JP2020203880A - Aprepitant-containing suppository - Google Patents

Abstract

To provide an aprepitant preparation that can be administered even with strong nausea, and provide an aprepitant-containing suppository that has excellent moldability and releasability and can be stably produced without cracking or chipping, and has no stickiness, offering excellent handlability in use.SOLUTION: A suppository contains aprepitant as an active ingredient.SELECTED DRAWING: Figure 1

Description

The present invention relates to an aprepitant-containing suppository, and more specifically, it has good moldability and releasability, suppresses cracking and chipping, and has excellent productivity, and is not sticky and has excellent usability on the surface. The present invention relates to an aprepitant-containing suppository having a moderate luster and a good appearance.

Nausea and vomiting induced by cancer chemotherapy causes extremely strong discomfort and distress to the cancer patient, leading to deterioration of the patient's physical and mental condition, and as a result, continuation of chemotherapy. Can be difficult. Therefore, prevention and alleviation of nausea and vomiting is important for maintaining the QOL of cancer patients and continuing chemotherapy.

Aprepitant is a selective neurokinin 1 (NK1) receptor antagonist that acts on the NK1 receptor, which is a receptor for the neurotransmitter substance P, which is deeply involved in the development of vomiting and pain, and accepts substance P and NK1. It is thought to suppress nausea and vomiting by selectively blocking the binding to the body, and is used for nausea and vomiting associated with administration of antineoplastic agents such as cisplatin. Capsules and injections have been formulated as pharmaceuticals containing aprepitant as an active ingredient, and other dosage forms such as oral liquid preparations have been studied (Non-Patent Documents 1 and 2). However, if the patient has strong nausea, it may be difficult to take oral preparations such as capsules. On the other hand, regarding injections, if other injections are used in combination, the administration route may not be secured. Therefore, it is necessary to expand the route of administration of aprepitant preparations, and it is considered that suppositories are suitable as a dosage form that can be administered even if nausea is particularly strong.

However, when the present inventors prepared an oil-based suppository in which aprepitant was dispersed in an oil-based base and conducted an in vitro dissolution test, elution of aprepitant into the elution phase was hardly observed. On the other hand, it is conceivable to use a water-soluble base, but in general, when a water-soluble base is used, moldability and releasability deteriorate, productivity decreases such as cracking and chipping, and stickiness occurs. It is easy to cause problems such as reduced usability.

Special Table 2015-521190 Special Table 2016-532660

The present invention provides an aprepitant preparation that can be administered even with strong nausea, is excellent in moldability and releasability, can be stably produced without cracks, chips, etc., and is not sticky during use. An object of the present invention is to provide a suppository containing aprepitant, which is also excellent in handling.

As a result of diligent research to solve the above problems, the present inventors can administer aprepitant as a suppository in the rectum to patients with strong nausea, and further, it is specific as a base. By using an aqueous base and mixing and dispersing aprepitant in the base for molding, moldability and releasability are improved, cracks and chips are reduced, and there is no stickiness and usability. They have found that a suppository having an excellent, glossy and good appearance can be obtained, and have completed the present invention.

That is, the present invention is a suppository containing aprepitant as an active ingredient.

The suppository of the present invention is excellent in moldability and releasability, suppresses the occurrence of cracks and chips, and is excellent in productivity. Moreover, since the surface is not sticky, it is excellent in handleability during use. Further, the surface has an appropriate luster and is good in appearance. Further, by adding sodium caprate, the absorption rate and absorption amount of aprepitant can be increased.

It is a graph which shows the aprepitant concentration in plasma after administration of a suppository to a rat in Test Example 1.

In the suppository of the present invention, aprepitant is used as an active ingredient. Aprepitant is a white to grayish white solid having the following structure and having a molecular weight of 534.43.

From the viewpoint of elution and bioavailability, the aprepitant preferably has a volume median particle diameter (D ₅₀ ) of 0.1 to 100 μm, and more preferably 0.1 to ₅₀ μm. In the present specification, the volume median particle size (D ₅₀ ) means a particle size in which the cumulative volume frequency calculated by the volume fraction is 50% calculated from the smaller particle size. The aprepitant can be adjusted to such a range of the medium volume particle size according to a known particle pulverization method, for example, a wet pulverization method using a bead mill or the like.

The content of aprepitant in the suppository of the present invention is not particularly limited, but is preferably 1 to 20% by mass (hereinafter, simply referred to as "%") from the viewpoint of moldability and usability. More preferably 1-10%.

