JP2020094042A - Solid preparation containing rivaroxaban and flavoring agent - Google Patents

Abstract

To provide technical means for producing a solid preparation containing rivaroxaban, wherein a color change is suppressed during its storage.SOLUTION: A solid preparation contains rivaroxaban and a flavoring agent other than aspartame. The flavoring agent is preferably selected from menthol, sucralose, and acesulfame potassium.SELECTED DRAWING: None

Description

The present invention relates to a formulation containing rivaroxaban as a drug substance.

Rivaroxaban (generic name) has the chemical name 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidine. It is an oral Factor Xa inhibitor, designated as -5-yl}methyl)-2-thiophenecarboxamide. Rivaroxaban is a useful drug for suppressing the onset of ischemic stroke and systemic embolism, treating deep vein thrombosis and pulmonary thromboembolism, and suppressing recurrence in patients with non-valvular atrial fibrillation. (Reference to Non-Patent Document 1, etc.).

Currently, rivaroxaban is provided in medical forms in Japan in dosage forms such as tablets (see Non-Patent Document 1, etc.). The formulation and manufacturing method of the preparation containing rivaroxaban are also introduced in the following prior art documents such as Patent Documents 1 to 3. Patent Document 3 introduces a preparation containing solid particles in which a solubilizer is adsorbed on the surface of a poorly soluble drug (rivaloxaban, etc.) in order to enhance the solubility of the drug.

Japanese Patent No. 5285913 Patent No. 6166781 Japanese Patent Publication No. 2017-500332

"Exarelto (registered trademark) Tablets 10 mg 15 mg Fine particle packaging 10 mg 15 mg" Pharmaceutical Interview Form Revised January 2018 (11th edition)

An object of the present invention is to provide a technical means for producing a solid preparation containing rivaroxaban, in which color change under storage conditions is suppressed, and the like.

As a result of intensive studies to solve the above problems, the present inventor has found that in the case of a tablet containing rivaroxaban and a specific flavoring agent, its color change (coloring) is suppressed. The present inventor has conducted further diligent studies based on the findings, and has completed the following present invention.

The present invention relates to a solid preparation containing rivaroxaban and a specific taste-improving agent or a method for producing the solid preparation, and its preferable constitutions are described in the following (1) to (6). ..
(1) A solid preparation containing rivaroxaban, which contains a flavoring agent other than aspartame.
(2) A solid preparation characterized in that the flavoring agent is selected from menthol, sucralose, and acesulfame potassium.
(3) The solid preparation according to (1) or (2) above, which is a tablet (particularly an orally disintegrating tablet).
(4) The solid preparation according to any one of (1) to (3) above, which contains 0.1 to 10.0% by weight of the flavoring agent with respect to the total weight of the solid preparation.
(5) The solid preparation according to any one of (1) to (4), wherein the taste-improving agent is contained in the granulated product.
(6) Wet granulation (preferably agitation granulation) by adding a granulation liquid (including a binder, etc.) to a mixture of rivaroxaban and other additives (excipient, disintegrant, etc.) The method for producing a solid preparation according to any one of (1) to (5) above, which comprises:

According to the present invention, it is possible to provide a solid preparation containing rivaroxaban, in which color change under storage conditions is suppressed.

The solid preparation containing rivaroxaban and the specific flavoring agent or the method for producing the same according to the present invention will be described in detail below. However, the following description is an example for explaining the present invention, and the technical scope of the present invention is not intended to be limited only to this description range.

<Drug substance>
Regarding the particle size distribution of rivaroxaban according to the present invention, the volume-based cumulative 10% particle size (d ₁₀ ) is preferably 0.1 to 3.0 μm, and the volume-based cumulative 50% particle size (d ₅₀ ) is The volume-based cumulative 90% particle diameter (d ₉₀ ) is preferably 0.5 to 12.0 μm, more preferably 0.5 to 7.0 μm, and 1.0 to 40.0 μm. The particle diameter can be measured by a laser diffraction/scattering method, and the detailed measurement conditions can be according to the dry measurement described in [paragraph 0023].

