Compound artemether dispersible tablet and preparation method thereof

Abstract

The invention discloses a compound artemether dispersible tablet and a preparation method thereof. The compound artemether dispersible tablet is prepared from the following components in parts by mass: 20 parts of artemether, 120 parts of benflumetol, 120 to 160 parts of filler, 20 to 30 parts of disintegrating agent, 5 to 15 parts of adhesive, 15 parts of lubricant and 0.5 to 2 parts of surfactant, the disintegrating agent is at least one of croscarmellose sodium, carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose. According to the invention, by adopting a double disintegrating agent system (cross-linked sodium carboxymethyl cellulose and carboxymethyl starch sodium) and a surfactant (lauryl sodium sulfate), the disintegration performance and stability of the product are obviously improved, and the adopted wet mixing granulation process is simple and easy to realize industrial production; in the obtained dispersible tablet, the dissolution rate of artemether within 3 hours reaches 85% or above. The product has the advantages of rapid disintegration, good stability and the like, and is suitable for children, old people and patients with dysphagia.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a compound artemether dispersible tablet and a preparation method thereof. BACKGROUND

[0002] Artemisinin drugs are currently the first-line drugs for treating malaria. Artemether, as a methoxylated derivative of artemisinin, has a strong killing effect on the schizonts of Plasmodium vivax and is effective for various drug-resistant malaria, especially chloroquine-resistant falciparum malaria. However, artemether has the disadvantages of short action time and high recurrence rate.

[0003] Piperaquine is an effective antimalarial drug that can effectively kill Plasmodium falciparum asexual forms with a high efficiency, but has a slow onset. The compound preparation of artemether and piperaquine can achieve synergistic effect: artemether has a rapid onset, and piperaquine has a long-lasting effect, which complement each other, not only overcoming the deficiencies of short action time of artemether and slow onset of piperaquine, but also reducing the dosage and improving the clinical efficacy. At present, the compound preparation has been included in the core directory of the World Health Organization's Essential Medicine Standard List and has become an important choice for treating malaria. However, both artemether and piperaquine have poor water solubility, resulting in slow oral absorption and low bioavailability; and the injection thereof is prone to cause allergic reactions and irritation to the injection site, causing pain and poor safety compared with oral preparations. In addition, the commercially available artemether-piperaquine compound tablets have the problems of long disintegration time and low dissolution rate, which affect the bioavailability and therapeutic effect of the drug.

[0004] In order to improve the above-mentioned defects, it is imperative to develop a new dosage form. The compound preparation is prepared into a dispersible tablet, which can significantly shorten the disintegration time, improve the dissolution rate, and thus improve the bioavailability and clinical efficacy. SUMMARY

[0005] In view of the deficiencies of the prior art, the purpose of the present application is to provide a compound artemether dispersible tablet and a preparation method thereof, so as to solve the problems of long disintegration time, low dissolution rate and poor bioavailability of the existing compound artemether preparations.

[0006] The purpose of the present application is achieved by the following technical solutions. A compound artemether dispersible tablet comprises the following components in parts by mass: 20 parts of artemether, 120 parts of piperaquine, 120-160 parts of a filler, 20-30 parts of a disintegrant, 5-15 parts of a binder, 15 parts of a lubricant and 0.5-2 parts of a surfactant; the disintegrant is at least one of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose.

[0007] Preferably, the filler is a mixture of corn starch and microcrystalline cellulose.

[0008] Preferably, the disintegrant is a mixture of croscarmellose sodium and sodium starch glycolate.

[0009] Preferably, the binder is povidone.

[0010] Preferably, the lubricant is at least one of magnesium stearate and silicon dioxide.

[0011] Preferably, the surfactant is sodium lauryl sulfate.

[0012] Preferably, the compound artemether dispersible tablets comprise the following components in parts by mass: 20 parts of artemether, 120 parts of benflumetol, 60-80 parts of corn starch, 60-80 parts of microcrystalline cellulose, 10 parts of croscarmellose sodium, 10 parts of sodium starch glycolate, 10 parts of povidone, 10 parts of magnesium stearate, 5 parts of silicon dioxide, and 1 part of sodium lauryl sulfate.

