Artemether-containing composition and preparation method thereof

Abstract

The invention relates to a composition containing artemether and a preparation method thereof. The composition comprises the following raw materials: artemether, a filler, a disintegrating agent, an adhesive, a lubricant, a solubilizer and water. The filling agent is prepared from hydroxypropyl-beta-cyclodextrin, lactose and monopotassium phosphate; the solubilizer comprises sodium oleate and laureth sorbitan. The sodium oleate and the laurel sorbitan are used as solubilizers, so that the dispersion effect of the main medicine can be improved, the content uniformity of the composition can be improved, and the curative effect of medication can be further ensured. The hydroxypropyl-beta-cyclodextrin, the lactose and the monopotassium phosphate are used as filling agents and are matched with one another, so that the hardness of the prepared composition is moderate, and the situation that the integrity of a medicine is damaged due to the fact that the composition is broken and the like in the transportation and storage processes can be avoided; and the filler can also improve the disintegration effect of the composition in the oral cavity, so that the purpose of quickly taking effect is achieved.

Description

TECHNICAL FIELD

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

[0002] Artemether is a highly effective artemisinin derivative, mainly used for rescue treatment of severe malaria, especially for chloroquine-resistant Plasmodium falciparum.

[0003] Artemether is insoluble in water, and has the disadvantages of slow dissolution rate, low dissolution degree and low bioavailability, which has a certain influence on the absorption of the drug in the body.

[0004] Chinese patent CN119745814A discloses a compound artemether tablet and a preparation method thereof. The compound artemether tablet comprises artemether, benflumetol, anhydrous calcium hydrogen phosphate, pregelatinized starch, mannitol, magnesium stearate, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, povidone and sodium dodecyl sulfate. The 1h dissolution degree of the compound artemether tablet prepared by the patent is 65%. At the same time, the tablet is a swallowing tablet, and the gastrointestinal first-pass effect can easily lead to a decrease in the bioavailability of the compound artemether tablet, resulting in poor use effect. Therefore, it is necessary to prepare a composition containing artemether which can realize rapid disintegration in the oral cavity after contacting a small amount of saliva, so as to achieve the purpose of rapid effect after medication. SUMMARY

[0005] In view of this, a composition containing artemether and a preparation method thereof are proposed to solve the above problems.

[0006] In a first aspect, the present application provides a composition containing artemether. The raw materials of the composition include artemether 4-8 parts, a filler 65-85 parts, a disintegrant 3-7 parts, a binder 12-15 parts, a lubricant 1-2 parts, a solubilizer 0.1-1 part and water 20-30 parts by weight.

[0007] The filler is hydroxypropyl-beta-cyclodextrin, lactose and potassium dihydrogen phosphate with a mass ratio of 1:6-8:2-4.

[0008] The solubilizer is sodium oleate and lauryl sorbitan with a mass ratio of 1:1.7-2.2.

[0009] Preferably, the disintegrant is one or more of sodium carboxymethyl starch, cross-linked povidone and cross-linked sodium carboxymethyl cellulose.

[0010] Preferably, the binder is one or more of polyethylene glycol, hydroxypropyl cellulose, pregelatinized starch, polyvinyl alcohol, dextrin and carbomer.

[0011] Preferably, the lubricant is one or more of microfine silica, talc, glyceryl behenate, stearic acid, sodium stearate, calcium stearate, zinc stearate, magnesium stearate and sodium stearyl fumarate.

[0012] Preferably, the composition further comprises 0.01-1 parts by weight of a flavoring agent, which is one or more of aspartame, acesulfame, sucrose.

[0013] Preferably, the composition further comprises 0.01-1 parts by weight of a preservative, which is any one of sodium methyl hydroxybenzoate, sodium propyl hydroxybenzoate.