The solid preparation of the present invention contains rivaroxaban as a drug substance, and is preferably a single drug containing no other drug substance. Rivaroxaban is 2.0 to 30.0% by weight, preferably 6.0, based on the total weight of the solid preparation {desirably uncoated tablets (refers to tablets not covered with a film coating layer. The same applies hereinafter)}. It is contained in the solid preparation (preferably uncoated tablet) within the range of ˜18.0% by weight. The content of rivaroxaban per tablet is preferably 10 mg or 15 mg.

<Flavor>
The solid preparation of the present invention does not contain aspartame but contains a flavoring agent other than aspartame. Specific examples of the corrigent include menthol, sucralose, acesulfame potassium, saccharin, stevia extract, stevia extract and purified product, thaumatin, and D-mannitol, and preferably menthol, sucralose, and acesulfame potassium. The above-mentioned flavoring agent is preferably 0.1 to 10.0% by weight, more preferably 1.0 to 5.0% by weight, based on the total weight of the solid preparation (preferably uncoated tablet). Contained in the formulation.

<Form of solid formulation>
The dosage form of the solid preparation of the present invention is preferably in the form of granules, capsules, tablets or the like, more preferably tablets, in order to be provided in the medical field. The tablet of the present invention is provided in the medical field as it is as an uncoated tablet compression-molded by tableting or the like, or after coating the uncoated tablet with a film coating layer containing a coating agent to obtain a film coated tablet. The shape of the tablet according to the present invention may be any shape such as a circular tablet, a circular R tablet, a circular corner tablet, a circular two-tiered R tablet and a modified tablet (elliptical tablet etc.). The weight of the uncoated tablet according to the present invention is preferably 50.0 to 150.0 mg, more preferably 75.0 to 95.0 mg.

<Oral disintegrating tablet>
The orally disintegrating tablet of the present invention is preferably an uncoated tablet (a tablet that has not been covered with a film coating layer, a sugar coating layer or the like, and is as-molded by tableting. The same applies hereinafter.) It is also possible to make a film-coated tablet by applying a film-coating layer to.
The orally disintegrating tablet is provided as a tablet that rapidly disintegrates in the oral cavity in distinction from an ordinary tablet, and the orally disintegrating time is less than 60 seconds, and particularly preferably less than 40 seconds. The disintegration time in the oral cavity is obtained, for example, by measuring the time required for disintegration when a tablet is placed on the tongue and infiltrated with saliva, or an orally disintegrating tablet tester (eg, OD-mate). /Higuchi Shokai Co., Ltd.) may be used to measure the time required for the tablet to disintegrate under the conditions of test liquid: water (37° C.), and a person skilled in the art to which the present invention belongs may disintegrate in the oral cavity. It may be determined by a method that can be generally performed for measuring time. The shape of the orally disintegrating tablet of the present invention is not particularly limited, and it may be a circular tablet (a circular flat tablet (including a corner tablet, etc.), a circular R tablet (including a corner tablet, a two-tiered R tablet, etc.), etc.) and an irregular shape. Although it may have any shape such as a tablet, a circular tablet is particularly preferable. In addition, it is preferable that the compression pressure of the orally disintegrating tablet of the present invention when compression-molded by compression is within the range of 300 to 1500 kgf.

<Additive>
In order to produce the solid preparation of the present invention, commonly used additives such as binders, disintegrants, lubricants, coating agents, solubilizers and the like can be used. Also, it should be understood that the drug substance is not included in the interpretation of the terms of additive in the present specification.

<Excipient>
The excipient is specifically selected from lactose hydrate, crystalline cellulose, anhydrous lactose, D-mannitol, isomalt, erythritol, starch (corn starch etc.), cyclodextrin, etc., preferably lactose hydrate or crystals. It is cellulose. The above-mentioned excipient is preferably contained in the range of 25.0 to 90.0% by weight, more preferably 60.0 to 75.0% by weight, based on the total weight of the solid preparation (desirably uncoated tablet). It is contained in a solid preparation.

<Binder>
Specific examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hypromellose), methyl cellulose, povidone, ethyl cellulose, polyvinyl alcohol, polyvinyl alcohol/polyethylene glycol/graft copolymer, polyethylene glycol, methacrylic acid copolymer, ethyl acrylate/methacrylic acid. Examples thereof include a methyl copolymer dispersion liquid, and hypromellose is preferable. The above-mentioned binder is preferably in the range of 0.1 to 10.0% by weight, more preferably 1.0 to 5.0% by weight, based on the total weight of the solid preparation (preferably uncoated tablet). It is contained in a solid preparation.