[0013] The preparation method of the compound artemether dispersible tablets comprises the following steps: According to the proportion of each raw material, artemether, benflumetol, fillers, and part of the disintegrant are uniformly mixed, a binder aqueous solution containing a surfactant is added, wet granulation is performed, drying is performed, and the granules are sized; then the remaining disintegrant and lubricant are uniformly mixed, and the tablets are compressed, thereby obtaining the compound artemether dispersible tablets.

[0014] Preferably, according to the proportion of each raw material, artemether, benflumetol, fillers, and 50% of the disintegrant are uniformly mixed.

[0015] Preferably, the concentration of the binder aqueous solution is 5 wt%.

[0016] Preferably, the drying temperature is 55°C, and the sizing refers to sizing through a 1.2 mm screen.

[0017] Compared with the prior art, the beneficial effects of the present application include: (1) The present application optimizes the prescription composition of the dispersible tablets by reasonably selecting the disintegrant, fillers, binder, and disintegrant, thereby improving the drug dissolution and dispersibility.

[0018] (2) The compound artemether dispersible tablets prepared by the present application have the advantages of short disintegration time and high dissolution, can effectively improve the treatment effect, and reduce the dosage and frequency of administration. DETAILED DESCRIPTION

[0019] In order to make the purpose, technical scheme and advantages of the present application clearer and more apparent, the present application is further described in detail below in combination with examples. It should be understood that the specific examples described herein are only used to explain the present application and do not limit the present application.

[0020] Example 1 A compound artemether dispersible tablet, the prescription composition (by weight, 1000 tablets) is: 20g artemether, 120g benflumetol, 60g corn starch, 80g microcrystalline cellulose, 20g crosslinked sodium carboxymethyl cellulose, 10g povidone K30 (from 200g concentration of 5% povidone aqueous solution), 10g magnesium stearate, 5g silicon dioxide and 1g sodium dodecyl sulfate.

[0021] The preparation method of the above compound artemether dispersible tablet, the specific steps are as follows: (1) The artemether, benflumetol, starch, microcrystalline cellulose and 50% crosslinked sodium carboxymethyl cellulose are placed in a mixing container, the stirring speed is set to 500r / min, the granulating knife speed is 1000r / min, and the mixing time is 180s; (2) Under the conditions of continuous stirring (500r / min) and granulation (1000r / min), add 5% povidone K30 aqueous solution containing sodium dodecyl sulfate, and the slurry time is 180s; After the slurry is completed, the granulating knife speed is adjusted to 2000r / min, and the mixing is continued for 60s, and the wet granules are obtained; (3) The wet granules are dried at 55℃, and the particles are sieved through a 1.2mm sieve; The obtained particles are mixed uniformly with the remaining 50% crosslinked sodium carboxymethyl cellulose, magnesium stearate and silicon dioxide, and then pressed into tablets to obtain the compound artemether dispersible tablet.

[0022] Example 2 A compound artemether dispersible tablet, the prescription composition (by weight, 1000 tablets) is: 20g artemether, 120g benflumetol, 60g corn starch, 80g microcrystalline cellulose, 20g carboxymethyl starch sodium, 10g povidone K30 (from 200g concentration of 5% povidone aqueous solution), 10g magnesium stearate, 5g silicon dioxide and 1g sodium dodecyl sulfate.

[0023] The preparation method of the above compound artemether dispersible tablet is the same as that of example 1.

[0024] Example 3 A compound artemether dispersible tablet, the prescription composition (by weight, 1000 tablets) is: 20g artemether, 120g benflumetol, 60g corn starch, 80g microcrystalline cellulose, 20g low-substituted hydroxypropyl cellulose, 10g povidone K30 (from 200g concentration of 5% povidone aqueous solution), 10g magnesium stearate, 5g silicon dioxide and 1g sodium dodecyl sulfate.

