High-dissolution aprepitant preparation and preparation method thereof

Abstract

The invention belongs to the field of biological medicine, and particularly relates to a high-dissolution aprepitant preparation and a preparation method thereof. The high-dissolution aprepitant preparation is prepared from the following components in parts by weight: 50 to 80 parts of aprepitant, 5 to 10 parts of a surfactant, 20 to 40 parts of a filling agent, 5 to 10 parts of a disintegrating agent and 0.5 to 3 parts of a lubricating agent, wherein the surface active agent is composed of triethanolamine oleate and another surface active agent, and the other surface active agent is selected from one or more of span 20, span 40, span 60, span 80 and span 83. It has been found that by adopting the combination of triethanolamine oleate and another surfactant, the solubility of aprepitant can be effectively improved, dissolution of aprepitant is promoted, meanwhile, the preparation technology is simple, and too high cost pressure cannot be brought to the technological process.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and in particular relates to a high-dissolution aprepitant preparation and a preparation method thereof. Background Art

[0002] Aprepitant is a selective neurokinin 1 (NK1) receptor antagonist, mainly used to prevent and treat chemotherapy-induced nausea and vomiting. Due to the low solubility of aprepitant in water, the approximate saturated solubility is less than 1ug / mL, and the solubility at different pH values ​​is extremely low, resulting in limited oral bioavailability, which limits its clinical application effect.

[0003] In order to increase its water solubility and thus increase its oral bioavailability, WO2003049718 discloses for the first time a nanoparticle composition containing aprepitant, wherein a surface stabilizer is adsorbed on the surface of aprepitant, so that the particle size is less than 1000nm. The preparation method provided in the embodiment is specifically to disperse the active ingredient aprepitant in a liquid dispersion medium, and to wet-mill by a mechanical method in the presence of a grinding medium and a surface stabilizer to reduce the average particle size of the active ingredient, and then to separate the resulting nanocomposition from the grinding medium. Since wet milling cannot produce particles with a particle size of less than 100 nanometers, its effect on improving the dissolution of aprepitant is limited. However, if the process is improved, the cost will be significantly increased.

[0004] Therefore, there is still a need to develop a high-solubility aprepitant formulation that does not impose excessive cost pressure on the process. Summary of the invention

[0005] In order to solve the above problems, in the first aspect, the present invention provides a high-dissolution aprepitant preparation, which comprises the following components in parts by weight: 50-80 parts of aprepitant, 5-10 parts of surfactant, 20-40 parts of filler, 5-10 parts of disintegrant, and 0.5-3 parts of lubricant.

[0006] Furthermore, the surfactant consists of triethanolamine oleate and another surfactant.

[0007] Further, the another surfactant is selected from one or more of Span 20, Span 40, Span 60, Span 80 and Span 83.

[0008] Furthermore, the surfactant consists of triethanolamine oleate and Span 80.

[0009] Furthermore, the mass ratio of the triethanolamine oleate to another surfactant is 1:1-5.

[0010] Furthermore, the filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, starch, and dextrin.

[0011] Furthermore, the disintegrant is selected from one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and low-substituted hydroxypropyl cellulose.

[0012] Furthermore, the lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate, talc, and silicon dioxide.

[0013] Furthermore, the preparation is in the form of powder, granules, tablets or capsules.

[0014] In a second aspect, the present invention provides a method for preparing the high-dissolution aprepitant formulation as described herein, comprising the following steps:

[0015] (1) dissolving the required amount of aprepitant in a solvent and heating in a water bath at 50-60° C. for 30-50 min;

[0016] (2) Mix the required amounts of surfactant, filler, disintegrant and lubricant, grind and pass through a 250-300 mesh sieve;

[0017] (3) Add the mixture obtained in step (2) to the solution in step (1) and perform wet granulation to obtain the product.

[0018] Furthermore, the solvent in step (1) is ethanol or acetone.

[0019] Furthermore, the grinding in step (2) is performed using a ball mill at a speed of 600-1000 r / min for 12-24 h.

[0020] Advantageous Effects of the Invention

[0021] Surfactants (such as polyvinyl alcohol, Tween, cyclodextrin, etc.) can reduce the surface tension of aprepitant particles and promote their dissolution in water, and are therefore one of the effective means to improve the solubility and bioavailability of aprepitant. However, the improvement effect of a single surfactant is limited, and it is usually necessary to use it in combination with other means (such as solubility enhancers, such as polyethylene glycol, polyvinyl pyrrolidone, etc.).

