Lisinopril amlodipine compound sustained-release tablet and preparation method thereof

Abstract

The invention discloses a lisinopril amlodipine compound sustained-release tablet and a preparation method thereof, the compound sustained-release tablet comprises a sustained-release part and a quick-release part, the sustained-release part is a sustained-release pellet and comprises lisinopril, amlodipine besylate, a sustained-release substrate ethyl cellulose, hydroxypropyl methylcellulose and talcum powder, and the quick-release part is a sustained-release pellet and comprises a sustained-release part and a quick-release part. The quick release part comprises lisinopril, amlodipine, microcrystalline cellulose and carboxymethyl starch sodium. The compound sustained release tablet can maintain drug sustained release within 24 hours, and the phenomenon of large peak valley is avoided, so that stable pressure reduction during administration is realized.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a lisinopril-amlodipine compound sustained-release tablet and a preparation method thereof. Background Art

[0002] Amlodipine besylate is a third-generation calcium channel blocker (CCB) that blocks extracellular calcium influx into myocardial and vascular smooth muscle cells, moderates and prolongs the dilation of peripheral and coronary arteries, and reduces vascular resistance. It is used to treat various degrees of hypertension, as well as variant angina and stable angina. It has few adverse reactions and is one of the most clinically effective antihypertensive drugs. Lisinopril is a new-generation angiotensin-converting enzyme inhibitor (ACEI) that primarily lowers blood pressure by inhibiting the renin-angiotensin-aldosterone system.

[0003] Existing research shows that amlodipine besylate and lisinopril are two different types of antihypertensive drugs. Their combined use has a certain synergistic effect, can improve clinical efficacy, and has high clinical application value. The preparation of amlodipine besylate and lisinopril into a compound preparation can improve patient compliance.

[0004] Chinese patent CN102423482B discloses a method for preparing compound amlodipine and lisinopril tablets, which uses a tert-butyl alcohol solution as a binder and a wet granulation method to prepare granules. This method can maintain good drug content uniformity, but does not have sustained-release properties.

[0005] Chinese patent CN107029208A discloses a lisinopril compound preparation for treating cardiovascular diseases, which contains lisinopril, levamlodipine besylate, and hydrochlorothiazide. The preparation only embodies the three antihypertensive drugs as a new compound preparation and does not have sustained-release properties. Summary of the Invention

[0006] The present invention aims to provide a lisinopril-amlodipine compound sustained-release tablet and a preparation method thereof. In the compound sustained-release tablet, lisinopril and amlodipine in the immediate-release portion are rapidly released to quickly exert a blood pressure-lowering effect, while lisinopril and amlodipine in the sustained-release portion are slowly released to maintain continuous drug release within 24 hours, avoiding large peaks and valleys, thereby achieving stable blood pressure reduction during administration.

[0007] To achieve the purpose of the present invention, the following embodiments are provided.

[0008] In one embodiment, a lisinopril and amlodipine compound sustained-release tablet of the present invention comprises a sustained-release portion and a rapid-release portion, wherein the sustained-release portion is a sustained-release pellet comprising lisinopril, amlodipine besylate, a sustained-release matrix material ethyl cellulose, hypromellose and talc, and the rapid-release portion comprises lisinopril, amlodipine, microcrystalline cellulose and sodium starch glycolate.

[0009] In a specific embodiment, a lisinopril and amlodipine compound sustained-release tablet of the present invention comprises a sustained-release portion and a rapid-release portion, wherein the sustained-release portion is a sustained-release pellet comprising 5 parts of amlodipine besylate (calculated as amlodipine), 10 parts of lisinopril, 18-26 parts of sucrose pellet cores, 4.5-5.5 parts of ethyl cellulose, 5 parts of hypromellose and 5 parts of talc; and the rapid-release portion comprises, in parts by weight, 5 parts of amlodipine besylate (calculated as amlodipine), 10 parts of lisinopril, 175-187 parts of microcrystalline cellulose and 4-8 parts of sodium starch glycolate.

[0010] Preferably, in the above-mentioned compound sustained-release tablet of the present invention, the weight ratio of amlodipine besylate in the sustained-release portion to amlodipine besylate in the immediate-release portion is 1:1, and the weight ratio of lisinopril in the sustained-release portion to lisinopril in the immediate-release portion is 1:1.

[0011] Preferably, the above-mentioned compound sustained-release tablet of the present invention further comprises 2-4 parts by weight of magnesium stearate, and the magnesium stearate is an external lubricant and basically belongs to the immediate-release part.