[0025] The preparation method of the above compound artemether dispersible tablet is the same as that of example 1.

[0026] Example 4 A compound artemether dispersible tablet, the prescription composition (by weight, 1000 tablets) is: 20g artemether, 120g benflumetol, 60g corn starch, 80g microcrystalline cellulose, 10g cross-linked sodium carboxymethyl cellulose, 10g sodium carboxymethyl starch, 10g povidone K30 (from 200g concentration of 5% povidone aqueous solution), 10g magnesium stearate, 5g silicon dioxide and 1g sodium dodecyl sulfate.

[0027] The preparation method of the above compound artemether dispersible tablet is the same as that of Example 1.

[0028] Example 5 A compound artemether dispersible tablet, the prescription composition (by weight, 1000 tablets) is: 20g artemether, 120g benflumetol, 60g corn starch, 80g microcrystalline cellulose, 10g cross-linked sodium carboxymethyl cellulose, 10g low-substituted hydroxypropyl cellulose, 10g povidone K30 (from 200g concentration of 5% povidone aqueous solution), 10g magnesium stearate, 5g silicon dioxide and 1g sodium dodecyl sulfate.

[0029] The preparation method of the above compound artemether dispersible tablet is the same as that of Example 1.

[0030] Example 6 A compound artemether dispersible tablet, the prescription composition (by weight, 1000 tablets) is: 20g artemether, 120g benflumetol, 60g corn starch, 80g microcrystalline cellulose, 10g cross-linked sodium carboxymethyl cellulose, 10g low-substituted hydroxypropyl cellulose, 10g povidone K30 (from 200g concentration of 5% povidone aqueous solution), 10g magnesium stearate, 5g silicon dioxide and 1g sodium dodecyl sulfate.

[0031] The preparation method of the above compound artemether dispersible tablet is the same as that of Example 1.

[0032] Comparative Example 1 A compound artemether dispersible tablet, the prescription composition (by weight, 1000 tablets) is: 20g artemether, 120g benflumetol, 60g corn starch, 80g microcrystalline cellulose, 10g cross-linked sodium carboxymethyl cellulose, 10g low-substituted hydroxypropyl cellulose, 10g povidone K30 (from 200g concentration of 5% povidone aqueous solution), 10g magnesium stearate, 5g silicon dioxide and 1g sodium dodecyl sulfate.

[0033] The preparation method of the above compound artemether dispersible tablet is the same as that of Example 1.

[0034] Comparative Example 2 A compound artemether dispersible tablet, the prescription composition (by weight, 1000 tablets) is: 20g artemether, 120g benflumetol, 60g corn starch, 80g microcrystalline cellulose, 10g cross-linked sodium carboxymethyl cellulose, 10g sodium carboxymethyl starch, 10g hydroxypropyl methyl cellulose (from 200g concentration of 5% hydroxypropyl methyl cellulose aqueous solution), 10g magnesium stearate, 5g silicon dioxide and 1g sodium dodecyl sulfate.

[0035] The preparation method of the above compound artemether dispersible tablet is the same as that of Example 1.

[0036] Comparative Example 3 A compound artemether dispersible tablet, the prescription composition (by weight, 1000 tablets) is: 20g artemether, 120g benflumetol, 60g corn starch, 80g microcrystalline cellulose, 10g cross-linked sodium carboxymethyl cellulose, 10g sodium carboxymethyl starch, 10g hydroxypropyl methyl cellulose (from 200g concentration of 5% hydroxypropyl methyl cellulose aqueous solution), 10g magnesium stearate, 5g silicon dioxide and 1g sodium dodecyl sulfate.

[0037] The preparation method of the above compound artemether dispersible tablet is the same as that of Example 1.

[0038] The component corresponding to the prescription of Example 1~6 and Comparative Example 1~3 is shown in Table 1.

