[0016] Figure 1 The dissolution curves of the formulation in Example 2 are shown in PBS at pH 6.5 and in artificial gastric fluid.

[0017] Figure 2 Dissolution profiles of formulations 1-4 in PBS and artificial gastric fluid at pH 6.5 are shown.

[0018] Figure 3 Dissolution profiles of formulations 1-1, 1-2, 3-1, and 3-2 in PBS and artificial gastric fluid at pH 6.5 are shown.

[0019] Figure 4 Dissolution curves of candesartan cilexetil in artificial gastric fluid for formulations 1-1 and 1-3 with adjusted disintegrant ratios (upper part is the improvement of 1-1, lower part is the improvement of 1-3).

[0020] Figure 5 Dissolution profiles of the preferred technical solutions (Formulations 1-2, Ratio 4) in PBS and artificial gastric fluid at pH 6.5. Detailed Implementation Example 1: Main Raw Materials and Methods

[0021] raw material: Candesartan medoxomil (D90: 60 μm) was purchased from Wuhan Kabel.

[0022] Hydrochlorothiazide (D90: 90μm) was purchased from Panlong Yihai, Shanxi.

[0023] PEG 8000, lactose monohydrate, croscarmellose sodium cellulose, calcium alginate, sodium alginate, chitosan, sodium carboxymethyl starch, Tween 80 (spray-prepared powder form), and Span 80 were purchased from Shanghai Yuanye, Xi'an Tianzheng Pharmaceutical, Wuhan Lvjingfenghua, etc., and are all pharmaceutical grade.

[0024] Artificial gastric fluid was purchased from Shanghai Yuanye.

[0025] Chromatographic detection methods: The contents of candesartan medoxomil and hydrochlorothiazide were determined using HPLC. Standard curves were constructed using candesartan medoxomil and hydrochlorothiazide standards. The recoveries (ranges of 99.87-100.12% for different samples) and precision (RSDs of 0.77-1.36% for different samples) were determined. Specific equipment and parameters are as follows. Instrument: Waters Alliance 2695 with C18 column (Waters, 50mm × 4.6mm, 5μm); Mobile phase: Acetonitrile-water in a volume ratio of 40:60 (pH adjusted to 2.5 with phosphoric acid); Column temperature: 30℃; flow rate: 1.0mL / min; detection wavelength: 210nm; injection volume: 5μL. Example 2: Basic Formulation and Properties of Tablets

[0026] The basic formulation for existing tablet designs is shown in Table 1: Table 1. Basic Formula for 110mg Tablets

[0027] Mix candesartan medoxomil, hydrochlorothiazide, PEG 8000, lactose monohydrate and croscarmellose sodium evenly; add 10% HPMC solution to the mixture to make a soft mass, granulate through a 20-mesh sieve, dry and granulate; add magnesium stearate and mix evenly; compress into tablets (tablet weight 110mg, weight difference ≤2.3%, hardness 103-118N).

[0028] According to the pharmacopoeia, the dissolution rate was determined in PBS at pH 6.5 (slurry method, 75 rpm), and the dissolution rate in artificial gastric fluid was also determined. The results are as follows: Figure 1 As shown, the dissolution performance of both drugs in PBS at pH 6.5 basically met the requirements. In simulated gastric fluid, the dissolution performance of hydrochlorothiazide was largely unaffected, but the dissolution rate of candesartan medoxomil was significantly reduced. This problem not only existed in the formulation of Example 2, but also, according to testing, commercially available joint-venture brand candesartiazide drugs exhibited the same issue. Since the actual dissolution of the drugs primarily occurs in the gastrointestinal tract, such dissolution defects at low pH, especially the dissolution problem of candesartan medoxomil, are a significant limitation on the correct and rapid exertion of the drug's efficacy. Example 3 Replacement of disintegrant

[0029] The applicant attempted to replace several similar disintegrants to address the dissolution problem in Example 2, as detailed in Table 2: Table 2 shows the formulation for replacing the disintegrant (other ingredients are the same as in Table 1).