[0012] In another embodiment, the present invention provides a method for preparing lisinopril and amlodipine compound sustained-release tablets, comprising the following steps:

[0013] 1) dispersing the sustained-release matrix ethylcellulose in purified water, and then adding amlodipine besylate and lisinopril to form a suspension;

[0014] 2) Dispersing hypromellose and talc in purified water to prepare an outer coating solution;

[0015] 3) Using the sucrose pellets as the base, spray the suspension from step 1) onto the sucrose pellets using a fluidized bed bottom spray method, dry the resulting pellets, and pass them through a 20-40 mesh sieve;

[0016] 4) The pellets prepared in the previous step are coated with the outer coating solution of step 2) by spraying in a fluidized bed bottom spraying method, and dried to obtain sustained-release pellets;

[0017] 5) adding amlodipine besylate, lisinopril, microcrystalline cellulose, and sodium starch glycolate into a mixer and mixing uniformly to prepare an immediate-release powder;

[0018] 6) The sustained-release pellets from step 4) and the immediate-release powder from step 5) are added to a mixer and mixed, and magnesium stearate is added and continued to mix. After mixing, the mixture is compressed into tablets to obtain the target compound sustained-release tablets.

[0019] Preferably, in the above preparation method, in step 1), the weight portion of purified water is 56-64 parts.

[0020] Preferably, in the above preparation method, in step 2), the weight portion of purified water is 50 parts.

[0021] In a specific embodiment, the method for preparing the lisinopril and amlodipine compound sustained-release tablets of the present invention comprises the following steps:

[0022] 1) Preparation of sustained-release pellets: Disperse 4.5-5.5 parts of the sustained-release matrix ethylcellulose in 56-64 parts of purified water, then add 5 parts of amlodipine besylate (calculated as amlodipine) and 10 parts of lisinopril to prepare a sustained-release drug suspension;

[0023] 2) Dispersing 5 parts of hypromellose and 5 parts of talc in 50 parts of purified water to prepare an outer coating solution;

[0024] 3) Using a fluidized bed bottom spray method, the drug suspension is sprayed onto 18-26 parts of sucrose pellet cores, dried after spraying, and passed through a 20-40 mesh sieve to obtain micropellets. The outer coating liquid is then sprayed onto the surface of the micropellets for coating. After coating, the pellets are dried to obtain sustained-release micropellets;

[0025] 4) adding 5 parts of amlodipine besylate (calculated as amlodipine), 10 parts of lisinopril, 175.5-186.5 parts of microcrystalline cellulose, and 4-8 parts of sodium starch glycolate into a mixer and mixing until uniformly mixed to obtain an immediate-release powder;

[0026] 5) Add the sustained-release pellets and immediate-release powder to a mixer and mix, then add 2-4 parts of magnesium stearate and continue mixing. After mixing evenly, the total mixed material is obtained, and then tablets are pressed to obtain compound sustained-release tablets.

[0027] Another object of the present invention is to provide a use of the lisinopril-amlodipine compound sustained-release tablets of the present invention in the manufacture of drugs for treating hypertension, variant angina pectoris and stable angina pectoris.

[0028] Technical effects:

[0029] In the lisinopril and amlodipine compound sustained-release tablets of the present invention, the lisinopril and amlodipine in the immediate-release portion are rapidly released to quickly exert a blood pressure-lowering effect, while the lisinopril and amlodipine in the sustained-release portion are slowly released to maintain continuous drug release within 24 hours, avoiding large peaks and valleys, thereby achieving stable blood pressure reduction during drug administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 is a dissolution curve diagram of the compound sustained-release tablet of Example 1;

[0031] Figure 2 is a dissolution curve diagram of the compound sustained-release tablet of Example 2;

[0032] Figure 3is a dissolution curve diagram of the compound sustained-release tablet of Example 3;

[0033] Figure 4 is the dissolution curve of the compound immediate-release tablet of Comparative Example 1;

[0034] Figure 5 This is the dissolution curve of the compound matrix sustained-release tablet of Comparative Example 2. DETAILED DESCRIPTION

[0035] The following examples are provided to describe the present invention in more detail. However, the following examples are provided only to help further understand the present invention and are not intended to limit the present invention. Those skilled in the art will appreciate that any equivalent substitutions made to the present invention, or corresponding improvements, still fall within the scope of protection of the present invention.

[0036] Example 1 Lisinopril and Amlodipine Compound Sustained-Release Tablets

[0037] The prescription of compound sustained-release tablets is shown in Table 1:

[0038] Table 1. Prescription of compound sustained-release tablets

[0039]

[0040] Preparation method:

[0041] (1) Preparation of sustained-release micropellets: Weigh all materials according to the prescription amount of sustained-release micropellets, disperse the sustained-release base material ethyl cellulose in purified water, then add amlodipine besylate and lisinopril to it to prepare a sustained-release drug suspension for use; disperse hydropropyl methylcellulose and talc in purified water to prepare the outer coating solution (also called outer layer coating solution).

