JP2019014700A - Ezetimibe-containing intraoral disintegrable tablet and method for producing the same - Google Patents

Abstract

To provide an ezetimibe-containing intraoral disintegrable tablet having excellent elution properties and orally disintegrable properties and a method of producing the same.SOLUTION: An intraoral disintegrable tablet contains ezetimibe particles with d90 of 8.0 μm or less, and a sugar alcohol of 50.0 wt.% or more and sodium lauryl sulfate of 0.0-0.1 wt.% relative to the total weight of the tablet, with the weight ratio of sugar alcohol to ezetimibe (sugar alcohol/ezetimibe) being 6.0 or more.SELECTED DRAWING: None

Description

  The present invention relates to an ezetimibe-containing orally disintegrating tablet excellent in dissolution and orally disintegrating properties and a method for producing the same.

  Ezetimibe (chemical name: (3R, 4S) -1- (4-fluorophenyl)-[3 (S) -hydroxy-3- (4-fluorophenyl) propyl]-(4-hydroxyphenyl) -2-azetidinone) Is a compound represented by the following formula (1), which is a pharmaceutical active ingredient that suppresses cholesterol absorption from the small intestine and lowers blood cholesterol level.

  Ezetimibe is marketed in Japan as a small intestine cholesterol transporter inhibitor and an antihyperlipidemic agent that lowers the amount of cholesterol in the blood under the product name “Zetia Tablets 10 mg”.

  In order to obtain an effective medicine, it is important to improve the bioavailability of the active ingredient. However, in order to provide an oral preparation having a high bioavailability, a high solubility of the active ingredient is required.

  So far, it has been reported that the particle size is adjusted for the purpose of enhancing the dissolution property in a preparation containing ezetimibe. For example, Patent Document 1 discloses that in the combined preparation of ezetimibe and rosuvastatin, the average particle size (d (0.9)) of ezetimibe is 10 μm or less. In addition, in a method for preparing a pharmaceutical composition containing a low-solubility pharmaceutically active ingredient such as ezetimibe, it has been reported that the primary particle size distribution d (0.5) such as ezetimibe is less than about 5 μm.

Special table 2017-500303 gazette Special table 2014-500294 gazette

  It has been found that ezetimibe dissolution is improved by micronizing. However, it has been found by the study of the present inventor that there is a limit to the effect of improving the dissolution property by simply pulverizing. That is, it was considered that ingenuity other than pulverization was necessary to further improve the efficient dissolution by pulverizing ezetimibe.

  On the other hand, ezetimibe is known to be poorly soluble, and sodium lauryl sulfate is added as a surfactant in the commercial products as described above. However, according to the research of the present inventors, it has been found that the ezetimibe preparation to which sodium lauryl sulfate is added cannot provide sufficient oral disintegration.

  This invention is made | formed in view of said point, and makes it a main objective to provide the ezetimibe containing orally disintegrating tablet provided with the further outstanding dissolution property and favorable oral disintegration property than before.

  The present inventor has intensively studied and found that the above-mentioned problems can be solved by a preparation having the following constitution, and based on the knowledge, further studies have been made to complete the following invention.

  An orally disintegrating tablet according to one embodiment of the present invention is provided with ezetimibe particles having a d90 of 8.0 μm or less, 50.0% by weight or more of sugar alcohol and 0.0 to 0.1% by weight based on the total weight of the tablet. In addition to sodium lauryl sulfate, and the weight ratio of sugar alcohol to ezetimibe (sugar alcohol / ezetimibe) is 6.0 or more.

  In the orally disintegrating tablet, the sugar alcohol is preferably D-mannitol.

  Further, the orally disintegrating tablet preferably contains at least one of polyvinyl alcohol and povidone as a binder.

  In the orally disintegrating tablet, the weight ratio of sugar alcohol to ezetimibe (sugar alcohol / ezetimibe) is preferably 8.0 or more.

  Furthermore, the sugar alcohol is preferably contained as drug granules together with the ezetimibe.

  In addition, in the method for producing an orally disintegrating tablet according to another aspect of the present invention, the ezetimibe particles are pulverized until the d90 is 8.0 μm or less, and the ezetimibe particles after pulverization are 50 And a step of mixing sodium lauryl sulfate in an addition amount such that the weight ratio to ezetimibe is 6.0 or more.

  ADVANTAGE OF THE INVENTION According to this invention, the ezetimibe containing orally disintegrating tablet excellent in both the dissolution property and the orally disintegrating property and its manufacturing method can be provided.