As the base used for the suppository of the present invention, a water-soluble base is preferably used from the viewpoint of elution, bioavailability and the like. Examples of the water-soluble base include macrogol (polyethylene glycol), glycerin and the like, and one or more of these can be used. Among these, macrogol is preferable from the viewpoint of moldability and usability. As the macrogol, it is preferable to use a macrogol (component (a1)) that is liquid at room temperature (25 ° C.), and for example, macrogol 200, macrogol 300, macrogol 400 and the like are preferably used, and particularly macrogol. 400 is preferable.

In the suppository of the present invention, it is preferable to use macrogol (component (a2)) which is solid at room temperature in addition to the above-mentioned macrogol which is liquid at room temperature because stickiness is further reduced and usability is improved. .. Examples of macrogol solid at room temperature include macrogol 4000, macrogol 6000, macrogol 20000, and the like, and one or more of these can be used. Among these, Macrogol 6000 is preferably used from the viewpoint of usability and moldability.

When macrogol liquid at room temperature and macrogol solid at room temperature are used in combination, the content mass ratio (a1: a2) should be 3: 1 to 1: 1 from the viewpoint of usability and moldability. It is preferably 2: 1 to 3: 2.5, more preferably.

By further using the paste-like macrogol (component (a3)) at room temperature in the suppository of the present invention, moldability, usability and the like can be improved. When (a1) macrogol liquid at room temperature, (a2) solid macrogol and (a3) paste-like macrogol are used in combination, the content mass ratio (a1: a2: a3) is 3: (0.8). ~ 1.6): (1.2 to 0.4) is preferable, and 3: (0.8 to 1.2) :( 1.2 to 0.8) is more preferable. The total mass ratio (a1: (a2 + a3)) of (a1) macrogol liquid at room temperature, (a2) solid macrogol, and (a3) paste-like macrogol is 3: 1.5 to It is preferably 2.5, more preferably 3: 1.8 to 2.2.

The content of the water-soluble base in the suppository of the present invention is not particularly limited, but is preferably 50 to 99.9%, preferably 80 to 99.5%, from the viewpoint of moldability and usability. More preferred.

The suppository of the present invention can further increase the absorption rate of aprepitant by further containing sodium caprate. The content of sodium caprate in the suppository of the present invention is preferably 0.5 to 15%, more preferably 1 to 12%, still more preferably 2 to 10%, from the viewpoint of increasing the absorption rate of aprepitant.

In addition to the above components, the suppository of the present invention may contain any component as long as the effects of the present invention are not impaired. Examples of such optional components include surfactants, antioxidants, cooling agents, preservatives, pigments, fragrances, solubilizers, dispersants, stabilizers, excipients, curing agents and the like. Dissolution can be improved by blending about 0.1 to 5% of a surfactant such as sodium dodecyl sulfate, fatty acid ester, fatty acid ether, and fatty acid in the suppository.

The method for producing the suppository of the present invention is not particularly limited, and it can be produced by stirring and mixing each component according to a known method and molding. For example, the suppository of the present invention can be obtained by melting and mixing aprepitant and macrogol, filling the container, cooling and molding. When a pulverized product adjusted to the above volume medium particle size (D ₅₀ ) is used as the aprepitant, the wet pulverization treatment is carried out by using the above (a1) macrogol liquid at room temperature as the dispersion medium for wet pulverization. The process can be simplified by adding other components such as the above-mentioned (a2) solid macrogol and sodium caprate to the mixture of the aprepitant particles and the liquid macrogol to be melted and mixed.

Next, the present invention will be described in more detail with reference to Examples and the like, but the present invention is not limited by these Examples and the like.

Example 1
A suppository having the composition shown in Table 1 below was prepared by the following production method. Regarding the obtained suppository, each item of "moldability", "release property", "cracking", "chip", "stickiness", and "gloss" was evaluated according to the following criteria, and the total score was calculated. .. The results are also shown in Table 1. The numerical values in the composition of the table mean parts by mass.

(Production method)
Aprepitant (medium volume particle size (D ₅₀ ) 20 μm) and macrogol were melted and mixed at 70-80 ° C. This is poured into a straw with a diameter of 4 mm, the temperature is gradually lowered from a hot bath at 70 ° C., cooled to 40 ° C., molded, cut to a length of 5 mm, and a columnar suppository having a diameter of 4 mm and a length of 5 mm. Got
(Evaluation criteria)
The evaluation panel of 4 people showed each suppository "moldability; ease of forming the desired shape", "removability; ease of detachment from the straw", "cracking; presence or absence of cracks in the suppository", " For each item of "chip; presence or absence of chipping of suppository", "stickiness; stickiness of suppository surface", "gloss; degree of gloss of suppository surface", excellent: 3 points, good: 2 points, defective: 1 Judgment was made as points, the average score of each item was calculated, and the total score was used for comprehensive evaluation.