[0042] (2) The drug suspension is sprayed into the fluidized bed bottom spraying method to coat the sucrose pellets. After coating, the pellets are dried and sieved to 20-40 mesh. The outer coating liquid is sprayed into the fluidized bed bottom spraying method to coat the pellets. After coating, the pellets are dried to obtain sustained-release pellets.

[0043] (3) Preparation of immediate-release powder: Weigh all materials according to the prescribed amount of immediate-release powder, and mix amlodipine besylate, lisinopril, microcrystalline cellulose, and sodium starch glycolate in a mixer for 20 minutes to obtain the immediate-release powder.

[0044] (4) The sustained-release pellets and immediate-release powder were mixed in a mixer for 20 minutes, and then the prescribed amount of magnesium stearate was added and the mixture was continued for 5 minutes. The mixture was then uniformly mixed to obtain the total mixed material.

[0045] (5) The total mixed material is compressed into tablets to obtain tablets with both rapid-release and sustained-release functions.

[0046] Example 2 Lisinopril and Amlodipine Compound Sustained-Release Tablets

[0047] The prescription of compound sustained-release tablets is shown in Table 2:

[0048] Table 2. Prescription of compound sustained-release tablets

[0049]

[0050] Preparation method:

[0051] (1) Preparation of sustained-release microcapsules: Weigh all materials according to the prescription amount of sustained-release microcapsules, disperse the sustained-release base material ethyl cellulose in purified water, then add amlodipine besylate and lisinopril to it to prepare a sustained-release drug suspension for use; disperse hydropropyl methylcellulose and talc in purified water to prepare the outer coating solution.

[0052] (2) The drug suspension is sprayed into the fluidized bed bottom spraying method to coat the sucrose pellets. After coating, the pellets are dried and sieved to 20-40 mesh. The outer coating liquid is sprayed into the fluidized bed bottom spraying method to coat the pellets. After coating, the pellets are dried to obtain sustained-release pellets.

[0053] (3) Preparation of immediate-release powder: Weigh all materials according to the prescribed amount of immediate-release powder, and mix amlodipine besylate, lisinopril, microcrystalline cellulose, and sodium starch glycolate in a mixer for 20 minutes to obtain the immediate-release powder.

[0054] (4) The sustained-release pellets and immediate-release powder were mixed in a mixer for 20 minutes, and then the prescribed amount of magnesium stearate was added and the mixture was continued for 5 minutes. The mixture was then uniformly mixed to obtain the total mixed material.

[0055] (5) The total mixed material is compressed into tablets to obtain tablets with both rapid-release and sustained-release functions.

[0056] Example 3 Lisinopril and Amlodipine Compound Sustained-Release Tablets

[0057] The prescription of compound sustained-release tablets is shown in Table 3:

[0058] Table 3. Prescription of compound sustained-release tablets

[0059]

[0060] The preparation method is the same as that of Example 1.

[0061] Comparative Example 1 Lisinopril and Amlodipine Compound Rapid-Release Tablets

[0062] The formulation of the immediate-release tablets is shown in Table 4.

[0063] Table 4. Prescription of immediate-release tablets

[0064]

[0065] Preparation method:

[0066] (1) Preparation of immediate-release powder: Weigh each material according to the prescribed amount of immediate-release powder, and mix amlodipine besylate, lisinopril, microcrystalline cellulose, and sodium starch glycolate in a mixer for 20 minutes to obtain a premixed powder.

[0067] (2) Add the prescribed amount of magnesium stearate to the premixed powder and continue mixing for 5 minutes to obtain the total mixed material.

[0068] (3) The total mixed material is compressed into tablets to obtain rapid-release tablets.

[0069] Comparative Example 2: Lisinopril and Amlodipine Compound Matrix Sustained-Release / Immediate-Release Tablets

[0070] The formulation of matrix sustained-release / immediate-release tablets is shown in Table 5.

[0071] Table 5. Prescription of matrix sustained-release / immediate-release tablets

[0072]

[0073] Preparation method:

[0074] (1) Preparation of skeleton sustained-release granules: Weigh all materials according to the sustained-release formula, disperse the binder povidone K30 in purified water, and set aside. Add amlodipine besylate, lisinopril, and hypromellose E15 to a wet granulator and mix evenly. Then, spray the K30 binder solution to form a soft material, pass through a 20-mesh sieve to form wet granules, dry at 40°C, and then pass through a 20-mesh sieve to dry the whole granules. Skeleton sustained-release granules are obtained.

[0075] (2) Preparation of immediate-release powder: Weigh all materials according to the prescribed amount of immediate-release powder, and mix amlodipine besylate, lisinopril, microcrystalline cellulose, and sodium starch glycolate in a mixer for 20 minutes to obtain the immediate-release powder.

[0076] (3) The skeleton sustained-release granules and the immediate-release powder were mixed in a mixer for 20 minutes, and then the prescribed amount of magnesium stearate was added and the mixture was continued for 5 minutes to obtain the total mixed material.