[0022] The present invention has found that by using a combination of triethanolamine oleate and another surfactant, the solubility of aprepitant can be effectively improved and its dissolution can be promoted. The other surfactant is selected from one or more of Span 20, Span 40, Span 60, Span 80 and Span 83, especially Span 80. From the results in the examples, it can be seen that the combination of the two produces an unexpected improvement effect relative to the use of the two alone, and triethanolamine oleate can make reagents such as Span 60, which are originally unsuitable for the preparation of aprepitant preparations, become available, especially Span 80, and the improvement effect produced is even stronger than Span 20, which has an unexpected technical effect. DETAILED DESCRIPTION

[0023] The present invention is further described below with reference to specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0024] Embodiment 1:

[0025] A high-dissolution aprepitant preparation is prepared from the following components in parts by weight: 60 parts of aprepitant, 3 parts of triethanolamine oleate, 203 parts of Span, 15 parts of microcrystalline cellulose KG802, 12 parts of mannitol, 6 parts of cross-linked carboxymethyl cellulose sodium, and 1 part of magnesium stearate.

[0026] Preparation process:

[0027] (1) Dissolve aprepitant calcium in ethanol and heat in a 60°C water bath for 30 min;

[0028] (2) triethanolamine oleate, Span 20, microcrystalline cellulose KG802, mannitol, croscarmellose sodium and magnesium stearate were mixed evenly, ground and passed through a 250-mesh sieve;

[0029] (3) The mixture obtained in step (2) is added to the solution in step (1) to prepare a soft material, granulated with a 20-mesh sieve, dried at 55° C. for 2 hours, and sieved with a 24-mesh sieve to obtain granules. The granules are placed on a capsule filling plate to obtain an aprepitant preparation.

[0030] Embodiment 2:

[0031] A high-dissolution aprepitant preparation, whose ingredients and preparation process are the same as those of Example 1, except that Span 20 is replaced by Span 40.

[0032] Embodiment 3:

[0033] A high-dissolution aprepitant preparation, whose ingredients and preparation process are the same as those of Example 1, except that Span 20 is replaced by Span 60.

[0034] Embodiment 4:

[0035] A high-dissolution aprepitant preparation, whose ingredients and preparation process are the same as those of Example 1, except that Span 20 is replaced by Span 80.

[0036] Embodiment 5:

[0037] A high-dissolution aprepitant preparation, whose ingredients and preparation process are the same as those of Example 1, except that Span 20 is replaced by Span 83.

[0038] Comparative Example 1:

[0039] An aprepitant preparation, whose ingredients and preparation process are the same as those of Example 1, except that Span 20 is replaced by Span 65.

[0040] Comparative Example 2:

[0041] An aprepitant preparation, whose ingredients and preparation process are the same as those of Example 1, except that Span 20 is replaced by Span 85.

[0042] Comparative Example 3:

[0043] An aprepitant preparation, whose ingredients and preparation process are the same as those of Example 1, except that triethanolamine oleate is not used.

[0044] Comparative Example 4:

[0045] An aprepitant preparation, whose ingredients and preparation process are the same as those of Example 3, except that triethanolamine oleate is not used.

[0046] Comparative Example 5:

[0047] An aprepitant preparation, whose ingredients and preparation process are the same as those of Example 4, except that triethanolamine oleate is not used.

[0048] Comparative Example 6:

[0049] An aprepitant preparation, whose ingredients and preparation process are the same as those of Example 1, except that triethanolamine oleate is replaced by sodium oleate.

[0050] Comparative Example 7:

[0051] An aprepitant preparation, whose ingredients and preparation process are the same as those of Example 1, except that triethanolamine oleate is replaced by polyvinyl pyrrolidone.

[0052] Test example:

[0053] The dissolution of aprepitant preparation was determined by high performance liquid chromatography. The chromatographic conditions were as follows: an octadecylsilane bonded silica gel column; water:acetonitrile (40:60) as the mobile phase; a flow rate of 1.0 mL / min; and a detection wavelength of 210 nm. The dissolution of aprepitant in the test solution was calculated by the peak area using the external standard method.