[0014] In a second aspect, the present application provides a preparation method of the composition containing artemether according to the first aspect, comprising the following steps:

[0015] (1) mixing artemether, a binder, a solubilizer and water to obtain a mixed solution;

[0016] (2) mixing hydroxypropyl-β-cyclodextrin, lactose and a disintegrant as a pre-made granule;

[0017] (3) using an atomizing spray gun to spray the mixed solution onto the pre-made granule to perform fluidized bed granulation to obtain artemether granules;

[0018] (4) mixing the artemether granules and the remaining raw materials uniformly, and then tabletting to obtain the finished product.

[0019] Preferably, in step (3), the water content of the artemether granules is 2-3%.

[0020] Preferably, in step (3), the process parameters of the fluidized bed granulation are as follows: the air inlet flow rate is 50-70 m3 / h, the air inlet temperature is 50-70℃, the material temperature is 50-60℃, the liquid spraying rate is 4-8 g / min, the atomizing pressure is 0.8-1.2 bar, and the peristaltic pump speed is 10-15 rpm.

[0021] Preferably, in step (4), the tabletting pressure is 5-20 kN.

[0022] Compared with the prior art, the present application has the following beneficial effects:

[0023] In the present application, artemether is used as the main drug, and fillers, disintegrants, binders, lubricants, solubilizers and other excipients are used to prepare a composition which can be rapidly disintegrated in the oral cavity and rapidly absorbed through the oral mucosa to achieve a rapid effect.

[0024] In this invention, hydroxypropyl-β-cyclodextrin, lactose, and potassium dihydrogen phosphate are used as fillers. These three components work synergistically and are added to the composition in batches, which reduces the viscosity of artemether and prevents loss during preparation. Furthermore, the fillers selected in this invention can fully bind with artemether, resulting in a composition with moderate hardness and excellent compressibility, preventing damage to the integrity of the drug due to breakage during transportation and storage. More importantly, the fillers of this invention also improve the disintegration effect of the composition in the oral cavity, thereby achieving rapid onset of action.

[0025] In this invention, sodium oleate and sorbitan lauryl are used as solubilizers, which can improve the dispersion effect of artemether, thereby improving the content uniformity of the composition and reducing the gritty feeling that occurs during oral administration of the composition. Detailed Implementation

[0026] This invention provides a composition containing artemether, its preparation method, and its application. To make the objectives, technical solutions, and effects of this invention clearer and more explicit, the invention is further described in detail below. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

[0027] Unless otherwise specified, the experimental methods used in the examples are conventional methods; the materials and reagents used are commercially available unless otherwise specified.

[0028] Example 1

[0029] Weigh the following raw materials by weight: 4 parts artemether, 65 parts filler, 3 parts disintegrant, 12 parts binder, 1 part lubricant, 0.1 part solubilizer, 0.01 part flavoring agent, 0.01 part preservative, and 20 parts water.

[0030] The filler is hydroxypropyl-β-cyclodextrin, lactose, and potassium dihydrogen phosphate in a mass ratio of 1:6:2; the solubilizer is sodium oleate and sorbitan in a mass ratio of 1:1.7; the disintegrant is crospovidone; the binder is polyethylene glycol; the lubricant is sodium stearate fumarate; the flavoring agent is aspartame; and the preservative is sodium methylparaben.

[0031] A method for preparing a composition containing artemether, comprising the following steps:

[0032] (1) Artemether, binder, solubilizer and water are mixed to prepare a mixed solution;

[0033] (2) Hydroxypropyl-β-cyclodextrin, lactose and disintegrant are mixed to form pre-formed granules;

[0034] (3) The mixed solution is sprayed onto the pre-made particles using an atomizing spray gun to perform fluidized bed granulation, thereby obtaining artemether particles with a water content of 2%; the process parameters for fluidized bed granulation are as follows: air inlet volume is 50 m3 / h, air inlet temperature is 50℃, material temperature is 50℃, spraying rate is 4 g / min, atomization pressure is 0.8 bar, and peristaltic pump speed is 10 rpm.

[0035] (4) Mix the artemether granules and the remaining raw materials evenly, and compress them into tablets using a tablet press with a pressure of 5kN to obtain a finished product with a weight of 0.1g.