[0077] (4) The total mixed material is compressed into tablets to obtain tablets with both rapid-release and sustained-release functions.

[0078] Example 4 Dissolution Determination

[0079] The samples prepared in Examples 1-3, Comparative Example 1, and Comparative Example 2 were subjected to dissolution tests using the following method: the release medium was initially 0.1N HCl 675 ml for 2 hours, and then adjusted to pH 6.8 phosphate buffer 900 ml after 2 hours. The paddle method was used at a speed of 150 rpm and a release medium temperature of 37°C ± 0.5°C. Samples were taken at 0.5, 1, 2, 4, 6, 8, 12, 16, 20, and 24 hours. The dissolution rate was tested, and the results are shown in Table 6. The dissolution curve is shown in Table 6. Figure 1-Figure 5 .

[0080] Table 6. Dissolution test results

[0081]

[0082] Dissolution curve:

[0083] The data and dissolution curve results of Table 6 show that: Example 1, Example 2, and Example 3 can all achieve rapid release of the quick-release portion and sustained release within 24 hours of the sustained-release portion, indicating that the drug will be continuously released within one day of taking the medicine, stabilizing the drug efficacy. The quick-release preparation of Comparative Example 1 is almost completely released within half an hour, and the drug is gradually reduced through metabolism after the release is completed, resulting in a decrease in blood drug concentration in the second half of the administration, thereby causing blood pressure fluctuations. Comparative Example 2 is tableted using skeleton sustained-release particles and quick-release powder. The resulting preparation releases about 50% in 0.5h and is almost completely released in 8h, which cannot last for 24 hours. Therefore, the preparation of the present invention can achieve rapid release and sustained release by tableting with sustained-release pellets and quick-release powder, prolonging the release time of the drug, effectively protecting the blood drug concentration within the administration cycle, and achieving a stable blood pressure-lowering effect.

Claims

1. A lisinopril and amlodipine compound sustained-release tablet, characterized in that: The invention comprises a sustained-release part and a rapid-release part, wherein the sustained-release part is a sustained-release micropellet comprising lisinopril, amlodipine besylate, a sustained-release matrix material ethyl cellulose, hypromellose and talc; and the rapid-release part comprises lisinopril, amlodipine, microcrystalline cellulose and sodium starch glycolate.

2. The compound sustained-release tablet according to claim 1, wherein The sustained-release pellets contain 5 parts of amlodipine besylate (calculated as amlodipine), 10 parts of lisinopril, 18-26 parts of sucrose pellet cores, 4.5-5.5 parts of ethyl cellulose, 5 parts of hypromellose and 5 parts of talc, calculated in parts by weight.

3. The compound sustained-release tablet according to claim 1, characterized in that The rapid-release portion comprises 5 parts of amlodipine besylate (calculated as amlodipine), 10 parts of lisinopril, 175-187 parts of microcrystalline cellulose and 4-8 parts of sodium starch glycolate.

4. The compound sustained-release tablet according to any one of claims 1 to 3, characterized in that: The weight ratio of amlodipine besylate in the sustained-release portion to amlodipine besylate in the immediate-release portion is 1:

1.

5. The compound sustained-release tablet according to any one of claims 1 to 3, characterized in that: The weight ratio of lisinopril in the sustained-release portion to lisinopril in the immediate-release portion was 1:

1.

6. The compound sustained-release tablet according to claim 1, wherein It further contains 2-4 parts by weight of magnesium stearate.

7. A method for preparing the compound sustained-release tablet according to any one of claims 1 to 6, characterized in that: The following steps are involved: 1) dispersing the sustained-release matrix ethylcellulose in purified water, and then adding amlodipine besylate and lisinopril to form a suspension; 2) Dispersing hypromellose and talc in purified water to prepare an outer coating solution; 3) Using the sucrose pellets as the base, spray the suspension from step 1) onto the sucrose pellets using a fluidized bed bottom spray method, dry the resulting pellets, and pass them through a 20-40 mesh sieve; 4) The pellets prepared in step 3) are coated with the outer coating solution prepared in step 2) by spraying the pellets in a fluidized bed bottom spraying manner, and then dried to obtain sustained-release pellets; 5) adding amlodipine besylate, lisinopril, microcrystalline cellulose, and sodium starch glycolate into a mixer and mixing uniformly to prepare an immediate-release powder; 6) The sustained-release pellets from step 4) and the immediate-release powder from step 5) are added to a mixer and mixed, and magnesium stearate is added and continued to mix. After mixing evenly, the mixture is compressed into tablets to obtain the target compound sustained-release tablets.

8. The preparation method according to claim 7, wherein In step 1), the weight portion of purified water is 56-64 parts.

9. The preparation method according to claim 7, wherein In step 2), the weight portion of purified water is 50 parts.

Images