  Hereinafter, although the embodiment concerning the present invention is described, the present invention is not limited to these.

  The orally disintegrating tablet of this embodiment comprises ezetimibe particles having a d90 of 8.0 μm or less, 50.0% by weight or more of sugar alcohol and 0.0 to 0.1% by weight of lauryl sulfate relative to the total weight of the preparation. It contains sodium, and the weight ratio of sugar alcohol to ezetimibe (sugar alcohol / ezetimibe) is 6.0 or more.

  The inventor of the present invention has a remarkably improved dissolution property by adding a sugar alcohol at a high blending amount to the above-described structure, that is, micronized ezetimibe particles, and the addition amount of sodium lauryl sulfate is reduced to 0. It has been found that the disintegration property in the oral cavity becomes excellent when the amount is as small as 1% by weight or less or not added.

(Active ingredient)
Ezetimibe, which is an active ingredient in the orally disintegrating tablet of this embodiment, is represented by the above formula (1) (3R, 4S) -1- (4-fluorophenyl)-[3 (S) -hydroxy-3- It is a compound having the chemical name (4-fluorophenyl) propyl]-(4-hydroxyphenyl) -2-azetidinone.

  The ezetimibe used in the present embodiment is ezetimibe particles that are micronized so that d90 is 8.0 μm or less. When d90 of ezetimibe particles exceeds 8.0 μm, there is a possibility that sufficient elution property cannot be secured. A more preferable particle size of ezetimibe is that d90 is in the range of 1.0 to 5.0 μm, and more preferably, d90 is in the range of 2.0 to 3.5 μm. The lower limit of the particle size (d90) of ezetimibe is not particularly limited, but is 1.0 μm or more, preferably 2.0 μm or more as described above, from the viewpoint of improving the fluidity during the production process.

  The amount of ezetimibe in the orally disintegrating tablet of this embodiment is preferably such that the daily dose of ezetimibe for human patients is usually about 10 mg (once per day).

  Therefore, 10.0 mg of ezetimibe is contained in the orally disintegrating tablet of this embodiment.

(Sugar alcohol)
Next, the orally disintegrating tablet of this embodiment contains sugar alcohol in a proportion of 50.0% by weight or more with respect to the total weight of the tablet, and the edetimibe of sugar alcohol in the orally disintegrating tablet of this embodiment. The weight ratio (sugar alcohol / ezetimibe) is 6.0 or more. Thus, by including sugar alcohol at a high blending amount (and a high blending amount with respect to ezetimibe) in the tablet, the dissolution property of micronized ezetimibe is further improved.

  Specific examples of the sugar alcohol include D-mannitol, D-sorbitol, xylitol, erythritol, maltitol and the like. Especially, it is preferable to use D-mannitol from a viewpoint of stability of a main ingredient and moisture absorption stability. These may be used individually by 1 type and may use 2 or more types together.

  The amount of sugar alcohol in the orally disintegrating tablet of this embodiment is not particularly limited as long as it is 50.0% by weight or more with respect to the total weight of the tablet as described above, but it is difficult to take if the tablet is too large. In view of the above, it is preferably 90.0% by weight or less. A more preferable range is 50.0% by weight or more and 85.0% by weight or less, and a further preferable range is 60.0% by weight or more and 80.0% by weight or less.

  Furthermore, although the weight ratio of sugar alcohol to ezetimibe (sugar alcohol / ezetimibe) in the orally disintegrating tablet of this embodiment is 6.0 or more, excellent dissolution can be achieved, but a more preferable weight ratio is 8.0. As described above, the more preferable weight ratio is 10.0 or more, and most preferably 12.0 or more. The upper limit of the weight ratio (sugar alcohol / ezetimibe) is not particularly limited, but is preferably 20.0 or less, more preferably 15.0 or less from the viewpoint that it is difficult to take if the tablet is too large. .

(Sodium lauryl sulfate)
In the orally disintegrating tablet of this embodiment, it is important that sodium lauryl sulfate is not added (content: 0% by weight), but it is very small even if it is added. Thus, when the addition amount of sodium lauryl sulfate is 0.0 to 0.1% by weight based on the total weight of the tablet, an ezetimibe-containing orally disintegrating tablet excellent in orally disintegrating property can be obtained. The addition amount of sodium lauryl sulfate is more preferably 0.1% by weight or less, and it is further preferable not to add (addition amount 0.0% by weight).