[0039] Table 1 Comparison of prescription composition of Example 1~6 and Comparative Example 1~3

[0040] The dissolution and content of the compound artemether dispersible tablets prepared in Example 1~6 and Comparative Example 1 are determined according to the method under "Compound Artemether Tablets" in Chinese Pharmacopoeia Volume II, and the dispersibility is detected according to Chinese Pharmacopoeia Volume IV General Rule 0101 Tablets, and the test results are shown in Table 2.

[0041] Table 2 Test results of dissolution, content and dispersibility

[0042] Referring to Table 1 and Table 2: For Example 1~6, the mixture of cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch is used as the disintegrating agent (i.e. Example 4), and the dispersibility of the compound artemether dispersible tablet prepared is the best, only 50s. The dispersibility of the rest of the examples is not as good as Example 4, but they can all be completely disintegrated in 3min (in water at 20℃±1℃), which is significantly better than the commercially available product.

[0043] Comparing Example 4 and Comparative Example 1, we can see that when the filler is replaced with lactose and anhydrous calcium hydrogen phosphate, the dispersion time of the prepared artemether dispersible tablets is extended to 4 min 20 s. This shows that the rational selection of filler is crucial to controlling the dispersion time of the dispersible tablets.

[0044] Furthermore, the dispersibility of the artemether dispersible tablets prepared in Example 4 and Comparative Examples 2-3 was tested according to the General Chapter 0101 of Part IV of the Chinese Pharmacopoeia. The test results are shown in Table 3.

[0045] Table 3. Dispersion test results of Example 4 and Comparative Examples 2-3

[0046] Referring to Table 3, we can see that in Example 4, which uses povidone as a binder, the dispersion time is only 50 seconds. However, when hydroxypropyl cellulose or hydroxypropyl methylcellulose is used as the binder, the corresponding dispersion times are extended to 3 min 50 s and 2 min, respectively. This indicates that the appropriate selection of the binder is also very important for controlling the dispersion time of the dispersion sheet.

[0047] The specific embodiments of the present invention described above do not constitute a limitation on the scope of protection of the present invention. Any other corresponding changes and modifications made in accordance with the technical concept of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A compound artemether dispersible tablet, characterized in that, By weight, it comprises the following components: 20 parts artemether, 120 parts benzyl alcohol, 120-160 parts filler, 20-30 parts disintegrant, 5-15 parts binder, 15 parts lubricant and 0.5-2 parts surfactant; The disintegrant is at least one of croscarmellose sodium, carboxymethyl starch sodium, and low-substituted hydroxypropyl cellulose.

2. The artemether dispersible tablets according to claim 1, characterized in that, The filler is a mixture of corn starch and microcrystalline cellulose.

3. The artemether dispersible tablets according to claim 1, characterized in that, The disintegrant is a mixture of croscarmellose sodium and carboxymethyl starch sodium.

4. The artemether dispersible tablets according to claim 1, characterized in that, The adhesive is polyvinyl chloride.

5. The artemether dispersible tablets according to claim 1, characterized in that, The lubricant is at least one of magnesium stearate and silicon dioxide.

6. The artemether dispersible tablets according to claim 1, characterized in that, The surfactant is sodium dodecyl sulfate.

7. The method for preparing the artemether dispersible tablets according to any one of claims 1 to 6, characterized in that, Includes the following steps: According to the proportions of each raw material, the artemether, benfluorenol, filler and part of the disintegrant are mixed evenly, and an aqueous binder containing surfactant is added. The mixture is wet-granulated, dried and granulated. Then it is mixed evenly with the remaining disintegrant and lubricant, and compressed into tablets to obtain compound artemether dispersible tablets.

8. The method for preparing artemether dispersible tablets according to claim 7, characterized in that, According to the proportions of each raw material, the artemether, benzyl alcohol, filler and 50% disintegrant are mixed evenly.

9. The method for preparing artemether dispersible tablets according to claim 7, characterized in that, The concentration of the adhesive aqueous solution is 5 wt%.

10. The method for preparing artemether dispersible tablets according to claim 7, characterized in that, The drying temperature is 55°C, and the granulation refers to granulation through a 1.2mm sieve.

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