[0036] Example 2

[0037] Weigh the following raw materials by weight: 8 parts artemether, 85 parts filler, 7 parts disintegrant, 15 parts binder, 2 parts lubricant, 1 part solubilizer, 1 part flavoring agent, 1 part preservative, and 30 parts water.

[0038] The filler is hydroxypropyl-β-cyclodextrin, lactose, and potassium dihydrogen phosphate in a mass ratio of 1:8:4; the solubilizer is sodium oleate and sorbitan in a mass ratio of 1:2.2; the disintegrant is crospovidone; the binder is polyethylene glycol; the lubricant is sodium stearate fumarate; the flavoring agent is aspartame; and the preservative is sodium methylparaben.

[0039] A method for preparing a composition containing artemether, comprising the following steps:

[0040] (1) Artemether, binder, solubilizer and water are mixed to prepare a mixed solution;

[0041] (2) Hydroxypropyl-β-cyclodextrin, lactose and disintegrant are mixed to form pre-formed granules;

[0042] (3) The mixed solution is sprayed onto the pre-made particles using an atomizing spray gun to perform fluidized bed granulation, thereby obtaining artemether particles with a water content of 3%; the process parameters for fluidized bed granulation are as follows: air volume of 70 m3 / h, air temperature of 70℃, material temperature of 60℃, spraying rate of 8 g / min, atomization pressure of 1.2 bar, and peristaltic pump speed of 15 rpm;

[0043] (4) Mix the artemether granules and the remaining raw materials evenly, and compress them into tablets using a tablet press with a pressure of 20kN to obtain a finished product with a weight of 0.1g.

[0044] Example 3

[0045] Weigh the following raw materials by weight: 6 parts artemether, 75 parts filler, 5 parts disintegrant, 13 parts binder, 1.5 parts lubricant, 0.5 parts solubilizer, 0.1 parts flavoring agent, 0.1 parts preservative and 28 parts water.

[0046] The filler is hydroxypropyl-β-cyclodextrin, lactose, and potassium dihydrogen phosphate in a mass ratio of 1:7:3; the solubilizer is sodium oleate and sorbitan in a mass ratio of 1:2; the disintegrant is crospovidone; the binder is polyethylene glycol; the lubricant is sodium stearate fumarate; the flavoring agent is aspartame; and the preservative is sodium methylparaben.

[0047] A method for preparing a composition containing artemether, comprising the following steps:

[0048] (1) Artemether, binder, solubilizer and water are mixed to prepare a mixed solution;

[0049] (2) Hydroxypropyl-β-cyclodextrin, lactose and disintegrant are mixed to form pre-formed granules;

[0050] (3) The mixed solution is sprayed onto the pre-made particles using an atomizing spray gun to perform fluidized bed granulation, thereby obtaining artemether particles with a water content of 2.5%; the process parameters for fluidized bed granulation are as follows: air inlet volume is 60 m3 / h, air inlet temperature is 60℃, material temperature is 55℃, spraying rate is 6 g / min, atomization pressure is 1 bar, and peristaltic pump speed is 13 rpm.

[0051] (4) Mix the artemether granules and the remaining raw materials evenly, and compress them into tablets using a tablet press at a pressure of 15kN to obtain a finished product with a weight of 0.1g.

[0052] Comparative Example 1

[0053] Compared with Example 3, the only difference in Comparative Example 1 is the order in which the filler is added, specifically:

[0054] (1) Artemether, binder, solubilizer and water are mixed to prepare a mixed solution;

[0055] (2) Mix potassium dihydrogen phosphate and disintegrant to make pre-formed granules;

[0056] (3) The mixed solution is sprayed onto the pre-made particles using an atomizing spray gun to perform fluidized bed granulation, thereby obtaining artemether particles with a water content of 2.5%; the process parameters for fluidized bed granulation are as follows: air inlet volume is 60 m3 / h, air inlet temperature is 60℃, material temperature is 55℃, spraying rate is 6 g / min, atomization pressure is 1 bar, and peristaltic pump speed is 13 rpm.

[0057] (4) Mix the artemether granules and the remaining raw materials evenly, and compress them into tablets using a tablet press at a pressure of 15kN to obtain a finished product with a weight of 0.1g.