[0054] 900 ml of pH 6.8 phosphate buffer containing 0.2% (w / v) sodium dodecyl sulfate was used as the dissolution medium, and the stirring blade speed was 100 rpm. According to the second method of 0931 of the fourth general rule of the 2015 edition of the Chinese Pharmacopoeia, samples were taken and measured at 15 minutes and 45 minutes. The results are shown in Table 1.

[0055] Table 1: Aprepitant assay results

[0056]

[0057]

[0058] It can be seen from the results in Table 1 that in the combination test of Span 20 to Span 85 with triethanolamine oleate, Span 20, Span 40, Span 60, Span 80 and Span 83 all achieved more than 80% dissolution at 45 min, while Span 65 and Span 85 had relatively low solubility due to their high hydrophobicity, so these two surfactants were not selected in the present invention.

[0059] At the same time, it can be seen from Comparative Examples 3-5 that the solubility of the preparations prepared with Span 20, 60 and 80 alone gradually decreases. Among them, Span 60 and 80 have low solubility due to their high hydrophobicity, and are generally not suitable for use as surfactants for preparing aprepitant preparations. However, the present invention uses triethanolamine oleate together with them, and it is found that their solubility is significantly improved, especially Span 80, which has a significant improvement effect. This may be because Span 80 interacts with triethanolamine oleate through the olefin group in the molecular chain, making it have a higher affinity for aprepitant, thereby more significantly improving the solubility of aprepitant.

[0060] As can be seen from Comparative Example 6, sodium oleate does not have the same effect as triethanolamine oleate, indicating that the unique structure of triethanolamine is essential for improving the efficacy of Span surfactants.

[0061] It should be noted that the preferred embodiments of the present invention are given in the specification of the present invention, but the present invention can be implemented in many different forms and is not limited to the embodiments described in this specification. These embodiments are not intended to be additional limitations on the content of the present invention. The purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive. In addition, the above-mentioned technical features continue to be combined with each other to form various embodiments not listed above, which are all considered to be within the scope of the present invention specification; further, for ordinary technicians in this field, they can be improved or transformed according to the above description, and all these improvements and transformations should belong to the protection scope of the claims attached to the present invention.

Claims

1. A high-dissolution aprepitant preparation, characterized in that: The composition comprises the following components in parts by weight: 50-80 parts of aprepitant, 5-10 parts of surfactant, 20-40 parts of filler, 5-10 parts of disintegrant, and 0.5-3 parts of lubricant; The surfactant is composed of triethanolamine oleate and another surfactant, and the other surfactant is selected from one or more of Span 20, Span 40, Span 60, Span 80 and Span 83.

2. The high-dissolution aprepitant preparation according to claim 1, characterized in that The surfactant consists of triethanolamine oleate and Span 80.

3. The high-dissolution aprepitant preparation according to claim 1 or 2, characterized in that: The mass ratio of the triethanolamine oleate to another surfactant is 1:1-5.

4. The high-dissolution aprepitant preparation according to claim 1, characterized in that The filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, starch, and dextrin.

5. The high-dissolution aprepitant preparation according to claim 1, characterized in that: The disintegrant is selected from one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and low-substituted hydroxypropyl cellulose.

6. The high-dissolution aprepitant preparation according to claim 1, characterized in that: The lubricant is selected from one or more of magnesium stearate, sodium stearate fumarate, talc and silicon dioxide.

7. The high-dissolution aprepitant preparation according to claim 1, characterized in that: The preparation is in the form of powder, granules, tablets or capsules.

8. A method for preparing a high-dissolution aprepitant preparation according to any one of claims 1 to 7, characterized in that: The following steps are involved: (1) dissolving the required amount of aprepitant in a solvent and heating in a water bath at 50-60° C. for 30-50 min; (2) Mix the required amounts of surfactant, filler, disintegrant and lubricant, grind and pass through a 250-300 mesh sieve; (3) Add the mixture obtained in step (2) to the solution in step (1) and perform wet granulation to obtain the product.

9. The preparation method according to claim 8, characterized in that: The solvent is ethanol or acetone.

10. The preparation method according to claim 8, characterized in that: The grinding is performed using a ball mill at a speed of 600-1000 r / min for 12-24 hours.

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