  Furthermore, in addition to the above, the orally disintegrating tablet of this embodiment may contain a pharmaceutically acceptable additive. Specifically, commonly used binders, excipients, disintegrants, lubricants, surfactants, colorants and the like can be used. Specific examples thereof will be described below.

(Binder)
Examples of the binder that can be used in the present embodiment include polyvinyl alcohol, povidone, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, and methyl cellulose. These may be used individually by 1 type and may use 2 or more types together. Preferably it contains at least one of polyvinyl alcohol and povidone. Although not particularly limited, the binder is preferably contained in the range of 0.1 to 10.0% by weight with respect to the total weight of the tablet.

(Excipient)
Examples of excipients that can be used in the present embodiment include sugar alcohol, lactose hydrate, crystalline cellulose, anhydrous lactose, corn starch, calcium hydrogen phosphate, and the like. Preferably, sugar alcohol, crystalline cellulose or the like can be used. These may be used individually by 1 type and may use 2 or more types together. Although not particularly limited, the excipient is preferably contained in the range of 5.0 to 90.0% by weight based on the total weight of the tablet.

(Disintegrant)
Examples of disintegrants that can be used in this embodiment include crystalline cellulose, corn starch, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and the like. Is mentioned. More preferred is carmellose, carmellose calcium, croscarmellose sodium, crospovidone, and most preferred is croscarmellose sodium. These may be used individually by 1 type and may use 2 or more types together. Although not particularly limited, the disintegrant is preferably contained in the range of 3.0 to 50.0% by weight with respect to the total weight of the orally disintegrating tablet.

(Surfactant)
Examples of the surfactant that can be used in the present embodiment include sucrose fatty acid ester, polysorbate, macrogol, sodium lauryl sulfate, lauromacrogol and the like. Sodium lauryl sulfate is preferred. The surfactant is preferably contained in the uncoated tablet in the range of 0.5 to 5.0% by weight based on the total weight of the preparation. In addition, when using sodium lauryl sulfate among these, the content will be 0.0 to 0.1 weight% as above-mentioned.

(lubricant)
Examples of the lubricant that can be used in the present embodiment include magnesium stearate, calcium stearate, sodium stearyl fumarate, soft anhydrous silicic acid, and the like. Preferably it is sodium stearyl fumarate. These may be used individually by 1 type and may use 2 or more types together. The lubricant is preferably contained in the range of 0.1 to 5.0% by weight with respect to the total weight of the preparation.

  In the orally disintegrating tablet of this embodiment, the ezetimibe is preferably contained in the orally disintegrating tablet as a drug granule together with sugar alcohol and other excipients (that is, at least ezetimibe and sugar alcohol are granules). Contained in). The orally disintegrating tablet of this embodiment can be tableted by tableting the mixture containing the drug granules and other additives. Furthermore, the tablet may be coated to form a coated tablet or the like.

  Since the ezetimibe-containing orally disintegrating tablet of this embodiment has an effect of reducing the amount of cholesterol in the blood, it can be effectively used for the treatment and / or prevention of hyperlipidemia.

(Production method)
Next, the manufacturing method of the ezetimibe containing orally disintegrating tablet of this embodiment is demonstrated. In the production method of the present embodiment, at least the step of pulverizing ezetimibe particles until d90 is 8.0 μm or less, the ezetimibe particles after pulverization is 50.0% by weight or more based on the total weight of the tablet, and A step of mixing sugar alcohol with an addition amount such that the weight ratio to ezetimibe is 6.0 or more and sodium lauryl sulfate with an addition amount such that the weight ratio is 0.0 to 0.1% by weight.

  Hereinafter, the production method of this embodiment will be described with specific examples, but the production method of the orally disintegrating tablet of the present invention is not limited thereto.

  In the manufacturing method in the present embodiment, first, ezetimibe particles are pulverized until d90 is 8.0 μm or less. The pulverization method is not particularly limited. Desirable by dry pulverization (rotary impact mill (pin mill, hammer mill, etc.), jet mill, ball mill, etc.) or wet pulverization (rotor-stator mixing, ball mill, high pressure homogenizer, etc.). Can be pulverized to a particle size of.

  Next, sugar alcohol is added to the pulverized ezetimibe particles above in an amount of 50.0% by weight or more based on the total weight of the preparation, and the weight ratio (sugar alcohol / ezetimibe) to ezetimibe is 6.0 or more. Sugar alcohol is mixed in an addition amount, and sodium lauryl sulfate is further mixed in an addition amount so as to be 0.0 to 0.1% by weight based on the total weight of the preparation.