[0058] Comparative Example 2

[0059] Compared with Example 3, the only difference in Comparative Example 2 is the method of adding the filler, specifically:

[0060] (1) Artemether, binder, solubilizer and water are mixed to prepare a mixed solution;

[0061] (2) Hydroxypropyl-β-cyclodextrin, lactose, potassium dihydrogen phosphate and disintegrant are mixed together to form pre-made granules;

[0062] (3) The mixed solution is sprayed onto the pre-made particles using an atomizing spray gun to perform fluidized bed granulation, thereby obtaining artemether particles with a water content of 2.5%; the process parameters for fluidized bed granulation are as follows: air inlet volume is 60 m3 / h, air inlet temperature is 60℃, material temperature is 55℃, spraying rate is 6 g / min, atomization pressure is 1 bar, and peristaltic pump speed is 13 rpm.

[0063] (4) Mix the artemether granules and the remaining raw materials evenly, and compress them into tablets using a tablet press at a pressure of 15kN to obtain a finished product with a weight of 0.1g.

[0064] Comparative Example 3

[0065] Compared with Example 3, the only difference in Comparative Example 3 is that the filler is hydroxypropyl-β-cyclodextrin, lactose and potassium dihydrogen phosphate in a mass ratio of 1:3:3.

[0066] Comparative Example 4

[0067] Compared with Example 3, the only difference in Comparative Example 4 is that potassium dihydrogen phosphate in the filler is replaced with an equal amount of sorbitol.

[0068] Comparative Example 5

[0069] Compared with Example 3, the only difference in Comparative Example 5 is that the solubilizer is sodium oleate.

[0070] Comparative Example 6

[0071] Compared with Example 3, the only difference in Comparative Example 6 is that the solubilizer is lauryl sorbitan.

[0072] Comparative Example 7

[0073] Compared with Example 3, the only difference in Comparative Example 7 is that the solubilizer is sodium oleate and sorbitan in a mass ratio of 1:1.

[0074] Comparative Example 8

[0075] Compared with Example 3, the only difference in Comparative Example 8 is that the solubilizer is sodium oleate and sodium dodecyl sulfate in a mass ratio of 1:2.

[0076] Experimental Example 1

[0077] The content uniformity of the finished products obtained in Examples 1-3 and Comparative Examples 1-8 was determined according to the content detection method of artemether in Part II of the 2020 edition of the Chinese Pharmacopoeia and General Chapter 0941 under Part IV of the 2020 edition of the Chinese Pharmacopoeia; the disintegration was determined according to General Chapter 0921 under Part IV of the 2020 edition of the Chinese Pharmacopoeia, with water as the solute and disintegration time as the detection index; the friability was determined according to General Chapter 0923 under Part IV of the 2020 edition of the Chinese Pharmacopoeia. The test results are shown in Table 1.

[0078] Table 1

[0079]

[0080]

[0081] The Chinese Pharmacopoeia sets the content uniformity standard at 90%–110%, the disintegration time standard at less than 60 seconds, and the friability standard at a weight loss of no more than 1%, with no detectable signs of breakage, cracking, or pulverization.

[0082] Experimental results show that the finished product prepared in the embodiments of the present invention meets the requirements of the Chinese Pharmacopoeia for content uniformity, disintegration time and friability.

[0083] Compared with Example 3, the adjustments to the order and method of adding fillers in Comparative Examples 1-2 resulted in a decrease in the quality of the finished product, particularly affecting disintegration time and friability. The results show that using hydroxypropyl-β-cyclodextrin, lactose, and potassium dihydrogen phosphate as fillers in this invention, and first adding hydroxypropyl-β-cyclodextrin and lactose to prepare artemether particles, followed by mixing the artemether particles with other excipients such as potassium dihydrogen phosphate to prepare an artemether-containing composition, can improve the compressibility of the artemether product while also providing good wettability, further improving the disintegration effect of the composition in the oral cavity.