[0030] The dissolution effects of formulations 1-4 in PBS at pH 6.5 and in simulated gastric fluid were tested as described in Example 2, and the results are as follows: Figure 2 As shown (for ease of comparison), Figure 2 (Only representative 20-minute dissolution ratios are shown): The dissolution effect of hydrochlorothiazide is similar in all formulations. Calcium alginate and chitosan help improve the dissolution performance of candesartan cilexetil in artificial gastric fluid, but the improvement is limited and has an adverse effect on dissolution at high pH.

[0031] Further attempts were made to introduce surfactants into formulations 1 and 3, as shown in Table 3: Table 3 further introduces surfactants (other components are the same as in Table 1).

[0032] The dissolution effect of the formulation in Table 3 in PBS at pH 6.5 and in simulated gastric fluid was tested according to the description in Example 2, and the results are as follows: Figure 3 As shown (for ease of comparison), Figure 3 (Only representative dissolution ratios at 20 minutes are shown). The results show that the addition of Span80 effectively improved the problems of formulations 1 and 3, with good dissolution effects in pH 6.5 PBS and artificial gastric fluid, showing significant improvement over the formulation of Example 1. Example 4: Optimization of Disintegrant Ratio

[0033] The dosage of disintegrant (calcium alginate or chitosan plus Span 60) was kept constant at 4.5 mg / tablet. Ratios of calcium alginate or chitosan to Span 80 were tested at 2:2.5 (ratio 1), 2.5:2 (ratio 2), 3:1.5 (ratio 3), and 3.5:1 (ratio 4). The results are as follows... Figure 4 As shown (due to the minimal change in the dissolution properties of hydrochlorothiazide at pH 6.5). Figure 4 (Only the dissolution effect of candesartan cilexetil at low pH is shown): The dissolution effects of different ratios of chitosan and Span 60 are not significantly different, but the dissolution effect of the 3.5:1 ratio of calcium alginate and Span 60 is further improved. For the complete dissolution effect of the 3.5:1 ratio of calcium alginate and Span 60, see [link to full dissolution data]. Figure 5While maintaining the dissolution performance under pharmacopoeia standards, the dissolution performance in gastric juice has also been significantly improved, approaching the dissolution effect at pH 6.5.

Claims

1. A candelabiol tablet, characterized in that, Each 110mg dose of the candesartan tablets contains 6-10mg of candesartan medoxomil, 5-8mg of hydrochlorothiazide, 7-10mg of PEG 8000, 60-90mg of lactose monohydrate, 3-8mg of HPMC, 0.1-1mg of magnesium stearate, and 3-8mg of disintegrant.

2. The candesartan tablets according to claim 1, wherein each 110mg of candesartan tablets comprises 8mg of candesartan medoxomil, 6.25mg of hydrochlorothiazide, 8.75mg of PEG 8000, 78mg of lactose monohydrate, 4mg of HPMC, 0.5mg of magnesium stearate, and 4.5mg of disintegrant.

3. The candelabiol tablets according to claim 1, wherein the disintegrant is calcium alginate or chitosan and Span 60.

4. The candelabiol tablets according to claim 3, wherein the disintegrant is calcium alginate and Span 60 in a mass ratio of 3.5:

1.

5. The candelabiol tablets according to claim 3, wherein the disintegrant is chitosan and Span 60 in a mass ratio of 3:1.

5.

6. The candelabhione tablets according to any one of claims 1-5, wherein the method for preparing the candelabhione tablets comprises: Mix candesartan medoxomil, hydrochlorothiazide, PEG 8000, lactose monohydrate and disintegrant evenly; add 10% HPMC solution to the mixture to make a soft mass, sieve and granulate, dry and granulate; add magnesium stearate and mix evenly; compress into tablets.

7. The candelabhione tablets according to claim 6, wherein the preparation method of the candelabhione tablets further includes a raw material sieving step.

8. The candelabhione tablets according to claim 6, wherein the preparation method of the candelabhione tablets further includes a packaging step.

9. The use of candelabiol tablets according to any one of claims 1-8 in the preparation of a medicament for treating essential hypertension.

10. The application according to claim 9, wherein the primary hypertension is primary hypertension that is not well controlled by a single drug.

Images