<Disintegrant>
Specific examples of the disintegrant include low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, hydroxypropyl starch, croscarmellose sodium, sodium carboxymethyl starch, crospovidone, and the like. Croscarmellose sodium. The disintegrant is preferably in the range of 2.0 to 20.0% by weight, more preferably 1.0 to 10.0% by weight, based on the total weight of the solid formulation (desirably uncoated tablet). Contained in.

<Lubricant>
Specific examples of the lubricant include light anhydrous silicic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, glycerin fatty acid ester, hardened oil, and the like, and magnesium stearate is preferable. The lubricant is preferably 0.1 to 5.0% by weight, more preferably 0.5 to 3.0% by weight, based on the total weight of the solid preparation (desirably uncoated tablet). Contained in the formulation.

<Solubilizer>
Specific examples of the solubilizer include sodium lauryl sulfate, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) glycol, polyethylene glycol, propylene glycol, and glycerin, and sodium lauryl sulfate is preferable. is there. The solubilizer is preferably 0.1 to 5.0% by weight, more preferably 0.3 to 2.0% by weight, based on the total weight of the solid preparation (desirably uncoated tablet). Contained in the formulation.

<Granulated material>
The solid preparation according to the present invention preferably contains a granulated product containing rivaroxaban. The granules are contained in the solid preparation preferably in the range of 30.0 to 99.5% by weight based on the total weight of the solid preparation (desirably uncoated tablet). The granules containing rivaroxaban preferably contain 8.0 to 30.0 parts by weight of rivaroxaban, based on the total parts by weight of the granulate. Granules containing rivaroxaban also preferably include excipients or disintegrants (desirably both), and also binders (desirably solubilizers). Incidentally, it is preferable that a corrigent is also contained in the granulated product containing rivaroxaban.

<Granulation method>
In the method for producing a solid preparation of the present invention, it is preferable to granulate using rivaroxaban. Examples of the granulation method according to the present invention include a wet granulation method (fluidized bed granulation method, agitation granulation method) and the like, and the agitation granulation method is preferable. The agitation granulation method is characterized in that a granulation liquid containing a binder is dropped into powder mixed with a stirring blade and the mixture is kneaded to granulate.

<Method for manufacturing solid preparation>
The solid preparation of the present invention can be produced by a general production method, for example, the following production method (stir granulation method/fluidized bed granulation method).
First, while agitating/fluidizing the drug substance and additives (excipient, disintegrating agent, or corrigent), a granulating liquid containing a binder (preferably also a solubilizing agent) is dropped/sprayed to form a mixture. Produce granules. Then, the obtained granulated product is sized, mixed with a lubricant and the like, and compression-molded by a tableting machine to give tablets (plain tablets). The pressing pressure at the time of tableting and manufacturing the uncoated tablet is preferably selected from any numerical value within the range of 100 to 1100 kgf. It is also possible to manufacture granules and capsules using the granulated product obtained above.

Moreover, it is possible to obtain a PTP sheet product containing the tablet of the present invention by covering the tablet with a packaging sheet and an aluminum foil or the like and covering the tablet with heat and sealing. Specific materials used for the packaging sheet include polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene and the like. In order to improve the stability of the tablet of the present invention against humidity, a PTP sheet product is manufactured using a material having a drying function, the PTP sheet product is packed in an aluminum pillow, and a desiccant is used together with the tablet. It is possible to perform a well-known method such as sealing in a bottle.

Hereinafter, the present invention will be described with reference to examples and the like, but the present invention is not limited to these examples and the like. The particle size of rivaroxaban (type I crystal was used) described in the following Examples and Comparative Examples was measured by a laser diffraction/scattering method (volume basis). The measurement was performed by a dry measurement under the condition of sample refractive index: 1.60.