[0084] Compared to Example 3, Comparative Examples 3-4, by changing the proportions and types of each component in the filler, resulted in a decrease in the quality of the finished product, particularly affecting disintegration time and friability. The results indicate that the quality of the finished product can only be improved when the filler composition of the present invention is at a specific mass ratio.

[0085] Compared to Example 3, Comparative Examples 5, 6, and 8 changed the composition of the solubilizer, and Comparative Example 7 changed the proportions of each component in the solubilizer, resulting in a decrease in the quality of the finished product, especially affecting the uniformity of content. Observation of the disintegration process of the finished products from Comparative Examples 5-8 and Example 3 showed that in Example 3, the excipients and active pharmaceutical ingredient disintegrated completely at the same time, while in Comparative Examples 5-8, small particles appeared in the later stages of disintegration. This may be because the excipients had disintegrated, but the oil-soluble active pharmaceutical ingredient had not yet dissolved. The results indicate that the rational formulation of the solubilizer in this invention can not only improve the uniformity of content in the finished product but also enable the excipients and active pharmaceutical ingredient to disintegrate at the same time, avoiding undesirable phenomena such as a gritty texture or unpleasant taste in the composition.

[0086] The above description is merely a preferred embodiment of the present invention and is not intended to limit this application. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A composition containing artemether, characterized in that, By weight, the raw materials of the composition include 4-8 parts of artemether, 65-85 parts of filler, 3-7 parts of disintegrant, 12-15 parts of binder, 1-2 parts of lubricant, 0.1-1 parts of solubilizer and 20-30 parts of water; The filler is hydroxypropyl-β-cyclodextrin, lactose and potassium dihydrogen phosphate in a mass ratio of 1:6-8:2-4; The solubilizer is sodium oleate and lauryl sorbitan in a mass ratio of 1:1.7-2.

2.

2. The composition containing artemether as described in claim 1, characterized in that, The disintegrant is one or more of sodium carboxymethyl starch, crospovidone, and crospovidone carboxymethyl cellulose.

3. The composition containing artemether as described in claim 1, characterized in that, The adhesive is one or more of polyethylene glycol, hydroxypropyl cellulose, pregelatinized starch, polyvinyl alcohol, dextrin, and carbomer.

4. The composition containing artemether as described in claim 1, characterized in that, The lubricant is one or more of the following: micronized silica gel, talc, glyceryl behenate, stearic acid, sodium stearate, calcium stearate, zinc stearate, magnesium stearate, and sodium stearate fumarate.

5. The composition containing artemether as described in claim 1, characterized in that, The composition further comprises 0.01-1 parts by weight of a flavoring agent, wherein the flavoring agent is one or more of aspartame, acesulfame potassium, and sucrose.

6. The composition containing artemether as described in claim 1, characterized in that, The composition further comprises 0.01-1 parts by weight of a preservative, wherein the preservative is either sodium methylparaben or sodium propylparaben.

7. The method for preparing the composition containing artemether as described in claim 1, characterized in that, Includes the following steps: (1) Artemether, binder, solubilizer and water are mixed to prepare a mixed solution; (2) Hydroxypropyl-β-cyclodextrin, lactose and disintegrant are mixed to form pre-formed granules; (3) Use an atomizing spray gun to spray the mixed solution onto the pre-made particles for fluidized bed granulation to obtain artemether particles; (4) Mix artemether granules and the remaining raw materials evenly, compress into tablets, and obtain the finished product.

8. The method for preparing the composition containing artemether as described in claim 7, characterized in that, In step (3), the water content of the artemether particles is 2-3%.

9. The method for preparing the composition containing artemether as described in claim 7, characterized in that, In step (3), the process parameters for fluidized bed granulation are: inlet air volume of 50-70 m³ / h. 3 / h, inlet air temperature is 50-70℃, material temperature is 50-60℃, spray rate is 4-8g / min, atomization pressure is 0.8-1.2bar, and peristaltic pump speed is 10-15rpm.

10. The method for preparing the composition containing artemether as described in claim 7, characterized in that, In step (4), the pressure of the tablet is 5-20 kN.

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