  Thereafter, for example, ezetimibe and sugar alcohol mixed in a fluidized bed granulator, and if necessary, further charged with a diluent, a disintegrant, etc., sprayed with a binder dissolved in purified water, dried after granulation -Granulated to form granules, and further, a disintegrant and a lubricant are further mixed to obtain a mixed powder, which can be compression-molded by tableting to form an uncoated tablet. For tableting, for example, a hydraulic hand press, a single-shot tableting machine, or a rotary tableting machine can be used. The tableting pressure can be appropriately set according to the tablet weight as the tablet to be produced.

  Although the orally disintegrating tablet of this embodiment is preferably an uncoated tablet, it can be formed into a film-coated tablet using a coating agent or the like, if necessary.

  The shape of the orally disintegrating tablet of the present embodiment is not particularly limited, but may be a disc shape, a donut shape, a polygonal plate shape, a spherical shape, an elliptical shape, or the like.

  The present invention will be described more specifically with reference to the following examples. However, the scope of the present invention is not limited to these examples.

<Test Example 1: Effect of sodium lauryl sulfate on oral disintegration>
(Comparative Example 1)
Povidone, ezetimibe and sodium lauryl sulfate were added to purified water. Next, this ezetimibe dispersion (granulation liquid) is wet-pulverized with a high-pressure homogenizer (“Microfluidizer M-110P” (device name), manufactured by Pou Lec Co., Ltd.) to obtain a predetermined particle size (d10: 0.8 μm, A dispersion of ezetimibe having d50: 1.6 μm, d90: 2.6 μm) was prepared.

  Furthermore, D-mannitol and croscarmellose sodium were put into a fluidized bed granulator ("MP-01" (device name), manufactured by POWREC), granulated by spraying the finely divided dispersion of ezetimibe, Dry to obtain granules. Crystalline cellulose, mannitol, crospovidone, and magnesium stearate were added to the obtained granules and mixed to obtain a mixed powder. The obtained mixed powder was compression-molded into a tablet having a weight of 90 mg with a rotary tableting machine (“VIRGO” (device name), manufactured by Kikusui Seisakusho Co., Ltd.) to obtain an uncoated tablet.

  In addition, each component was added so that the composition of each component in the uncoated tablet would be the composition (% by weight) shown in Table 1 below.

  The particle size of ezetimibe in the dispersion was measured by a laser diffraction scattering method (LS13 320, Beckman Coulter, Inc.).

Example 1
An orally disintegrating tablet (uncoated tablet) containing ezetimibe was obtained in the same manner as in Comparative Example 1 except that sodium lauryl sulfate was not added and the amount of D-mannitol at the time of tableting was increased instead.

(Oral disintegration test)
The disintegration time assumed in the oral cavity was measured using an intraoral (fast) disintegrating tablet measuring device (Okada Seiko Co., Ltd. product: Tricorp Tester). The measurement was performed at a discharge amount of 3.0 ml per minute. In the present embodiment, if the decay time is within 60 seconds, it is considered acceptable.

(Dissolution test)
About the obtained ezetimibe containing uncoated tablet of each Example, the dissolution test with respect to ezetimibe was done on condition of the following.
-Dissolution test method: Based on the Japanese Pharmacopoeia Dissolution Test Method 2-Test solution: Dissolution test solution 2 with 0.1% polysorbate 80 added-Test solution volume: 900 mL
・ Tester temperature: 37 ℃
Paddle rotation speed: 50 times per minute Table 2 shows the results of the above evaluation tests.

  From the results of Table 2, it was shown that in Example 1 in which sodium lauryl sulfate was not added, the disintegration time in the oral cavity was significantly shortened as compared with Comparative Example 1 containing 2% by weight or more of sodium lauryl sulfate. It was done.

<Test Example 2: Sugar alcohol content and dissolution>
(Example 2)
First, ezetimibe particles having a predetermined particle size (d10: 0.9 μm, d50: 1.8 μm, d90: 3.2 μm), which were dry-ground by a jet mill, were prepared.