From the results shown in Table 1, the suppositories of the products of the present invention were all excellent in moldability and releasability, had few cracks and chips, suppressed stickiness, and had good luster. In particular, the product 7 of the present invention in which macrogol 400, 1000 and 4000 were used in combination at a ratio of 3: 1: 1 had the highest overall evaluation.

Example 2
A suppository having the composition shown in Table 2 below was prepared by the following production method.

(Production method)
Aprepitant (medium volume particle size (D ₅₀ ) 20 μm), macrogol and sodium caprinate were melted and mixed at 70-80 ° C. This was poured into a syringe having a diameter of 4 mm, and the temperature was gradually lowered from a hot bath at 70 ° C. to cool to 40 ° C. for molding.

Test Example 1
In vivo rat absorption test After fasting SD rats (male, weight 250-300 g, 8 weeks old) for 24 hours, the suppositories of the present invention products 7, 12 and 13 were inserted through the anus under ether anesthesia, and the anus was inserted. The outlet was anastomosed with a surgical adhesive to prevent the suppository from falling off. Regarding the suppositories of the products 12 and 13 of the present invention, the tip of the syringe was applied to the anus and a length of 5 mm was extruded and administered. The dose was 10 mg / kg in terms of drug substance. Blood was collected from the jugular vein 15 minutes, 30 minutes, 1, 2, 4, and 6 hours after administration, and the plasma aprepitant concentration was measured. The results are shown in FIG. 1 (mean value of 3 animals in each group).

As shown in FIG. 1, it was confirmed that aprepitant was rectally absorbed by administration of the suppository of the product 7 of the present invention. Furthermore, the addition of sodium caprate was observed to increase the absorption rate of aprepitant in a concentration-dependent manner (Products 12 and 13 of the present invention).

Since the aprepitant-containing suppository of the present invention is highly productive and has excellent usability, it can be used as a dosage form that can be administered even if nausea is strong and can be used as a preparation that can expand the choice of administration route.

Claims (16)

A suppository containing aprepitant as an active ingredient. The suppository according to claim 1, wherein the base of the suppository is a water-soluble base. The suppository according to claim 2, wherein the water-soluble base is macrogol. The suppository according to claim 3, wherein the macrogol contains (a1) macrogol that is liquid at room temperature. (A1) The suppository according to claim 4, wherein the macrogol liquid at room temperature is one or more selected from the group consisting of macrogol 200, macrogol 300 and macrogol 400. The suppository according to claim 4 or 5, wherein the macrogol further contains (a2) macrogol in a solid state at room temperature. (A2) The suppository according to claim 6, wherein the macrogol solid at room temperature is one or more selected from the group consisting of macrogol 4000, macrogol 6000 and macrogol 20000. The suppository according to claim 6 or 7, wherein the content mass ratio (a1: a2) of macrogol (a1) liquid at room temperature and macrogol (a2) solid at room temperature is 3: 1 to 1: 1. .. The suppository according to any one of claims 4 to 8, wherein the macrogol further contains (a3) a paste-like macrogol at room temperature. (A3) The suppository according to claim 9, wherein the paste-like macrogol at room temperature is one or more selected from the group consisting of macrogol 1000, macrogol 1500 and macrogol 1540. The content mass ratio (a1: a2: a3) of macrogol (a1) liquid at room temperature, macrogol (a2) solid at room temperature, and macrogol (a3) pasty at room temperature is 3: (0). .8-1.6): The suppository according to claim 9 or 10, which is (1.2-0.4). The suppository according to any one of claims 1 to 11, wherein the aprepitant is a particle having a volume median particle diameter (D ₅₀ ) of 0.1 to 100 μm. The suppository according to any one of claims 1 to 12, further containing sodium caprate. The suppository according to claim 13, wherein the content of sodium caprate is 0.5 to 15% by mass. A method for producing an aprepitant-containing suppository, which comprises a step of pulverizing aprepitant particles by wet pulverization using macrogol, which is liquid at room temperature, as a dispersion medium. The method for producing an aprepitant-containing suppository according to claim 15, wherein the aprepitant is pulverized to a volume medium particle size (D ₅₀ ) of 0.1 to 100 μm.

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