A high-dissolution aprepitant preparation and preparation method thereof

Abstract

The present invention belongs to the field of biopharmaceuticals, and specifically relates to a high-dissolution aprepitant formulation and a preparation method thereof. The high-dissolution aprepitant formulation comprises the following components in parts by weight: 50-80 parts of aprepitant, 5-10 parts of a surfactant, 20-40 parts of a filler, 5-10 parts of a disintegrant, and 0.5-3 parts of a lubricant; wherein 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. The present invention has found that by using a combination of triethanolamine oleate and the other surfactant, the solubility of aprepitant can be effectively improved and its dissolution can be promoted. At the same time, the preparation process is simple and does not bring excessive cost pressure to the process.

Description

Technical Field

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

[0002] Aprepitant is a selective neurokinin 1 (NK1) receptor antagonist primarily used to prevent and treat chemotherapy-induced nausea and vomiting. Due to its low solubility in water (approximate saturation solubility less than 1 μg / mL) and extremely low solubility at various pH values, aprepitant's oral bioavailability is limited, limiting its clinical efficacy.

[0003] To increase its water solubility and, therefore, its oral bioavailability, WO2003049718 disclosed for the first time a nanoparticle composition containing aprepitant, wherein a surface stabilizer is adsorbed on the surface of the aprepitant, thereby reducing the particle size to less than 1000 nm. The preparation method provided in the embodiment specifically comprises dispersing the active ingredient aprepitant in a liquid dispersion medium, and mechanically wet-milling the mixture in the presence of a grinding medium and a surface stabilizer to reduce the average particle size of the active ingredient, followed by separation of the resulting nanocomposition from the grinding medium. Because wet milling cannot produce particles with a particle size less than 100 nanometers, its effect on improving the dissolution of aprepitant is limited. However, improvements to this process would significantly increase costs.

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

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

[0007] Furthermore, 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) Dissolve the required amount of aprepitant in a solvent and heat in a water bath at 50-60°C for 30-50 minutes;

[0016] (2) Mix the required amount 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.

[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 surfactants alone is limited and usually needs to be combined with other means (such as solubility enhancers such as polyethylene glycol and polyvinyl pyrrolidone).

[0022] The present invention has discovered that the solubility of aprepitant can be effectively improved and its dissolution promoted by combining triethanolamine oleate with another surfactant. The other surfactant is selected from one or more of Span 20, Span 40, Span 60, Span 80, and Span 83, particularly Span 80. As can be seen from the results in the examples, the combination of the two surfactants produces unexpected improvements compared to their use alone. Furthermore, triethanolamine oleate can make reagents such as Span 60, which were originally unsuitable for use in the preparation of aprepitant formulations, usable. In particular, Span 80 produces an improvement that is even greater than that of Span 20, resulting in surprising technical benefits. DETAILED DESCRIPTION

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

[0024] Example 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 croscarmellose 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 uniformly, ground, and passed through a 250-mesh sieve;

[0029] (3) The mixture obtained in step (2) was 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 were placed on a capsule filling plate to obtain an aprepitant preparation.

[0030] Example 2:

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

[0032] Example 3:

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

[0034] Example 4:

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

[0036] Example 5:

[0037] A high-dissolution aprepitant preparation, whose ingredients and preparation process are the same as those in 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 in 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 in 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 in 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 in 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 in 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 in Example 1, except that triethanolamine oleate is replaced by polyvinylpyrrolidone.

[0052] Test example:

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

[0054] The dissolution medium was 900 ml of pH 6.8 phosphate buffer containing 0.2% (w / v) sodium lauryl sulfate, with a stirring speed of 100 rpm. The procedure was performed according to Method 0931, Part 4, General Rules, Chinese Pharmacopoeia 2015 Edition, Method 2. Samples were taken and analyzed at 15 and 45 minutes. The results are detailed in Table 1.

[0055] Table 1: Aprepitant test results

[0056]

[0057]

[0058] From the results in Table 1, it can be seen that in the combination tests of Span 20 to Span 85 with triethanolamine oleate, Span 20, Span 40, Span 60, Span 80 and Span 83 all achieved a dissolution rate of more than 80% at 45 min. However, 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 it, and it is found that its 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 alkenyl 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 description of the present invention. However, the present invention can be implemented in many different forms and is not limited to the embodiments described in this description. 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 are further combined with each other to form various embodiments not listed above, which are all considered to be within the scope of the description of the present invention. Furthermore, it is obvious to those skilled in the art that improvements or changes can be made based on the above description, and all such improvements and changes should fall within the scope of protection of the claims attached to the present invention.

Claims

1. A high-dissolution aprepitant preparation, characterized in that: The invention 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; wherein 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; The mass ratio of the triethanolamine oleate to another surfactant is 1:1-5.

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

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

4. The high-dissolution aprepitant preparation according to claim 1, wherein 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.

5. The high-dissolution aprepitant preparation according to claim 1, wherein The lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate, talc, and silicon dioxide.

6. The high-dissolution aprepitant preparation according to claim 1, wherein The preparation is in the form of granules, tablets or capsules.

7. A method for preparing a high-dissolution aprepitant preparation according to any one of claims 1 to 6, characterized in that: The following steps are involved: (1) Dissolve the required amount of aprepitant in a solvent and heat in a water bath at 50-60°C for 30-50 minutes; (2) Mix the required amount of surfactant, filler, disintegrant and lubricant evenly, grind and pass through a 250-300 mesh sieve; (3) The mixture obtained in step (2) is added to the solution in step (1) and wet granulation is performed.

8. The preparation method according to claim 7, characterized in that The solvent is ethanol or acetone.

9. The preparation method according to claim 7, 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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