  Then, pulverized ezetimibe particles, D-mannitol, and croscarmellose sodium are charged into a stirring granulator (“VG-01” (device name), manufactured by POWREC), and 60 g of purified water and povidone are dissolved in 40 g of purified water. The obtained liquid (granulating liquid) was added and granulated. The obtained granulated product was dried with a fluidized bed dryer ("MP-01" (device name), manufactured by POWREC) to obtain granules. Crystalline cellulose, soft silicic acid anhydride and sodium stearyl fumarate were added to the obtained granules and mixed to obtain a mixed powder. The obtained mixed powder was compressed into a tablet having a weight of 180.1 mg by a rotary tableting machine (“VIRGO” (device name), manufactured by Kikusui Seisakusho Co., Ltd.) to obtain an uncoated tablet.

  In addition, each component was added so that the composition of each component in the uncoated tablet would be the composition (% by weight) shown in Table 3 below.

  The particle size of ezetimibe was measured by the same method as in Example 1.

  Using the obtained uncoated tablets of Example 2, an oral disintegration test and a dissolution test were performed in the same manner as in Test Example 1. The results are shown in Table 4 below.

  From the results in Table 2, it has been found that the dissolution tends to be slightly worse if sodium lauryl sulfate is not added. From the results in Table 4, the dissolution is improved by increasing the amount of sugar alcohol added. I understood.

<Test Example 3: Sodium lauryl sulfate amount and oral disintegration>
(Examples 3 to 6)
First, ezetimibe particles having a predetermined particle size (d10: 0.9 μm, d50: 1.8 μm, d90: 3.2 μm), which were dry-ground by a jet mill, were prepared.

  Then, finely divided ezetimibe particles, D-mannitol, and croscarmellose sodium were charged into a stirring granulator (“VG-01” (device name), manufactured by POWREC), 60 g of purified water, povidone, and Examples 4 to 6 Was granulated by adding a solution (granulating solution) of sodium lauryl sulfate dissolved in 40 g of purified water. The obtained granulated product was dried with a fluidized bed dryer ("MP-01" (device name), manufactured by POWREC) to obtain granules. Crystalline cellulose, sucralose, soft anhydrous silicic acid, and sodium stearyl fumarate were added to and mixed with the obtained granules to obtain a mixed powder. The obtained mixed powder was compression-molded into tablets each having a weight of 200.0 to 200.2 mg with a rotary tableting machine (“VIRGO” (device name), manufactured by Kikusui Seisakusho Co., Ltd.) to obtain uncoated tablets.

  In addition, each component was added so that the composition of each component in the uncoated tablet would be the composition (% by weight) shown in Table 5 below.

  The particle size of ezetimibe was measured by the same method as in Example 1.

  Using the obtained uncoated tablet, an oral disintegration test was performed in the same manner as in Test Example 1. The results are shown in Table 5 below.

  From the results of Table 5, it was found that sodium lauryl sulfate affects the disintegration property in the oral cavity even when added in a small amount. However, it was also found that if the amount of sodium lauryl sulfate added is 0.1% by weight or less, the oral disintegration of the acceptable line (oral disintegration time: within 60 seconds) can be obtained.

  From the above Test Examples 1 to 3, it was shown that the ezetimibe-containing orally disintegrating tablet of the present invention is excellent in orally disintegrating property and dissolution property.

Claims (6)

  Ezetimibe particles having a d90 of 8.0 μm or less, 50.0% by weight or more of sugar alcohol and 0.0 to 0.1% by weight of sodium lauryl sulfate relative to the total weight of the tablet, and sugar alcohol ezetimibe Orally disintegrating tablet, wherein the weight ratio to sugar (sugar alcohol / ezetimibe) is 6.0 or more.   The orally disintegrating tablet according to claim 1, wherein the sugar alcohol is D-mannitol.   The orally disintegrating tablet according to claim 1 or 2, further comprising at least one of polyvinyl alcohol and povidone as a binder.   The orally disintegrating tablet according to any one of claims 1 to 3, wherein a weight ratio of the sugar alcohol to ezetimibe (sugar alcohol / ezetimibe) is 8.0 or more.   The orally disintegrating tablet according to any one of claims 1 to 4, wherein the sugar alcohol is contained as drug granules together with the ezetimibe. Crushing ezetimibe particles until d90 is 8.0 μm or less;
To the ezetimibe particles after pulverization, sugar alcohol and 0.0 to 0.1 with an addition amount such that the weight ratio to the ezetimibe is 50.0% by weight or more and the weight ratio to ezetimibe is 6.0 or more. A method for producing an orally disintegrating tablet, comprising a step of mixing sodium lauryl sulfate in an addition amount so as to be in% by weight.