Rivaroxaban (particle size distribution: d ₁₀ =1.8 μm/d ₅₀ =6.5 μm/d ₉₀ =20.9 μm) 30.0 g, crystalline cellulose 111.0 g, lactose hydrate 83.7 g and croscarmellose A liquid (granulation liquid) in which 9.0 g of sodium was charged into a fluidized bed granulator (MP-01 type manufactured by Paulec) and 9.0 g of hypromellose and 1.5 g of sodium lauryl sulfate were dissolved in 213.0 g of purified water. Was sprayed, granulated and dried. The dried product was sieved with a 30 mesh (mesh opening 500 μm) sieve to obtain granules.
After mixing 24.42 g of the obtained granules with 0.9 g of 1-menthol (flavoring agent), 0.18 g of magnesium stearate was added and further mixed, and the mixture was tableted at a tableting pressure of 400 kgf to give a tablet mass of 85.0 mg. A tablet (R tablet) having a diameter of 6.0 mm and a thickness of 2.8 mm was obtained.

Tablets were obtained in the same manner as in Example 1 except that "l-menthol (flavoring agent) 0.9 g" was replaced with "sucralose (flavoring agent) 0.9 g".

Tablets were obtained in the same manner as in Example 1 except that "0.9 g of l-menthol (flavoring agent)" was replaced with "0.9 g of acesulfame potassium (flavoring agent)".

[Comparative Example 1]
Tablets were obtained in the same manner as in Example 1 except that "l-menthol (flavoring agent) 0.9 g" was replaced with "aspartame (flavoring agent) 0.9 g".

A common prescription for the tablets of Examples 1 to 3 and Comparative Example 1 is shown in Table 1 below (numerical unit is mg).

[Test Example 1] Color difference measurement before and after light irradiation For each tablet obtained in Examples 1 to 3 and Comparative Example 1, immediately after production and after storage for 14 days at 60° C. and 75% relative humidity, each tablet was tested. The lightness (L*) and the chromaticity (a* and b*) indicating hue and saturation were measured using a spectral color difference meter (SE6000 model manufactured by Nippon Denshoku Industries Co., Ltd.). From these results, the color difference (ΔE) before and after storage was calculated and shown in Table 2 below. The color difference was calculated by the following formula for ΔE using L*a*b* defined in CIELab1976 as a chromaticity value. ΔE={(ΔL*)^2+(Δa*)^2(Δb*)^2}^1/2 (Nippon Denshoku Industries Co., Ltd., Spectrophotometer SE6000 type, instruction manual).

[Test Example 2] Sensory test of orally disintegrating tablets For each of three test subjects who are adult males, for each of the tablets described in Examples 1 to 3 and Comparative Example 1, only one tablet was included in the oral cavity. I had them disintegrate in the mouth while gently moving the tongue. The taste of each orally disintegrating tablet felt in the oral cavity at that time was evaluated by each of the above subjects, and the average value of the evaluation results is shown in Table 2 below. The above-mentioned evaluation by each test subject was performed by having the test subject select the most appropriate value from the numerical items of 0: discomfort, 1: normal, 2: good.

From Table 2, it was found that the tablets of Examples 1 to 3 containing a flavoring agent other than aspartame (menthol, sucralose, or acesulfame potassium) had a significantly lower ΔE than the tablets of Comparative Example 1 containing aspartame. .. Therefore, it is shown that the solid preparation containing the rivaroxaban of the present invention and the specific flavoring agent has suppressed color change under storage conditions.
In addition, from Table 2, it was confirmed that the tablets of Examples 1 to 3 were good in taste, and thus it was confirmed that the solid preparation of the present invention has no problem in taste.

Claims (6)

A solid preparation containing rivaroxaban, which comprises a flavoring agent other than aspartame. The solid preparation according to claim 1, wherein the flavoring agent is selected from menthol, sucralose, and acesulfame potassium. The solid preparation according to claim 1 or 2, wherein the solid preparation is a tablet. The solid preparation according to any one of claims 1 to 3, wherein the flavoring agent is contained in an amount of 0.1 to 10.0% by weight based on the total weight of the solid preparation. The solid preparation according to claim 1, wherein the flavoring agent is contained in the granulated product. A step of adding a granulation liquid (including a binder, etc.) to a mixture of rivaloxaban and other additives (excipient, disintegrating agent, etc.) and performing wet granulation (preferably stirring granulation), A method for producing the solid preparation according to any one of claims 1 to 5.